Effects of 7-day continuous D-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys.

PubMed

Schwienteck, Kathryn L; Banks, Matthew L

2015-10-01

Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice. In addition, 7-day cocaine treatment effects were also examined. Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1mg/kg/h), methylphenidate (0.032-0.32mg/kg/h), or cocaine (0.1-0.32mg/kg/h). During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. The present subchronic treatment results support the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: Evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys.

PubMed

Banks, Matthew L; Snyder, Rodney W; Fennell, Timothy R; Negus, S Stevens

2017-05-01

Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine.

PubMed

Musshoff, F

2000-02-01

The interpretation of methamphetamine and amphetamine positive test results in biological samples is a challenge to clinical and forensic toxicology for several reasons. The effects of pH and dilution of urine samples and the knowledge about legitimate and illicit sources have to be taken into account. Besides a potentially legal prescription of amphetamines, many substances metabolize to methamphetamine or amphetamine in the body: amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Especially the knowledge of potential origins of methamphetamine and amphetamine turns out to be very important to prevent a misinterpretation of the surrounding circumstances and to prove illegal drug abuse. In this review, potential precursor compounds are described, including their medical use and major clinical effects and their metabolic profiles, as well as some clues which help to identify the sources.

Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys

PubMed Central

Banks, Matthew L.; Snyder, Rodney W.; Fennell, Timothy R.; Negus, S. Stevens

2017-01-01

Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an “agonist” medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10–18 mg/kg, intramuscular (IM)) and d-amphetamine (0.032–0.32 mg/kg, IM) in monkeys (n=3–4) trained to discriminate IM cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥ 90% cocaine-appropriate responding,in all monkeys without altering response rates. The time course of d-amphetamine’s cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100 min) and d-amphetamine (peak at 24 h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. PMID:28373066

Evaluation of a direct high-capacity target screening approach for urine drug testing using liquid chromatography-time-of-flight mass spectrometry.

PubMed

Saleh, Aljona; Stephanson, Niclas Nikolai; Granelli, Ingrid; Villén, Tomas; Beck, Olof

2012-11-15

In this study a rapid liquid chromatography-time-of-flight mass spectrometry method was developed, validated and applied in order to evaluate the potential of this technique for routine urine drug testing. Approximately 800 authentic patient samples were analyzed for amphetamines (amphetamine and methamphetamine), opiates (morphine, morphine-3-glucuronide, morphine-6-glucuronide, codeine and codeine-6-glucuronide) and buprenorphines (buprenorphine and buprenorphine-glucuronide) using immunochemical screening assays and mass spectrometry confirmation methods for comparison. The chromatographic application utilized a rapid gradient with high flow and a reversed phase column with 1.8 μm particles. Total analysis time was 4 min. The mass spectrometer operated with an electrospray interface in positive mode with a resolution power of >10,000 at m/z 956. The applied reporting limits were 100 ng/mL for amphetamines and opiates, and 5 ng/mL for buprenorphines, with lower limits of quantification were 2.8-41 ng/mL. Calibration curves showed a linear response with coefficients of correlation of 0.97-0.99. The intra- and interday imprecision in quantification at the reporting limits were <10% for all analytes but for buprenorphines <20%. Method validation data met performance criteria for a qualitative and quantitative method. The liquid chromatography-time-of-flight mass spectrometry method was found to be more selective than the immunochemical method by producing lower rates of false positives (0% for amphetamines and opiates; 3.2% for buprenorphines) and negatives (1.8% for amphetamines; 0.6% for opiates; 0% for buprenorphines). The overall agreement between the two screening methods was between 94.2 and 97.4%. Comparison of data with the confirmation (LC-MS) results for all individual 9 analytes showed that most deviating results were produced in samples with low levels of analytes. False negatives were mainly related to failure of detected peak to meet mass accuracy criteria (±20 mDa). False positives was related to presence of interfering peaks meeting mass accuracy and retention time criteria and occurred mainly at low levels. It is concluded that liquid chromatography-time-of-flight mass spectrometry has potential both as a complement and as replacement of immunochemical screening assays. Copyright © 2012 Elsevier B.V. All rights reserved.

Development and validation of a single LC-MS/MS assay following SPE for simultaneous hair analysis of amphetamines, opiates, cocaine and metabolites.

PubMed

Imbert, L; Dulaurent, S; Mercerolle, M; Morichon, J; Lachâtre, G; Gaulier, J-M

2014-01-01

The two major challenges in hair analysis are the limited amount of samples usually available and the low targeted concentrations. To overcome these limitations, a liquid chromatography-electrospray-tandem mass spectrometry method (LC-ESI-MS/MS) allowing the simultaneous analysis of 17 amphetamines (amphetamine, BDB, m-CPP, dexfenfluramine, DOB, DOM, ephedrine, MBDB, MDA, MDEA, MDMA, methamphetamine, methylphenidate, 4-MTA, norephedrine, norfenfluramine and PMA), 5 opiates (morphine, codeine, heroin, ethylmorphine, and 6AM), cocaine and 5 metabolites [ecgonine methyl ester (EME), benzoylecgonine (BZE), anhydroecgonine methyl ester (AME), cocaethylene, and norcocaine] has been developed. The validation procedure included linearity, intra-day and inter-day variability and accuracy for 5 days (5 replicates at 3 concentration levels). Proficiency studies were used to check the accuracy of the method. As a result, all amphetamines, opiates and cocaine derivatives were satisfactory identified by 2 MRM transitions in 15 min. Calibration curves were performed by a quadratic 1/X weighted regression. The calibration model fits from 0.05 to 10 ng/mg. The limits of detection (LODs) range between 0.005 and 0.030 ng/mg. Precision has been checked by intra-day and inter-day RSD, and associated relative bias, which were lower than 25% for the limits of quantifications (LOQs) and lower than 20% for the other levels tested. This method was routinely applied to hair samples: two positive results of adult drug addicts are presented. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Stability of drugs of abuse in urine samples stored at -20 degrees C.

PubMed

Dugan, S; Bogema, S; Schwartz, R W; Lappas, N T

1994-01-01

Isolated studies of the stability of individual drugs of abuse have been reported. However, few have evaluated stability in frozen urine samples stored for 12 months. We have determined the stability of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (9-COOH-THC), amphetamine, methamphetamine, morphine, codeine, cocaine, benzoylecgonine, and phencyclidine in 236 physiological urine samples. Following the initial quantitative analysis, the samples were stored at -20 degrees C for 12 months and then reanalyzed. All drug concentrations were determined by gas chromatographic-mass spectrometric methods with cutoff concentrations of 5 ng/mL for 9-COOH-THC and phencyclidine and 100 ng/mL for each of the other drugs. The average change in the concentrations of these drugs following this long-term storage was not extensive except for an average change of -37% in cocaine concentrations.

Methamphetamine protects against MPTP neurotoxicity in C57BL mice.

PubMed

Sziráki, I; Kardos, V; Patthy, M; Pátfalusi, M; Budai, G

1994-01-14

Methamphetamine (5 mg/kg) administered 30 min prior to each injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (3 x 30 mg/kg, at 24 h intervals) prevents the reduction of striatal levels of dopamine and its metabolites in C57BL mice. Methamphetamine and amphetamine inhibit the uptake of 1-methyl-4-phenylpyridinium (MPP+) by striatal synaptosomes of rats. A 30-min post-treatment with methamphetamine or amphetamine also prevents the MPTP-induced dopamine depletion, suggesting that their protective effect is related to the blockade of MPP+ uptake into dopaminergic neurons. Since amphetamine and methamphetamine are themselves neurotoxins at higher doses, this work demonstrated the protection against the actions of one neurotoxin by the administration of another.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys.

PubMed

Smith, Douglas A; Blough, Bruce E; Banks, Matthew L

2017-01-01

Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models. The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90 % cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016). The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys

PubMed Central

Smith, Douglas A.; Blough, Bruce. E.; Banks, Matthew L.

2016-01-01

Rationale Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SAR) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in nonhuman primate models. Objectives The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, (±)-methamphetamine, and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Methods Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Results Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full, ≥90% cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than methamphetamine or previously published methcathinone (Smith et al. 2016). Conclusion The presence of an N-methyl group blunted both the potency and efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs. PMID:27709249

Surveillance of drug abuse in Hong Kong by hair analysis using LC-MS/MS.

PubMed

Leung, K Wing; Wong, Zack C F; Ho, Janet Y M; Yip, Ada W S; Cheung, Jerry K H; Ho, Karen K L; Duan, Ran; Tsim, Karl W K

2018-06-01

The aim of this study is to reveal the habits of drug abusers in hair samples from drug rehabilitation units in Hong Kong. With the application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, a total of 1771 hair samples were analyzed during the period of hair testing service (January 2012 to March 2016) provided to 14 drug rehabilitation units including non-governmental organizations (NGOs), rehabilitation centers, and medical clinics. Hair samples were analyzed for abused drugs and their metabolites simultaneously, including ketamine, norketamine, cocaine, benzoylecgonine, cocaethylene, norcocaine, codeine, MDMA, MDA, MDEA, amphetamine, methamphetamine, morphine, 6-acetylmorphine, phencyclidine, and methadone. The results showed that ketamine (77.2%), cocaine (21.3%), and methamphetamine (16.5%) were the frequently detected drugs among those drug abusers, which is consistent with the reported data. In addition, the usage of multiple drugs was also observed in the hair samples. About 29% of drug-positive samples were detected with multiple drug use. Our studies prove that our locally developed hair drug-testing method and service can be a valid tool to monitor the use of abused drugs, and which could facilitate rehabilitation program management. Copyright © 2017 John Wiley & Sons, Ltd.

Methamphetamine and Amphetamine Isomer Concentrations in Human Urine Following Controlled Vicks VapoInhaler Administration

PubMed Central

Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; Flegel, Ron; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

2014-01-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography–mass spectrometry (GC–MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC–MS method with >99% purity of R-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC–MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0–1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT® II Plus, KIMS® II and DRI® had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT® II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. PMID:25217541

Increased risk of Parkinson's disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs.

PubMed

Callaghan, Russell C; Cunningham, James K; Sykes, Jenna; Kish, Stephen J

2012-01-01

Since methamphetamine and other amphetamine-type stimulants (meth/amphetamine) can damage dopaminergic neurons, researchers have long speculated that these drugs may predispose users to develop Parkinson's disease (PD), a dopamine deficiency neurological disorder. We employed a retrospective population-based cohort study using all linked statewide California inpatient hospital episodes and death records from January 1, 1990 through December 31, 2005. Patients at least 30 years of age were followed for up to 16 years. Competing risks analysis was used to determine whether the meth/amphetamine cohort had elevated risk of developing PD (ICD-9 332.0; ICD-10 G20) in comparison to a matched population-proxy appendicitis group and a matched cocaine drug control group. Individuals admitted to hospital with meth/amphetamine-related conditions (n=40,472; ICD-9 codes 304.4, 305.7, 969.7, E854.2) were matched on age, race, sex, date of index admission, and patterns of hospital admission with patients with appendicitis conditions (n=207,831; ICD-9 codes 540-542) and also individuals with cocaine-use disorders (n=35,335; ICD-9 codes 304.2, 305.6, 968.5). The meth/amphetamine cohort showed increased risk of PD compared to both that of the matched appendicitis group [hazard ratio (HR)=1.76, 95% CI: 1.12-2.75, p=0.017] and the matched cocaine group [HR=2.44, 95% CI: 1.32-4.41, p=0.004]. The cocaine group did not show elevated hazard of PD compared to the matched appendicitis group [HR=1.04, 95% CI: 0.56-1.93, p=0.80]. These data provide evidence that meth/amphetamine users have above-normal risk for developing PD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

PubMed

Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten

2016-04-01

One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users. © The Author 2015. Published by Oxford University Press on behalf of CINP.

75 FR 56137 - Controlled Substances: Proposed Aggregate Production Quotas for 2011

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-15

...,500,000 Amphetamine (for sale) 18,600,000 Cocaine 247,000 Codeine (for conversion) 65,000,000 Codeine... Business Regulatory Enforcement Fairness Act of 1996. This action will not result in an annual effect on... effects on competition, employment, investment, productivity, innovation, or on the ability of United...

Phentermine interference and high L-methamphetamine concentration problems in GC-EI-MS SIM Analyses of R-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride-derivatized amphetamines and methamphetamines†.

PubMed

Hamilton, Theron J; Qui, Harry Z; Dozier, Katherine V R; Fuller, Zachary J

2014-09-01

In order to achieve chromatographic separation, urine samples shown to be initially positive for amphetamines and methamphetamines in US Department of Defense immunoassays are derivatized with R-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (R-(-)-MTPA) prior to gas chromatography-electron impact-mass spectrometry (GC-EI-MS) analysis. Phentermine, a member of the phenethylamine class of drugs and a common appetite suppressant, interferes with GC-EI-MS assays of R-(-)-MTPA-derivatized d-amphetamine, degrading the chromatography of the internal standard and analyte ions and skewing concentration calculations. Additionally, when specimens with high concentrations of l-methamphetamine are derivatized with R-(-)-MTPA, signal peaks have the potential to be misidentified by integration software as d-methamphetamine. We have found that replacing R-(-) MTPA with (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride reduces phentermine interference problems related to internal standard chromatography, reduces the possibility of concentrated l-methamphetamine peaks being misidentified by integration software, improves resolution of d-methamphetamine in the presence of high l-methamphetamine concentrations, and is a cost-neutral change that can be applied to current amphetamines GC-EI-MS methods without the need for method modification. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Distinguishing sympathomimetic amines from amphetamine and methamphetamine in urine by gas chromatography/mass spectrometry.

PubMed

Thurman, E M; Pedersen, M J; Stout, R L; Martin, T

1992-01-01

Derivatives of seven commonly used sympathomimetic amines and two "designer amines" were isolated from urine, separated chromatographically from amphetamine and methamphetamine, and determined by mass spectrometry with selected ion monitoring. The drugs included ephedrine, propylhexedrine, pseudoephedrine, phenylpropanolamine, hydroxynorephedrine, phenylephrine, phentermine, methylenedioxyamphetamine (MDA), and methylenedioxy methamphetamine (MDMA). The drugs were liquid extracted from urine and derivatized by either heptafluorobutyric anhydride (HFBA) or 4-carbethoxyhexafluorobutyryl chloride (4-CB). Because the base peak ions for ephedrine, pseudoephedrine, propylhexedrine, MDMA, and phentermine are identical to methamphetamine (e.g. 254 amu for HFBA) and those for phenylephrine, hydroxynorephedrine, phenylpropanolamine, and MDA are identical to amphetamine (e.g. 240 amu for HFBA), a table of selected ions was developed for all 11 drugs that distinguished amphetamine and methamphetamine from the sympathomimetic amines with either HFBA or 4-CB. The distinguishing ions rely on the ring structure of the different drugs and fragmentation associated with that structure. The 4-CB reagent partially derivatized the hydroxy-containing sympathomimetic amines, while the HFBA completely derivatized all the sympathomimetic amines. Furthermore, false positive results for the 4-CB reagent were found only for methamphetamine (20-2250 ng/mL of methamphetamine) when high concentrations (greater than 5 micrograms) of ephedrine or pseudoephedrine were present in the specimen. These results are related to a combination of injection port temperature and cleanliness of the injection port sleeve.

Methamphetamine and amphetamine isomer concentrations in human urine following controlled Vicks VapoInhaler administration.

PubMed

Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; Flegel, Ron; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

2014-10-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography-mass spectrometry (GC-MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC-MS method with >99% purity of R-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC-MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0-1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤ 4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT(®) II Plus, KIMS(®) II and DRI(®) had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT(®) II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers.

PubMed

Gustavsen, Ingebjørg; Mørland, Jørg; Bramness, Jørgen G

2006-05-01

Experimental studies have investigated effects of low oral doses of amphetamine and methamphetamine on psychomotor functions, while less work has been done on effects of high doses taken by abusers in real-life settings. There are indications that intake of high doses may impair traffic related skills, and that abuse of amphetamines may cause hypersomnolence at the end-of-binge. The present study aimed at investigating the concentration-effect relationship between blood amphetamines concentrations and impairment in a population of real-life users. Eight hundred and seventy-eight cases with amphetamine or methamphetamine as the only drugs present in the blood samples were selected from the impaired driver registry at The Norwegian Institute of Public Health. In each case the police physician had concluded on whether the driver was impaired or not. 27% of the drivers were judged as not impaired, while 73% were judged as impaired. There was a positive relationship between blood amphetamines concentrations and impairment. The relationship reached a ceiling at blood amphetamines concentrations of 0.27-0.53 mg/l. Younger drivers were more often judged impaired than older drivers at similar concentrations. Despite the performance enhancing qualities of amphetamines demonstrated in some low dose laboratory experiments; this study revealed a positive relationship between blood amphetamines concentration and traffic related impairment.

Matrix effect and cross-reactivity of select amphetamine-type substances, designer analogues, and putrefactive amines using the Bio-Quant direct ELISA presumptive assays for amphetamine and methamphetamine.

PubMed

Apollonio, Luigino G; Whittall, Ian R; Pianca, Dennis J; Kyd, Jennelle M; Maher, William A

2007-05-01

The aim of this study was to evaluate the Bio-Quant Direct ELISA assays for amphetamine and methamphetamine in the routine presumptive screening of biological fluids. Standard concentration curves of the target analytes were assayed to assess sensitivity, and known concentrations of common amphetamine-type substances (ephedrine, pseudoephedrine, phentermine), designer analogues (MDA, MDMA, MDEA, MBDB, PMA, 4-MTA, 2CB), and putrefactive amines (phenylethylamine, putrescine, tryptamine, tyramine) were analyzed to determine cross-reactivity. Results of the standard curve studies show the capacity of both Direct ELISA kits to confidently detect down to 3 ng/mL interday (PBS matrix; CVs 6.3-15.5%). Cross-reactivity relative to that of 50 ng/mL preparations of the target compounds demonstrated that the Direct ELISA kit for amphetamine also detected MDA (282%), PMA (265%), 4-MTA (280%), and phentermine (61%), and the Direct ELISA for methamphetamine also assayed positive for MDMA (73%), MDEA (18%), pseudoephedrine (19%), MBDB (8%), and ephedrine (9%). Matrix studies demonstrated that both ELISA kits could be applied to screening of blood, urine, and saliva to a concentration of 6 ng/mL or lower. In conclusion, the Bio-Quant Direct ELISA kits for amphetamine and methamphetamine are fast and accurate and have demonstrated themselves to be useful tools in routine toxicological testing.

Prospective associations between meth/amphetamine (speed) and MDMA (ecstasy) use and depressive symptoms in secondary school students.

PubMed

Brière, Frédéric N; Fallu, Jean-Sébastien; Janosz, Michel; Pagani, Linda S

2012-11-01

Research has raised significant concern regarding the affective consequences of synthetic drug use. However, little evidence from well-controlled longitudinal studies exists on these consequences. The aim of this study was to determine whether use of meth/amphetamine (speed) and ±3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is independently predictive of subsequent depressive symptoms in adolescents. A sample of 3880 adolescents from secondary schools in disadvantaged areas of Quebec, Canada, were followed over time (2003-2008). Logistic regression was used to test the association between meth/amphetamine and MDMA use in grade 10 (ages 15-16 years) and elevated depressive symptoms on an abridged Center for Epidemiologic Studies-Depression scale in grade 11, controlling for pre-existing individual and contextual characteristics. After adjustment, both MDMA use (OR 1.7, 95% CI 1.1 to 2.6) and meth/amphetamine use (OR 1.6, 95% CI 1.1 to 2.3) in grade 10 significantly increased the odds of elevated depressive symptoms in grade 11. These relationships did not vary by gender or pre-existing depressive symptoms. Increased risk was particularly observed in concurrent usage (OR 1.9, 95% CI 1.2 to 2.9). Adolescent use of meth/amphetamine and MDMA (particularly concurrent use) is independently associated with subsequent depressive symptoms. Further enquiry must determine whether these associations reflect drug-induced neurotoxicity and whether adolescence is a period of increased vulnerability to the hazards of synthetic drug exposure.

Hospital separations for cannabis- and methamphetamine-related psychotic episodes in Australia.

PubMed

Degenhardt, Louisa; Roxburgh, Amanda; McKetin, Rebecca

2007-04-02

To examine trends in hospital separations related to "drug-induced" psychosis for cannabis and methamphetamine, in the context of patterns of cannabis and methamphetamine use in the Australian population. Analysis of prospectively collected data from the National Hospital Morbidity Database on hospital separations primarily attributed to drug-induced psychosis (July 1993 - June 2004), and specifically for cannabis and amphetamines (1999-2004). Calculation of Australian population-adjusted rates of drug-induced psychosis hospital separations using estimated resident population data from the Australian Bureau of Statistics (at 30 June each year) and data on cannabis and methamphetamine use from the 2004 National Drug Strategy Household Survey. Number of hospital separations due to drug-induced psychosis, and standardised (age-specific) rates per million population and per million users. There have been notable increases in hospital separations due to drug-induced psychosis, which appear to have been driven by amphetamine-related rather than cannabis-related episodes. The rate of hospital separations was higher for amphetamine users than for cannabis users in all age groups, and the rate increased among older amphetamine users. The risk of hospitalisation for a drug-induced psychotic episode associated with amphetamine use appears to be greater than that for cannabis use in all age groups.

A systematic review of risk factors for methamphetamine-associated psychosis.

PubMed

Arunogiri, Shalini; Foulds, James A; McKetin, Rebecca; Lubman, Dan I

2018-06-01

Chronic methamphetamine use is commonly associated with the development of psychotic symptoms. The predictors and correlates of methamphetamine-associated psychosis are poorly understood. We sought to systematically review factors associated with psychotic symptoms in adults using illicit amphetamine or methamphetamine. A systematic literature search was performed on MEDLINE (OVID), PsycINFO and EMBASE databases from inception to 8 December 2016. The search strategy combined three concept areas: methamphetamine or amphetamine, psychosis and risk factors. Included studies needed to compare adults using illicit methamphetamine or amphetamine, using a validated measure of psychosis, on a range of risk factors. Of 402 identified articles, we removed 45 duplicates, 320 articles based on abstract/title and 17 ineligible full-text articles, leaving 20 included studies that were conducted in 13 populations. Two co-authors independently extracted the following data from each study: country, setting and design; participant demographic and clinical details; sample size; measure/s used and measures of association between psychosis outcomes and risk factors. Individual study quality was assessed using a modified Newcastle-Ottawa Scale, and strength of evidence was assessed using GRADE criteria. Frequency of methamphetamine use and severity of methamphetamine dependence were consistently found to be associated with psychosis, and sociodemographic factors were not. There was inconsistent evidence available for all other risk factors. Individual study quality was low-moderate for the majority of studies. Heterogeneity in study outcomes precluded quantitative synthesis of outcomes across studies. The most consistent correlates of psychotic symptoms were increased frequency of methamphetamine use and dependence on methamphetamine. The findings of this review highlight the need for targeted assessment and treatment of methamphetamine use in individuals presenting with psychosis.

Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2'-methyl-MPTP.

PubMed

Sziráki, I; Kardos, V; Patthy, M; Pátfalusi, M; Gaál, J; Solti, M; Kollár, E; Singer, J

1994-01-01

The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP(+)-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2'CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson's disease.

Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results.

PubMed

Cody, John T

2002-05-01

Medical Review Officer interpretation of laboratory results is an important component of drug testing programs. The clinical evaluation of laboratory results to assess the possibility of appropriate medical use of a drug is a task with many different facets, depending on the drug class considered. This intercession prevents the reporting of positive results unless it is apparent that drugs were used illicitly. In addition to the commonly encountered prescribed drugs that yield positive drug testing results, other sources of positive results must be considered. This review describes a series of compounds referred to as "precursor" drugs that are metabolized by the body to amphetamine and/or methamphetamine. These compounds lead to positive results for amphetamines even though neither amphetamine nor methamphetamine were used, a possibility that must be considered in the review of laboratory results. Description of the drugs, their clinical indications, and results seen following administration are provided. This information allows for the informed evaluation of results with regard to the potential involvement of these drugs.

Hair drug testing of children suspected of exposure to the manufacture of methamphetamine.

PubMed

Farst, Karen; Reading Meyer, J A; Mac Bird, T; James, Laura; Robbins, James M

2011-04-01

This study compares hair color and age in children tested for methamphetamine by hair analysis due to suspicion of exposure to the manufacture of methamphetamine by their caregivers. A retrospective analysis evaluated differences in hair drug testing results of 107 children less than 12 years of age tested due to clinical suspicion of having been exposed to the manufacture of methamphetamine. Results (confirmed by gas chromatography-mass spectroscopy) were compared for differences in likelihood of testing positive in relation to the subject's age and having light or dark colored hair and reported with crude and adjusted odds ratios with 95% confidence intervals. Of 107 children, 103 had a sufficient hair specimen for analysis. A third (36%) of the study population was less than 3 years of age. Almost half (45%) of the children tested positive for methamphetamine. 15% of the total study population tested positive for methamphetamine in combination with amphetamine indicating some degree of systemic exposure. No children were positive for amphetamine without also being positive for methamphetamine. Children less than 3 years of age were more likely to test positive. Positive hair drug tests for the combination of methamphetamine and amphetamine occurred in children with both light and dark colored hair. Children living in homes where methamphetamine is being manufactured can have drug identified in their hair regardless of hair color. This testing can aid in illuminating the child's presence in an at-risk environment and a family in need of services. Copyright © 2011 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Crystal methamphetamine, its analogues, and HIV infection: medical and psychiatric aspects of a new epidemic.

PubMed

Urbina, Antonio; Jones, Kristina

2004-03-15

The use of the recreational drug crystal methamphetamine among younger homosexual men is expanding, and with it, unsafe sex behaviors that increase the transmission of human immunodeficiency virus (HIV). This article reviews available literature on the medical and psychiatric morbidities associated with methamphetamine abuse in HIV-infected patients. Medical complications include hypertension, hyperthermia, rhabdoymyolysis, and stroke. One fatal case of ingestion of methamphetamine with HIV medication has been documented. Two fatal cases of ingestion of HIV medication with the amphetamine analogue n-methyl-3,4 methylenedioxymethamphetamine (MDMA, or "ecstasy") have also been reported. Some molecular researchers suggest that dopaminergic systems are vulnerable to the combined neurotoxicity of HIV infection and methamphetamine. Population surveys indicate high rates of HIV infection among methamphetamine abusers and high rates of unprotected anal intercourse during drug intoxication. Intoxication can sometimes produce paranoia, auditory hallucinations, and, occasionally, violent behavior. Amphetamine withdrawal commonly results in symptoms of depression. Methamphetamine is a new challenge related to treatment and prevention of HIV infection.

NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines.

PubMed

2005-07-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Methamphetamine and amphetamine concentrations in postmortem rabbit tissues.

PubMed

Nagata, T; Kimura, K; Hara, K; Kudo, K

1990-11-01

The feasibility of detecting methamphetamine and its major metabolite, amphetamine, in postmortem tissues over a 2-year period was examined. It is important to determine if the abuse and toxic effects of drugs can be proved from evidence found in decayed, submerged, or stained tissue materials. The blood, urine, liver, skeletal muscle, skin and extremity bones from rabbits given methamphetamine intravenously were kept at room temperature, under 4 different conditions: sealed in a test tube, dried in the open air, submerged in tap water and stained on gauze. Methamphetamine was present in all the samples, with slight change in concentration in case of sealed and air dried tissues. Changes varied in bones kept in water. There were considerable decreases in methamphetamine in blood and urine stains. Despite long term storage, drug abuse and/or toxicity could be determined, in all tissues examined.

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

PubMed Central

Steinkellner, Thomas; Freissmuth, Michael; Sitte, Harald H.; Montgomery, Therese

2015-01-01

Amphetamine (‘Speed’), methamphetamine (‘Ice’) and its congener 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity. PMID:21194370

Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines.

PubMed

Thomas, David M; Dowgiert, Jennifer; Geddes, Timothy J; Francescutti-Verbeem, Dina; Liu, Xiuli; Kuhn, Donald M

2004-09-09

Neurotoxic amphetamines cause damage to monoamine nerve terminals of the striatum by unknown mechanisms. Microglial activation contributes to the neuronal damage that accompanies injury, disease, and inflammation, but a role for these cells in amphetamine-induced neurotoxicity has received little attention. We show presently that D-methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine, and p-chloroamphetamine, each of which has been linked to dopamine (DA) or serotonin nerve terminal damage, result in microglial activation in the striatum. The non-neurotoxic amphetamines l-methamphetamine, fenfluramine, and DOI do not have this effect. All drugs that cause microglial activation also increase expression of glial fibrillary acidic protein (GFAP). At a minimum, microglial activation serves as a pharmacologically specific marker for striatal nerve terminal damage resulting only from those amphetamines that exert neurotoxicity. Because microglia are known to produce many of the reactive species (e.g., nitric oxide, superoxide, cytokines) that mediate the neurotoxicity of the amphetamine-class of drugs, their activation could represent an early and essential event in the neurotoxic cascade associated with high-dose amphetamine intoxication.

Amphetamine-type stimulant use among men who have sex with men (MSM) in Vietnam: Results from a socio-ecological, community-based study.

PubMed

Vu, Nga Thi Thu; Holt, Martin; Phan, Huong Thi Thu; Le, Huong Thi; La, Lan Thi; Tran, Gioi Minh; Doan, Tung Thanh; Nguyen, Trang Nhu Nguyen; de Wit, John

2016-01-01

Amphetamine-type-stimulants (ATS) use is associated with HIV-related sexual risk behaviours and is an emergent problem among men who have sex with men (MSM) in Vietnam. The purpose of this study is to describe ATS use patterns and understand the correlates of recent methamphetamine use from a socio-ecological perspective. From September through December, 2014, 622 MSM were recruited in Hanoi and Ho Chi Minh City, Vietnam. We collected information on demographic characteristics, HIV testing behaviours, use of ATS and other recreational drugs (ever and recently), sexual sensation seeking, depressive mood, experienced and internalized stigma related to homosexuality, social involvement with other MSM, and perceptions of ATS use in MSM networks. We performed descriptive statistics to describe ATS use patterns and multivariate logistic regression to establish independent correlates of recent methamphetamine use. Nearly one-third (30.4%) had ever used ATS, including 23.6% who had used methamphetamine, 4.3% who had used amphetamine ('speed') and 20.9% who had used ecstasy. 20.1% and 11.9% had ever used methamphetamine and ecstasy, respectively, during sex. Eighteen percent of methamphetamine users were classified as engaged in high-risk use. Recent methamphetamine use (in the last 3 months) was associated with participants perceiving more methamphetamine use in their MSM network, recent sex work, and higher sexual sensation seeking scores. ATS use is relatively prevalent among MSM sampled in Vietnam's main cities. Interventions to address methamphetamine are warranted for MSM in Vietnam. Methamphetamine treatments are needed for high-risk users. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Quantification of Methamphetamine in Mouse Thighbones Buried in Soil.

PubMed

Nakao, Ken-Ichiro; Tatara, Yuki; Kibayashi, Kazuhiko

2017-11-01

Bone samples are used for analysis of drugs in decomposed or skeletonized bodies. Toxicological analyses of buried bones are important for determining the causes and circumstances of death. In this study, methamphetamine and amphetamine concentrations in heart blood, thigh muscles, and thighbones were analyzed using solid-phase extraction with liquid chromatography-tandem mass spectrometry. Methamphetamine concentrations in heart blood, thigh muscle, and thighbone ranged from 0.041 to 0.873 μg/mL, 0.649 to 2.623 μg/g, and 56.543 to 643.371 μg/g, respectively. Thighbone concentrations were significantly higher than those in heart blood or thigh muscles were. Methamphetamine concentrations in buried thighbone (4.010-45.785 μg/g) were significantly lower than those of unburied thighbones were (56.543-643.371 μg/g). Methamphetamine and amphetamine were detected in thighbones buried for 7-180 days. These findings indicate that the methamphetamine concentrations in bone are higher and decrease after burial in soil. © 2017 American Academy of Forensic Sciences.

Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives.

PubMed

Kraemer, Thomas; Maurer, Hans H

2002-04-01

This paper reviews the toxicokinetics of amphetamines. The designer drugs MDA (methylenedioxy-amphetamine, R,S-1-(3;,4;-methylenedioxyphenyl)2-propanamine), MDMA (R,S-methylenedioxymethamphetamine), and MDE (R,S-methylenedioxyethylamphetamine), as well as BDB (benzodioxolylbutanamine; R,S-1-(1;,3;-benzodioxol-5;-yl)-2-butanamine or R,S-1-(3;,4;-methylenedioxyphenyl)-2-butanamine) and MBDB (R,S-N-methyl-benzodioxolylbutanamine), were taken into consideration, as were the following N-alkylated amphetamine derivatives: amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, methamphetamine, prenylamine, and selegiline. English-language publications from 1995 to 2000 were reviewed. Papers describing identification of metabolites or cytochrome P450 isoenzyme-dependent metabolism and papers containing pharmacokinetic/toxicokinetic data were considered and summarized. The implications of toxicokinetics for toxicologic assessment or for interpretation in forensic cases are discussed.

A new screening method for amphetamine and methamphetamine using dansyl chloride derivatization and cartridge fluorescence.

PubMed

Yamada, H; Ikeda-Wada, S; Oguri, K

1998-07-01

A new screening method for amphetamines was developed. It consists of derivatization with dansyl chloride, extraction of the derivative using a Sep-Pak C18 or a Bond Elut C18, solid phase extraction columns, and visualization of the fluorescence of the cartridge. A control test using drug-free urine showed no fluorescence. Amphetamine, methamphetamine and the methylenedioxy derivatives exhibited strong fluorescence, while related compounds, such as N-ethylamphetamine and fenetylline, were negative or weakly positive. The disadvantage of the present method is that it is a multi-step procedure and 20-30 min is required for screening. However, since it has a different specificity from the widely used immunochemical technique, it is suggested to be a useful screen for amphetamines.

Teenagers and drugs

MedlinePlus

... PCP use Loss of appetite (occurs with amphetamine, methamphetamine, or cocaine use ) Increased appetite (with marijuana use) ... as seen with uppers such as cocaine and methamphetamine) You also may notice changes in your teen's ...

Occurrence of illicit drugs in two wastewater treatment plants in the South of Italy.

PubMed

Cosenza, Alida; Maida, Carmelo Massimo; Piscionieri, Donatella; Fanara, Serena; Di Gaudio, Francesca; Viviani, Gaspare

2018-05-01

In this study the occurrence and the behavior of illicit drugs and their metabolites have been investigated for two wastewater treatment plants (WWTPs) (namely, WWTP-1 and WWTP-2) located in Sicily (island of Italy). Samples were analyzed for methamphetamine, cocaine (COC), 3,4-methylenedioxymethamphetamine (MDMA), methadone (METH), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 3,4-methylenedioxy amphetamine (MDA); 3,4-methylenedioxy ethylamphetamine (MDEA), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) and Benzoylecgonine (BEG). The BEG, COC, MOR and THC-COOH were found at the highest concentration in both WWTPs. The Wastewater-based epidemiology calculation for BEG, COC, cannabinoids and THC-COOH was performed. On average, for both plants, population consumes 1.6 and 23.4 dose 1000 inh -1 day -1 of cocaine and cannabis, respectively. For WWTP-1 negative removals of illicit drugs were observed. For WWTP-2 the following average removal efficiencies were obtained: BEG (77.85%), COC (92.34%), CODEINE (64.75%), MOR (90.16%) and THC-COOH (68.64%). Copyright © 2018 Elsevier Ltd. All rights reserved.

A GC-MS method for the detection and quantitation of ten major drugs of abuse in human hair samples.

PubMed

Orfanidis, A; Mastrogianni, O; Koukou, A; Psarros, G; Gika, H; Theodoridis, G; Raikos, N

2017-03-15

A sensitive analytical method has been developed in order to identify and quantify major drugs of abuse (DOA), namely morphine, codeine, 6-monoacetylmorphine, cocaine, ecgonine methyl ester, benzoylecgonine, amphetamine, methamphetamine, methylenedioxymethamphetamine and methylenedioxyamphetamine in human hair. Samples of hair were extracted with methanol under ultrasonication at 50°C after a three step rinsing process to remove external contamination and dirt hair. Derivatization with BSTFA was selected in order to increase detection sensitivity of GC/MS analysis. Optimization of derivatization parameters was based on experiments for the selection of derivatization time, temperature and volume of derivatising agent. Validation of the method included evaluation of linearity which ranged from 2 to 350ng/mg of hair mean concentration for all DOA, evaluation of sensitivity, accuracy, precision and repeatability. Limits of detection ranged from 0.05 to 0.46ng/mg of hair. The developed method was applied for the analysis of hair samples obtained from three human subjects and were found positive in cocaine, and opiates. Published by Elsevier B.V.

Maintaining class, producing gender: enhancement discourses about amphetamine in entertainment media.

PubMed

McKenna, Stacey A

2011-11-01

Since the 1930s, amphetamine has been used for a variety of socially and medically condoned purposes including personal and performance enhancement. In the contemporary U.S., although amphetamine and its derivatives share a history, similar chemical composition, and physiological and psychiatric effects, they are typically treated and researched as two distinct groups: illegally produced methamphetamine and prescription amphetamine. This study is an examination of the social meanings of these categories and their users as represented in popular media. To complement existing research on drug discourses in popular news media, this study analysed entertainment media: ten novels, three seasons of Breaking Bad, six television episodes, and eight movies. Media were coded inductively and deductively using tenets of critical discourse analysis and rhetorical criticism. The author identified discourses about user subject positions and ideologies pertaining to enhancement-related motivations for use. Two important themes emerged from this analysis that construct amphetamine use and users in ways that reflect, legitimize and reproduce class and gender ideologies. First, discourses illustrate that distinct meanings of methamphetamine versus prescription amphetamine are linked to expectations about the respective socioeconomic class and social status of their users. Second, the discourses reflect gendered values and ideals about productivity and sexuality. In reality, American cultural and political-economic contexts may encourage the use of amphetamine to meet a variety of social expectations and economic needs. However, many policy and prevention efforts surrounding amphetamine use disproportionately target methamphetamine users and women. Because policy and prevention efforts can be influenced as much by social values as by data, it is important to examine the many arenas in which social values are produced and disseminated. Copyright © 2011 Elsevier B.V. All rights reserved.

Application of drug testing using exhaled breath for compliance monitoring of drug addicts in treatment.

PubMed

Carlsson, Sten; Olsson, Robert; Lindkvist, Irene; Beck, Olof

2015-04-01

Exhaled breath has recently been identified as a possible matrix for drug testing. This study explored the potential of this new method for compliance monitoring of patients being treated for dependence disorders. Outpatients in treatment programs were recruited for this study. Urine was collected as part of clinical routine and a breath sample was collected in parallel together with a questionnaire about their views of the testing procedure. Urine was analyzed for amphetamines, benzodiazepines, cannabis, cocaine, buprenorphine, methadone and opiates using CEDIA immunochemical screening and mass spectrometry confirmation. The exhaled breath was collected using the SensAbues device and analyzed by mass spectrometry for amphetamine, methamphetamine, diazepam, oxazepam, tetrahydrocannabinol, cocaine, benzoylecgonine, buprenorphine, methadone, morphine, codeine and 6-acetylmorphine. A total of 122 cases with parallel urine and breath samples were collected; 34 of these were negative both in urine and breath. Out of 88 cases with positive urine samples 51 (58%) were also positive in breath. Among the patients on methadone treatment, all were positive for methadone in urine and 83% were positive in breath. Among patients in treatment with buprenorphine, 92% were positive in urine and among those 80% were also positive in breath. The questionnaire response documented that in general, patients accepted drug testing well and that the breath sampling procedure was preferred. Compliance testing for the intake of prescribed and unprescribed drugs among patients in treatment for dependence disorders using the exhaled breath sampling technique is a viable method and deserves future attention.

Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography-tandem mass spectrometry

PubMed Central

Jones, Joseph; Rios, Rosemarie; Jones, Mary; Lewis, Douglas; Plate, Charles

2009-01-01

The use of meconium as a drug-screening matrix for newborns has been the gold standard of care for the past two decades. A recent study using matched pairs of meconium and umbilical cord demonstrated a high degree of agreement. The use of liquid chromatography-tandem mass spectrometry as a means to confirm amphetamines presumptive positive umbilical cord specimens for amphetamine and methamphetamine is described here for the first time. The limit of detection for both compounds was 0.2 ng/g. The limit of quantitation for both compounds was 0.6 ng/g. The assay was linear for both compounds up to 100 ng/g. PMID:19783234

[Study of selegiline and related compounds with x-ray diffraction].

PubMed

Simon, K; Böcskei, Z; Török, Z

1992-09-01

Selegiline and its parent compounds were studied by X-ray diffraction. It was established that the racemates of primary and secondary amines (p-fluoro-amphetamine, methamphetamine, p-fluoro-methamphetamine) hydrochloride do not form racemic compounds but crystalline as conglomerates, at the same time tertiary amines like selegiline and p-fluoro-selegiline hydrochlorides do. The crystalline structure of five enantiomeric hydrochlorides were determined, the CPhe-C-C-N torsion angle is anti-periplanar in all cases but in p-fluoro-amphetamine where it is gauche.

Histopathological study of cardiac lesions in methamphetamine poisoning-related deaths.

PubMed

Akhgari, Maryam; Mobaraki, Homeira; Etemadi-Aleagha, Afshar

2017-02-17

Methamphetamine abuse is a worldwide health concern. Methamphetamine causes health hazards in many vital organs. It can cause damage to cardiac tissue via catecholamines release. Methamphetamine related deaths are becoming one of the most important problems in Iran. The purpose of the present study was to determine cardiac pathology in methamphetamine poisoning-related deaths. The study included 100 cases of methamphetamine poisoning-related deaths and 100 cases as control group. Toxicology analysis of liver, gastric content, bile, urine, blood and vitreous humor were conducted to detect drugs, poisons and alcohols using thin layer chromatography, gas chromatography/mass spectrometry, and high performance liquid chromatography. Positive toxicology analysis results except for amphetamine and methamphetamine were excluded from the study in order to omit interfering factors. The most striking features of cardiac damage were observed by light microscopy. Methamphetamine and amphetamine were detected in either urine or gastric content samples. In all of the cases methamphetamine toxicity was determined to be a direct cause of death by forensic medicine practitioner. Cardiovascular pathology was noted in 68% of studied cases. The most common histopathologic features were myocardial fiber hypertrophy, mild, moderate to severe atherosclerosis and focal degeneration/necrosis. The results of the present study indicate that cardiotoxicity is one of the major contributing factors in methamphetamine poisoning related deaths. Overall, the current study highlights the fact that cardiotoxic effects of methamphetamine can explain increasing reports of heart failure and consequently death in young abusers. Not applicable. Histopathological study of cardiac lesions in methamphetamine poisoning-related deaths.

Crystalline methamphetamine use and methamphetamine-related harms in Australia.

PubMed

Degenhardt, Louisa; Sara, Grant; McKetin, Rebecca; Roxburgh, Amanda; Dobbins, Timothy; Farrell, Michael; Burns, Lucinda; Hall, Wayne D

2017-03-01

Concerns about crystal methamphetamine use and harm have increased in multiple countries. This paper describes how changes in the availability and use of crystal methamphetamine have impacted on methamphetamine-related harms in Australia. Data on methamphetamine use were obtained from population-level surveys, health service data and surveys of drug use among sentinel groups of ecstasy users and people who inject drugs. Data were obtained on seizures, arrests, clandestine laboratory detections, hospital separations, mental health unit admissions, drug telephone helpline calls and drug treatment episodes. Segmented linear regression models were fitted to identify changes in these series using log-transformed data where appropriate. The availability of crystal methamphetamine has increased as evidenced by increased laboratory detections, domestic seizures and purity of the seized drug. Population surveys do not report an increase in the number of people who used at least once in the past year. However, more users report using crystal methamphetamine rather than lower-purity powder methamphetamine and more regular use. Indicators of methamphetamine-related harms have increased in parallel with this change. Amphetamine-related helpline calls, drug treatment, arrests and hospital admissions for amphetamine disorders and psychosis all peaked in the mid-2000s, declined for several years and have increased steeply since 2010. The increased availability and use of crystal methamphetamine have been associated with increased regular use and harms. Treatment is required for those experiencing problems and the capacity of health services to provide care needs to be enhanced.[Degenhardt L, Sara G, Connor JP, McKetin R, Roxburgh A, Dobbins T, Farrell M, Burns L, Hall WD. Crystalline methamphetamine use and methamphetamine-related harms in Australia. Drug Alcohol Rev 2017;36:160-170]. © 2016 Australasian Professional Society on Alcohol and other Drugs.

Pharmacological approaches to methamphetamine dependence: a focused review.

PubMed

Karila, Laurent; Weinstein, Aviv; Aubin, Henri-Jean; Benyamina, Amine; Reynaud, Michel; Batki, Steven L

2010-06-01

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

No evidence of subgroups found in amphetamine consumers in Iran.

PubMed

Bananej, Atireza; Völkl-Kernstock, Sabine; Lesch, Otto; Walter, Henriette; Skala, Katrin

2018-06-01

Amphetamine type substances are the second most commonly consumed illicit drug type and their use is an important contributor to the global burden of disease. This investigation set out to determine whether, similar to alcohol or nicotine addiction, subgroups of consumers can also be found in amphetamine addicts. 204 consumers of methamphetamine only (n = 50) or both methamphetamine and heroin (n = 154) have been investigated in Mashhad, Iran by means of "Lesch Alcoholism Typology". No significant differences in consumption pattern or age of onset have been found between the different types. Many subjects, however, reported symptoms of anxiety (n=78) or depression (n = 129) prior to drug use. These findings highlight the need for high quality epidemiological studies further addressing this issue.

Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users

PubMed Central

Boileau, Isabelle; Payer, Doris; Rusjan, Pablo M; Houle, Sylvain; Tong, Junchao; McCluskey, Tina; Wilson, Alan A; Kish, Stephen J

2016-01-01

Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D3 receptor levels in stimulant users prompting the view that D3 antagonism may help prevent relapse. Here we tested whether a ‘blunted' response to amphetamine in methamphetamine (MA) users extends to D3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D3-preferring probe [11C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [11C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D3-rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported ‘drug wanting'. We did not observe a ‘blunted' dopamine response to amphetamine in D2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [11C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal ‘D3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction. PMID:27353309

Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users.

PubMed

Boileau, Isabelle; Payer, Doris; Rusjan, Pablo M; Houle, Sylvain; Tong, Junchao; McCluskey, Tina; Wilson, Alan A; Kish, Stephen J

2016-12-01

Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D 2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D 3 receptor levels in stimulant users prompting the view that D 3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D 3 -rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D 3 -preferring probe [ 11 C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [ 11 C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D 3 -rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D 2 -rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [ 11 C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D 3 -areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D 3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D 3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D 3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.

Effects of Amphetamine-CNS Depressant Combinations and of Other CNS Stimulants in Four-Choice Drug Discriminations

ERIC Educational Resources Information Center

Li, Mi; Wessinger, William D.; McMillan, D. E.

2005-01-01

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine--pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs…

On-line liquid chromatography/tandem mass spectrometry simultaneous determination of opiates, cocainics and amphetamines in dried blood spots.

PubMed

Saussereau, E; Lacroix, C; Gaulier, J M; Goulle, J P

2012-02-15

A novel approach has been developed for the illicit drugs quantitative determination using dried blood spots (DBS) on filter paper. The illicit drugs tested were opiates (morphine and its 3- and 6-glucuronide metabolites, codeine, 6-monoacetylmorphine), cocainics (ecgonine methylester, benzoylecgonine, cocaine, cocaethylene) and amphetamines (amphetamine, methamphetamine, MDA, MDMA, MDEA). The described method, requiring a small blood volume, is based on high performance liquid chromatography coupled to tandem mass spectrometry using on-line extraction. A Whatman card 903 was spotted with 30μL of whole blood and left overnight to dry at room temperature. A 3-mm diameter disk was removed using a manual punch, suspended in 150μL of water for 10min with ultrasonication, and then 100μL was injected in the on-line LC-MS/MS system. An Oasis HLB was used as an extraction column and a C18 Atlantis as an analytical column. The chromatographic cycle was performed with 20mM ammonium formate buffer (pH 2.8) (solvent A) and acetonitrile/solvent A (90:10, v/v) gradient in 16min. Detection was performed in positive electrospray ionization mode (ESI+) with a Quattro Micro (Waters). Recoveries of all analytes were up to 80%. DBS were stored in duplicate at 4°C and -20°C for up to 6 months. Illicit drugs seemed to be much more stabled at -20°C. Furthermore, it was tested whether analysis of DBS may be as reliable as that of whole blood investigating authentic samples; significant correlations were obtained. This DBS assay has potential as rapid, sensitive and inexpensive option for the illicit drugs determination in small blood volumes, which seems of great interest in suspected cases of driving under the influence of drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

High prevalence of previous arrests for illicit drug use and/or impaired driving among drivers killed in motor vehicle crashes in Sweden with amphetamine in blood at autopsy.

PubMed

Jones, Alan Wayne; Holmgren, Anita; Ahlner, Johan

2015-08-01

Amphetamine, and to a lesser extent the secondary amine methamphetamine, are major recreational drugs of abuse in Sweden. These central stimulant amines are identified in blood from roughly 50% of people arrested for driving under the influence of drugs (DUID). However, much less information is available about the presence of amphetamine in blood of drivers killed in road-traffic crashes. This retrospective 10-year study (2001-2010) used a forensic toxicology database (TOXBASE) to retrieve information about road-traffic crashes when the driver had amphetamine and/or methamphetamine in autopsy blood. Forensic toxicology results were available from over 95% of all drivers killed on Swedish roads during this 10-year period. Amphetamine was present in the blood of 106 drivers (3.9%) either alone or together with other psychoactive substances (e.g. alcohol, cannabis, diazepam, alprazolam, etc.). The vast majority of fatalities were male (95%) with a mean age (±standard deviation) of 37±11.4 years (range 16-67 years). The mean (median) and highest concentrations of amphetamine in femoral blood were 1.36 mg/L (1.0mg/L) and 6.74 mg/L, respectively. Many of the victims (75%) had been arrested previously for use of illicit drugs or DUID. The median number of previous arrests was 4 (range 0-83) and amphetamine or methamphetamine were among the drugs identified in blood samples from 89% of cases (0-100%). The high prevalence of repeat DUID offending and/or use of illicit drugs among the drivers killed in road-traffic crashes suggests that an early intervention and treatment for stimulant abuse might have been more beneficial than conventional punishments for such drug-related crimes. Copyright © 2015 Elsevier B.V. All rights reserved.

Barriers to accessing methamphetamine treatment: A systematic review and meta-analysis.

PubMed

Cumming, Craig; Troeung, Lakkhina; Young, Jesse T; Kelty, Erin; Preen, David B

2016-11-01

Methamphetamine use is associated with a range of poor health, social and justice outcomes. In many parts of the world increased methamphetamine use has been identified as a major public health concern. Methamphetamine treatment programmes have been effective in reducing and ceasing use, however a range of barriers have prevented these programmes being widely adopted by methamphetamine users. This review examines the barriers to accessing meth/amphetamine treatment identified in the literature. Databases were systematically searched using relevant terms for peer-reviewed articles describing original research exploring the barriers to accessing treatment for meth/amphetamine use. Reviews and grey literature were excluded. Eleven studies conducted in 5 countries were included in data synthesis; this involved a systematic review of all 11 studies, and meta-analysis of the prevalence of barriers reported in 6 studies that published sufficient quantitative data. Psychosocial/internal barriers to accessing methamphetamine treatment were most prevalent across studies (10/11 studies). Meta-analysis confirmed the four most commonly endorsed barriers to treatment access across studies all psychosocial barriers were embarrassment or stigma (60%, 95% CI: 54-67%); belief that treatment was unnecessary (59%, 95% CI:54-65%); preferring to withdraw alone without assistance (55%, 95% CI:45-65); and privacy concerns (51%, 95% CI:44-59%). The primary barriers to accessing methamphetamine treatment are psychosocial/internal. Services and treatment models that address these barriers are urgently required. There is a growing need for methamphetamine-appropriate treatment services. Further research evaluating treatment engagement and effectiveness for methamphetamine and polysubstance use, including the development of effective pharmacotherapies is warranted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pharmacotherapy of amphetamine-type stimulant dependence: an update.

PubMed

Brensilver, Matthew; Heinzerling, Keith G; Shoptaw, Steven

2013-09-01

Methamphetamine- or amphetamine-type stimulants are the second most frequently used illicit drug worldwide, second only to cannabis. Behavioural treatments are efficacious, but their impact is limited underscoring the need for other treatment options, notably, pharmacotherapy. A review of randomised controlled trials of pharmacotherapies for methamphetamine- or amphetamine-type stimulants was performed using PubMed and Google Scholar databases. Evidence for efficacy of medications is reported. Clinical trials have yielded no broadly effective pharmacotherapy. Promising signals have been observed for methylphenidate, naltrexone, bupropion and mirtazapine in subgroups of patients in reducing stimulant use (e.g. patients with less severe dependence at baseline and men who have sex with men), though none has produced an unambiguous, replicable signal of efficacy. Problems in Phase II trials, including high dropout rates, missing data and a lack of agreement on outcomes, complicate efforts to find a broadly effective pharmacotherapy for amphetamine-type stimulant disorders. Efforts to address these problems include calls for better validation of pharmacological target exposure, receptor binding and functional modulation. As well, there is a need for agreement in using findings from preclinical and early phases of the medication development process for selecting better pharmacotherapy candidates. After over 20 years of efforts worldwide to develop a broadly effective medication for dependence on methamphetamine- or amphetamine-type stimulants, no candidate has emerged. This highlights the need for new compounds, consistent and stringent research methods, better integration between preclinical and clinical stages of medication development, and improved collaboration between government, industry and researchers. © 2013 Australasian Professional Society on Alcohol and other Drugs.

Discriminative-Stimulus, Subject-rated and Physiological Effects of Methamphetamine in Humans Pretreated with Aripiprazole

PubMed Central

Sevak, Rajkumar J.; Vansickel, Andrea R.; Stoops, William W.; Glaser, Paul E. A.; Hays, Lon R.; Rush, Craig R.

2013-01-01

Methamphetamine is thought to produce its behavioral effects by releasing dopamine (DA), serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, while results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human laboratory procedures of drug-discrimination are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, six participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (i.e., ≥80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10 and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (e.g., increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine. PMID:21694622

The infant development, environment, and lifestyle study: effects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth.

PubMed

Smith, Lynne M; LaGasse, Linda L; Derauf, Chris; Grant, Penny; Shah, Rizwan; Arria, Amelia; Huestis, Marilyn; Haning, William; Strauss, Arthur; Della Grotta, Sheri; Liu, Jing; Lester, Barry M

2006-09-01

Methamphetamine use among pregnant women is an increasing problem in the United States. Effects of methamphetamine use during pregnancy on fetal growth have not been reported in large, prospective studies. We examined the neonatal growth effects of prenatal methamphetamine exposure in the multicenter, longitudinal Infant Development, Environment and Lifestyle study. The Infant Development, Environment and Lifestyle study screened 13808 subjects at 4 clinical centers: 1618 were eligible and consented, among which 84 were methamphetamine exposed, and 1534 were unexposed. Those who were methamphetamine exposed were identified by self-report and/or gas chromatography-mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Those who were unexposed denied amphetamine use and had a negative meconium screen. Both groups included prenatal alcohol, tobacco, or marijuana use, but excluded use of opiates, LSD, PCP or cocaine only. Neonatal parameters included birth weight and gestational age in weeks. One-way analysis of variance and linear-regression analyses were conducted on birth weight by exposure. The relationship of methamphetamine exposure and the incidence of small for gestational age was analyzed using multivariate logistic-regression analyses. The methamphetamine exposed group was 3.5 times more likely to be small for gestational age than the unexposed group. Mothers who used tobacco during pregnancy were nearly 2 times more likely to have small-for-gestational-age infants. In addition, less maternal weight gain during pregnancy was more likely to result in a small-for-gestational-age infant. Birthweight in the methamphetamine exposed group was lower than the unexposed group. These findings suggest that prenatal methamphetamine use is associated with fetal growth restriction after adjusting for covariates. Continued follow-up will determine if these infants are at increased risk for growth abnormalities in the future.

Prenatal exposure to amphetamines. Risks and adverse outcomes in pregnancy.

PubMed

Plessinger, M A

1998-03-01

Based on findings in humans and the confirmation of prenatal exposures in animals, amphetamines and methamphetamines increase the risk of an adverse outcome when abused during pregnancy. Clefting, cardiac anomalies, and fetal growth reduction deficits that have been seen in infants exposed to amphetamines during pregnancy have all been reproduced in animal studies involving prenatal exposures to amphetamines. The differential effects of amphetamines between genetic strains of mice and between species demonstrate that pharmacokinetics and the genetic disposition of the mother and developing embryo can have an enormous influence on enhancing or reducing these potential risks. The effects of prenatal exposure to amphetamines in producing altered behavior in humans appear less compelling when one considers other confounding variables of human environment, genetics, and polydrug abuse. In view of the animal data concerning altered behavior and learning tasks in comparison with learning deficits observed in humans, the influence of the confounding variables in humans may serve to increase the sensitivity of the developing embryo/fetus to prenatal exposure to amphetamines. These factors and others may predispose the developing conceptus to the damaging effects of amphetamines by actually lowering the threshold of susceptibility at the sites where damage occurs. Knowledge of the effects of prenatal exposure of the fetus and the mother to designer amphetamines is lacking. Based on the few studies in which designer drugs have been examined in animal models, more questions are raised than answered. Possible reasons why no malformations or significant fetal effects were found in the study by St. Omer include the genetic strain of rat used, the conservative exposure profile, or the fact that the placenta metabolized MDMA before reaching the embryo. These questions underscore the need for further investigations concerning the prenatal exposure effects of designer compounds and the effects of amphetamine and methamphetamine in general.

Methamphetamine-related brainstem haemorrhage.

PubMed

Chiu, Zelia K; Bennett, Iwan E; Chan, Patrick; Rosenfeld, Jeffrey V

2016-10-01

We report the case of an otherwise healthy 29-year-old woman who presented with a brainstem haemorrhage following intravenous methamphetamine use. Extensive investigation did not reveal an underlying pathology, and the development of symptoms was temporally related to methamphetamine injection. Although intracerebral haemorrhage secondary to methamphetamine use is well documented, this report describes a haemorrhage within the brainstem which is a rare location. While animal studies have demonstrated the potential of methamphetamines to produce brainstem haemorrhages, there has only been one previous report describing a haemorrhage in this location due to amphetamine use in humans. We conclude with a brief discussion of the clinical features and aetiology of methamphetamine-related stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine.

PubMed

Halpin, Laura E; Collins, Stuart A; Yamamoto, Bryan K

2014-02-27

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as 'bath salts' that have gained popularity among drug abusers. © 2013.

Neurotoxicity of Methamphetamine and 3,4-methylenedioxymethamphetamine

PubMed Central

Halpin, Laura E.; Collins, Stuart A.; Yamamoto, Bryan K.

2013-01-01

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as ‘bath salts’ that have gained popularity amongst drug abusers. PMID:23892199

Gender differences in the behavioral effects of methamphetamine.

PubMed

Schindler, Charles W; Bross, Joshua G; Thorndike, Eric B

2002-05-10

The effects of methamphetamine were tested in male and female rats on two different behavioral tasks. Following habituation to a locomotor activity chamber, female rats were more sensitive to the locomotor activating effect of i.p. methamphetamine (0.1-3.0 mg/kg) than were male rats. A similar effect has been observed for other psychomotor stimulants, including cocaine and amphetamine. However, males and females did not differ on methamphetamine-induced place preference following eight conditioning trials with a wide range of doses (0.1-5.6 mg/kg). These results suggest that males and females differ in their response to methamphetamine for only some behavioral tasks.

Screening determination of four amphetamine-type drugs in street-grade illegal tablets and urine samples by portable capillary electrophoresis with contactless conductivity detection.

PubMed

Nguyen, Thi Anh Huong; Pham, Thi Ngoc Mai; Ta, Thi Thao; Nguyen, Xuan Truong; Nguyen, Thi Lien; Le, Thi Hong Hao; Koenka, Israel Joel; Sáiz, Jorge; Hauser, Peter C; Mai, Thanh Duc

2015-12-01

A simple and inexpensive method for the identification of four substituted amphetamines, namely, 3,4-methylenedioxy methamphetamine (MDMA), methamphetamine (MA), 3,4-methylenedioxy amphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDEA) was developed using an in-house constructed semi-automated portable capillary electrophoresis instrument (CE) with capacitively coupled contactless conductivity detection (C(4)D). Arginine 10mM adjusted to pH4.5 with acetic acid was found to be the optimal background electrolyte for the CE-C(4)D determination of these compounds. The best detection limits achieved with and without a sample preconcentration process were 10ppb and 500ppb, respectively. Substituted amphetamines were found in different seized illicit club drug tablets and urine samples collected from different suspected users. Good agreement between results from CE-C(4)D and those with the confirmation method (GC-MS) was achieved, with correlation coefficients for the two pairs of data of more than 0.99. Copyright © 2015 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.

Mephedrone Does not Damage Dopamine Nerve Endings of the Striatum but Enhances the Neurotoxicity of Methamphetamine, Amphetamine and MDMA

PubMed Central

Angoa-Pérez, Mariana; Kane, Michael J.; Briggs, Denise I.; Francescutti, Dina M.; Sykes, Catherine E.; Shah, Mrudang M.; Thomas, David M.; Kuhn, Donald M.

2012-01-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its reuptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20 or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (4 injections of 2.5 or 5.0 mg/kg at 2 hr intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and MDMA on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. Because mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. PMID:23205838

Adulteration of urine by "Urine Luck".

PubMed

Wu, A H; Bristol, B; Sexton, K; Cassella-McLane, G; Holtman, V; Hill, D W

1999-07-01

In vitro adulterants are used to invalidate assays for urine drugs of abuse. The present study examined the effect of pyridinium chlorochromate (PCC) found in the product "Urine Luck". PCC was prepared and added to positive urine controls at concentrations of 0, 10, 50, and 100 g/L. The controls were assayed for methamphetamine, benzoylecgonine (BE), codeine and morphine, tetrahydrocannabinol (THC), and phencyclidine (PCP) with the Emit II (Syva) and Abuscreen Online (Roche) immunoassays, and by gas chromatography/mass spectrometry (GC/MS). Two tests were also developed to detect PCC in urine: a spot test to detect chromate ions using 10 g/L 1,5-diphenylcarbazide as the indicator, and a GC/MS assay for pyridine. We tested 150 samples submitted for routine urinalysis, compliance, and workplace drug testing for PCC, using these assays. Response rates decreased at 100 g/L PCC for all Emit II drug assays and for the Abuscreen morphine and THC assays. In contrast, the Abuscreen amphetamine assay produced apparently higher results, and no effect was seen on the results for BE or PCP. The PCC did not affect the GC/MS recovery of methamphetamine, BE, PCP, or their deuterated internal standards, but decreased GC/MS recovery of the opiates at both intermediate (50 g/L) and high (100 g/L) PCC concentrations and apparent concentrations of THC and THC-d3 at all PCC concentrations. Two of 50 samples submitted for workplace drug testing under chain-of-custody conditions were positive for PCC, whereas none of the remaining 100 specimens submitted for routine urinalysis or compliance drug testing were positive. PCC is an effective adulterant for urine drug testing of THC and opiates. Identification of PCC use can be accomplished with use of a spot test for the oxidant.

Spontaneous pneumomediastinum: A rare complication of methamphetamine use.

PubMed

Albanese, Jessica; Gross, Cole; Azab, Mohamed; Mahalean, Sinziana; Makar, Ranjit

2017-01-01

To present an unusual case of spontaneous pneumomediastinum subsequent to recreational amphetamine use. A young African American adult male was admitted to internal medicine service for treatment of rhabdomyolysis secondary to methamphetamine use. On admission, he was complaining of chest pain in addition to nausea and generalized muscle aches. By his second hospital day, chest pain had resolved yet physical exam demonstrated crepitation of the anterior chest and left axilla. Portable chest x-ray revealed subcutaneous emphysema in addition to pneumomediastinum. Spontaneous pneumomediastinum is a rare complication of amphetamine use that is often associated with subcutaneous emphysema and can be diagnosed with chest x-ray. Management is conservative, with observation, pain control, and supplemental oxygen as needed.

Methamphetamine Cured my Cocaine Addiction

PubMed Central

Haile, Colin N.; De La Garza, Richard; Newton, Thomas F.

2011-01-01

Cocaine dependence is an enduring problem and years of research and drug development has yet to produce an efficacious pharmacotherapy. Recent clinical research suggests that chronic treatment with amphetamine-like medications produces tolerance to cocaine’s reinforcing effects and may offer a viable pharmacotherapy. Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously addicted to cocaine are reviewed. Data obtained from initial screen and informal conversation suggested that all participants considered methamphetamine to have helped them stop using cocaine and eliminate cocaine craving. Methamphetamine also significantly decreased their alcohol consumption but did not alter cannabis or nicotine use. PMID:23066512

Psychological treatments for stimulant misuse, comparing and contrasting those for amphetamine dependence and those for cocaine dependence.

PubMed

Vocci, Frank J; Montoya, Iván D

2009-05-01

The aim is to compare and contrast psychological treatments for amphetamine and cocaine dependence. Stimulant dependence, in the form of cocaine or amphetamine/methamphetamine dependence, is prevalent worldwide, and their ratio may vary across different countries and regions of countries. The treatment of stimulant disorders has greatly advanced in recent years, and scientific evaluation of behavioral therapies, using randomized clinical trials designs and a stage-wise approach, have demonstrated the safety and efficacy of interventions. Psychological interventions such as cognitive behavioral therapy and contingency management for cocaine and methamphetamines use disorders are well tolerated and moderately effective in achieving drug abstinence. There is evidence that contingency management interventions can help to improve retention in treatment and, in turn, other treatment outcomes. Although there are important differences in the neuropsychiatric and medical consequences of cocaine and amphetamine use disorders, there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of these disorders. As there are no Food and Drug Administration-approved medications for the treatment of these disorders, psychological interventions form the basis of their treatment. More research is needed to address the specific psychosocial needs of cocaine and amphetamine-dependent individuals in order to improve their treatment outcomes.

[Driving under the influence of amphetamine and metamphetamine].

PubMed

Lia, Kjersti; Spigset, Olav; Slørdal, Lars

2009-01-15

The CNS stimulatory agents amphetamine and methamphetamine are often detected in blood samples from apprehended subjects driving under the influence of drugs. Relevant literature was identified through searches in PubMed and Google Scholar. The current state of knowledge regarding effects of amphetamines on traffic behaviour is reviewed and discussed. Limited epidemiological data and a small number of experimental studies using low doses of amphetamines are available. Low amphetamine doses have been associated with enhanced performance in studies of sleep-deprived subjects. Theoretical considerations and empirical observations suggest that higher doses may impede performance, but not in accordance with usual concentration/effect relationships. There is a conspicuous lack of data on how to handle cases of driving under the influence of amphetamines.

Microfluidic chip based nano liquid chromatography coupled to tandem mass spectrometry for the determination of abused drugs and metabolites in human hair.

PubMed

Zhu, Kevin Y; Leung, K Wing; Ting, Annie K L; Wong, Zack C F; Ng, Winki Y Y; Choi, Roy C Y; Dong, Tina T X; Wang, Tiejie; Lau, David T W; Tsim, Karl W K

2012-03-01

A microfluidic chip based nano-HPLC coupled to tandem mass spectrometry (nano-HPLC-Chip-MS/MS) has been developed for simultaneous measurement of abused drugs and metabolites: cocaine, benzoylecgonine, cocaethylene, norcocaine, morphine, codeine, 6-acetylmorphine, phencyclidine, amphetamine, methamphetamine, MDMA, MDA, MDEA, and methadone in the hair of drug abusers. The microfluidic chip was fabricated by laminating polyimide films and it integrated an enrichment column, an analytical column and a nanospray tip. Drugs were extracted from hairs by sonication, and the chromatographic separation was achieved in 15 min. The drug identification and quantification criteria were fulfilled by the triple quardropule tandem mass spectrometry. The linear regression analysis was calibrated by deuterated internal standards with all of the R(2) at least over 0.993. The limit of detection (LOD) and the limit of quantification (LOQ) were from 0.1 to 0.75 and 0.2 to 1.25 pg/mg, respectively. The validation parameters including selectivity, accuracy, precision, stability, and matrix effect were also evaluated here. In conclusion, the developed sample preparation method coupled with the nano-HPLC-Chip-MS/MS method was able to reveal the presence of drugs in hairs from the drug abusers, with the enhanced sensitivity, compared with the conventional HPLC-MS/MS.

Which drugs are associated with highest risk for being arrested for driving under the influence? A case-control study.

PubMed

Bogstrand, Stig Tore; Gjerde, Hallvard

2014-07-01

The aim of this study was to determine the association between drug type and arrest for driving under the influence of drugs (DUID) by calculating odds ratios (ORs) using a case-control design. A DUID arrest is in most cases related to aberrant or risky driving and might therefore be regarded as a proxy for a drug related traffic crash. The 'cases' were 2738 drivers arrested on suspicion of drugged driving from April 2008 to March 2009 with blood alcohol concentrations below the legal limit of 0.2g/L; 794 were arrested due to involvement in road traffic crashes, whereas 1944 were arrested for other reasons, mainly dangerous driving, suspected impairment when stopped in traffic controls, or because of phone calls to the police from other road users or observers. The 'controls' were 9375 random drivers in normal traffic, also with alcohol concentrations below this limit. Blood samples from 'cases' and oral fluid samples from 'controls' were analyzed for 15 drugs that have legislative concentration limits in Norway, in addition to two other commonly detected psychoactive drugs. The most prevalent illicit drug in the control group was tetrahydrocannabinol (THC; 0.58%), which was also commonly found in samples from drivers arrested due to road crash (15.6%) or arrested for other reasons (21.8%). Amphetamine/methamphetamine was most prevalent among arrested drivers involved in crashes (30.6%) and drivers arrested for other reasons (56.9%), whereas only 0.18% of the control group was positive for amphetamine/methamphetamine. The single-use substances which gave highest OR for police arrest were amphetamine/methamphetamine, alprazolam, clonazepam and oxazepam. The majority of the alprazolam and clonazepam findings were probably due to non-therapeutic use of medicinal drugs purchased on the illegal market. Combinations of two or more drugs yielded higher ORs than the use of single substances; combinations of amphetamine/methamphetamine and benzodiazepines gave the highest risk. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Francescutti, Dina M; Sykes, Catherine E; Shah, Mrudang M; Thomas, David M; Kuhn, Donald M

2013-04-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. © 2012 International Society for Neurochemistry.

3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

PubMed Central

Anneken, John H.; Angoa-Pérez, Mariana; Kuhn, Donald M.

2016-01-01

Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. PMID:25626880

The impact of substance abuse on mortality in patients with severe traumatic brain injury.

PubMed

O'Phelan, Kristine; McArthur, David L; Chang, Cherylee W J; Green, Deborah; Hovda, David A

2008-09-01

Drug and alcohol use are common in neurotrauma patients. Despite growing methamphetamine use there are few studies of the impact of methamphetamine use on outcome after traumatic brain injury (TBI). We conducted a retrospective review of 5-years of data from a trauma database. Inclusion criteria included severe TBI and diagnosis codes indicating head injury. The entire database was analyzed and then a subset of patients with complete toxicology data were examined separately. Primary outcome was mortality. Four hundred eighty-three patients were included. Toxicology results were available for 52.6% of patients. Alcohol, amphetamines, and cannabis were the most commonly detected substances. Overall mortality was 50.9%. When the group with complete tox screen data were analyzed, a toxicology screen that was positive for alcohol or amphetamine was associated with decreased mortality with an odds ratio of 0.23 (CI: 0.10-0.56, p = 0.001) and 0.25 (CI: 0.08-0.79, p = 0.02), respectively. When the subset of patients for whom toxicology data were available was analyzed the amphetamine-positive group was more likely to use cannabis and less likely to use alcohol. We unexpectedly found alcohol and methamphetamine use to be associated with decreased mortality. Neurotoxic and possible neuroprotective mechanisms of these substances are discussed as well as possible interactions between cannabis and methamphetamine. The potential influence of psycho-social factors are also considered. Prospective studies are needed to further investigate the effects of drug and alcohol use on outcome after severe TBI.

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters.

PubMed

Wagner, David J; Sager, Jennifer E; Duan, Haichuan; Isoherranen, Nina; Wang, Joanne

2017-07-01

Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance. Yet the mechanism of active renal secretion is poorly understood. The goals of this study were to characterize the interaction of methamphetamine and its major metabolites with organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters and to identify the major transporters involved in the disposition of methamphetamine and its major metabolites, amphetamine and para -hydroxymethamphetamine ( p -OHMA). We used cell lines stably expressing relevant transporters to show that methamphetamine and its metabolites inhibit human OCTs 1-3 (hOCT1-3) and hMATE1/2-K with the greatest potencies against hOCT1 and hOCT2. Methamphetamine and amphetamine are substrates of hOCT2, hMATE1, and hMATE2-K, but not hOCT1 and hOCT3. p -OHMA is transported by hOCT1-3 and hMATE1, but not hMATE2-K. In contrast, organic anion transporters 1 and 3 do not interact with or transport these compounds. Methamphetamine and its metabolites exhibited complex interactions with hOCT1 and hOCT2, suggesting the existence of multiple binding sites. Our studies suggest the involvement of the renal OCT2/MATE pathway in tubular secretion of methamphetamine and its major metabolites and the potential of drug-drug interactions with substrates or inhibitors of the OCTs. This information may be considered when prescribing medications to suspected or known abusers of methamphetamine to mitigate the risk of increased toxicity or reduced therapeutic efficacy. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Disruptive Effect of Amphetamines on Pavlovian to Instrumental Transfer

PubMed Central

Hall, Darien A.; Gulley, Joshua M.

2010-01-01

Reward seeking behavior can be powerfully modulated by exposure to a conditioned stimulus (CS) that was previously associated with that reward. This can be demonstrated in a Pavlovian-to-instrumental transfer (PIT) task where presentation of a CS (e.g., tone and light) previously paired with a rewarding unconditioned stimulus (US; e.g., food) leads to increases in a behavioral response, such as a lever press, that was also paired with the same US. The transfer effect can be enhanced in rats by exposing them repeatedly to amphetamine after they have undergone Pavlovian conditioning and instrumental training. However, it is not clear if amphetamine injections given immediately after Pavlovian conditioning, which are predicted to enhance memory consolidation for the CS-US association, would also enhance the transfer effect. We tested this hypothesis by giving male, Sprague-Dawley rats i.p. injections of saline or drug (0.5, 1.0, or 3.0 mg/kg amphetamine or methamphetamine) immediately following Pavlovian conditioning sessions. We found that amphetamine, but not methamphetamine, enhanced Pavlovian approach behavior. During a subsequent PIT test done under extinction conditions, we found that rats given either drug, particularly at the highest dose, exhibited deficits in PIT relative to saline-treated controls. These results suggest that treatment with amphetamines after Pavlovian conditioning sessions, when memory consolidation of the CS-US association is hypothesized to occur, inhibits the ability of the CS to subsequently elicit reward-seeking behavior. PMID:20817041

Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Mei-Fang

The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O{sub 2} demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp,more » and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100 μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8 Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine > methamphetamine > hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation and, possibly, normal blood flow in the brainstem. - Highlights: • Ketamine/amphetamines inhibit nicotine-induced cerebral neurogenic vasdilation. • Ketamine/amphetamines block cerebral perivascular sympathetic nAChR-mediated current. • The inhibitory potency is ketamine > D-amphetamine > methamphetamine > OH-amphetamine.« less

Optimization and application of an extraction procedure to determine drugs of abuse in solid environmental matrices of Turia River Basin

NASA Astrophysics Data System (ADS)

Andres, Maria Jesus; Alvarez, Rodrigo; Andreu, Vicente; Pico, Yolanda

2015-04-01

After their consumption, drug of abuse are excreted through urine or faeces, as parent compound or as secondary metabolites that arrive to wastewater treatment plants. Accordingly, the incomplete removal of these compounds in the treatment plants could release them into environmental compartments [1]. This scenario needs attention from an ecotoxicological perspective because their possible negative effects [2]. The aim of this study is to optimize and apply a solvent extraction and solid phase clean-up methodology to obtain a valid procedure for the extraction of these compounds in different solid matrices. Amphetamine, methamphetamine, ethylamphetamine, ecstasy, ethylone, bk-MMBDB and MBDB belong to phenylethylamine group; codeine and ketamine belong to opioid and phencyclidine group, respectively, and benzoylecgonine is the major excreted metabolite of the alkaloid cocaine. To optimize the method to determinate drugs of abuse in environmental solid matrices, two replicates and one blank were prepared for each sample of sediment. They were prepared by adding 1 g of sediment sample, 5 mL of buffer (methanol-Mc Ilvaine 50:50) and internal standard to obtain a final concentration in the extract of 25 ng/g. Also standards of drugs of abuse were added to the replicates to obtain a final concentration of 100 ng/g. Then all samples were shaken, sonicated and centrifuged and the supernatant was separated and placed in a 250 mL volumetric flask, which was filled the rest with distilled water. SPE was carried out with Strata-X cartridges and 250 mL of sample were passed through them. The extracts were eluted with 6 mL of methanol, evaporated to dryness and reconstituted in 1 mL of methanol-water 1:9. One of the replicates was filtrated through 0.22 μm pore size and the others were not. The samples were determined by liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS/MS) using an electrospray ionization source (ESI) in positive ionization mode. The results show that extraction recoveries of phenylethylamine group were from 39.3 to 92.4%. For codeine and ketamine, the recoveries ranged from 44.4 to 90.6% and from 61.3 to 79.5%, respectively. Benzoylecgonine presented recoveries ranged from 72 to 77.5%. The precision of the method was below 20% for all the compounds. The method was applied to determine these drugs of abuse in sediments of the Turia River Basin. Ecstasy, codeine, ketamine and benzoylecgonine were found at concentrations ranging from 0.22 ng/g to 25 ng/g in 6 sampling points. Very limited information exists on the presence of drugs of abuse in environmental matrices. Nothing can be concluded about the differences between the recoveries obtained in unfiltered and filtered samples because they do not follow any trend. These results confirm the reliability of the method as well as its suitability to be applied in environmental studies. Acknowledgements This work has been supported by the Spanish Ministry of Economy and Competitiveness trough the project SCARCE-CDS 2009-0065, CGL 2011-29703-C02-01 and CGL 2011-29703-C02-02. MJ Andrés Costa also acknowledges to this Ministry the FPI grant to perform her PhD. References [1] T.H. Boles, M.J.M. Wells, Analysis of amphetamine and methamphetamine as emerging pollutants in wastewater and wastewater-impacted streams, Journal of Chromatography A 1217 (2010) 2561. [2] C. Postigo, M.J. López de Alda, D. Barceló, Drugs of abuse and their metabolites in the Ebro River basin: Occurrence in sewage and surface water, sewage treatment plants removal efficiency, and collective drug usage estimation Environment International 36 (2010) 75.

Quite a lot of smoke but very limited fire--the use of methamphetamine in Europe.

PubMed

Griffiths, Paul; Mravcik, Viktor; Lopez, Dominique; Klempova, Danica

2008-05-01

This paper provides an overview of the historical development, current situation and potential future diffusion of methamphetamine (MA) use in Europe. The analysis is based on a review of published and grey literature, as well as data collected as part of the ongoing monitoring of the drug situation in Europe. Some qualitative surveys among high-risk populations do exist, but overall the general low prevalence of methamphetamine use in most of Europe means that the data available to explore patterns of use are limited. In many parts of Europe, amphetamine use is well established and the injecting of amphetamines has historically constituted an important component of the drug problem in many Nordic countries. Methamphetamine problems are long documented in the Czech and Slovak republics, but there is no current evidence of widespread use of MA elsewhere in Europe. Concern that MA use is spreading in Europe is prompted by some reports of use among high-risk groups. However, the evidence available suggests that even in high-risk populations, the use of MA currently remains uncommon. Europe accounted for less than 1% of worldwide MA seizures in 2005, and over the period 2004-05 European ephedrine seizures amounted for 6% of the global figure. The spread of MA use is limited and no strong evidence exists that significant diffusion is occurring. It appears likely that methamphetamine diffusion in Europe is impeded by a strong market for other stimulant drugs [cocaine, amphetamine and methylenedioxymethamphetamine (MDMA)]. The future potential for the diffusion of MA may be influenced by factors such as: the relative availability and popularity of other drugs; possible 'leakage' from areas of historical high prevalence; travel by young Europeans to areas of high prevalence; and how users perceive MA as a desirable, suitable and cost-effective alternative to other stimulants available on the European illicit drug market.

Wastewater-based assessment of regional and temporal consumption patterns of illicit drugs and therapeutic opioids in Croatia.

PubMed

Krizman, Ivona; Senta, Ivan; Ahel, Marijan; Terzic, Senka

2016-10-01

A comprehensive study of spatial and temporal consumption patterns of the selected illicit drugs (heroin, cocaine, amphetamine, MDMA, methamphetamine, cannabis) and therapeutic opioids (codeine, methadone) has been performed in six Croatian cities by applying wastewater-based epidemiology. The investigated cities (Bjelovar, Vinkovci, Varazdin, Karlovac, Zadar and Zagreb) varied widely in the population size (27,000-688,000 inhabitants) as well as in the number of registered drug consumers included in compulsory and voluntary medical treatment and rehabilitation programs (30-513 persons/100,000 inhabitants of age 15-64). The most consumed illicit drugs were cannabis (10-70doses/day/1000 inhabitants), heroin (<0.2-10doses/day/1000 inhabitants) and cocaine (0.2-8.7doses/day/1000 inhabitants), while the consumption of amphetamine-type drugs was much lower (<0.01-4.4doses/day/1000 inhabitants). Enhanced consumption of illegal drugs was generally associated with larger urban centers (Zagreb and Zadar) however comparatively high consumption rate of cocaine, MDMA and methadone was determined in some smaller cities as well. The overall average dose number of 3 major illegal stimulants (cocaine, MDMA, amphetamine) was rather similar to the number of corresponding heroin doses, which is in disagreement with a comparatively much higher proportion of heroin users in the total number of registered drug users in Croatia. Furthermore, the illicit drug consumption pattern in the large continental city (Zagreb) was characterized by a significant enhancement of the consumption of all stimulants during the weekend, which could not be confirmed neither for the coastal city of Zadar nor for the remaining small continental cities. On the other hand, the city of Zadar exhibited a significant increase of stimulant drug usage during summer vacation period, as a result of pronounced seasonal changes of the population composition and lifestyle in coastal tourist centers. The obtained results represent a valuable complementary data source for the optimisation and implementation of strategies to combat drug abuse in Croatia. Copyright © 2016. Published by Elsevier B.V.

A direct comparison of the behavioral and physiological effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in humans

PubMed Central

Kirkpatrick, Matthew G.; Gunderson, Erik W.; Perez, Audrey Y.; Haney, Margaret; Foltin, Richard W.

2015-01-01

Rationale Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals. Objectives This study examined the effects of methamphetamine and MDMA using a within-subject design. Methods Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed. Results Acutely, both drugs increased cardiovascular measures and “positive” subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased “negative” subjective-effect ratings. Few residual drug effects were noted for either drug. Conclusions It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential). PMID:21713605

75 FR 35838 - Controlled Substances: Proposed Revised Aggregate Production Quotas for 2010

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-23

...,000,000 g Amphetamine (for conversion) 6,500,000 g 6,500,000 g Cocaine 247,000 g 247,000 g Codeine... Fairness Act of 1996 (Congressional Review Act). This action will not result in an annual effect on the economy of $100,000,000 or more; a major increase in costs or prices; or significant adverse effects on...

Adults with a history of illicit amphetamine use exhibit abnormal substantia nigra morphology and parkinsonism.

PubMed

Todd, Gabrielle; Pearson-Dennett, Verity; Wilcox, Robert A; Chau, Minh T; Thoirs, Kerry; Thewlis, Dominic; Vogel, Adam P; White, Jason M

2016-04-01

The sonographic appearance of the substantia nigra is abnormally bright and enlarged (hyperechogenic) in young adults with a history of illicit stimulant use. The abnormality is a risk factor for Parkinson's disease. The aim of the current study was to identify the type of illicit stimulant drug associated with substantia nigra hyperechogenicity and to determine if individuals with a history of illicit stimulant use exhibit clinical signs of parkinsonism. We hypothesised that use of amphetamines (primarily methamphetamine) is associated with substantia nigra hyperechogenicity and clinical signs of parkinsonism. The area of echogenic signal in the substantia nigra was measured in abstinent human amphetamine users (n = 27; 33 ± 8 years) and in three control groups comprising a) 'ecstasy' users (n = 19; 23 ± 3 years), b) cannabis users (n = 30; 26 ± 8 years), and c) non-drug users (n = 37; 25 ± 7 years). A subset of subjects (n = 55) also underwent a neurological examination comprising the third and fifth part of the Unified Parkinson's Disease Rating Scale. Area of substantia nigra echogenicity was significantly larger in the amphetamine group (0.276 ± 0.080 cm(2)) than in the control groups (0.200 ± 0.075, 0.190 ± 0.049, 0.191 ± 0.055 cm(2), respectively; P < 0.002). The score on the clinical rating scale was also significantly higher in the amphetamine group (8.4 ± 8.1) than in pooled controls (3.3 ± 2.8; P = 0.002). Illicit use of amphetamines is associated with abnormal substantia nigra morphology and subtle clinical signs of parkinsonism. The results support epidemiological findings linking use of amphetamines, particularly methamphetamine, with increased risk of developing Parkinson's disease later in life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Amphetamine Dependence and Co-Morbid Alcohol Abuse: Associations to Brain Cortical Thickness

PubMed Central

2010-01-01

Background Long-term amphetamine and methamphetamine dependence has been linked to cerebral blood perfusion, metabolic, and white matter abnormalities. Several studies have linked methamphetamine abuse to cortical grey matter reduction, though with divergent findings. Few publications investigate unmethylated amphetamine's potential effects on cortical grey matter. This work investigated if amphetamine dependent patients showed reduced cortical grey matter thickness. Subjects were 40 amphetamine dependent subjects and 40 healthy controls. While all subjects were recruited to be free of alcohol dependence, structured clinical interviews revealed significant patterns of alcohol use in the patients. Structural magnetic resonance brain images were obtained from the subjects using a 1.5 Tesla GE Signa machine. Brain cortical thickness was measured with submillimeter precision at multiple finely spaced cortical locations using semi-automated post-processing (FreeSurfer). Contrast analysis of a general linear model was used to test for differences between the two groups at each cortical location. In addition to contrasting patients with controls, a number of analyses sought to identify possible confounding effects from alcohol. Results No significant cortical thickness differences were observed between the full patient group and controls, nor between non-drinking patients and controls. Patients with a history of co-morbid heavy alcohol use (n = 29) showed reductions in the superior-frontal right hemisphere and pre-central left hemisphere when compared to healthy controls (n = 40). Conclusions Amphetamine usage was associated with reduced cortical thickness only in patients co-morbid for heavy alcohol use. Since cortical thickness is but one measure of brain structure and does not capture brain function, further studies of brain structure and function in amphetamine dependence are warranted. PMID:20487539

Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys.

PubMed

Kohut, Stephen J; Jacobs, David S; Rothman, Richard B; Partilla, John S; Bergman, Jack; Blough, Bruce E

2017-12-01

The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability. The present study examined the effects of several novel "norepinephrine (NE)-preferring" monoamine releasers relative to non-selective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329 < l-methamphetamine < PAL-169). Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine. Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the "NE-preferring" releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine's discriminative stimulus effects. These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other "NE-preferring" monoamine releasers should provide insight into their potential for the management of cocaine addiction.

Nanoparticle Based Galectin-1 Gene Silencing, Implications in Methamphetamine Regulation of HIV-1 Infection in Monocyte Derived Macrophages

PubMed Central

Law, Wing Cheung; Mahajan, Supriya D.; Aalinkeel, Ravikumar; Nair, Bindukumar; Sykes, Donald E.; Yong, Ken-Tye; Hui, Rui; Prasad, Paras N.; Schwartz, Stanley A.

2012-01-01

Galectin-1, an adhesion molecule, is expressed in macrophages and implicated in human immunodeficiency virus (HIV-1) viral adsorption. In this study, we investigated the effects of methamphetamine on galectin-1 production in human monocyte derived macrophages (MDM) and the role of galectin-1 in methamphetamine potentiation of HIV-1 infection. Herein we show that levels of galectin-1 gene and protein expression are significantly increased by meth-amphetamine. Furthermore, concomitant incubation of MDM with galectin-1 and methamphetamine facilitates HIV-1 infection compared to galectin-1 alone or methamphetamine alone. We utilized a nanotechnology approach that uses gold nanorod (GNR)-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. Nanoplexes significantly silenced gene expression for galectin-1 and reversed the effects of methamphetamine on galectin-1 gene expression. Moreover, the effects of methamphetamine on HIV-1 infection were attenuated in the presence of the nanoplex in MDM. PMID:22689223

Methamphetamine, d-amphetamine and p-chloroamphetamine induced neurotoxicity differentially effect impulsive responding on the stop-signal task in rats

PubMed Central

Furlong, Teri M.; Leavitt, Lee S.; Keefe, Kristen A.; Son, Jong-Hyun

2016-01-01

Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e. a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e. a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning one week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e. impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ. PMID:26846719

Acute recreational drug toxicity

PubMed Central

Liakoni, Evangelia; Yates, Christopher; Dines, Alison M.; Dargan, Paul I.; Heyerdahl, Fridtjof; Hovda, Knut Erik; Wood, David M.; Eyer, Florian; Liechti, Matthias E.

2018-01-01

Abstract The aim of the study was to compare self-reported and analytically confirmed substance use in cases of acute recreational drug toxicity. We performed a retrospective analysis of emergency department presentations of acute recreational drug toxicity over 2 years (October 2013 to September 2015) within the European Drug Emergencies Network Plus project. Among the 10,956 cases of acute recreational drug toxicity during the study period, 831 could be included. Between the self-reported substance use and the toxicological results, the highest agreement was found for heroin (86.1%) and cocaine (74.1%), whereas inhalants, poppers, and magic mushrooms were self-reported but not analytically detected. Cathinones and other new psychoactive substances (NPS) could be detected using additional analytical methods. Among cases with both immunoassay (IA) and confirmation with mass spectrometry (MS), the results were consistent for methadone (100%) and cocaine (95.5%) and less consistent for amphetamines (81.8%). In cases with a positive IA for amphetamines (n = 54), MS confirmed the presence of 3,4-methylenedioxymethamphetamine (MDMA), amphetamine, methamphetamine, and NPS in 37, 20, 10, and 6 cases, respectively, also revealing use of more than 1 substance in some cases. MS yielded positive results in 21 cases with a negative IA for amphetamines, including amphetamine, MDMA, methamphetamine, and NPS, in 14, 7, 2, and 2 cases, respectively. In conclusion, the highest agreement was found between self-reports and analytical findings for heroin and cocaine. The diagnosis of NPS use was mainly based on self-report. The IAs accurately identified methadone and cocaine, and MS had advantages for the detection of NPS and amphetamine derivatives. PMID:29384873

Development of a micropulverized extraction method for rapid toxicological analysis of methamphetamine in hair.

PubMed

Miyaguchi, Hajime; Kakuta, Masaya; Iwata, Yuko T; Matsuda, Hideaki; Tazawa, Hidekatsu; Kimura, Hiroko; Inoue, Hiroyuki

2007-09-07

We developed a rapid sample preparation method for the toxicological analysis of methamphetamine and amphetamine (the major metabolite of methamphetamine) in human hair by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), to facilitate fast screening and quantitation. Two milligrams of hair were mechanically micropulverized for 5 min in a 2-ml plastic tube together with 100 microl of an aqueous solvent containing 10% acetonitrile, 100 mM trifluoroacetic acid and the corresponding deuterium analogues as internal standards. The pulverizing highly disintegrated the hair components, simultaneously allowing the extraction of any drugs present in the hair. After filtering the suspension with a membrane-filter unit, the clear filtrate was directly analyzed by HPLC-MS/MS. No evaporation processes were required for sample preparation. Method optimization and validation study were carried out using real-case specimens and fortified samples in which the drugs had been artificially absorbed, respectively. Concentration ranges for quantitation were 0.040-125 and 0.040-25 ng/mg for methamphetamine and amphetamine, respectively. Real-case specimens were analyzed by the method presented here and by conventional ones to verify the applicability of our method to real-world analysis. Our method took less than 30 min for a set of chromatograms to be obtained from a washed hair sample.

Development of a home cage locomotor tracking system capable of detecting the stimulant and sedative properties of drugs in rats.

PubMed

Dunne, Fergal; O'Halloran, Ambrose; Kelly, John P

2007-10-01

The advent of automated locomotor activity methodologies has been extremely useful in removing the subjectivity and bias out of measuring this parameter in rodents. However, many of these behavioural studies are still conducted in novel environments, rather than in ones that the animals are familiar with, such as their home cage. The purpose of the present series of experiments was to develop an automated home cage tracking (HCT) profile using EthoVision software and assessing the acute effects of stimulant (amphetamine and methamphetamine, 0-5 mg/kg, sc) and sedative (diazepam, 0-20 mg/kg, sc and chlordiazepoxide, 0-50 mg/kg sc) drugs in this apparatus. Young adult male Sprague-Dawley rats were used, and the home cage locomotor activity was recorded for 11-60 min following administration (n=4 per group). For amphetamine and methamphetamine, a dose-dependent increase in home cage activity was evident for both drugs, with a plateau, followed by reduction at higher doses. Methamphetamine was more potent, whereas amphetamine produced greater maximal responses. Both diazepam and chlordiazepoxide dose-dependently reduced locomotor activity, with diazepam exhibiting a greater potency and having stronger sedative effects than chlordiazepoxide. Three doses of each drug were selected at the 31-40 min time period following administration, and compared to open field responses. Diazepam, chlordiazepoxide and amphetamine did not produce significant changes in the open field, whilst methamphetamine produced a significant increase in the 2.5 mg/kg group. In conclusion, these studies have successfully developed a sensitive HCT methodology that has been validated using drugs with stimulant and sedative properties in the same test conditions, with relatively small numbers of animals required to produce statistically significant results. It has proven superior to the open field investigations in allowing dose-response effects to be observed over a relatively short observation period (i.e. 10 min) for both stimulants and sedatives. In addition, the HCT system can determine differences in potency and efficacy between drugs of a similar chemical class.

Amphetamine-type stimulants and HIV infection among men who have sex with men: implications on HIV research and prevention from a systematic review and meta-analysis

PubMed Central

Thu Vu, Nga Thi; Maher, Lisa; Zablotska, Iryna

2015-01-01

Introduction HIV infections and the use of amphetamine-type stimulants (ATS) among men who have sex with men (MSM) have been increasing internationally, but the role of ATS use as a co-factor for HIV infection remains unclear. We aimed to summarize the association between ATS use and HIV infection among MSM. Methods We conducted a systematic search of MEDLINE, EMBASE, GLOBAL HEALTH and PsycINFO for relevant English, peer-reviewed articles of quantitative studies published between 1980 and 25 April 2013. Pooled estimates of the association – prevalence rate ratios (PRR, cross-sectional studies), odds ratio (OR, case-control studies) and hazard ratio (HR, longitudinal studies), with 95% Confidence Intervals (CI) – were calculated using random-effects models stratified by study design and ATS group (meth/amphetamines vs. ecstasy). We assessed the existence of publication bias in funnel plots and checked for sources of heterogeneity using meta-regression and subgroup analysis. Results We identified 6710 article titles, screened 1716 abstracts and reviewed 267 full text articles. A total of 35 publications were eligible for data abstraction and meta-analysis, resulting in 56 records of ATS use. Most studies (31/35) were conducted in high-income countries. Published studies used different research designs, samples and measures of ATS use. The pooled association between meth/amphetamine use and HIV infection was statistically significant in all three designs (PRR=1.86; 95% CI: 1.57–2.17; OR=2.73; 95% CI: 2.16–3.46 and HR=3.43; 95% CI: 2.98–3.95, respectively, for cross-sectional, case-control and longitudinal studies). Ecstasy use was not associated with HIV infection in cross-sectional studies (PRR=1.15; 95% CI: 0.88–1.49; OR=3.04; 95% CI: 1.29–7.18 and HR=2.48; 95% CI: 1.42–4.35, respectively, for cross-sectional, case-control and longitudinal studies). Results in cross-sectional studies were highly heterogeneous due to issues with ATS measurement and different sampling frames. Conclusions While meth/amphetamine use was significantly associated with HIV infection among MSM in high-income countries in all study designs, evidence of the role of ecstasy in HIV infection was lacking in cross-sectional studies. Cross-sectional study design, measurement approaches and source populations may also be important modifiers of the strength and the direction of associations. Event-specific measure of individual drug is required to establish temporal relationship between ATS use and HIV infection. HIV prevention programmes targeting MSM should consider including interventions designed to address meth/amphetamine use. PMID:25609214

Methamphetamine/Dextroamphetamine and Pregnancy

MedlinePlus

... d-amphetamine is a prescription medication used for attention deficit hyperactivity disorder (ADHD) and narcolepsy (extreme daytime sleepiness). ... of dexamphetamine into breast milk during treatment for attention deficit hyperactivity disorder. Br J Clin Pharmacol. 63(3): ...

Monolithic silica spin column extraction and simultaneous derivatization of amphetamines and 3,4-methylenedioxyamphetamines in human urine for gas chromatographic-mass spectrometric detection.

PubMed

Nakamoto, Akihiro; Nishida, Manami; Saito, Takeshi; Kishiyama, Izumi; Miyazaki, Shota; Murakami, Katsunori; Nagao, Masataka; Namura, Akira

2010-02-19

A simple, sensitive, and specific method with gas chromatography-mass spectrometry was developed for simultaneous extraction and derivatization of amphetamines (APs) and 3,4-methylenedioxyamphetamines (MDAs) in human urine by using a monolithic silica spin column. All the procedures, such as sample loading, washing, and elution were performed by centrifugation. APs and MDAs in urine were adsorbed on the monolithic silica and derivatized with propyl chloroformate in the column. Methamphetamine-d(5) was used as an internal standard. The linear ranges were 0.01-5.0 microg mL(-1) for methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) and 0.02-5.0 microg mL(-1) for amphetamine (AP) and 3,4-methylenedioxyamphetamine (MDA) (coefficient of correlation > or = 0.995). The recovery of APs and MDAs in urine was 84-94%, and the relative standard deviation of the intra- and interday reproducibility for urine samples containing 0.1, 1.0, and 4.0 microg mL(-1) of APs and MDAs ranged from 1.4% to 13.6%. The lowest detection limit (signal-to-noise ratio > or = 3) in urine was 5 ng mL(-1) for MA and MDMA and 10 ng mL(-1) for AP and MDA. The proposed method can be used to perform simultaneous extraction and derivatization on spin columns that have been loaded with a small quantity of solvent by using centrifugation. Copyright 2009 Elsevier B.V. All rights reserved.

Frequency of osteoporosis in 46 men with methamphetamine abuse hospitalized in a National Hospital.

PubMed

Kim, Eun Young; Kwon, Do Hoon; Lee, Byung Dae; Kim, Yang Tae; Ahn, Young Bok; Yoon, Kuee Young; Sa, Sok Jin; Cho, Woong; Cho, Sung Nam

2009-07-01

Methamphetamine, a derivative of amphetamine, has been well known to cause mental problems in humans; however, its physical effects are little known. Despite relevant information on the effect of methamphetamine abuse on bone quality being available, data regarding the frequency of osteoporosis in methamphetamine abusers are limited. We selected 46 hospitalized male methamphetamine abusers and 188 reference male controls in whom any conditions affecting bone metabolism were ruled out. Bone mineral density (BMD) in the lumbar spine was measured by dual energy X-ray absorptiometry (DXA). We compared the BMD between methamphetamine abusers and controls and evaluated the frequency of osteoporosis in both groups. The mean BMD value was lower in methamphetamine abusers (mean+/-SD, 0.71+/-0.07 g/cm(2)) than in the controls (mean+/-SD, 0.98+/-0.14 g/cm(2)). The frequency of osteoporosis was 22% according to WHO diagnostic guidelines, and osteopenia at the lumbar spine was 76%. The correlation between the extent of methamphetamine abuse and BMD was very clear. There was considerable loss of bone mineral in a high percentage of methamphetamine abusers. Our study is the first clinical study to determine the frequency of osteoporosis in male methamphetamine abusers.

Target screening and confirmation of 35 licit and illicit drugs and metabolites in hair by LC-MSMS.

PubMed

Lendoiro, Elena; Quintela, Oscar; de Castro, Ana; Cruz, Angelines; López-Rivadulla, Manuel; Concheiro, Marta

2012-04-10

A liquid chromatography-tandem mass spectrometry (LC-MSMS) target screening in 50mg hair was developed and fully validated for 35 analytes (Δ9-tetrahidrocannabinol (THC), morphine, 6-acetylmorphine, codeine, methadone, fentanyl, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, benzoylecgonine, cocaine, lysergic acid diethylamide, ketamine, scopolamine, alprazolam, bromazepam, clonazepam, diazepam, flunitrazepam, 7-aminoflunitrazepam, lorazepam, lormetazepam, nordiazepam, oxazepam, tetrazepam, triazolam, zolpidem, zopiclone, amitriptyline, citalopram, clomipramine, fluoxetine, paroxetine and venlafaxine). Hair decontamination was performed with dichloromethane, and incubation in 2 mL of acetonitrile at 50°C overnight. Extraction procedure was performed in 2 steps, first liquid-liquid extraction, hexane:ethyl acetate (55:45, v:v) at pH 9, followed by solid-phase extraction (Strata-X cartridges). Chromatographic separation was performed in AtlantisT3 (2.1 mm × 100 mm, 3 μm) column, acetonitrile and ammonium formate pH 3 as mobile phase, and 32 min total run time. One transition per analyte was monitored in MRM mode. To confirm a positive result, a second injection monitoring 2 transitions was performed. The method was specific (no endogenous interferences, n=9); LOD was 0.2-50 pg/mg and LOQ 0.5-100 pg/mg; linearity ranged from 0.5-100 to 2000-20,000 pg/mg; imprecision <15%; analytical recovery 85-115%; extraction efficiency 4.1-85.6%; and process efficiency 2.5-207.7%; 27 analytes showed ion suppression (up to -86.2%), 4 ion enhancement (up to 647.1%), and 4 no matrix effect; compounds showed good stability 24-48 h in autosampler. The method was applied to 17 forensic cases. In conclusion, a sensitive and specific target screening of 35 analytes in 50mg hair, including drugs of abuse (THC, cocaine, opiates, amphetamines) and medicines (benzodiazepines, antidepressants) was developed and validated, achieving lower cut-offs than Society of Hair Testing recommendations. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Differentiation of ring-substituted regioisomers of amphetamine and methamphetamine by supercritical fluid chromatography.

PubMed

Segawa, Hiroki; T Iwata, Yuko; Yamamuro, Tadashi; Kuwayama, Kenji; Tsujikawa, Kenji; Kanamori, Tatsuyuki; Inoue, Hiroyuki

2017-03-01

Chromatographic differentiation of the ring-substituted regioisomers of amphetamine (AMP) and methamphetamine (MA) was performed by supercritical fluid chromatography (SFC). The behaviour of the retention against the changes of column temperature and co-solvent proportion was studied. The obtained information facilitated the optimization of the each regioisomer. As a result, 2-, 3-, and 4-ring-substituted analogues of AMP and MA with methyl, methoxy, fluoro, chloro, and bromo groups were separated, generally within 6 min. In addition, we found that the separation pattern of the examined regioisomers was classified into two, which depended on the electron donating/withdrawing effect of the substituent. Our results indicate that SFC could be used in forensic drug analysis for fast, reliable identification of structurally similar drugs of abuse. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Are ecstasy users biased toward endorsing somatic mental health symptoms? Results from a general community sample.

PubMed

George, Amanda M; Windsor, Tim D; Rodgers, Bryan

2011-04-01

Whether the reported poorer mental health of ecstasy users is due to a bias in endorsement of somatic symptoms has been postulated, but rarely examined. The purpose of this study is to investigate whether levels of ecstasy use were associated with differential probabilities of endorsing somatic mental health symptoms. Current ecstasy users aged 24-30 years (n = 316) were identified from a population-based Australian study. Measures included frequency of ecstasy, meth/amphetamine, and cannabis use and the Goldberg anxiety/depression symptom scales. Multiple indicator, multiple cause models demonstrated no bias towards endorsing somatic symptoms with higher ecstasy use, both with and without adjustment for gender, cannabis, and meth/amphetamine use. Other studies using alternate measures of mental health should adopt this approach to determine if there is a bias in the endorsement of somatic symptoms among ecstasy users.

The effects and consequences of selected club drugs.

PubMed

Freese, Thomas E; Miotto, Karen; Reback, Cathy J

2002-09-01

Ecstasy (MDMA), gamma-hydroxybutyrate (GHB), ketamine, and methamphetamine are 4 examples of club drugs that are increasing in popularity. Although the pharmacological classifications of these drugs vary, MDMA has structural similarities to both amphetamine and the hallucinogen mescaline. Ketamine and GHB are anesthetic agents and methamphetamine is a long-acting psychostimulant. Medical visits for club drug-related toxicity have sharply increased across the country. This article provides a brief review of the literature on club drugs. Copyright 2002 Elsevier Science Inc.

Methamphetamine use and dependence in vulnerable female populations.

PubMed

Kittirattanapaiboon, Phunnapa; Srikosai, Soontaree; Wittayanookulluk, Apisak

2017-07-01

The study reviews recent publications on methamphetamine use and dependence women in term of their epidemic, physical health impact, psychosocial impacts, and also in the identified vulnerable issues. Studies of vulnerable populations of women are wide ranging and include sex workers, sexual minorities, homeless, psychiatric patients, suburban women, and pregnant women, in which amphetamine type stimulants (ATSs) are the most commonly reported illicit drug used among them. The prenatal exposure of ATS demonstrated the small for gestational age and low birth weight; however, more research is needed on long-term studies of methamphetamine-exposed children. Intimate partner violence (IPV) is commonly reported by female methamphetamine users as perpetrators and victims. However, statistics and gendered power dynamics suggest that methamphetamine-related IPV indicates a higher chance of femicide. Methamphetamine-abusing women often have unresolved childhood trauma and are introduced to ATS through families or partners. Vulnerable populations of women at risk of methamphetamine abuse and dependence. Impacts on their physical and mental health, IPV, and pregnancy have been reported continuing, which guide that empowering and holistic substance abuse are necessary for specific group.

Amphetamine-induced psychosis - a separate diagnostic entity or primary psychosis triggered in the vulnerable?

PubMed Central

2012-01-01

Use of amphetamine and methamphetamine is widespread in the general population and common among patients with psychiatric disorders. Amphetamines may induce symptoms of psychosis very similar to those of acute schizophrenia spectrum psychosis. This has been an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders. To distinguish the two types of psychosis on the basis of acute symptoms is difficult. However, acute psychosis induced by amphetamines seems to have a faster recovery and appears to resolve more completely compared to schizophrenic psychosis. The increased vulnerability for acute amphetamine induced psychosis seen among those with schizophrenia, schizotypal personality and, to a certain degree other psychiatric disorders, is also shared by non-psychiatric individuals who previously have experienced amphetamine-induced psychosis. Schizophrenia spectrum disorder and amphetamine-induced psychosis are further linked together by the finding of several susceptibility genes common to both conditions. These genes probably lower the threshold for becoming psychotic and increase the risk for a poorer clinical course of the disease. The complex relationship between amphetamine use and psychosis has received much attention but is still not adequately explored. Our paper reviews the literature in this field and proposes a stress-vulnerability model for understanding the relationship between amphetamine use and psychosis. PMID:23216941

Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans.

PubMed

Stoops, William W; Vansickel, Andrea R; Lile, Joshua A; Rush, Craig R

2007-05-01

Recent clinical research indicates that d-amphetamine is effective in treating cocaine and methamphetamine dependence. There is concern, however, with the use of d-amphetamine as a pharmacotherapy because acute administration of d-amphetamine decreases inhibition in cocaine-using individuals and may increase drug-taking behavior. The purpose of the present experiment was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine. To this end, 7 human volunteers first sampled doses of oral d-amphetamine (0, 8, and 16 mg). These doses engender moderate drug taking and were selected to avoid a ceiling or floor effect. Volunteers were then allowed to self-administer these sampled doses using a modified progressive-ratio procedure in two sessions in which they received pretreatment with either 0 or 15 mg oral d-amphetamine 2 h prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects (e.g., increased ratings of stimulated, elevated blood pressure) and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg oral d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressive-ratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration.

Medical Readings on Drug Abuse.

ERIC Educational Resources Information Center

Byrd, Oliver E.

Summaries are presented of over 150 articles in the recent medical and psychiatric literature. Topics covered are: effects of drugs, tobacco, alcohol, drugs used in medicine, vapor sniffing, marijuana, barbiturates, tranquilizers, amphetamines, methamphetamine, lysergic acid diethylamide, other hallucinogens, heroin and the opiates, psychiatric…

Does prenatal methamphetamine exposure affect the drug-seeking behavior of adult male rats?

PubMed

Slamberová, Romana; Schutová, Barbora; Hrubá, Lenka; Pometlová, Marie

2011-10-10

Methamphetamine (MA) is one of the most frequently used illicit drugs worldwide and also one of the most common drugs abused by pregnant women. Repeated administration of psychostimulants induces behavioral sensitization in response to treatment of the same or related drugs in rodents. The effect of prenatal MA exposure on sensitivity to drugs in adulthood is not yet fully determined. Because our most recent studies demonstrated that prenatal MA (5mg/kg) exposure makes adult rats more sensitive to acute injection of the same drug, we were interested whether the increased sensitivity corresponds with the increased drug-seeking behavior. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the conditioned place preference (CPP). The following psychostimulant drugs were used as a challenge in adulthood: MA (5mg/kg), amphetamine (5mg/kg) and cocaine (10mg/kg). All psychostimulant drugs induced increased drug-seeking behavior in adult male rats. However, while MA and amphetamine-induced increase in drug-seeking behavior did not differ based on the prenatal drug exposure, prenatally MA-exposed rats displayed tolerance effect to cocaine in adulthood. In addition, prenatally MA-exposed rats had decreased weight gain after administration of MA or amphetamine, while the weight of prenatally MA-exposed rats stayed unchanged after cocaine administration. Defecation was increased by all the drugs (MA, amphetamine and cocaine), while only amphetamine increased the tail temperature. In conclusion, our results did not confirm our hypothesis that prenatal MA exposure increases drug-seeking behavior in adulthood in the CPP test. Copyright © 2011 Elsevier B.V. All rights reserved.

Estimating the number of regular and dependent methamphetamine users in Australia, 2002-2014.

PubMed

Degenhardt, Louisa; Larney, Sarah; Chan, Gary; Dobbins, Timothy; Weier, Megan; Roxburgh, Amanda; Hall, Wayne D; McKetin, Rebecca

2016-03-07

To estimate the number of regular and dependent methamphetamine users in Australia. Indirect prevalence estimates were made for each year from 2002-03 to 2013-14. We applied multiplier methods to data on treatment episodes for amphetamines (eg, counselling, rehabilitation, detoxification) and amphetamine-related hospitalisations to estimate the numbers of regular (at least monthly) and dependent methamphetamine users for each year. Dependent users comprised a subgroup of those who used the drug regularly, so that estimates of the sizes of these two populations were not additive. We estimated that during 2013-14 there were 268 000 regular methamphetamine users (95% CI, 187 000-385 000) and 160 000 dependent users (95% CI, 110 000-232 000) aged 15-54 years in Australia. This equated to population rates of 2.09% (95% CI, 1.45-3.00%) for regular and 1.24% (95% CI, 0.85-1.81%) for dependent use. The rate of dependent use had increased since 2009-10 (when the rate was estimated to be 0.74%), and was higher than the previous peak (1.22% in 2006-07). The highest rates were consistently among those aged 25-34 years, in whom the rate of dependent use during 2012-2013 was estimated to be 1.50% (95% CI, 1.05-2.22%). There had also been an increase in the rate of dependent use among those aged 15-24 years (in 2012-13 reaching 1.14%; 95% CI, 0.80-1.69%). There have been increases over the past 12 years in the numbers of regular and dependent methamphetamine users in Australia. Our estimates suggest that the most recent numbers are the highest for this period, and that the increase has been most marked among young adults (those aged 15-34 years). There is an increasing need for health services to engage with people who have developed problems related to their methamphetamine use.

Effects of pyridinium chlorochromate adulterant (urine luck) on testing for drugs of abuse and a method for quantitative detection of chromium (VI) in urine.

PubMed

Paul, B D; Martin, K K; Maguilo, J; Smith, M L

2000-01-01

Pyridinium chlorochromate (PCC) as an adulterant is popular for concealing drug-positive results. When 11-nor-delta9-THC-9-carboxylic acid (THC-acid) in urine was treated with 2 mmol/L of PCC (Cr6+ 104 microg/mL), 58-100% of the THC-acid was lost. The loss increased with decreasing pH and increasing reaction time (0-3 days). Free codeine and free morphine remained unaffected by PCC at pH within the physiological range of the urine (pH 5-7). At lower pH, the loss of free morphine varied from 0 to 100%. Amphetamine, methamphetamine, benzoylecgonine, and PCP remained unaffected by PCC when exposed to the oxidant for three days in urine pH of 3-7. Chromium (VI) from PCC in a urine solution was detected by a color reaction with 1,5-diphenylcarbazide (DPC). When the reagent was added to the urine, an immediate red-violet color appeared. The chromium-DPC complex showed a characteristic absorption peak at wavelength 544 nm with a shoulder at wavelength 575 nm. The ratio of absorption was used to identify the chromium compound. The concentration of chromium (VI) was determined by measuring absorption at wavelength 544 nm and was linear over 0.5-20 microg/mL. The limit of detection of the procedure was 0.37 microg/mL.

[Acute poisoning with weight-loss dietary supplement falsely suggesting the use of amphetamine].

PubMed

Łukasik-Głebocka, Magdalena; Sommerfeld, Karina; Tezyk, Artur; Zielińska-Psuja, Barbara

2013-01-01

We report a case of abuse of weight-loss dietary supplement in 27-year-old man, with characteristic for amphetamine sympathomimetic symptoms and positive analysis of this drug in the urine by immunoassay method (FPIA; Axsym, Abbott). However positive result was not confirmed by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). The patient ate nine tablets of the Thermal Pro with declared composition of caffeine (250 mg), bitter orange (200 mg), beta-phenylethylamine (100 mg), willow bark (75 mg), Cayenne pepper (40 mg), 1,3-dimethyloamyloamine (DMAA, 35 mg), gooseberry extract (20 mg), bergamot orange (20 mg), black pepper (5 mg), after two-month period of regular consumption at dose of 2-3 capsules per day. After 4 hours, during admission to the Department of Toxicology, patient manifested typical sympathomimetic symptoms: anxiety, agitation, pale skin, sweats, tachycardia 120/min, mydriasis. Following the outcome of detecting amphetamine/methamphetamine in the patient's urine at 2377 ng/mL concentration using FPIA method, drug intoxication was suspected. It was considered that the ingestion was intentional or unconscious of adulterated dietary supplement. In view of the strong opposition of the patient, who denied any use of psychoactive substances, it was decided to re-examine collected speciments. The liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) method did not confirm the presence of amphetamine in the patient's blood and urine. Based on the composition of dietary supplements for substances which could be responsible for the positive amphetamine result in urine by FPIA method and available literature data, it was concluded that the substances that may react in the immunoassay could be dimethylamyloamine (DMAA, geranamine) or bitter orange components. False positive urinalysis towards amphetamine/methamphetamine by immunoassay and presence of sympathomimetic effects may contribute to a false diagnosis of this drug poisoning. Definitive confirmation of such intoxication requires the use of the reference methods.

[Addiction to cocaine and other stimulants].

PubMed

Lacoste, Jérôme; Delavenne-Garcia, Héloïse; Charles-Nicolas, Aimé; Duarte Garcia, Frederico; Jehel, Louis

2012-12-01

Due to many available forms (powder, pasta base, freebase and crack…) and because of multiple routes of administration (intranasal, intravenous, or smoked), cocaine has become in 30 years one of the most consumed illegal drugs worldwide, after cannabis. While the frequency of consumption decreases in North America, it continues to rise in Europe, and in some countries in South America, including Brazil, despite a growing knowledge of its specific effects, physical complications and psychiatric consequences. Elsewhere (notably in Asia and Indian Ocean), amphetamine and other stimulants (including methamphetamine), whose properties and patterns of use are very similar to those of cocaine, tend to replace it. Another amphetamine derivative, MDMA or ecstasy, is also consumed by many young people of less than 25 years, in Europe and North America, in a festive setting, with specific consequences and special procedures of care. Although there is currently no consensus for a specific medication, the most appropriate therapeutic approach seems to involve a psychosocial treatment associated with an anticraving medication, which will reduce compulsive desire to consume, in order to facilitate the psychotherapeutic and social care. However, pharmacological research remains very active, and many options are explored (GABAergic or dopaminergic agonists, amphetamine derivatives with long half-life, vaccine…), whether to treat addiction to cocaine or to methamphetamine. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

“We’re Supposed to Be Asleep?” Vigilance, Paranoia, and the Alert Methamphetamine User

PubMed Central

McKenna, Stacey A.

2015-01-01

The stimulant “benefits” of amphetamine and its derivative, methamphetamine, have endured since the drugs first became popular nearly a century ago. The concepts of increasing energy for functional purposes related to work and productivity have been well studied. However, the broader idea of increased alertness, and what this means in the lives of users, has not yet been sufficiently examined. This article draws from ongoing research with active methamphetamine users to explore the perceived benefits, drawbacks, and meanings of remaining alert—awake and vigilant—while most of the world sleeps. The experiences of several users are situated in the contexts of sociostructural and mental health issues that shape cycles of use and meanings of addiction. PMID:26366049

Affinity improvement of a therapeutic antibody to methamphetamine and amphetamine through structure-based antibody engineering

PubMed Central

Thakkar, Shraddha; Nanaware-Kharade, Nisha; Celikel, Reha; Peterson, Eric C.; Varughese, Kottayil I.

2014-01-01

Methamphetamine (METH) abuse is a worldwide threat, without any FDA approved medications. Anti-METH IgGs and single chain fragments (scFvs) have shown efficacy in preclinical studies. Here we report affinity enhancement of an anti-METH scFv for METH and its active metabolite amphetamine (AMP), through the introduction of point mutations, rationally designed to optimize the shape and hydrophobicity of the antibody binding pocket. The binding affinity was measured using saturation binding technique. The mutant scFv-S93T showed 3.1 fold enhancement in affinity for METH and 26 fold for AMP. The scFv-I37M and scFv-Y34M mutants showed enhancement of 94, and 8 fold for AMP, respectively. Structural analysis of scFv-S93T:METH revealed that the substitution of Ser residue by Thr caused the expulsion of a water molecule from the cavity, creating a more hydrophobic environment for the binding that dramatically increases the affinities for METH and AMP. PMID:24419156

Assessing geographical differences in illicit drug consumption--A comparison of results from epidemiological and wastewater data in Germany and Switzerland.

PubMed

Been, Frederic; Bijlsma, Lubertus; Benaglia, Lisa; Berset, Jean-Daniel; Botero-Coy, Ana M; Castiglioni, Sara; Kraus, Ludwig; Zobel, Frank; Schaub, Michael P; Bücheli, Alexander; Hernández, Félix; Delémont, Olivier; Esseiva, Pierre; Ort, Christoph

2016-04-01

Wastewater analysis is an innovative approach that allows monitoring illicit drug use at the community level. This study focused on investigating geographical differences in drug consumption by comparing epidemiological, crime and wastewater data. Wastewater samples were collected in 19 cities across Germany and Switzerland during one week, covering a population of approximately 8.1 million people. Self-report data and consumption offences for the investigated areas were used for comparison and to investigate differences between the indicators. Good agreement between data sources was observed for cannabis and amphetamine-type stimulants, whereas substantial discrepancies were observed for cocaine. In Germany, an important distinction could be made between Berlin, Dortmund and Munich, where cocaine and particularly amphetamine were more prevalent, and Dresden, where methamphetamine consumption was clearly predominant. Cocaine consumption was relatively homogenous in the larger urban areas of Switzerland, although prevalence and offences data suggested a more heterogeneous picture. Conversely, marked regional differences in amphetamine and methamphetamine consumption could be highlighted. Combining the available data allowed for a better understanding of the geographical differences regarding prevalence, typology and amounts of substances consumed. For cannabis and amphetamine-type stimulants, the complementarity of survey, police and wastewater data could be highlighted, although notable differences could be identified when considering more stigmatised drugs (i.e. cocaine and heroin). Understanding illicit drug consumption at the national scale remains a difficult task, yet this research illustrates the added value of combining complementary data sources to obtain a more comprehensive and accurate picture of the situation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

High ambient temperature increases intravenous methamphetamine self-administration on fixed and progressive ratio schedules in rats.

PubMed

Cornish, Jennifer L; Clemens, Kelly J; Thompson, Murray R; Callaghan, Paul D; Dawson, Bronwyn; McGregor, Iain S

2008-01-01

Methamphetamine is a drug that is often consumed at dance parties or nightclubs where the ambient temperature is high. The present study determined whether such high ambient temperatures alter intravenous methamphetamine self-administration in the rat. Male Hooded Wistar rats were trained to self-administer intravenous methamphetamine (0.1 mg/kg/infusion) under a fixed ratio 1 (FR1) or progressive ratio (PR) schedule of reinforcement at an ambient temperature of 23 +/- 1 degrees C. They were then given their daily self-administration session at a raised ambient temperature of 30 +/- 1 degrees C. Methamphetamine self-administration was increased at 30 degrees C under both FR1 and PR reinforcement schedules, with the latter effect indicating that heat enhances the motivation to obtain methamphetamine. High temperatures did not alter self-administration of the D1 receptor agonist SKF 82958 in methamphetamine-experienced rats suggesting some specificity in the methamphetamine effect. When rats were given access to drink isotonic saline solution during methamphetamine self-administration sessions they drank much more solution at 30 degrees C than 23 degrees C. However, availability of isotonic saline to drink did not alter the heat-induced facilitation of methamphetamine self-administration (PR schedule) indicating that the heat effect does not simply reflect increased motivation for intravenous fluids. Hyperthermia was evident in rats self-administering methamphetamine at high ambient temperatures and fluid consumption did not prevent this effect. Heat did not affect blood levels of methamphetamine, or its principal metabolite amphetamine indicating that the facilitatory effect of heat did not reflect altered methamphetamine pharmacokinetics. Overall, these results show that high ambient temperatures increase the reinforcing efficacy of methamphetamine and encourage higher levels of drug intake.

Oral health of the methamphetamine abuser.

PubMed

Donaldson, Mark; Goodchild, Jason H

2006-11-01

The pharmacology of methamphetamine is reviewed, and the effects of methamphetamine use on oral health are described. Methamphetamine is a highly addictive amphetamine analogue, initially synthesized in 1919. Illicit methamphetamine use leads to devastating effects on health, particularly the dentition. Illegal production of methamphetamine has skyrocketed in recent years, as have the number of users. The chief complaint of methamphetamine users is xerostomia. Without the protective effects of saliva, caries development in these patients is rampant. The typical pattern of decay involves the facial and cervical areas of both the maxillary and mandibular teeth, with eventual progression to frank coronal involvement. The acidic substances used to manufacture this drug have also been implicated as a cause of tooth decay and wear in users, as has bruxism as a result of drug-induced hyperactivity. When possible, these patients should be referred to a dentist to improve their oral health status and minimize the potential for adverse cardiovascular sequelae. Other preventive measures for methamphetamine users include stimulating saliva flow and increasing fluoride supplementation. Pharmacists should also counsel users to avoid carbohydrate-rich soft drinks in favor of water. Oral moisturizers may also be effective. Methamphetamine use causes xerostomia secondary to sympathetic central nervous system activation, rampant caries caused by high-sugar intake in the absence of protective saliva, and bruxism as a result of hyperactivity. Practitioners should know how to recognize the signs of and manage the oral health of patients with a history of methamphetamine use.

NTP-CERHR EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF AMPHETAMINE AND METHAMPHETAMINE.

EPA Science Inventory

A manuscript describes the results of an expert panel meeting of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR). The purpose CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects ...

76 FR 10067 - Importer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-23

... this Section to a bulk manufacturer of a controlled substance in schedule I or II, and prior to issuing... Manufacturing LLC., 3500 Dekalb Street, St. Louis, Missouri 63118, made application by renewal to the Drug...) I Amphetamine (1100) II Methamphetamine (1105) II Methylphenidate (1724) II Amobarbital (2125) II...

Adverse Health Effects Associated with Living in a Former Methamphetamine Drug Laboratory - Victoria, Australia, 2015.

PubMed

Wright, Jackie; Kenneally, Michaela E; Edwards, John W; Walker, G Stewart

2017-01-06

The manufacture of methamphetamine in clandestine drug laboratories occurs in various locations, including residential houses and apartments. Unlike the controlled manufacture of chemicals and drugs, clandestine manufacture results in the uncontrolled storage, use, generation, and disposal of a wide range of chemicals and the deposit of methamphetamine drug residues on indoor surfaces (1). These residues have been found at high levels on porous and nonporous surfaces and have been shown to persist for months to years (1). Persons exposed to these environments often have poorly defined exposures and health effects. It is commonly assumed that these levels of exposure are low compared with those related to illicit drug use or therapeutic use of amphetamine-based drugs for managing behavioral issues such as attention deficit hyperactivity disorder (2). In 2015, a family that was unknowingly exposed to methamphetamine residues in a house in Australia was found to have adverse health effects and elevated methamphetamine levels in hair samples, highlighting the potential for public health risks for persons who might live in methamphetamine-contaminated dwellings. This case study highlights the importance of the identification and effective decontamination of former clandestine drug laboratories.

Wastewater analysis reveals regional variability in exposure to abused drugs and opioids in Finland.

PubMed

Vuori, Erkki; Happonen, Maiju; Gergov, Merja; Nenonen, Timo; Järvinen, Ari; Ketola, Raimo A; Vahala, Riku

2014-07-15

Abused drug concentrations were determined in nine Finnish wastewater treatment plants (WWTPs), representing the metropolitan area, university cities and rural towns. In an eight-day study period in August 2012, 24-hour composite influent wastewater samples were collected. Biological markers and census-based information were used to estimate the size of the population served. The analytical method included solid phase extraction, liquid chromatographic separation, tandem mass spectrometric identification, and quantification using isotope-labeled internal standards. The study covered amphetamines, cannabis and cocaine. The levels of some opioids used in treatment and their metabolites were also determined. Amphetamine was the most prevalent drug of abuse, the median loads varying between the cities from 4.16 to 29.6 mg/1000 inhabitants/d. In three western cities methamphetamine was detected in even higher amounts, ranging from 0.87 to 47.5mg/1000 inhabitants/d. Ecstasy (MDMA) and cocaine (as benzoylecgonine, BE) were found in higher concentrations during weekends compared to weekdays, the difference being statistically significant. The concentration of tetrahydrocannabinol-9-carboxylic acid (THCA) was below the limit of quantification in the two rural towns, while in the other cities the load varied between 3.77 and 20.7 mg/1000 inhabitants/d. The average variation in BE load was 0.05-6.82 and that of MDMA 0-20.6 mg/1000 inhabitants/d. While the metropolitan area showed the highest loads of abused drugs, the substances were continuously detected at all WWTPs included in the study. The median concentration of codeine ranged from 164 to 325 mg/1000 inhabitants/d and that of morphine from 18.8 to 31.5mg/1000 inhabitants/d. The methadone load was below the level of detection in two towns, and at the other locations were 1.22-9.46 mg/1000 inhabitants/d. The first metabolite of heroin, 6-monoacetylmorphine (6-MAM), was not detected at all. Although the method has limitations, wastewater analysis gives additional information for assessing the degree of drug abuse and range of drugs abused in a society. Copyright © 2013 Elsevier B.V. All rights reserved.

Randomized controlled trial of dexamphetamine maintenance for the treatment of methamphetamine dependence.

PubMed

Longo, Marie; Wickes, Wendy; Smout, Matthew; Harrison, Sonia; Cahill, Sharon; White, Jason M

2010-01-01

To investigate the safety and efficacy of once-daily supervised oral administration of sustained-release dexamphetamine in people dependent on methamphetamine. Randomized, double-blind, placebo-controlled trial. Forty-nine methamphetamine-dependent drug users from Drug and Alcohol Services South Australia (DASSA) clinics. Participants were assigned randomly to receive up to 110 mg/day sustained-release dexamphetamine (n = 23) or placebo (n = 26) for a maximum of 12 weeks, with gradual reduction of the study medication over an additional 4 weeks. Medication was taken daily under pharmacist supervision. Primary outcome measures included treatment retention, measures of methamphetamine consumption (self-report and hair analysis), degree of methamphetamine dependence and severity of methamphetamine withdrawal. Hair samples were analysed for methamphetamine using liquid chromatography-mass spectrometry. Treatment retention was significantly different between groups, with those who received dexamphetamine remaining in treatment for an average of 86.3 days compared with 48.6 days for those receiving placebo (P = 0.014). There were significant reductions in self-reported methamphetamine use between baseline and follow-up within each group (P < 0.0001), with a trend to a greater reduction among the dexamphetamine group (P = 0.086). Based on hair analysis, there was a significant decrease in methamphetamine concentration for both groups (P < 0.0001). At follow-up, degree of methamphetamine dependence was significantly lower in the dexamphetamine group (P = 0.042). Dexamphetamine maintenance was not associated with serious adverse events. The results of this preliminary study have demonstrated that a maintenance pharmacotherapy programme of daily sustained-release amphetamine dispensing under pharmacist supervision is both feasible and safe. The increased retention in the dexamphetamine group, together with the general decreases in methamphetamine use, degree of dependence and withdrawal symptom severity, provide preliminary evidence that this may be an efficacious treatment option for methamphetamine dependence.

Segmental analysis of amphetamines in hair using a sensitive UHPLC-MS/MS method.

PubMed

Jakobsson, Gerd; Kronstrand, Robert

2014-06-01

A sensitive and robust ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy methamphetamine in hair samples. Segmented hair (10 mg) was incubated in 2M sodium hydroxide (80°C, 10 min) before liquid-liquid extraction with isooctane followed by centrifugation and evaporation of the organic phase to dryness. The residue was reconstituted in methanol:formate buffer pH 3 (20:80). The total run time was 4 min and after optimization of UHPLC-MS/MS-parameters validation included selectivity, matrix effects, recovery, process efficiency, calibration model and range, lower limit of quantification, precision and bias. The calibration curve ranged from 0.02 to 12.5 ng/mg, and the recovery was between 62 and 83%. During validation the bias was less than ±7% and the imprecision was less than 5% for all analytes. In routine analysis, fortified control samples demonstrated an imprecision <13% and control samples made from authentic hair demonstrated an imprecision <26%. The method was applied to samples from a controlled study of amphetamine intake as well as forensic hair samples previously analyzed with an ultra high performance liquid chromatography time of flight mass spectrometry (UHPLC-TOF-MS) screening method. The proposed method was suitable for quantification of these drugs in forensic cases including violent crimes, autopsy cases, drug testing and re-granting of driving licences. This study also demonstrated that if hair samples are divided into several short segments, the time point for intake of a small dose of amphetamine can be estimated, which might be useful when drug facilitated crimes are investigated. Copyright © 2014 John Wiley & Sons, Ltd.

Designation of Alpha-Phenylacetoacetonitrile (APAAN), a Precursor Chemical Used in the Illicit Manufacture of Phenylacetone, Methamphetamine, and Amphetamine, as a List I Chemical. Final rule.

PubMed

2017-07-14

The Drug Enforcement Administration (DEA) is finalizing the designation of the chemical alpha-phenylacetoacetonitrile (APAAN) and its salts, optical isomers, and salts of optical isomers, as a list I chemical under the Controlled Substances Act (CSA). The DEA proposed control of APAAN, due to its use in clandestine laboratories to illicitly manufacture the schedule II controlled substances phenylacetone (also known as phenyl-2-propanone or P2P), methamphetamine, and amphetamine. This rulemaking finalizes, without change, the control of APAAN as a list I chemical. This action does not establish a threshold for domestic and international transactions of APAAN. As such, all transactions involving APAAN, regardless of size, shall be regulated. In addition, chemical mixtures containing APAAN are not exempt from regulatory requirements at any concentration. Therefore, all transactions of chemical mixtures containing any quantity of APAAN shall be regulated pursuant to the CSA. However, manufacturers may submit an application for exemption for those mixtures that do not qualify for automatic exemption.

Release of (/sup 3/H)-monoamines from superfused rat striatal slices by methylenedioxymethamphetamine (MDMA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levin, J.A.; Schmidt, C.J.; Lovenberg, W.

1986-03-05

MDMA is a phenylisopropylamine which is reported to have unique behavioral effects in man. Because of its structural similarities to the amphetamines the authors have compared the effects of MDMA and two related amphetamines on the spontaneous release of tritiated dopamine (DA) and serotonin (5HT) from superfused rat striatal slices. At concentrations of 10/sup -7/ - 10/sup -5/M MDMA and the serotonergic neurotoxin, p-chloroamphetamine, were equipotent releasers of (/sup 3/H)5HT being approximately 10x more potent than methamphetamine. However, methamphetamine was the more potent releaser of (/sup 3/H)DA by a factor of approximately 10x. MDMA-induced release of both (/sup 5/H)5HT andmore » (/sup 3/H)DA was Ca/sup 2 +/-independent and inhibited by selective monoamine uptake blockers suggesting a carrier-dependent release mechanism. Synaptosomal uptake experiments with (+)(/sup 3/H)MDMA indicated no specific uptake of the drug further suggesting the effect of uptake blockers may be to inhibit the carrier-mediated export of amines displaced by MDMA.« less

Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2.

PubMed

Cadet, J L; Ordonez, S V; Ordonez, J V

1997-02-01

Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. We thus tested if the anti-death proto-oncogene, bcl-2 could protect against METH-induced cytotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2-expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoresis, we also show that METH exposure can cause DNA strand breaks, chromatin condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by bcl-2 expression. These observations provide further support for the involvement of oxidative stress in the toxic effects of amphetamine analogs. They also document that METH-induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway.

Novel Selectivity-Based Forensic Toxicological Validation of a Paper Spray Mass Spectrometry Method for the Quantitative Determination of Eight Amphetamines in Whole Blood.

PubMed

Teunissen, Sebastiaan F; Fedick, Patrick W; Berendsen, Bjorn J A; Nielen, Michel W F; Eberlin, Marcos N; Graham Cooks, R; van Asten, Arian C

2017-12-01

Paper spray tandem mass spectrometry is used to identify and quantify eight individual amphetamines in whole blood in 1.3 min. The method has been optimized and fully validated according to forensic toxicology guidelines, for the quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-N-methylamphetamine (MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), and 4-fluoroamphetamine (4-FA). Additionally, a new concept of intrinsic and application-based selectivity is discussed, featuring increased confidence in the power to discriminate the amphetamines from other chemically similar compounds when applying an ambient mass spectrometric method without chromatographic separation. Accuracy was within ±15% and average precision was better than 15%, and better than 20% at the LLOQ. Detection limits between 15 and 50 ng/mL were obtained using only 12 μL of whole blood. Graphical abstract ᅟ.

Novel Selectivity-Based Forensic Toxicological Validation of a Paper Spray Mass Spectrometry Method for the Quantitative Determination of Eight Amphetamines in Whole Blood

NASA Astrophysics Data System (ADS)

Teunissen, Sebastiaan F.; Fedick, Patrick W.; Berendsen, Bjorn J. A.; Nielen, Michel W. F.; Eberlin, Marcos N.; Graham Cooks, R.; van Asten, Arian C.

2017-12-01

Paper spray tandem mass spectrometry is used to identify and quantify eight individual amphetamines in whole blood in 1.3 min. The method has been optimized and fully validated according to forensic toxicology guidelines, for the quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy- N-methylamphetamine (MDMA), 3,4-methylenedioxy- N-ethylamphetamine (MDEA), para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), and 4-fluoroamphetamine (4-FA). Additionally, a new concept of intrinsic and application-based selectivity is discussed, featuring increased confidence in the power to discriminate the amphetamines from other chemically similar compounds when applying an ambient mass spectrometric method without chromatographic separation. Accuracy was within ±15% and average precision was better than 15%, and better than 20% at the LLOQ. Detection limits between 15 and 50 ng/mL were obtained using only 12 μL of whole blood. [Figure not available: see fulltext.

[Intoxation with paramethoxymethamphetamine].

PubMed

Al-Samarraie, Muhammad S; Vevelstad, Merete; Nygaard, Ilah Le; Bachs, Liliana; Mørland, Jørg

2013-05-07

Since the summer of 2010, there has been an epidemic of deaths related to paramethoxymethamphetamine (PMMA) in Norway. We present a review of the pharmacology and toxicology of the substance. The review is based on a literature search in the databases PubMed, Ovid and MEDLINE. A discretionary selection was made of relevant articles. Paramethoxymethamphetamine and paramethoxyamphetamine (PMA) are two so-called designer amphetamines which appear from time to time on the illegal narcotics market in many countries. They are frequently sold as ecstasy or amphetamine, often mixed with amphetamine or methamphetamine. The substances, known on the street as «Death», have potent serotonergic effects and are associated with significant toxicity. Many deaths have been reported worldwide, even after intake of an «ordinary user dose». The narcotic effect is not very pronounced and the onset is slow, which may lead to unintentional overdosing. In cases of severe intoxation that are apparently related to intake of amphetamine or ecstasy, PMMA/PMA intoxation should be suspected.

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation.

PubMed

Sriram, Uma; Cenna, Jonathan M; Haldar, Bijayesh; Fernandes, Nicole C; Razmpour, Roshanak; Fan, Shongshan; Ramirez, Servio H; Potula, Raghava

2016-01-01

The novel transmembrane G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), represents a potential, direct target for drugs of abuse and monoaminergic compounds, including amphetamines. For the first time, our studies have illustrated that there is an induction of TAAR1 mRNA expression in resting T lymphocytes in response to methamphetamine. Methamphetamine treatment for 6 h significantly increased TAAR1 mRNA expression (P < 0.001) and protein expression (P < 0.01) at 24 h. With the use of TAAR1 gene silencing, we demonstrate that methamphetamine-induced cAMP, a classic response to methamphetamine stimulation, is regulated via TAAR1. We also show by TAAR1 knockdown that the down-regulation of IL-2 in T cells by methamphetamine, which we reported earlier, is indeed regulated by TAAR1. Our results also show the presence of TAAR1 in human lymph nodes from HIV-1-infected patients, with or without a history of methamphetamine abuse. TAAR1 expression on lymphocytes was largely in the paracortical lymphoid area of the lymph nodes with enhanced expression in lymph nodes of HIV-1-infected methamphetamine abusers rather than infected-only subjects. In vitro analysis of HIV-1 infection of human PBMCs revealed increased TAAR1 expression in the presence of methamphetamine. In summary, the ability of methamphetamine to activate trace TAAR1 in vitro and to regulate important T cell functions, such as cAMP activation and IL-2 production; the expression of TAAR1 in T lymphocytes in peripheral lymphoid organs, such as lymph nodes; and our in vitro HIV-1 infection model in PBMCs suggests that TAAR1 may play an important role in methamphetamine -mediated immune-modulatory responses. © Society for Leukocyte Biology.

Morning administration of oral methamphetamine dose-dependently disrupts nighttime sleep in recreational stimulant users.

PubMed

Herrmann, Evan S; Johnson, Patrick S; Bruner, Natalie R; Vandrey, Ryan; Johnson, Matthew W

2017-09-01

Use of amphetamine-type stimulants (e.g., methamphetamine) is associated with acute sleep disruptions. No prior reports have characterized the acute effects of methamphetamine on sleep using polysomnography, the gold standard for objective sleep monitoring. Recreational stimulant users (n=19) completed a baseline assessment, which included questionnaires assessing demographic and substance use characteristics, and the Pittsburgh Sleep Quality Index (PSQI), which assesses sleep quality over the past month. Participants were administered 0mg (placebo), 20mg, or 40mg oral methamphetamine at 08:15h on study days, using a double-blind, randomized, within-subjects design. Sleep was monitored using polysomnography from 22:20 that evening until 06:15 the following morning. PSQI scores indicated more than half of participants reported poor sleep quality at baseline. Methamphetamine dose-dependently increased sleep latency, and decreased total sleep time, sleep efficiency, time in NREM 2 sleep, number of REM periods, and total time in REM sleep. Sleep under placebo conditions was consistent with what would be expected from healthy adults. Morning oral administration of methamphetamine produces robust disruptions in nighttime sleep. Future research should examine relations between stimulant use and sleep disruption in naturalistic settings, with regard to both stimulant abuse and licit prescription use. Copyright © 2017. Published by Elsevier B.V.

[Effect of rhynchophylline on behaviors of methamphetamine-dependent zebrafish and the mechanism].

PubMed

Chen, Yi-Fei; Peng, Ju; Fang, Miao; Liu, Yi; Nie, Ling-Hui; Mo, Zhi-Xian; Zhu, Ling-Ling

2016-11-20

To observe the effect of rhynchophylline on methamphetamine-dependent zebrafish and explore the possible mechanism. Zebrafish were divided into control group, amphetamine group, low- (50 mg/kg) and high (100 mg/kg)-dose rhynchophylline groups, and ketamine (150 mg/kg) group. Conditioned place preference (CPP) was induced in zebrafish with methamphetamine, and the staying time in the drug box and the tracking map of the zebrafish were observed with Noldus Ethovision XT system. The protein expressions of TH, NR2B and GLUR2 in the brain of zebrafish with CPP were detected with Western blotting. Compared with the control group, zebrafish in methamphetamine group showed significant variations in the staying time and swimming distance in the drug box after conditioning (P<0.05) with obvious alterations of NR2B, TH and GLUR2 expressions in the brain (P<0.05). Treatment of methamphetamine-dependent zebrafish with high-dose rhynchophylline significantly reduced the variations in the staying time and swimming distance in the drug box (P<0.05) and in the expressions of NR2B, TH and GLUR2 in the brain (P<0.05). Rhynchophylline can inhibit methamphetamine dependence in zebrafish, the mechanism of which may involve the expressions of TH, NR2B and GLUR2 proteins in the brain.

A placebo-controlled trial of mirtazapine for the management of methamphetamine withdrawal.

PubMed

Cruickshank, Christopher C; Montebello, Mark E; Dyer, Kyle R; Quigley, Allan; Blaszczyk, Jozef; Tomkins, Sally; Shand, Diana

2008-05-01

As an antidepressant with sedative and anxiolytic properties, mirtazapine may be an appropriate pharmacotherapy for methamphetamine withdrawal. This study sought to examine whether mirtazapine improves retention and alleviates methamphetamine withdrawal symptoms in an out-patient setting. An out-patient double-blind, randomised placebo-controlled trial of mirtazapine for the treatment of methamphetamine withdrawal was conducted (15 mg nocte for 2 days, 30 mg nocte for 12 days). Both groups were offered narrative therapy counselling. Measures recorded on days 0, 3, 7, 14 and 35 included: treatment retention, Amphetamine Cessation Symptoms Assessment, the Athens Insomnia Scale, the Brief Symptom Inventory, the Depression-Anxiety-Stress Scale (DASS), Severity of Dependence scale and the Opiate Treatment Index Drug Use subscale. Thirty-one participants were recruited (18 placebo, 13 mirtazapine) and 52% completed the 2-week medication phase. No significant differences between the mirtazapine and placebo groups in retention, or any symptom measure were observed, except greater DASS-anxiety and longer sleep duration were measured at baseline among the mirtazapine group. Results suggest that mirtazapine does not facilitate retention or recruitment in out-patient methamphetamine withdrawal treatment, although recruitment may have been insufficient to identify a significant treatment effect. The potential role of narrative therapy for methamphetamine dependent patients deserves further exploration.

Cannabinoid Receptors Mediate Methamphetamine Induction of High Frequency Gamma Oscillations in the Nucleus Accumbens

PubMed Central

Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

2012-01-01

Patients suffering from amphetamine---induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (~ 80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. PMID:22609048

Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

PubMed

Kraemer, Thomas; Roditis, Susanne K; Peters, Frank T; Maurer, Hans H

2003-03-01

Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

Brain abnormalities detected on magnetic resonance imaging of amphetamine users presenting to an emergency department: a pilot study.

PubMed

Fatovich, Daniel M; McCoubrie, David L; Song, Swithin J; Rosen, David M; Lawn, Nick D; Daly, Frank F

2010-09-06

To determine the prevalence of occult brain abnormalities in magnetic resonance imaging of active amphetamine users. Prospective convenience study in a tertiary hospital emergency department (ED). Patients presenting to the ED for an amphetamine-related reason were eligible for inclusion. We collected demographic data, drug use data, and performed a mini-mental state examination (MMSE). The proportion of patients with an abnormality on their MRI scan. Of 38 patients enrolled, 30 had MRI scans. Nineteen were male and their mean age was 26.7 +/- 5.4 years (range 19-41 years). The mean age of first amphetamine use was 18 years (range 13-26 years). Sixteen patients used crystal methamphetamine (mean amount 2.5 g/week), nine used amphetamine ("speed") (mean amount 2.9 g/week), and 23 used ecstasy (mean amount 2.3 tablets/week). Marijuana was smoked by 26 (mean amount 5.9 g/week), and 28 drank alcohol (mean amount 207 g/week). The median MMSE score was 27/30 (interquartile range, 26-29). Abnormalities on brain MRI scans were identified in six patients, most commonly an unidentified bright object (n = 4). In this pilot study of brain MRI of young people attending the ED with an amphetamine-related presentation, one in five had an occult brain lesion. While the significance of this is uncertain, it is congruent with evidence that amphetamines cause brain injury.

Detection of Delta9-tetrahydrocannabinol and amphetamine-type stimulants in oral fluid using the Rapid Stat point-of-collection drug-testing device.

PubMed

Röhrich, J; Zörntlein, S; Becker, J; Urban, R

2010-04-01

The Rapid Stat assay, a point-of-collection drug-testing device for detection of amphetamines, cannabinoids, cocaine, opiates, methadone, and benzodiazepines in oral fluid, was evaluated for cannabis and amphetamine-type stimulants. The Rapid Stat tests (n = 134) were applied by police officers in routine traffic checks. Oral fluid and blood samples were analyzed using gas chromatography-mass spectrometry (GC-MS) for Delta(9)-tetrahydrocannabinol, amphetamine, methamphetamine, methylenedioxymethamphetamine, methylenedioxyethylamphetamine, and methylenedioxyamphetamine. The comparison of GC-MS analysis of oral fluid with the Rapid Stat results for cannabis showed a sensitivity of 85%, a specificity of 87%, and a total confirmation rate of 87%. When compared with serum, the sensitivity of the cannabis assay decreased to 71%, the specificity to 60%, and the total confirmation rate to 66%. These findings were possibly caused by an incorrect reading of the THC test results. Comparison of the Rapid Stat amphetamine assay with GC-MS in oral fluid showed a sensitivity of 94%, a specificity of 97%, and a total confirmation rate of 97%. Compared with serum, a sensitivity of 100%, a specificity of 90%, and a total confirmation rate of 92% was found. The amphetamine assay must, therefore, be regarded as satisfactory.

Memory Disrupting Effects of Nonmuscle Myosin II Inhibition Depend on the Class of Abused Drug and Brain Region

ERIC Educational Resources Information Center

Briggs, Sherri B.; Blouin, Ashley M.; Young, Erica J.; Rumbaugh, Gavin; Miller, Courtney A.

2017-01-01

Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared…

Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA, ecstasy ), and amphetamines

PubMed Central

Gouzoulis-Mayfrank, Euphrosyne; Daumann, Joerg

2009-01-01

Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies. PMID:19877498

Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users.

PubMed

Morales, A M; Kohno, M; Robertson, C L; Dean, A C; Mandelkern, M A; London, E D

2015-06-01

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

Gray-Matter Volume, Midbrain Dopamine D2/D3 Receptors and Drug Craving in Methamphetamine Users

PubMed Central

Morales, Angelica A.; Kohno, Milky; Robertson, Chelsea L.; Dean, Andy C.; Mandelkern, Mark A.; London, Edythe D.

2015-01-01

Dysfunction of the mesocorticolimbic system plays a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [18F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, p<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum, and thalamus (p<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance use disorders. PMID:25896164

Inclusion dynamics in PC12 is comparable between amphetamines and MPTP.

PubMed

Gesi, Marco; Lazzeri, Gloria; Ferrucci, Michela; Pellegrini, Antonio; Lenzi, Paola; Ruggieri, Stefano; Fornai, Francesco; Paparelli, Antonio

2006-08-01

In previous studies it was demonstrated that amphetamine derivatives and 1-methyl article-4-phenylpyridinium produce neuronal cell bodies. In the present work, we compared the fine ultrastructure of the intracellular inclusions induced by these different neurotoxic treatments. In particular, we compared the dynamical changes occurring when a mild toxic stimulus acts for different time intervals. For this purpose, we exposed catecholamine-synthesizing PC12 cells to different amphetamine derivatives (methamphetamine and 3,4-methylenedioxymethamphetamine), or 1-methyl-4-phenylpyridinium ion, which represents the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,3,4,6-tetrahydropyridine. Despite inclusions that are elicited by different mechanisms depending on the specific neurotoxin, their ultrastructural features are similar and there is a high parallelism in their temporal evolution. This suggests that formation of inclusions is a multi-step process that might be elicited by different stimuli and, once triggered, leads to the same final effect.

A solid colorimetric sensor for the analysis of amphetamine-like street samples.

PubMed

Argente-García, A; Jornet-Martínez, N; Herráez-Hernández, R; Campíns-Falcó, P

2016-11-02

A solid sensor obtained by embedding 1,2-naphthoquinone-4-sulfonate (NQS) into polydimethylsiloxane/tetraethylortosilicate/silicon dioxide nanoparticles composite has been developed to identify and determine amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxymetamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA). The analytes are derivatized inside the composite for 10 min to create a colored product which can be then quantified by measuring the diffuse reflectance or the color intensity after processing the digitalized image. Satisfactory limits of detection (0.002-0.005 g mL -1 ) and relative standard deviations (<10%) have been achieved. The proposed kit has been successfully validated and applied to the analysis of amphetamine-like drugs street samples. The kit allows the in-situ screening of the mentioned illicit drugs owing to its simplicity, rapidity and portability, with excellent sensor stability and at a very low-cost. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of SERS spectroscopy to the identification of (3,4-methylenedioxy)amphetamine in forensic samples utilizing matrix stabilized silver halides.

PubMed

Sägmüller, B; Schwarze, B; Brehm, G; Schneider, S

2001-11-01

A method based on surface-enhanced Raman scattering (SERS) spectroscopy was developed to meet the need for the reliable and rapid identification of illicit drugs such as the 'designer drug' XTC, preferably to increase the security of legal certificates. A matrix stabilized silver halide dispersion on a microtiter plate is used as the SERS-active substrate, providing an easy to use system for sample preparation and probing by means of a Raman microscope. The potential of the method is demonstrated by applying it to the identification of the psychoactive ingredients of drug containing tablets which were confiscated by the local police at techno-music events. The samples of interest were 26 different brands of XTC tablets and several pieces of evidence (powders) containing amphetamine. For reference, we show SERS and Raman spectra of pristine amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethamphetamine.

Death by 'ice': fatal methamphetamine intoxication of a body packer case detected by postmortem computed tomography (PMCT) and validated by autopsy.

PubMed

Bin Abdul Rashid, Saiful Nizam; Rahim, Amir Saad Abdul; Thali, Michael J; Flach, Patricia M

2013-03-01

Fatal acute methamphetamine (MA) poisoning in cases of internal drug trafficking is rarely described in the literature. This case study reports an MA 'body packer' who died from fatal methamphetamine intoxication due to leaking drug packages in the alimentary tract. The deceased was examined by postmortem computed tomography (PMCT), and the results were correlated to subsequent autopsy and toxicological findings. The deceased was arrested by the police when he was found disoriented in the city of Kuala Lumpur. He was transferred to the emergency department on suspicion of drug abuse. The initial drug screening was reactive for amphetamines. Shortly after admission to the hospital, he died despite rigorous resuscitation attempts. The postmortem plain chest and abdominal radiographs revealed multiple suspicious opacities in the gastrointestinal tract attributable to body packages. An unenhanced whole body PMCT revealed twenty-five drug packages, twenty-four in the stomach and one in the transverse colon. At least two were disintegrating, and therefore leaking. The autopsy findings were consistent with the PMCT results. Toxicology confirmed the diagnosis of fatal methamphetamine intoxication.

Methamphetamine use can mimic testicular torsion.

PubMed

Doherty, Michael H; Gerscovich, Eugenio O; Corwin, Michael T; Wilkendorf, Stephen R

2013-09-01

We report the case of a patient presenting with the classic clinical appearance of testicular torsion. Ultrasound showed testicular ischemia supporting the clinical diagnosis, but the lack of visualization of spermatic cord torsion was of concern. An attempt of clinical detorsion was considered unsuccessful and the patient was explored. No torsion was found. On postoperative review of the patient's medical history, we found methamphetamine use, with a positive urine test at the time of his emergent consultation for the scrotal pain episode. The use of amphetamines has been previously reported as the cause of ischemia of multiple organs, but we could not find previous reports of involvement of the testis mimicking torsion. Copyright © 2013 Wiley Periodicals, Inc.

Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.

PubMed

Banks, Matthew L

2016-08-01

Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

School Reform for Rural America

ERIC Educational Resources Information Center

Fishman, Dan

2015-01-01

Overall, one in four rural children live in poverty, and of the 50 U.S. counties with the highest child-poverty rates, 48 are rural. Drug usage abounds. In the mid-2000s, rural 8th graders were 59 percent more likely than peers in large cities to use methamphetamines and 104 percent more likely to use any amphetamine, according to the National…

Retrospective study of urinalysis for dl-amphetamine and dl-methamphetamine analysis under current Department of Defense guidelines.

PubMed

Shippee, R L; Kippenberger, D J

2000-09-01

Under current Department of Defense (DOD) directive, the laboratories certified to conduct urinalyis testing in support of the DOD Drug Deterrence Program are required to conduct dl-isomer analysis on all specimens that confirm at a concentration greater than 500 ng/mL methamphetamine (METH). Although the same cutoff concentration is required for amphetamine (AMP) reporting, there is no requirement for dl-isomer analysis of AMP-positive specimens. Of the 894,823 specimens screened by the Army Drug Testing Laboratory at Ft. Meade, MD during a 19-month period, 339 confirmed positive for METH. From this positive population, seven specimens failed to confirm at or above the DOD cutoff of > 20% d-isomer. One of the seven specimens contained 534 ng/mL l-AMP and was reported positive for AMP. Although 100% of the AMP was the l-isomer, under current DOD directive, this information was not passed along to the Medical Review Officers (MRO) to assist them during the interview process. Although this situation appears to be a rare event, consideration should be given to requiring dl-isomer analysis of AMP-positive specimens and forwarding this information to the MRO.

Multi-residue screening of prioritised human pharmaceuticals, illicit drugs and bactericides in sediments and sludge.

PubMed

Langford, Katherine H; Reid, Malcolm; Thomas, Kevin V

2011-08-01

A robust multi-residue method was developed for the analysis of a selection of pharmaceutical compounds, illicit drugs and personal care product bactericides in sediments and sludges. Human pharmaceuticals were selected for analysis in Scottish sewage sludge and freshwater sediments based on prescription, physico-chemical and occurrence data. The method was suitable for the analysis of the selected illicit drugs amphetamine, benzoylecgonine, cocaine, and methamphetamine, the pharmaceuticals atenolol, bendroflumethiazide, carbamazepine, citalopram, diclofenac, fluoxetine, ibuprofen, and salbutamol, and the bactericides triclosan and triclocarban in sewage sludge and freshwater sediment. The method provided an overall recovery of between 56 and 128%, RSDs of between 2 and 19% and LODs of between 1 and 50 ng g(-1). Using the methodology the human pharmaceuticals atenolol, carbamazepine and citalopram and the bactericides triclosan and triclocarban were detected in Scottish sewage sludge. The illicit drugs cocaine, its metabolite benzoylecgonine, amphetamine and methamphetamine were not detected in any of the samples analysed. Triclosan and triclocarban were present at the highest concentrations with triclocarban detected in all but one sample and showing a pattern of co-occurrence in both sludge and sediment samples.

Understanding the microcrystal tests of three related phenethylamines: the ortho-metallated (±)-amphetamine formed with gold(III) chloride, and the tetrachloridoaurate(III) salts of (+)-methamphetamine and (±)-ephedrine.

PubMed

Wood, Matthew R; Lalancette, Roger A

2013-04-01

The ortho-metallation product of the reaction of (±)-amphetamine with gold(III) chloride, [D,L-2-(2-aminopropyl)phenyl-κ(2)N,C(1)]dichloridogold(III), [Au(C9H12N)Cl2], and the two salts resulting from crystallization of (+)-methamphetamine with gold(III) chloride, D-methyl(1-phenylpropan-2-yl)azanium tetrachloridoaurate(III), (C10H16N)[AuCl4], and of (±)-ephedrine with gold(III) chloride, D,L-(1-hydroxy-1-phenylpropan-2-yl)(methyl)azanium tetrachloridoaurate(III), (C10H16NO)[AuCl4], have different structures. The first makes a bidentate complex directly with a dichloridogold(III) group, forming a six-membered ring structure; the second and third each form a salt with [AuCl4](-) (each has two formula units in the asymmetric unit). The organic components are all members of the same class of stimulants that are prevalent in illicit drug use. These structures are important contributions to the understanding of the microcrystal tests for these drugs that have been employed for well over 100 years.

[Analysis of active components of evidence materials secured in the cases of drugs abuse associated with amphetamines and cannabis products].

PubMed

Wachowiak, Roman; Strach, Bogna

2006-01-01

The study takes advantage of the presently available effective physicochemical methods (isolation, crystallization, determination of melting point, TLC, GLC and UV spectrophotometry) for an objective and reliable qualitative and quantitative analysis of frequently abused drugs. The authors determined the conditions for qualitative and quantitative analysis of active components of the secured evidence materials containing amphetamine sulphate, methylamphetamine hydrochloride, 3,4-me-tylenedioxy-methamphetamine hydrochloride (MDMA, Ecstasy), as well as delta(9)-tetrahydrocannabinol (delta(9)-THC) as an active component of cannabis (marihuana, hashish). The usefulness of physicochemical tests of evidence materials for opinionating purposes is subject to a detailed forensic toxicological interpretation.

Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

PubMed

Dostalek, M; Hadasova, E; Hanesova, M; Pistovcakova, J; Sulcova, A; Jurica, J; Tomandl, J; Linhart, I

2005-01-01

Methamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam's metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

Chronic variable stress and intravenous methamphetamine self-administration – role of individual differences in behavioral and physiological reactivity to novelty

PubMed Central

Taylor, S.B.; Watterson, L.R.; Kufahl, P.R.; Nemirovsky, N.E.; Tomek, S.E.; Conrad, C.D.; Olive, M.F.

2016-01-01

Stress is a contributing factor to the development and maintenance of addiction in humans. However, few studies have shown that stress potentiates the rewarding and/or reinforcing effects of methamphetamine in rodent models of addiction. The present study assessed the effects of exposure to 14 days of chronic variable stress (CVS), or no stress as a control (CON), on the rewarding and reinforcing effects of methamphetamine in adult rats using the conditioned place preference (Experiment 1) and intravenous self-administration (Experiment 2) paradigms. In Experiment 2, we also assessed individual differences in open field locomotor activity, anxiety-like behavior in the elevated plus maze (EPM), and physiological responses to a novel environment as possible predictors of methamphetamine intake patterns. Exposure to CVS for 14 days did not affect overall measures of methamphetamine conditioned reward or reinforcement. However, analyses of individual differences and direct vs. indirect effects revealed that rats exhibiting high physiological reactivity and locomotor activity in the EPM and open field tests self-administered more methamphetamine and reached higher breakpoints for drug reinforcement than rats exhibiting low reactivity. In addition, CVS exposure significantly increased the proportion of rats that exhibited high reactivity, and high reactivity was significantly correlated with increased levels of methamphetamine intake. These findings suggest that individual differences in physiological and locomotor reactivity to novel environments, as well as their interactions with stress history, predict patterns of drug intake in rodent models of methamphetamine addiction. Such predictors may eventually inform future strategies for implementing individualized treatment strategies for amphetamine use disorders. PMID:27163191

Determination of 74 new psychoactive substances in serum using automated in-line solid-phase extraction-liquid chromatography-tandem mass spectrometry.

PubMed

Lehmann, Sabrina; Kieliba, Tobias; Beike, Justus; Thevis, Mario; Mercer-Chalmers-Bender, Katja

2017-10-01

A detailed description is given of the development and validation of a fully automated in-line solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method capable of detecting 90 central-stimulating new psychoactive substances (NPS) and 5 conventional amphetamine-type stimulants (amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxy-N-ethyl-amphetamine (MDEA), methamphetamine) in serum. The aim was to apply the validated method to forensic samples. The preparation of 150μL of serum was performed by an Instrument Top Sample Preparation (ITSP)-SPE with mixed mode cation exchanger cartridges. The extracts were directly injected into an LC-MS/MS system, using a biphenyl column and gradient elution with 2mM ammonium formate/0.1% formic acid and acetonitrile/0.1% formic acid as mobile phases. The chromatographic run time amounts to 9.3min (including re-equilibration). The total cycle time is 11min, due to the interlacing between sample preparation and analysis. The method was fully validated using 69 NPS and five conventional amphetamine-type stimulants, according to the guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh). The guidelines were fully achieved for 62 analytes (with a limit of detection (LOD) between 0.2 and 4μg/L), whilst full validation was not feasible for the remaining 12 analytes. For the fully validated analytes, the method achieved linearity in the 5μg/L (lower limit of quantification, LLOQ) to 250μg/L range (coefficients of determination>0.99). Recoveries for 69 of these compounds were greater than 50%, with relative standard deviations≤15%. The validated method was then tested for its capability in detecting a further 21 NPS, thus totalling 95 tested substances. An LOD between 0.4 and 1.6μg/L was obtained for these 21 additional qualitatively-measured substances. The method was subsequently successfully applied to 28 specimens from routine forensic case work, of which 7 samples were determined to be positive for NPS consumption. Copyright © 2017 Elsevier B.V. All rights reserved.

Cannabinoid receptors mediate methamphetamine induction of high frequency gamma oscillations in the nucleus accumbens.

PubMed

Morra, Joshua T; Glick, Stanley D; Cheer, Joseph F

2012-09-01

Patients suffering from amphetamine-induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely-moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (∼80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Discrete memory impairments in largely pure chronic users of MDMA.

PubMed

Wunderli, Michael D; Vonmoos, Matthias; Fürst, Marina; Schädelin, Katrin; Kraemer, Thomas; Baumgartner, Markus R; Seifritz, Erich; Quednow, Boris B

2017-10-01

Chronic use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") has repeatedly been associated with deficits in working memory, declarative memory, and executive functions. However, previous findings regarding working memory and executive function are inconclusive yet, as in most studies concomitant stimulant use, which is known to affect these functions, was not adequately controlled for. Therefore, we compared the cognitive performance of 26 stimulant-free and largely pure (primary) MDMA users, 25 stimulant-using polydrug MDMA users, and 56 MDMA/stimulant-naïve controls by applying a comprehensive neuropsychological test battery. Neuropsychological tests were grouped into four cognitive domains. Recent drug use was objectively quantified by 6-month hair analyses on 17 substances and metabolites. Considerably lower mean hair concentrations of stimulants (amphetamine, methamphetamine, methylphenidate, cocaine), opioids (morphine, methadone, codeine), and hallucinogens (ketamine, 2C-B) were detected in primary compared to polydrug users, while both user groups did not differ in their MDMA hair concentration. Cohen's d effect sizes for both comparisons, i.e., primary MDMA users vs. controls and polydrug MDMA users vs. controls, were highest for declarative memory (d primary =.90, d polydrug =1.21), followed by working memory (d primary =.52, d polydrug =.96), executive functions (d primary =.46, d polydrug =.86), and attention (d primary =.23, d polydrug =.70). Thus, primary MDMA users showed strong and relatively discrete declarative memory impairments, whereas MDMA polydrug users displayed broad and unspecific cognitive impairments. Consequently, even largely pure chronic MDMA use is associated with decreased performance in declarative memory, while additional deficits in working memory and executive functions displayed by polydrug MDMA users are likely driven by stimulant co-use. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

A practical approach to determination of laboratory GC-MS limits of detection.

PubMed

Underwood, P J; Kananen, G E; Armitage, E K

1997-01-01

Determination of limit of detection (LOD) values in a forensic laboratory serves a fundamental forensic requirement for assay performance. In addition to demonstrating assay capability, LOD values can also be used to fulfill certification requirements of a high-volume forensic drug laboratory. The LOD was defined as the lowest concentration of drug that the laboratory can detect in a specimen with forensic certainty at a minimum of 85% of the time. Overall batch acceptance criteria included acceptable quantitation of control materials (within 20% of target), acceptable chromatography (symmetry, peak integration, peak shape, peak, and baseline resolution), retention time within +/-1% of the extracted standard, and mass ion ratios within +/-20% of the extracted standard mass ion ratios. Individual specimen acceptance criteria were the same as the batch acceptance criteria excluding the quantitation requirement. Data were collected from all instruments on different runs. A minimum of ten data points was required for each certified instrument, and a minimum of 85% of data points was acceptable. Quantitation within +/-20% of the LOD concentration was not required, but acceptable mass ratios were required. Data points with poor chromatography (internal standard failed mass ratios; interference of the baseline, for example, shoulders; asymmetry; and baseline resolution) was omitted from the acceptable rate calculation. Data points with good chromatography with failed mass ion ratios were included in the acceptable rate calculation. With these criteria, we established the following LODs: 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid, 2 ng/mL; benzoylecgonine, 5 ng/mL; phencyclidine, 2.5 ng/mL; amphetamine, 150 ng/mL; methamphetamine, 100 ng/mL; codeine, 500 ng/mL; and morphine, 1000 ng/mL.

An aptamer folding-based sensory platform decorated with nanoparticles for simple cocaine testing.

PubMed

Guler, Emine; Bozokalfa, Guliz; Demir, Bilal; Gumus, Zinar Pinar; Guler, Bahar; Aldemir, Ebru; Timur, Suna; Coskunol, Hakan

2017-04-01

The consumption of illicit drugs such as cannabis, cocaine, and amphetamines is still a major health and social problem, creating an abuse in adults especially. Novel techniques which estimate the drug of abuse are needed for the detection of newly revealed psychoactive drugs. Herein, we have constructed a combinatorial platform by using quantum dots (QDs) and gold nanoparticles (AuNPs) as well as a functional aptamer which selectively recognizes cocaine and its metabolite benzoylecgonine (BE). We have called it an aptamer folding-based sensory device (AFSD). For the fabrication of AFSD, QDs were initially immobilized onto the poly-L-lysine coated μ-well surfaces. Then, the AuNP-aptamer conjugates were bound to the QDs. The addition of cocaine or BE caused a change in the aptamer structure which induced the close interaction of AuNPs with the QDs. Hence, quenching of the fluorescence of QDs was observed depending on the analyte amount. The linearity of cocaine and BE was 1.0-10 nM and 1.0-25 μM, respectively. Moreover, the limits of detection for cocaine and BE were calculated as 0.138 nM and 1.66 μM. The selectivity was tested by using different interfering substances (methamphetamine, bovine serum albumin, codeine, and 3-acetamidophenol). To investigate the use of AFSD in artificial urine matrix, cocaine/BE spiked samples were applied. Also, confirmatory analyses by using high performance liquid chromatography were performed. It is shown that AFSD has a good potential for testing the cocaine abuse and can be easily adapted for detection of various addictive drugs by changing the aptamer according to desired analytes. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Broad-spectrum drug screening of meconium by liquid chromatography with tandem mass spectrometry and time-of-flight mass spectrometry.

PubMed

Ristimaa, Johanna; Gergov, Merja; Pelander, Anna; Halmesmäki, Erja; Ojanperä, Ilkka

2010-09-01

Analysis of the major drugs of abuse in meconium has been established in clinical practice for detecting fetal exposure to illicit drugs, particularly for the ready availability of the sample and ease of collection from diapers, compared with neonatal hair and urine. Very little is known about the occurrence and detection possibilities of therapeutic and licit drugs in meconium. Meconium specimens (n = 209) were collected in delivery hospitals, from infants of mothers who were suspected to be drug abusers. A targeted analysis method by liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) was developed for abused drugs: amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, morphine, codeine, 6-monoacetylmorphine, oxycodone, methadone, tramadol, buprenorphine, and norbuprenorphine. A separate LC-MS/MS method was developed for 11-nor-∆(9)-tetrahydrocannabinol-9-carboxylic acid. A screening method based on LC coupled to time-of-flight MS was applied to a broad spectrum of drugs. As a result, a total of 77 different compounds were found. The main drug findings in meconium were as follows: local anesthetics 82.5% (n = 172), nicotine or its metabolites 61.5% (n = 129), opioids 48.5% (n = 101), stimulants 21.0% (n = 44), hypnotics and sedatives 19.0% (n = 40), antidepressants 18.0% (n = 38), antipsychotics 5.5% (n = 11), and cannabis 3.0% (n = 5). By revealing drugs and metabolites beyond the ordinary scope, the present procedure helps the pediatrician in cases where maternal denial is strong but the infant seems to suffer from typical drug-withdrawal symptoms. Intrapartum drug administration cannot be differentiated from gestational drug use by meconium analysis, which affects the interpretation of oxycodone, tramadol, fentanyl, pethidine, and ephedrine findings.

A Retrospective Analysis of Urine Drugs of Abuse Immunoassay True Positive Rates at a National Reference Laboratory.

PubMed

Johnson-Davis, Kamisha L; Sadler, Aaron J; Genzen, Jonathan R

2016-03-01

Urine drug screens are commonly performed to identify drug use or monitor adherence to drug therapy. The purpose of this retrospective study was to evaluate the true positive and false positive rates of one of our in-house urine drug screen panels. The urine drugs of abuse panel studied consists of screening by immunoassay then positive immunoassay results were confirmed by mass spectrometry. Reagents from Syva and Microgenics were used for the immunoassay screen. The screen was performed on a Beckman AU5810 random access automated clinical analyzer. The percent of true positives for each immunoassay was determined. Agreement with previously validated GC-MS or LC-MS-MS confirmatory methods was also evaluated. There were 8,825 de-identified screening results for each of the drugs in the panel, except for alcohol (N = 2,296). The percent of samples that screened positive were: 10.0% for amphetamine/methamphetamine/3,4-methylenedioxy-methamphetamine (MDMA), 12.8% for benzodiazepines, 43.7% for opiates (including oxycodone) and 20.3% for tetrahydrocannabinol (THC). The false positive rate for amphetamine/methamphetamine was ∼14%, ∼34% for opiates (excluding oxycodone), 25% for propoxyphene and 100% for phencyclidine and MDMA immunoassays. Based on the results from this retrospective study, the true positive rate for THC drug use among adults were similar to the rate of illicit drug use in young adults from the 2013 National Survey; however, our positivity rate for cocaine was higher than the National Survey. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Substance Testing in the Fire Service: Making Public Safety a Matter of National Policy

DTIC Science & Technology

2014-03-01

25). Leshner (1999) submits that virtually every addictive substance—be it cocaine, marijuana , methamphetamine, heroin, or nicotine— appears to...safety sensitive. The DOT test panel tests for five classifications of drugs: amphetamines, cocaine, marijuana , opiates, and phencyclidine. When the...methods are laws, political/socio-cultural, pricing of services, and individual fire departments. Marijuana has been legalized in a number of states

Disappearance of R/S-methamphetamine and R/S-amphetamine from human scalp hair after discontinuation of methamphetamine abuse.

PubMed

Wang, Ting; Shen, Baohua; Wu, Hejian; Hu, Jingying; Xu, Huili; Shen, Min; Xiang, Ping

2018-03-01

Methamphetamine (MA) and amphetamine (AM) are widely abused drugs. These compounds contain a chiral center, and their enantiomers exhibit different pharmacologic, pharmacokinetic, and metabolic properties due to differences in binding affinities to their receptor sites. Until now, there was a lack of information on the decline in the concentration of drugs in hair after abstinence. A simple procedure for the chiral separation and determination of methamphetamine (MA) and its metabolite amphetamine (AM) enantiomers by LC-MS/MS in hair samples has been developed and fully validated. The LODs and LLOQs were 0.02ng/mg and 0.05ng/mg for all analytes, respectively. This method was successfully applied to both real hair specimens from chronic MA users and after the discontinuation of MA. The concentration of total MA, and total AM in fifty-eight authentic hair specimens ranged from 7.8ng/mg to 521.0ng/mg, and from 0.3ng/mg to 84.0ng/mg, respectively. Both enantiomers of MA and/or AM were detected in seven of fifty-eight authentic hair specimens. Hair specimens were from thirteen women with a known history of MA abuse, who went to a rehabilitation center and ceased consuming MA (for 4-5 months). The S-isomers of MA and AM were detected in all the 5-6cm segments. Both enantiomers of MA were detected in nine of the 5-6cm segments and the enantiomers of AM were found in only five of the nine samples. Assuming a hair growth rate of 1cm/month, the mean hair elimination half-lives of S-MA, R-MA, S-AM, and R-AM were 0.64(95% CI, 0.46-0.96), 0.58(95% CI, 0.41-0.93), 0.62(0.49-0.88), and 0.50 months (95% CI, 0.42-0.56), respectively. With the developed method, R/S-MA and R/S-AM could be detected in the hair of former drug users for approximately 4 months after abstinence. S-MA is the most commonly found analyte in hair segments and is principally used by abusers. Our results suggest that to evaluate the discontinuation of MA abuse after a 6-month period of abstinence, a 3-cm proximal hair segment should be free of MA at the SOHT proposed cut-off level. Copyright © 2018 Elsevier B.V. All rights reserved.

Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

PubMed Central

Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

2016-01-01

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

Chronic variable stress and intravenous methamphetamine self-administration - Role of individual differences in behavioral and physiological reactivity to novelty.

PubMed

Taylor, S B; Watterson, L R; Kufahl, P R; Nemirovsky, N E; Tomek, S E; Conrad, C D; Olive, M F

2016-09-01

Stress is a contributing factor to the development and maintenance of addiction in humans. However, few studies have shown that stress potentiates the rewarding and/or reinforcing effects of methamphetamine in rodent models of addiction. The present study assessed the effects of exposure to 14 days of chronic variable stress (CVS), or no stress as a control (CON), on the rewarding and reinforcing effects of methamphetamine in adult rats using the conditioned place preference (Experiment 1) and intravenous self-administration (Experiment 2) paradigms. In Experiment 2, we also assessed individual differences in open field locomotor activity, anxiety-like behavior in the elevated plus maze (EPM), and physiological responses to a novel environment as possible predictors of methamphetamine intake patterns. Exposure to CVS for 14 days did not affect overall measures of methamphetamine conditioned reward or reinforcement. However, analyses of individual differences and direct vs. indirect effects revealed that rats exhibiting high physiological reactivity and locomotor activity in the EPM and open field tests self-administered more methamphetamine and reached higher breakpoints for drug reinforcement than rats exhibiting low reactivity. In addition, CVS exposure significantly increased the proportion of rats that exhibited high reactivity, and high reactivity was significantly correlated with increased levels of methamphetamine intake. These findings suggest that individual differences in physiological and locomotor reactivity to novel environments, as well as their interactions with stress history, predict patterns of drug intake in rodent models of methamphetamine addiction. Such predictors may eventually inform future strategies for implementing individualized treatment strategies for amphetamine use disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nitrosoamphetamine binding to myoglobin and hemoglobin: Crystal structure of the H64A myoglobin-nitrosoamphetamine adduct

PubMed Central

Wang, Bing; Powell, Samantha M.; Guan, Ye; Xu, Nan; Thomas, Leonard M.; Richter-Addo, George B.

2017-01-01

N-hydroxyamphetamine (AmphNHOH) is an oxidative metabolite of amphetamine and methamphetamine. It is known to form inhibitory complexes upon binding to heme proteins. However, its interactions with myoglobin (Mb) and hemoglobin (Hb) have not been reported. We demonstrate that the reactions of AmphNHOH with ferric Mb and Hb generate the respective heme-nitrosoamphetamine derivatives characterized by UV-vis spectroscopy. We have determined the X-ray crystal structure of the H64A Mb-nitrosoamphetamine complex to 1.73 Å resolution. The structure reveals the N-binding of the nitroso-d-amphetamine isomer, with no significant H-bonding interactions between the ligand and the distal pocket amino acid residues. PMID:28450187

Neurotransmitter and psychostimulant recognition by the dopamine transporter

PubMed Central

Wang, Kevin H.; Penmatsa, Aravind; Gouaux, Eric

2015-01-01

Na+/Cl−-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine x-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine (DA), a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine, methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters. PMID:25970245

Quantitative analysis of drugs in hair by UHPLC high resolution mass spectrometry.

PubMed

Kronstrand, Robert; Forsman, Malin; Roman, Markus

2018-02-01

Liquid chromatographic methods coupled to high resolution mass spectrometry are increasingly used to identify compounds in various matrices including hair but there are few recommendations regarding the parameters and their criteria to identify a compound. In this study we present a method for the identification and quantification of a range of drugs and discuss the parameters used to identify a compound with high resolution mass spectrometry. Drugs were extracted from hair by incubation in a buffer:solvent mixture at 37°C during 18h. Analysis was performed on a chromatographic system comprised of an Agilent 6550 QTOF coupled to a 1290 Infinity UHPLC system. High resolution accurate mass data were acquired in the All Ions mode and exported into Mass Hunter Quantitative software for quantitation and identification using qualifier fragment ions. Validation included selectivity, matrix effects, calibration range, within day and between day precision and accuracy. The analytes were 7-amino-flunitrazepam, 7-amino-clonazepam, 7-amino-nitrazepam, acetylmorphine, alimemazine, alprazolam, amphetamine, benzoylecgonine, buprenorphine, diazepam, ethylmorphine, fentanyl, hydroxyzine, ketobemidone, codeine, cocaine, MDMA, methadone, methamphetamine, morphine, oxycodone, promethazine, propiomazine, propoxyphene, tramadol, zaleplone, zolpidem, and zopiclone. As proof of concept, hair from 29 authentic post mortem cases were analysed. The calibration range was established between 0.05ng/mg to 5.0ng/mg for all analytes except fentanyl (0.02-2.0), buprenorphine (0.04-2.0), and ketobemidone (0.05-4.0) as well as for alimemazine, amphetamine, cocaine, methadone, and promethazine (0.10-5.0). For all analytes, the accuracy of the fortified pooled hair matrix was 84-108% at the low level and 89-106% at the high level. The within series precisions were between 1.4 and 6.7% and the between series precisions were between 1.4 and 10.1%. From the 29 autopsy cases, 121 positive findings were encountered from 23 of the analytes in concentrations similar to those previously published. We conclude that the developed method proved precise and accurate and that it had sufficient performance for the purpose of detecting regular use of drugs or treatment with prescription drugs. To identify a compound we recommend the use of ion ratios as a complement to instrument software "matching scores". Copyright © 2018 Elsevier B.V. All rights reserved.

The effect of methamphetamine on an animal model of erectile function

PubMed Central

Tar, Moses T.; Martinez, Luis R.; Nosanchuk, Joshua D.; Davies, Kelvin P.

2014-01-01

In the U.S. methamphetamine is considered a first-line treatment for attention-deficit hyperactivity disorder. It is also a common drug of abuse. Reports in patients and abusers suggest its use results in impotence. The efficacy of phosphodiesterase-5 inhibitors (PDE5i) to restore erectile function in these patient groups also has not been determined. In these studies we determined if the rat is a suitable animal model for the physiological effects of methamphetamine on erectile function, and if a PDE5i (tadalafil) has an effect on erectile function following methamphetamine treatment. In acute phase studies, erectile function was measured in male Sprague-Dawley rats, before and after administration of 10 mg/kg methamphetamine i.p. Chronically treated animals received escalating doses of methamphetamine (2.5 mg/kg (1st week), 5 mg/kg (2nd week), and 10 mg/kg (3rd week)) i.p. daily for three weeks and erectile function compared to untreated controls. The effect of co-administration of tadalafil was also investigated in rats acutely and chronically treated with methamphetamine. Erectile function was determined by measuring the intracorporal pressure/blood pressure ratio (ICP/BP) following cavernous nerve stimulation. In both acute and chronic phase studies we observed a significant increase in the rates of spontaneous erections after methamphetamine administration. In addition, following stimulation of the cavernous nerve at 4 and 6mA, there was a significant decrease in the ICP/BP ratio (approximately 50%), indicative of impaired erectile function. Tadalafil treatment reversed this effect. In chronically treated animals the ICP/BP ratio following 4 and 6mA stimulation decreased by approximately 50% compared to untreated animals and erectile dysfunction was also reversed by tadalafil. Overall our data suggests that the rat is a suitable animal model to study the physiological effect of methamphetamine on erectile function. Our work also provides a rationale for treating patients that report erectile dysfunction associated with therapeutics containing methamphetamine or amphetamine with PDE5i. PMID:24706617

Abuse of Amphetamines and Structural Abnormalities in Brain

PubMed Central

Berman, Steven; O’Neill, Joseph; Fears, Scott; Bartzokis, George; London, Edythe D.

2009-01-01

We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse, and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques that include manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common, and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre-existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure. PMID:18991959

Protection against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an excitatory amino acid antagonist.

PubMed

Fuller, R W; Hemrick-Luecke, S K; Ornstein, P L

1992-10-01

LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.

Neurotoxicity of drugs of abuse--the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines.

PubMed

Gouzoulis-Mayfrank, Euphrosyne; Daumann, Joerg

2009-01-01

Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies.

Detection, quantification, metabolism, and behavioral effects of selegiline in horses.

PubMed

Dirikolu, Levent; Lehner, Andreas F; Karpiesiuk, Wojciech; Hughes, Charlie; Woods, William E; Boyles, Jeff; Harkins, John D; Troppmann, Amy; Tobin, Thomas

2003-01-01

Selegiline ([R]-[-]N,alpha-dimethyl-N-2- propynylphenethylamine or l-deprenyl), an irreversible inhibitor of monoamine oxidase, is a classic antidyskinetic and antiparkinsonian agent widely used in human medicine both as monotherapy and as an adjunct to levodopa therapy. Selegiline is classified by the Association of Racing Commissioners International (ARCI) as a class 2 agent, and is considered to have high abuse potential in racing horses. A highly sensitive LC/MS/MS quantitative analytical method has been developed for selegiline and its potential metabolites amphetamine and methamphetamine using commercially available deuterated analogs of these compounds as internal standards. After administering 40 mg of selegiline orally to two horses, relatively low (<60 ng/ml) concentrations of parent selegiline, amphetamine, and methamphetamine were recovered in urine samples. However, relatively high urinary concentrations of another selegiline metabolite were found, tentatively identified as N- desmethylselegiline. This metabolite was synthesized and found to be indistinguishable from the new metabolite recovered from horse urine, thereby confirming the chemical identity of the equine metabolite. Additionally, analysis of urine samples from four horses dosed with 50 mg of selegiline confirmed that N-desmethylselegiline is the major urinary metabolite of selegiline in horses. In related behavior studies, p.o. and i.v. administration of 30 mg of selegiline produced no significant changes in either locomotor activities or heart rates.

Combined behavioral studies and in vivo imaging of inflammatory response and expression of mGlu5 receptors in schnurri-2 knockout mice.

PubMed

Choi, Ji-Kyung; Zhu, Aijun; Jenkins, Bruce G; Hattori, Satoko; Kil, Kun-Eek; Takagi, Tsuyoshi; Ishii, Shunsuke; Miyakawa, Tsuyoshi; Brownell, Anna-Liisa

2015-11-16

Schnurri-2 (Shn-2) knockout (KO) mice have been proposed as a preclinical neuroinflammatory schizophrenia model. We used behavioral studies and imaging markers that can be readily translated to human populations to explore brain effects of inflammation. Shn-2 KO mice and their littermate control mice were imaged with two novel PET ligands; an inflammation marker [(11)C]PBR28 and the mGluR5 ligand [(18)F]FPEB. Locomotor activity was measured using open field exploration with saline, methamphetamine or amphetamine challenge. A significantly increased accumulation of [(11)C]PBR28 was found in the cortex, striatum, hippocampus and olfactory bulb of Shn-2 KO mice. Increased mGluR5 binding was also observed in the cortex and hippocampus of the Shn-2 KO mice. Open field locomotor testing revealed a large increase in novelty-induced hyperlocomotion in Shn-2 KO mice with abnormal (decreased) responses to either methamphetamine or amphetamine. These data provide additional support to demonstrate that the Shn-2 KO mouse model exhibits several behavioral and pathological markers resembling human schizophrenia making it an attractive translational model for the disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Rapid simultaneous determination of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyethylamphetamine in urine by solid-phase extraction and GC-MS: a method optimized for high-volume laboratories.

PubMed

Stout, Peter R; Horn, Carl K; Klette, Kevin L

2002-01-01

To facilitate analysis of high sample volumes, an extraction, derivatization and gas chromatographic-mass spectrometric analysis method was developed to simultaneously determine amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxyamphetamine (MDA) 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA) in urine. This method utilized a positive-pressure manifold cation-exchange polymer-based solid-phase extraction followed by elution directly into automated liquid sampler (ALS) vials. Rapid derivatization was accomplished using heptafluorobutyric anhydride (HFBA). Recoveries averaged 90% or greater for each of the compounds. Limits of detection were 62.5 ng/mL (AMP and MDEA), 15.6 ng/mL (MAMP), and 31.3 ng/mL (MDA and MDMA) using a 2-mL sample volume. The method was linear to 5000 ng/mL for all compounds using MDMA-d5 and MAMP-d14 as internal standards. Over 200 human urine samples previously determined to contain the target analytes were analyzed using the method. Excellent agreement was seen with previous quantitations. The method was challenged with 75 potentially interfering compounds and no interferences were seen. These interfering compounds included ephedrine, pseudoephedrine, phenylpropanolamine, and phenethylamine. The method resulted in dramatic reductions in processing time and waste production.

The Prevalence and Correlates of HIV and Undiagnosed Infection among Men Who Have Sex with Men in Hanoi, Vietnam: Findings from a Cross-sectional, Biobehavioral Study.

PubMed

Vu, Nga Thi Thu; Holt, Martin; Phan, Huong Thi Thu; La, Lan Thi; Tran, Gioi Minh; Doan, Tung Thanh; de Wit, John

2016-01-01

Men who have sex with men (MSM) are a key population for HIV infection in Vietnam, and the use of amphetamine type substances (ATS) is prevalent and possibly increasing in this population. The reported analysis examines the association between ATS use before or during sex and HIV infection among MSM in Hanoi, Vietnam. This cross-sectional study of 210 MSM was conducted in Hanoi, Vietnam, in late 2014. Men tested for HIV and answered questions about demographic characteristics, sexual sensation seeking, depression, belief in HIV prevention strategies, homosexuality-related stigma and discrimination, recent accessing of HIV prevention services, sexual behaviors and ATS, and other drug use behaviors. We performed logistic regression to assess correlates of HIV infection. HIV prevalence was 6.7% (14/210), and 85.7% (12/14) of HIV-positive men were not aware of their HIV status. Of the 210 participants, 10.5, 2.9, and 3.8% of men had used methamphetamine, amphetamine, and ecstasy before or during sex in the last 3 months. In multivariable analysis, HIV infection was associated with recent sex-related methamphetamine use [adjusted odds ratio (AOR): 5.03, 95% confidence interval (CI): 1.35-18.68], engaging in recent sex work (AOR: 3.55, 95% CI: 1.07-11.75), and homosexuality-related perceived stigma (AOR: 2.32, 95% CI: 0.98-5.47). Findings underscore the importance of integrating methamphetamine use interventions into HIV prevention services and scaling-up of gay-friendly, non-stigmatizing HIV testing services for MSM in Hanoi. We recommend the routine assessment of ATS use and undiagnosed infection in this population.

A novel screening method for 64 new psychoactive substances and 5 amphetamines in blood by LC-MS/MS and application to real cases.

PubMed

Vaiano, Fabio; Busardò, Francesco P; Palumbo, Diego; Kyriakou, Chrystalla; Fioravanti, Alessia; Catalani, Valeria; Mari, Francesco; Bertol, Elisabetta

2016-09-10

Identification and quantification of new psychoactive substances (NPS), both in biological and non-biological samples, represent a hard challenge for forensic toxicologists. NPS are increasingly emerging on illegal drug market. Many cases of co-consumption of NPS and other substances have also been reported. Hence, the development of analytical methods aiming at the detection of a broad-spectrum of compounds (NPS and "traditional" drugs) could be helpful. In this paper, a fully validated screening method in blood for the simultaneous detection of 69 substances, including 64 NPS (28 synthetic cannabinoids, 19 synthetic cathinones, 5 phenethylamines, 3 indanes, 2 piperazines, 2 tryptamines, 2 phencyclidine, methoxetamine, ketamine and its metabolite) and 5 amphetamines (amphetamine, methamphetamine, MDMA, MDA, 3,4-methylenedioxy-N-ethylamphetamine - MDEA-) by a dynamic multiple reaction monitoring analysis through liquid chromatography - tandem mass spectrometry (LC-MS/MS) is described. This method is very fast, easy to perform and cheap as it only requires the deproteinization of 200μL of blood sample with acetonitrile. The chromatographic separation is achieved with a C18 column. The analysis is very sensitive, with limits of quantification ranging from 0.1 to 0.5ng/mL. The method is linear from 1 to 100ng/mL and the coefficient of determination (R(2)) was always above 0.9900. Precision and accuracy were acceptable at any quality control level and recovery efficiency range was 72-110%. Matrix effects did not negatively affect the analytical sensitivity. This method was successfully applied to three real cases, allowing identification and quantification of: mephedrone and methamphetamine (post-mortem); ketamine, MDMA and MDA (post-mortem); AB-FUBINACA (ante-mortem). Copyright © 2016 Elsevier B.V. All rights reserved.

Chemometrics-assisted chromatographic fingerprinting: An illicit methamphetamine case study.

PubMed

Shekari, Nafiseh; Vosough, Maryam; Tabar Heidar, Kourosh

2017-03-01

The volatile chemical constituents in complex mixtures can be analyzed using gas chromatography with mass spectrometry. This analysis allows the tentative identification of diverse impurities of an illicit methamphetamine sample. The acquired two-dimensional data of liquid-liquid extraction was resolved by multivariate curve resolution alternating curve resolution to elucidate the embedded peaks effectively. This is the first report on the application of a curve resolution approach for chromatogram fingerprinting to identify particularly the embedded impurities of a drug of abuse. Indeed, the strong and broad peak of methamphetamine makes identifying the underlying peaks problematic and even impossible. Mathematical separation instead of conventional chromatographic approaches was performed in a way that trace components embedded in methamphetamine peak were successfully resolved. Comprehensive analysis of the chromatogram, using multivariate curve resolution, resulted in elution profiles and mass spectra for each pure compound. Impurities such as benzaldehyde, benzyl alcohol, benzene, propenyl methyl ketone, benzyl methyl ketone, amphetamine, N-benzyl-2-methylaziridine, phenethylamine, N,N,α-trimethylamine, phenethylamine, N,α,α-trimethylmethamphetamine, N-acetylmethamphetamine, N-formylmethamphetamine, and other chemicals were identified. A route-specific impurity, N-benzyl-2-methylaziridine, indicating a synthesis route based on ephedrine/pseudoephedrine was identified. Moreover, this is the first report on the detection of impurities such as phenethylamine, N,α,α-trimethylamine (a structurally related impurity), and clonitazene (as an adulterant) in an illicit methamphetamine sample. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

School-Aged Outcomes following Prenatal Methamphetamine Exposure: 7.5 Year Follow-Up From The Infant Development, Environment, and Lifestyle (IDEAL) Study

PubMed Central

Eze, Nwando; Smith, Lynne M; LaGasse, Linda L; Derauf, Chris; Newman, Elana; Arria, Amelia; Huestis, Marilyn A.; Della Grotta, Sheri A; Dansereau, Lynne M; Neal, Charles; Lester, Barry M

2016-01-01

Objective To assess the relationship between prenatal methamphetamine exposure (PME) and behavior problems at age 7.5 years, and the extent to which early adversity mediated this relationship. Study design The multicenter, longitudinal IDEAL study enrolled 412 mother-infant pairs at 4 sites. Methamphetamine-exposed participants (n= 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched participants (n = 208) denied methamphetamine use and had a negative meconium screen. At the 7.5 year follow-up, 290 children with complete Child Behavior Checklist (CBCL) data and an early adversity index score were available for analysis (n=146 exposed). Results PME was significantly associated with an increased early adversity index score (P<0.001) and with increased externalizing, rule-breaking behavior, and aggressive behavior (P<0.05). Early adversity was also associated with higher externalizing behavior scores. Early adversity significantly mediated the relationship between PME and behavioral problems. After adjusting the mediation model for sex, prenatal tobacco, alcohol, and marijuana exposures, and study site, the association of PME with early adversity remained significant. Conclusion Though PME is associated with behavioral problems, early adversity may be a strong determinant of behavioral outcome for children exposed to methamphetamine in utero. Early adversity significantly mediated the relationship between PME and behavioral problems. PMID:26781836

School-Aged Outcomes following Prenatal Methamphetamine Exposure: 7.5-Year Follow-Up from the Infant Development, Environment, and Lifestyle Study.

PubMed

Eze, Nwando; Smith, Lynne M; LaGasse, Linda L; Derauf, Chris; Newman, Elana; Arria, Amelia; Huestis, Marilyn A; Della Grotta, Sheri A; Dansereau, Lynne M; Neal, Charles; Lester, Barry M

2016-03-01

To assess the relationship between prenatal methamphetamine exposure (PME) and behavior problems at age 7.5 years and the extent to which early adversity mediated this relationship. The multicenter, longitudinal Infant Development, Environment, and Lifestyle study enrolled 412 mother-infant pairs at 4 sites. Methamphetamine-exposed participants (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched participants (n = 208) denied methamphetamine use and had a negative meconium screen. At the 7.5-year follow-up, 290 children with complete Child Behavior Checklist data and an early adversity index score were available for analysis (n = 146 exposed). PME was significantly associated with an increased early adversity index score (P < .001) and with increased externalizing, rule-breaking behavior, and aggressive behavior (P < .05). Early adversity was also associated with higher externalizing behavior scores. Early adversity significantly mediated the relationship between PME and behavioral problems. After adjusting the mediation model for sex, prenatal tobacco, alcohol, and marijuana exposures, and study site, the association of PME with early adversity remained significant. Though PME is associated with behavioral problems, early adversity may be a strong determinant of behavioral outcome for children exposed to methamphetamine in utero. Early adversity significantly mediated the relationship between PME and behavioral problems. Copyright © 2016 Elsevier Inc. All rights reserved.

Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology

PubMed Central

Yu, Shaobin; Zhu, Ling; Shen, Qiang; Bai, Xue; Di, Xuhui

2015-01-01

Methamphetamine (METH) is a sympathomimetic amine that belongs to phenethylamine and amphetamine class of psychoactive drugs, which are widely abused for their stimulant, euphoric, empathogenic, and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, METH produces persistent damage to dopamine and serotonin release in nerve terminals, gliosis, and apoptosis. This review summarized the numerous interdependent mechanisms including excessive dopamine, ubiquitin-proteasome system dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression, inflammatory molecular, D3 receptor, microtubule deacetylation, and HIV-1 Tat protein that have been demonstrated to contribute to this damage. In addition, the feasible therapeutic strategies according to recent studies were also summarized ranging from drug and protein to gene level. PMID:25861156

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine

PubMed Central

Marks, Katherine R.; Lile, Joshua A.; Stoops, William W.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

2016-01-01

Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric acid type A (GABAA) receptors (e.g., alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of d-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and “positive” subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone. Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6–7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected. Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like “positive” subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10 mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior. PMID:27043121

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

PubMed

Marks, Katherine R; Lile, Joshua A; Stoops, William W; Glaser, Paul E A; Hays, Lon R; Rush, Craig R

2016-06-01

Opioid antagonists (eg, naltrexone) and positive modulators of γ-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and "positive" subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone.Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected.Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like "positive" subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

The acute effects of 3,4-methylenedioxymethamphetamine and d-methamphetamine on human cognitive functioning.

PubMed

Stough, Con; King, Rebecca; Papafotiou, Katherine; Swann, Phillip; Ogden, Edward; Wesnes, Keith; Downey, Luke A

2012-04-01

This study investigated the acute (3-h) and 24-h post-dose cognitive effects of oral 3,4-methylenedioxymethamphetamine (MDMA), d-methamphetamine, and placebo in a within-subject double-blind laboratory-based study in order to compare the effect of these two commonly used illicit drugs on a large number of recreational drug users. Sixty-one abstinent recreational users of illicit drugs comprised the participant sample, with 33 females and 28 males, mean age 25.45 years. The three testing sessions involved oral consumption of 100 mg MDMA, 0.42 mg/kg d-methamphetamine, or a matching placebo. The drug administration was counter-balanced, double-blind, and medically supervised. Cognitive performance was assessed during drug peak (3 h) and at 24 h post-dosing time-points. Blood samples were also taken to quantify the levels of drug present at the cognitive testing time-points. Blood concentrations of both methamphetamine and MDMA at drug peak samples were consistent with levels observed in previous studies. The major findings concern poorer performance in the MDMA condition at peak concentration for the trail-making measures and an index of working memory (trend level), and more accurate performance on a choice reaction task within the methamphetamine condition. Most of the differences in performance between the MDMA, methamphetamine, and placebo treatments diminished by the 24-h testing time-point, although some performance improvements subsisted for choice reaction time for the methamphetamine condition. Further research into the acute effects of amphetamine preparations is necessary to further quantify the acute disruption of aspects of human functioning crucial to complex activities such as attention, selective memory, and psychomotor performance.

Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus

PubMed Central

Angoa-Pérez, Mariana; Kane, Michael J.; Herrera-Mundo, Nieves; Francescutti, Dina M.; Kuhn, Donald M.

2013-01-01

Aims Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages 5HT nerve endings of the hippocampus. Main methods The status of 5HT nerve endings in hippocampus of female C57BL mice was assessed through measures of 5HT by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of 5HT nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4. Key findings Mephedrone alone did not cause persistent reductions in the levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5HT nerve endings to an extent that was different from either drug alone. Significance Mephedrone does not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together. PMID:23892197

Cardiovascular Complications of Acute Amphetamine Abuse

PubMed Central

Bazmi, Elham; Mousavi, Farinaz; Giahchin, Leila; Mokhtari, Tahmineh; Behnoush, Behnam

2017-01-01

Objectives This study aimed to evaluate cardiovascular complications among patients who abuse amphetamines. Methods This cross-sectional study took place between April 2014 and April 2015 among 3,870 patients referred to the Toxicology Emergency Department of Baharlou Hospital, Tehran University of Medical Sciences, Tehran, Iran. Those with clinical signs of drug abuse and positive urine screening tests were included in the study, while cases of chronic abuse were excluded. Cardiac complications were evaluated via electrocardiography (ECG) and transthoracic echocardiography. Results A total of 230 patients (5.9%) had a history of acute amphetamine abuse and positive urine tests. Of these, 32 patients (13.9%) were <20 years old and 196 (85.2%) were male. In total, 119 (51.7%) used amphetamine and methamphetamine compounds while 111 (48.3%) used amphetamines with morphine or benzodiazepines. The most common ECG finding was sinus tachycardia (43.0%), followed by sinus tachycardia plus a prolonged QT interval (34.3%). Mean creatine kinase-MB and troponin I levels were 35.9 ± 4.3 U/mL and 0.6 ± 0.2 ng/mL, respectively. A total of 60 patients (26.1%) were admitted to the Intensive Care Unit. The majority (83.3%) of these patients had normal echocardiography results. The mean aortic root diameter (ARD) was 27.2 ± 2.8 mm. Abnormalities related to the ARD were found in 10 patients (16.7%), three of whom subsequently died. Conclusion According to these findings, cardiac complications were common among Iranian patients who abuse amphetamines, although the majority of patients had normal echocardiography and ECG findings. PMID:28417026

Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry.

PubMed

Peters, Frank T; Schaefer, Simone; Staack, Roland F; Kraemer, Thomas; Maurer, Hans H

2003-06-01

The classical stimulants amphetamine, methamphetamine, ethylamphetamine and the amphetamine-derived designer drugs MDA, MDMA ('ecstasy'), MDEA, BDB and MBDB have been widely abused for a relatively long time. In recent years, a number of newer designer drugs have entered the illicit drug market. 4-Methylthioamphetamine (MTA), p-methoxyamphetamine (PMA) and p-methoxymethamphetamine (PMMA) are also derived from amphetamine. Other designer drugs are derived from piperazine, such as benzylpiperazine (BZP), methylenedioxybenzylpiperazine (MDBP), trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP) and p-methoxyphenylpiperazine (MeOPP). A number of severe or even fatal intoxications involving these newer substances, especially PMA, have been reported. This paper describes a method for screening for and simultaneous quantification of the above-mentioned compounds and the metabolites p-hydroxyamphetamine and p-hydroxymethamphetamine (pholedrine) in human blood plasma. The analytes were analyzed by gas chromatography/mass spectrometry in the selected-ion monitoring mode after mixed-mode solid-phase extraction (HCX) and derivatization with heptafluorobutyric anhydride. The method was fully validated according to international guidelines. It was linear from 5 to 1000 micro g l(-1) for all analytes. Data for accuracy and precision were within required limits with the exception of those for MDBP. The limit of quantification was 5 micro g l(-1) for all analytes. The applicability of the assay was proven by analysis of authentic plasma samples and of a certified reference sample. This procedure should also be suitable for confirmation of immunoassay results positive for amphetamines and/or designer drugs of the ecstasy type. Copyright 2003 John Wiley & Sons, Ltd.

Using cheminformatics to predict cross reactivity of “designer drugs” to their currently available immunoassays

PubMed Central

2014-01-01

Background A challenge for drug of abuse testing is presented by ‘designer drugs’, compounds typically discovered by modifications of existing clinical drug classes such as amphetamines and cannabinoids. Drug of abuse screening immunoassays directed at amphetamine or methamphetamine only detect a small subset of designer amphetamine-like drugs, and those immunoassays designed for tetrahydrocannabinol metabolites generally do not cross-react with synthetic cannabinoids lacking the classic cannabinoid chemical backbone. This suggests complexity in understanding how to detect and identify whether a patient has taken a molecule of one class or another, impacting clinical care. Methods Cross-reactivity data from immunoassays specifically targeting designer amphetamine-like and synthetic cannabinoid drugs was collected from multiple published sources, and virtual chemical libraries for molecular similarity analysis were built. The virtual library for synthetic cannabinoid analysis contained a total of 169 structures, while the virtual library for amphetamine-type stimulants contained 288 compounds. Two-dimensional (2D) similarity for each test compound was compared to the target molecule of the immunoassay undergoing analysis. Results 2D similarity differentiated between cross-reactive and non-cross-reactive compounds for immunoassays targeting mephedrone/methcathinone, 3,4-methylenedioxypyrovalerone, benzylpiperazine, mephentermine, and synthetic cannabinoids. Conclusions In this study, we applied 2D molecular similarity analysis to the designer amphetamine-type stimulants and synthetic cannabinoids. Similarity calculations can be used to more efficiently decide which drugs and metabolites should be tested in cross-reactivity studies, as well as to design experiments and potentially predict antigens that would lead to immunoassays with cross reactivity for a broader array of designer drugs. PMID:24851137

Simultaneous chiral separation of 3,4-methylenedioxymethamphet- amine, 3-4-methylenedioxyamphetamine, 3,4-methylenedioxyethylam- phetamine, ephedrine, amphetamine and methamphetamine by capillary electrophoresis in uncoated and coated capillaries with native beta-cyclodextrin as the chiral selector: preliminary application to the analysis of urine and hair.

PubMed

Tagliaro, F; Manetto, G; Bellini, S; Scarcella, D; Smith, F P; Marigo, M

1998-01-01

The importance of the chiral analysis of amphetamine-related substances in both clandestine preparations and biological samples is widely recognized. For this purpose, capillary electrophoresis was successfully applied by several authors, but only few reports concerned ring-substituted amphetamines, which represent the main components of "ecstasy", a widely abused "recreational" substance. In the present work, the simultaneous chiral analysis of ephedrine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3-4-methylenedioxyamphetamine (MDA) and 3,4-methalenedioxyethylamphetamine (MDE) is reported, by using capillary electrophoresis with native beta-cyclodextrin (15 mM) as the chiral selector. After preliminary tests at different pH values (phosphate buffer 100 mM, pH 2.5-9.0) and with bare or coated fused-silica capillaries, the optimized conditions were: pH 2.5 phosphate, uncoated capillary (45 cm x 50 microm inner diameter), potential 10 kV. Detection was either by fixed wavelength (200 nm) or multiwavelength (190-400 nm) UV absorbance. Under these conditions, good resolution was obtained for all the analytes, with excellent chiral selectivity and efficiency. The sensitivity for the individual enantiomers was better than 0.2 microg/mL, analytical precision was characterized by relative standard deviation values < 0.8% (< or = 0.15% with internal standardization) for migration times intra-day and < 2.0% (< or = 0.54% with internal standardization) day-to-day; linearity, in the range 0.156-40 microg/mL, and accuracy were also satisfactory. After a simple liquid-liquid extraction, urine samples could be analyzed with a sensitivity well below the recommended NIDA cut-off of 500 ng/mL. For hair samples, it was necessary to increase the sensitivity by applying a field-amplified sample stacking procedure, which allowed the chiral determination of MDA, MDMA and MDE at concentrations occurring in real samples from ecstasy users, with the possibility of recording UV spectra of the peaks.

An LC-MS/MS methodological approach to the analysis of hair for amphetamine-type-stimulant (ATS) drugs, including selected synthetic cathinones and piperazines.

PubMed

Lendoiro, Elena; Jiménez-Morigosa, Cristian; Cruz, Angelines; Páramo, Mario; López-Rivadulla, Manuel; de Castro, Ana

2017-01-01

Amphetamine-type-stimulants (ATS) are the second most commonly used group of illicit drugs worldwide. However, in the last few years, new psychoactive substances (NPS) with stimulant effects have appeared on the illegal market, which are not detected with traditional analytical methods. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination in hair of classic ATS (amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine), synthetic cathinones (methylone, methedrone, mephedrone, 3,4-methylenedioxypyrovalerone, (±)-4-fluoromethamphetamine and 4-fluoromethcathinone), synthetic piperazines (1-(3-chlorophenyl)piperazine (mCPP) and 3-trifluoromethylphenylpiperazine), and medicines (trazodone and phenazone) that produce mCPP as a metabolite, was developed and fully validated. Hair samples (30 mg) were incubated in acid methanol (0.1% HCl) and extracted by a mixed-mode solid-phase extraction. Chromatographic separation was performed using an Atlantis T3 (3 µm; 2.1x50 mm) analytical column, and ammonium formate 2 mM pH 3 and acetonitrile as mobile phase. The method was validated, including selectivity (no endogenous or exogenous interferences); linearity (2-20 to 2000-4000 pg/mg); limits of detection (0.2 to 5 pg/mg) and quantification (2 to 20 pg/mg); accuracy (93.4-109.4% of target concentration); imprecision (%CV<11.6%); extraction recovery (40.5-92.1%); matrix effect (24.1-227.2%); process efficiency (9.8-165.7%) and stability in the autosampler (-14.5% of loss). The method was applied to the analysis of 16 hair samples. Amphetamine (n=7; 69.1-777.1 pg/mg), methamphetamine (n=3; 120.4-1,538.9 pg/mg), MDA (n=2; 27.8-135.4 pg/mg) and MDMA (n=8; 73.4-3,654.5 pg/mg) were found. Moreover, 10 positive results for mCPP were detected (341.7->4000 pg/mg); however, in all cases trazodone identification (2085.3->4000 pg/mg) probed a licit origin of mCPP. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.

PubMed

White, Tara L; Monnig, Mollie A; Walsh, Edward G; Nitenson, Adam Z; Harris, Ashley D; Cohen, Ronald A; Porges, Eric C; Woods, Adam J; Lamb, Damon G; Boyd, Chelsea A; Fekir, Sinda

2018-06-01

Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy ( 1 H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1 H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 2 1 / 2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.

The effect of methamphetamine on an animal model of erectile function.

PubMed

Tar, M T; Martinez, L R; Nosanchuk, J D; Davies, K P

2014-07-01

In the US methamphetamine is considered a first-line treatment for attention-deficit hyperactivity disorder. It is also a common drug of abuse. Reports in patients and abusers suggest its use results in impotence. The efficacy of phosphodiesterase-5 inhibitors (PDE5i) to restore erectile function in these patient groups also has not been determined. In these studies, we determined if the rat is a suitable animal model for the physiological effects of methamphetamine on erectile function, and if a PDE5i (tadalafil) has an effect on erectile function following methamphetamine treatment. In acute phase studies, erectile function was measured in male Sprague-Dawley rats, before and after administration of 10 mg/kg methamphetamine i.p. Chronically treated animals received escalating doses of methamphetamine [2.5 mg/kg (1st week), 5 mg/kg (2nd week), and 10 mg/kg (3rd week)] i.p. daily for 3 weeks and erectile function compared with untreated controls. The effect of co-administration of tadalafil was also investigated in rats acutely and chronically treated with methamphetamine. Erectile function was determined by measuring the intracorporal pressure/blood pressure ratio (ICP/BP) following cavernous nerve stimulation. In both acute and chronic phase studies, we observed a significant increase in the rates of spontaneous erections after methamphetamine administration. In addition, following stimulation of the cavernous nerve at 4 and 6 mA, there was a significant decrease in the ICP/BP ratio (approximately 50%), indicative of impaired erectile function. Tadalafil treatment reversed this effect. In chronically treated animals, the ICP/BP ratio following 4 and 6 mA stimulation decreased by approximately 50% compared with untreated animals and erectile dysfunction (ED) was also reversed by tadalafil. Overall, our data suggest that the rat is a suitable animal model to study the physiological effect of methamphetamine on erectile function. Our work also provides a rationale for treating patients that report ED associated with therapeutics-containing methamphetamine or amphetamine with PDE5i. © 2014 American Society of Andrology and European Academy of Andrology.

Evaluation of commercial multi-drug oral fluid devices to identify 39 new amphetamine-designer drugs.

PubMed

Nieddu, Maria; Burrai, Lucia; Trignano, Claudia; Boatto, Gianpiero

2014-03-01

Recently, the diffusion on the black market of new psychoactive substances not controlled and often sold as 'legal highs', is exponentially increasing in Europe. Generally, the first analysis for these drugs involves an immunoassay screening in urine or plasma. Actually, there is growing interest in the use of oral fluid (OF) as alternative specimen over conventional biological fluids for drug testing, because of the significant advantages, as a non-invasive collection under direct observation without undue embarrassment or invasion of privacy, and a good correlation with plasma analytical data. Few assays have been developed for detection of new psychoactive compounds in biological samples, so it is important to investigate how they may or may not react in pre-existing commercial immunoassays. In this paper, two different multi-drugs oral fluid screen devices (OFDs) (Screen® Multi-Drug OFD and GIMA One Step Multi-Line Screen Test OFD) were evaluated to determine the cross-reactivity of thirty-nine new amphetamine designer drugs, including twelve substances officially recognized as illicit by italian legislation. Cross-reactivity towards most drugs analyzed was <1 in assays targeting amphetamine (AMP) or methamphetamine (MET). Only two (p-methoxyamphetamine and p-methoxymethamphetamine) of all tested amphetamines gave a positive result. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[CNS metabolism in high-risk drug abuse, German version : Insights gained from 1H- and 31P MRS and PET].

PubMed

Bodea, S V

2017-06-01

High-risk drug consumption is a considerable problem for public health actors in industrialised countries. The latest trends show a market tendency towards diversification and increasing demand for high-purity synthetic drugs. Whilst most consumers seek medical help after cannabis use, it is high-risk drugs like cocaine, heroin and amphetamines that account for most of the 1000 drug-related deaths that occur in Germany every year. This article presents the most prominent in vivo cerebral metabolic information in cocaine, heroin and methamphetamine users provided by MRI spectroscopy and PET imaging. We reviewed the literature reporting neuroimaging studies of in vivo metabolic data for methamphetamine, cocaine and heroin consumption published up to March 2017. The search was conducted using PubMed with the following key words: methamphetamine, cocaine, heroin, MR spectroscopy, PET. MRI and PET are indispensable tools in gauging brain metabolic response to illegal drug abuse. Future breakthroughs in this field will most likely come from the investigation of novel neurotransmitter systems in PET and imaging phosphorus and carbon metabolites in MRI.

Direct Analysis of Amphetamine Stimulants in a Whole Urine Sample by Atmospheric Solids Analysis Probe Tandem Mass Spectrometry

NASA Astrophysics Data System (ADS)

Crevelin, Eduardo J.; Salami, Fernanda H.; Alves, Marcela N. R.; De Martinis, Bruno S.; Crotti, Antônio E. M.; Moraes, Luiz A. B.

2016-05-01

Amphetamine-type stimulants (ATS) are among illicit stimulant drugs that are most often used worldwide. A major challenge is to develop a fast and efficient methodology involving minimal sample preparation to analyze ATS in biological fluids. In this study, a urine pool solution containing amphetamine, methamphetamine, ephedrine, sibutramine, and fenfluramine at concentrations ranging from 0.5 pg/mL to 100 ng/mL was prepared and analyzed by atmospheric solids analysis probe tandem mass spectrometry (ASAP-MS/MS) and multiple reaction monitoring (MRM). A urine sample and saliva collected from a volunteer contributor (V1) were also analyzed. The limit of detection of the tested compounds ranged between 0.002 and 0.4 ng/mL in urine samples; the signal-to-noise ratio was 5. These results demonstrated that the ASAP-MS/MS methodology is applicable for the fast detection of ATS in urine samples with great sensitivity and specificity, without the need for cleanup, preconcentration, or chromatographic separation. Thus ASAP-MS/MS could potentially be used in clinical and forensic toxicology applications.

Comparative analysis of 1-phenyl-2-propanone (P2P), an amphetamine-type stimulant precursor, using stable isotope ratio mass spectrometry: presented in part as a poster at the 2nd meeting of the Joint European Stable Isotope User Meeting (JESIUM), Giens, France, September 2008.

PubMed

Schneiders, S; Holdermann, T; Dahlenburg, R

2009-06-01

The isotope ratios of amphetamine type stimulants (ATS) depend as well on the precursor as the synthetic pathway. For clandestine production of amphetamine and methamphetamine, 1-phenyl-2-propanone (P2P, benzylmethylketone) is a commonly used precursor. Our aim was to determine the variation of the isotope ratios within precursor samples of one manufacturer and to compare seized samples of unknown sources to these values. delta13C(V-PDB), delta2H(V-SMOW) and delta118O(V-SMOW) isotope ratios were determined using elemental analysis (EA) and gas chromatography (GC) coupled toan isotope ratio mass spectrometer (IRMS). The comparison of all seized samples to the data of the samples of one manufacturer revealed considerable differences. The results show that IRMS provides a high potential in differentiating between precursors from different manufacturers for the clandestine production of ATS and identifying corresponding sources.

Distribution of methylone in four postmortem cases.

PubMed

Cawrse, Brian M; Levine, Barry; Jufer, Rebecca A; Fowler, David R; Vorce, Shawn P; Dickson, Amber J; Holler, Justin M

2012-07-01

Drugs derived from amphetamine, methamphetamine and their methylenedioxy- analogues, although being sold as plant food or bath salts, are being used as legal alternatives to scheduled amphetamine stimulants. These products often contain methylone, mephedrone and methylenedioxypyrovalerone (MDPV)--three amphetamine derivatives shown to have strong pharmacological effects. Four postmortem cases were analyzed for methylone, mephedrone and MDPV, with drug levels quantitated in multiple biological matrices. All four cases had detectable levels of methylone, with heart blood concentrations of 0.740, 0.118, 0.060 and 1.12 mg/L. Analysis of several tissue samples shows that methylone does not sequester in a particular tissue type after death. The average liver-to-blood ratio was 2.68. Two cases also had MDPV present, but insufficient data were collected to formulate a hypothesis on postmortem sequestration or redistribution. Two different extraction methods, as well as analysis of derivatized and underivatized methylone, show that the drug is suitable for analysis in either method. The cases are believed to show one instance of chronic methylone use, with a urine concentration of 38 mg/L.

Genes and pathways co-associated with the exposure to multiple drugs of abuse, including alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine, and/or nicotine: a review of proteomics analyses.

PubMed

Wang, Ju; Yuan, Wenji; Li, Ming D

2011-12-01

Drug addiction is a chronic neuronal disease. In recent years, proteomics technology has been widely used to assess the protein expression in the brain tissues of both animals and humans exposed to addictive drugs. Through this approach, a large number of proteins potentially involved in the etiology of drug addictions have been identified, which provide a valuable resource to study protein function, biochemical pathways, and networks related to the molecular mechanisms underlying drug dependence. In this article, we summarize the recent application of proteomics to profiling protein expression patterns in animal or human brain tissues after the administration of alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine/heroin/butorphanol, or nicotine. From available reports, we compiled a list of 497 proteins associated with exposure to one or more addictive drugs, with 160 being related to exposure to at least two abused drugs. A number of biochemical pathways and biological processes appear to be enriched among these proteins, including synaptic transmission and signaling pathways related to neuronal functions. The data included in this work provide a summary and extension of the proteomics studies on drug addiction. Furthermore, the proteins and biological processes highlighted here may provide valuable insight into the cellular activities and biological processes in neurons in the development of drug addiction.

Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand

PubMed Central

LaGasse, Linda L.; Wouldes, Trecia; Newman, Elana; Smith, Lynne M.; Shah, Rizwan Z.; Derauf, Chris; Huestis, Marilyn A.; Arria, Amelia M.; Grotta, Sheri Della; Wilcox, Tara; Lester, Barry M.

2010-01-01

Background Methamphetamine (MA) use among pregnant women is a world-wide problem, but little is known of its impact on exposed infants. Design The prospective, controlled longitudinal Infant Development, Environment and Lifestyle (IDEAL) study of prenatal MA exposure from birth to 36 months was conducted in the US and NZ. The US cohort has 183 exposed and 196 comparison infants; the NZ cohort has 85 exposed and 95 comparison infants. Exposure was determined by self-report and meconium assay with alcohol, marijuana, and tobacco exposures present in both groups. The NICU Neurobehavior Scale (NNNS) was administered within 5 days of life. NNNS summary scores were analyzed for exposure including heavy exposure and frequency of use by trimester and dose-response relationship with the amphetamine analyte. Results MA Exposure was associated with poorer quality of movement, more total stress/abstinence, physiological stress, and CNS stress with more nonoptimal reflexes in NZ but not in the USA. Heavy MA exposure was associated with lower arousal and excitability. First trimester MA use predicted more stress and third trimester use more lethargy and hypotonicity. Dose-response effects were observed between amphetamine concentration in meconium and CNS stress. Conclusion Across cultures, prenatal MA exposure was associated with a similar neurobehavioral pattern of under arousal, low tone, poorer quality of movement and increased stress. PMID:20615464

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, andmore » percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.« less

An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis.

PubMed

Dias da Silva, Diana; Carmo, Helena; Lynch, Adam; Silva, Elisabete

2013-12-01

The liver is a vulnerable target for amphetamine toxicity, but the mechanisms involved in the drug's hepatotoxicity remain poorly understood. The purpose of the current research was to characterize the mode of death elicited by four amphetamines and to evaluate whether their combination triggered similar mechanisms in immortalized human HepG2 cells. The obtained data revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy; 1.3 mM), methamphetamine (3 mM), 4-methylthioamphetamine (0.5 mM) and D-amphetamine (1.7 mM), alone or combined (1.6 mM mixture). At physiological temperature (37 °C), 24-h exposures caused HepG2 death preferentially by apoptosis, while a rise to 40.5 °C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5 °C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels, with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels was also seen. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (∆ψm) disruption, also mediated amphetamine-induced apoptosis. The cell dismantling was confirmed by poly(ADP-ribose)polymerase proteolysis. Overall, for all evaluated parameters, no relevant differences were detected between individual amphetamines and the mixture (all tested at equieffective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually, when eliciting HepG2 cell death.

Update on therapy for narcolepsy.

PubMed

Thorpy, Michael J

2015-05-01

Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy.

The effect of prenatal methamphetamine exposure on attention as assessed by continuous performance tests: results from the Infant Development, Environment, and Lifestyle study.

PubMed

Kiblawi, Zeina N; Smith, Lynne M; LaGasse, Linda L; Derauf, Chris; Newman, Elana; Shah, Rizwan; Arria, Amelia; Huestis, Marilyn; DellaGrotta, Sheri; Dansereau, Lynne M; Neal, Charles; Lester, Barry

2013-01-01

To assess for the increased risk of attention-deficit hyperactivity disorder (ADHD) in young children with prenatal methamphetamine exposure from the multicenter, longitudinal Infant Development, Environment, and Lifestyle (IDEAL) study. The IDEAL study enrolled 412 mother-infant pairs at 4 sites (Tulsa, OK; Des Moines, IA; Los Angeles, CA; and Honolulu, HI). Methamphetamine-exposed subjects (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched subjects (n = 208) denied methamphetamine use and had a negative meconium screen. This analysis included a subsample of 301 subjects who were administered the Conners' Kiddie Continuous Performance Test (K-CPT) at 5.5 years of age (153 exposed and 148 comparison). Hierarchical linear models adjusted for covariates tested exposure effects on K-CPT measures. Using the same covariates, logistic regression was used to determine the effect of exposure on the incidence of a positive ADHD confidence index score, defined as greater than 50%. There were no differences between the groups in omission or commission errors or reaction time for correct trials. However, methamphetamine exposure was associated with subtle differences in other outcomes predictive of ADHD, including increased slope of reaction time across blocks (p < .001), increased variability in reaction time with longer interstimulus intervals (p < .01), and increased likelihood of greater than 50% on the ADHD confidence index (odds ratio, 3.1; 95% confidence interval, 1.2-7.8; p = .02). Prenatal methamphetamine exposure was associated with subtle differences in K-CPT scores at 5.5 years of age. Even at this relatively young age, these children exhibit indicators of risk for ADHD and warrant monitoring.

Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users

PubMed Central

Marks, Katherine R.; Lile, Joshua A.; Stoops, William W.

2014-01-01

Rationale Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. Objectives The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Methods Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Results Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. Conclusions The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration. PMID:24464531

Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users.

PubMed

Marks, Katherine R; Lile, Joshua A; Stoops, William W; Rush, Craig R

2014-07-01

Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.

Treatment of addiction and addiction-related behavior

DOEpatents

Dewey, Stephen L.; Brodie, Jonathan D.; Ashby, Jr., Charles R.

2004-12-07

The present invention provides a highly efficient method for treating substance addiction and for changing addiction-related behavior of a mammal suffering from substance addiction. The method includes administering to a mammal an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof. The present invention also provides a method of treatment of cocaine, morphine, heroin, nicotine, amphetamine, methamphetamine, or ethanol addiction by treating a mammal with an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof.

Assessment of the ion-trap mass spectrometer for routine qualitative and quantitative analysis of drugs of abuse extracted from urine.

PubMed

Vorce, S P; Sklerov, J H; Kalasinsky, K S

2000-10-01

The ion-trap mass spectrometer (MS) has been available as a detector for gas chromatography (GC) for nearly two decades. However, it still occupies a minor role in forensic toxicology drug-testing laboratories. Quadrupole MS instruments make up the majority of GC detectors used in drug confirmation. This work addresses the use of these two MS detectors, comparing the ion ratio precision and quantitative accuracy for the analysis of different classes of abused drugs extracted from urine. Urine specimens were prepared at five concentrations each for amphetamine (AMP), methamphetamine (METH), benzoylecgonine (BZE), delta9-carboxy-tetrahydrocannabinol (delta9-THCCOOH), phencyclidine (PCP), morphine (MOR), codeine (COD), and 6-acetylmorphine (6-AM). Concentration ranges for AMP, METH, BZE, delta9-THCCOOH, PCP, MOR, COD, and 6-AM were 50-2500, 50-5000, 15-800, 1.5-65, 1-250, 500-32000, 250-21000, and 1.5-118 ng/mL, respectively. Sample extracts were injected into a GC-quadrupole MS operating in selected ion monitoring (SIM) mode and a GC-ion-trap MS operating in either selected ion storage (SIS) or full scan (FS) mode. Precision was assessed by the evaluation of five ion ratios for n = 15 injections at each concentration using a single-point calibration. Precision measurements for SIM ion ratios provided coefficients of variation (CV) between 2.6 and 9.8% for all drugs. By comparison, the SIS and FS data yielded CV ranges of 4.0-12.8% and 4.0-11.2%, respectively. The total ion ratio failure rates were 0.2% (SIM), 0.7% (SIS), and 1.2% (FS) for the eight drugs analyzed. Overall, the SIS mode produced stable, comparable mean ratios over the concentration ranges examined, but had greater variance within batch runs. Examination of postmortem and quality-control samples produced forensically accurate quantitation by SIS when compared to SIM. Furthermore, sensitivity of FS was equivalent to SIM for all compounds examined except for 6-AM.

Water quality in coastal wetlands: illicit drugs in surface waters of L'Albufera Natural Park (Valencia, Spain)

NASA Astrophysics Data System (ADS)

Vazquez-Roig, P.; Blasco, C.; Andreu, V.; Pascual, J. A.; Rubio, J. L.; Picó, Y.

2010-05-01

A wide range of emerging pollutants have been identified in environment: antibiotics, hormones, personal care products, etc. But quite recently a new class of ecological threat has been reported: the presence in waters of abuse drugs coming from human consumption [1,2]. Treatment of wastewaters may remove a portion of these compounds, but sometimes, these treatments are insufficient or nonexistent, residues can reach into the aquatic environment. ĹAlbufera Natural Park (Valencia, Spain) is a marsh area of a great interest because it is the habitat of a large quantity of unique species of flora and fauna, and a zone of refuge, feeding and breeding for a large number of migratory birds. However, this area is threatened by urban, industrial and agricultural pressures. The aim of this work has been to develop a fast and sensitive multi-residue analytical method for to establish the occurrence and distribution of commonly consumed illicit drugs in surface waters of ĹAlbufera lake. A representative set of abuse drugs with different mode of action was chosen for this purpose, including: amphetaminics, opiates, cocainics and cannabinoids (THC and nor-9-carboxy-THC). In April 2008 and October 2008 a total of 16 samples of water were collected, corresponding to different sampling points previously designed, and covering the most important channels that flow in to the lake. Samples of 250 mL of water were concentrated by Solid Phase Extraction through an Oasis HLB cartridge and extracted subsequently with methanol as solvent. Quantification was carried out by LC-MS/MS with an ESI interface. Performance characteristics of the PLE-SPE followed by LC-MS/MS were established by validation procedure. Selectivity, linearity, precision, recoveries and limits of detection (LOD) and quantification (LOQ) were studied. Our search shows that current sewage treatment systems do not completely remove illicit drug residues from urban wastewater. Benzoylecgonine, the main metabolite from cocaine, was found in 100% of the samples tested, at concentrations ranging from 0.14 to 78.71 ng/L. Other substances found were nor-9-carboxy-THC, methadone, codeine, cocaine, morphine, ecgonine methyl ester, extasis (MDMA) and amphetamine, while MDA, methamphetamine, heroin, 6-acetylmorphine and THC were undetectable. References: [1] M. Huerta-Fontela,M. T. Galceran, F. Ventura, Anal. Chem. 79 (2007), 3821-3829. [2] E. Zuccato, S. Castiglioni, R. Bagnati, C. Chiabrando, P. Grassi, R. Fanelli, Water Research 42 (2008) 961-968.

Drug problem in southeast and southwest Asia.

PubMed

Kulsudjarit, Kongpetch

2004-10-01

In 2002, the drug problem in Southeast and Southwest Asia was serious, particularly in the production of opium and heroin in Afghanistan, Myanmar, and Laos, the three largest producers of illicit opium in the world. The increasing illicit manufacture of ATS, particularly methamphetamine, in Southeast Asia, mainly in China and Myanmar, was also a major concern. Some reports indicated that ephedrine, used for illicitly producing methamphetamine in Southeast Asia, is diverted and smuggled out of China and India, whereas caffeine, the adulterant used for producing methamphetamine tablets, is mainly smuggled into Myanmar through its border with Thailand. Seizure data showed a dramatic increase in trafficking in MDMA through Southeast Asia. In terms of the drug epidemic, in 2002, cannabis remained overall the main drug of abuse in all of the countries of Southeast and Southwest Asia. Opiates, mainly opium and heroin, were also the drugs of choice except in Thailand, where opiate abuse declined, but ATS was the main drug of abuse due to its low cost and availability. A significant increase in ATS abuse, amphetamine, methamphetamine, and MDMA among the youth who smoked, sniffed, and inhaled them was reported in Cambodia, China, Indonesia, Laos, Myanmar, the Philippines, and Thailand. Injecting drug use among opiate abusers has been identified as the prime cause of the rapid spread of HIV/AIDS in Southeast and Southwest Asia.

Detox agents do not affect the pharmacokinetics of methamphetamine in the rat.

PubMed

Lee, Sang Kyu; Kim, Yoon; Suh, Sungill; Suh, Yong Jun; In, Moon Kyo; Kim, Dong-Hyun; Jin, Changbae; Yoo, Hye Hyun

2009-04-15

Recently, 'detox' agents have been popularly used as forms of diets or nutritional supplements. Especially, several cases have been reported that these detox agents have been used to mask drug tests among drug abusers. In the present study, capsule and drink types of detox agents were evaluated for their ability to alter the elimination of methamphetamine (MA) in rats. For this study, MA and its major metabolite, amphetamine (AP) in urine samples were determined using LC-tandem mass spectrometry after administration of the detox agents to MA-treated rats. As a result, significant differences were not shown between control and detox-dosed groups in the amounts of MA and AP excreted into urine as well as the volume of excreted urine. This result suggests that the detox agents tested may not affect the metabolism or elimination of MA and further might have minimal effect on narcotics detection in the urine samples of drug abusers.

Structural, functional and spectroscopic MRI studies of methamphetamine addiction.

PubMed

Salo, Ruth; Fassbender, Catherine

2012-01-01

This chapter reviews selected neuroimaging findings related to long-term amphetamine and methamphetamine (MA) use. An overview of structural and functional (fMRI) MR studies, Diffusion Tensor Imaging (DTI), Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) studies conducted in long-term MA abusers is presented. The focus of this chapter is to present the relevant studies as tools to understand brain changes following drug abstinence and recovery from addiction. The behavioral relevance of these neuroimaging studies is discussed as they relate to clinical symptoms and treatment. Within each imaging section this chapter includes a discussion of the relevant imaging studies as they relate to patterns of drug use (i.e., duration of MA use, cumulative lifetime dose and time MA abstinent) as well as an overview of studies that link the imaging findings to cognitive measures. In our conclusion we discuss some of the future directions of neuroimaging as it relates to the pathophysiology of addiction.

Drugs of abuse and their metabolites in the Ebro River basin: occurrence in sewage and surface water, sewage treatment plants removal efficiency, and collective drug usage estimation.

PubMed

Postigo, Cristina; López de Alda, María José; Barceló, Damià

2010-01-01

Drugs of abuse and their metabolites have been recently recognized as environmental emerging organic contaminants. Assessment of their concentration in different environmental compartments is essential to evaluate their potential ecotoxicological effects. It also constitutes an indirect tool to estimate drug abuse by the population at the community level. The present work reports for the first time the occurrence of drugs of abuse and metabolites residues along the Ebro River basin (NE Spain) and also evaluates the contribution of sewage treatment plants (STPs) effluents to the presence of these chemicals in natural surface waters. Concentrations measured in influent sewage waters were used to back calculate drug usage at the community level in the main urban areas of the investigated river basin. The most ubiquitous and abundant compounds in the studied aqueous matrices were cocaine, benzoylecgonine, ephedrine and ecstasy. Lysergic compounds, heroin, its metabolite 6-monoacetyl morphine, and Delta(9)-tetradhydrocannabinol were the substances less frequently detected. Overall, total levels of the studied illicit drugs and metabolites observed in surface water (in the low ng/L range) were one and two orders of magnitude lower than those determined in effluent (in the ng/L range) and influent sewage water (microg/L range), respectively. The investigated STPs showed overall removal efficiencies between 45 and 95%. Some compounds, such as cocaine and amphetamine, were very efficiently eliminated (>90%) whereas others, such as ecstasy, methamphetamine, nor-LSD, and THC-COOH where occasionally not eliminated at all. Drug consumption estimates pointed out cocaine as the most abused drug, followed by cannabis, amphetamine, heroin, ecstasy and methamphetamine, which slightly differs from national official estimates (cannabis, followed by cocaine, ecstasy, amphetamine and heroin). Extrapolation of the consumption data obtained for the studied area to Spain points out a total annual consumption of drugs of abuse of the order of 36 tonnes, which would translate into 1100million Euros in the black market.

Use of amphetamine-type stimulants in the Islamic Republic of Iran, 2004-2015: a review.

PubMed

Shadloo, Behrang; Amin-Esmaeili, Masoumeh; Haft-Baradaran, Minoo; Noroozi, Alireza; Ghorban-Jahromi, Reza; Rahimi-Movaghar, Afarin

2017-05-01

Amphetamine-type stimulants (ATS) are the second most commonly used illicit drugs in the world, after cannabis. The production of ATS has increased worldwide, including in the Middle East. This review aims to assess ATS use in the Islamic Republic of Iran. PubMed, Scientific Information Database (a national database) and Iranian Center for Addiction Studies were searched. The review included studies on the general population, university and high school students, other specific populations, and drug users. The result show that self-reported methamphetamine and ecstasy use in 2016 was < 1% in the general population and university and high-school students, but the prevalence was higher in certain groups. There has also been an increase in the proportion of ATS users among clients of drug treatment centres. The findings highlight the need for high quality epidemiological studies and closer monitoring of stimulant use in different populations.

Comparison of the discriminative stimulus effects of dimethyltryptamine with different classes of psychoactive compounds in rats.

PubMed

Gatch, Michael B; Rutledge, Margaret A; Carbonaro, Theresa; Forster, Michael J

2009-07-01

There has been increased recreational use of dimethyltryptamine (DMT), but little is known of its discriminative stimulus effects. The present study assessed the similarity of the discriminative stimulus effects of DMT to other types of hallucinogens and to psychostimulants. Rats were trained to discriminate DMT from saline. To test the similarity of DMT to known hallucinogens, the ability of (+)-lysergic acid diethylamide (LSD), (-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-methamphetamine, or (+/-)3,4-methylenedioxymethyl amphetamine (MDMA) to substitute in DMT-trained rats was tested. The ability of DMT to substitute in rats trained to discriminate each of these compounds was also tested. To assess the degree of similarity in discriminative stimulus effects, each of the compounds was tested for substitution in all of the other training groups. LSD, DOM, and MDMA all fully substituted in DMT-trained rats, whereas DMT fully substituted only in DOM-trained rats. Full cross-substitution occurred between DMT and DOM, LSD and DOM, and (+)-methamphetamine and MDMA. MDMA fully substituted for (+)-methamphetamine, DOM, and DMT, but only partially for LSD. In MDMA-trained rats, LSD and (+)-methamphetamine fully substituted, whereas DMT and DOM did not fully substitute. No cross-substitution was evident between (+)-methamphetamine and DMT, LSD, or DOM. DMT produces discriminative stimulus effects most similar to those of DOM, with some similarity to the discriminative stimulus effects of LSD and MDMA. Like DOM and LSD, DMT seems to produce predominately hallucinogenic-like discriminative stimulus effects and minimal psychostimulant effects, in contrast to MDMA which produced hallucinogen- and psychostimulant-like effects.

A single administration of methamphetamine to mice early in the light period decreases running wheel activity observed during the dark period

PubMed Central

Kitanaka, Nobue; Kitanaka, Junichi; Hall, F. Scott; Uhl, George R.; Watabe, Kaname; Kubo, Hitoshi; Takahashi, Hitoshi; Tatsuta, Tomohiro; Morita, Yoshio; Takemura, Motohiko

2014-01-01

Repeated intermittent administration of amphetamines acutely increases appetitive and consummatory aspects of motivated behaviors as well as general activity and exploratory behavior, including voluntary running wheel activity. Subsequently, if the drug is withdrawn, the frequency of these behaviors decrease, which is thought to be indicative of dysphoric symptoms associated with amphetamine withdrawal. Such decreases may be observed after chronic treatment or even after single drug administrations. In the present study, the effect of acute methamphetamine (METH) on running wheel activity, horizontal locomotion, appetitive behavior (food access), and consummatory behavior (food and water intake) was investigated in mice. A multi-configuration behavior apparatus designed to monitor the five behaviors was developed, where combined measures were recorded simultaneously. In the first experiment, naïve male ICR mice showed gradually increasing running wheel activity over three consecutive days after exposure to a running wheel, while mice without a running wheel showed gradually decreasing horizontal locomotion, consistent with running wheel activity being a positively motivated form of natural motor activity. In experiment 2, increased horizontal locomotion and food access, and decreased food intake, were observed for the initial 3 h after acute METH challenge. Subsequently, during the dark phase period decreased running wheel activity and horizontal locomotion were observed. The reductions in running wheel activity and horizontal locomotion may be indicative of reduced dopaminergic function, although it remains to be seen if these changes may be more pronounced after more prolonged METH treatments. PMID:22079320

Determination of the mechanism of demethylenation of (methylenedioxy)phenyl compounds by cytochrome P450 using deuterium isotope effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukuto, J.M.; Kumagai, Y.; Cho, A.K.

1991-09-01

The mechanism of demethylenation of (methylenedioxy)benzene (MDB), (methylenedioxy)amphetamine (MDA), and (methylenedioxy)methamphetamine (MDMA) by purified rabbit liver cytochrome P450IIB4 has been investigated by using deuterium isotope effects. A comparison of the magnitude and direction of the observed kinetic isotope effects indicates that the three compounds are demethylenated by different mechanisms. The different mechanisms of demethylenation have been proposed on the basis of comparisons of the observed biochemical isotope effects with the isotope effects from purely chemical systems.

Comparison of the Discriminative Stimulus Effects of Dimethyltryptamine with Different Classes of Psychoactive Compounds in Rats

PubMed Central

Gatch, Michael B.; Rutledge, Margaret A.; Carbonaro, Theresa; Forster, Michael J.

2010-01-01

Rationale There has been increased recreational use of dimethyltryptamine (DMT), but little is known of its discriminative stimulus effects. Objectives The present study assessed the similarity of the discriminative stimulus effects of DMT to other types of hallucinogens and to psychostimulants. Methods Rats were trained to discriminate DMT from saline. To test the similarity of DMT to known hallucinogens, the ability of (+)-lysergic acid diethylamide (LSD), (−)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-methamphetamine, or (±)3,4-methylenedioxymethyl-amphetamine (MDMA) to substitute in DMT-trained rats was tested. The ability of DMT to substitute in rats trained to discriminate each of these compounds was also tested. To assess the degree of similarity in discriminative stimulus effects, each of the compounds was tested for substitution in all of the other training groups. Results LSD, DOM, and MDMA all fully substituted in DMT-trained rats, whereas DMT fully substituted only in DOM-trained rats. Full cross-substitution occurred between DMT and DOM, LSD and DOM, and (+)-methamphetamine and MDMA. MDMA fully substituted for (+)-methamphetamine, DOM, and DMT, but only partially for LSD. In MDMA-trained rats, LSD and (+)-methamphetamine fully substituted, whereas DMT and DOM did not fully substitute. No cross-substitution was evident between (+)-methamphetamine and DMT, LSD, or DOM. Conclusions DMT produces discriminative stimulus effects most similar to those of DOM, with some similarity to the discriminative stimulus effects of LSD and MDMA. Like DOM and LSD, DMT seems to produce predominately hallucinogenic-like discriminative stimulus effects and minimal psychostimulant effects, in contrast to MDMA which produced hallucinogen- and psychostimulant-like effects. PMID:19288085

Risk for Neurobehavioral Disinhibition in Prenatal Methamphetamine-Exposed Young Children with Positive Hair Toxicology Results

PubMed Central

Himes, Sarah K.; LaGasse, Linda L.; Derauf, Chris; Newman, Elana; Smith, Lynne M.; Arria, Amelia M.; Grotta, Sheri A. Della; Dansereau, Lynne M.; Abar, Beau; Neal, Charles R.; Lester, Barry M.; Huestis, Marilyn A.

2014-01-01

Background The objective was to evaluate effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age. Methods Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child’s neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared to child hair results. Results A total of 264 children were evaluated. Significantly more PME children (n=133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n=131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared to PME children without postnatal exposure. Conclusions Child hair testing offered a non-invasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years. PMID:24518561

Prevalence and Correlates of Heroin-Methamphetamine Co-Injection Among Persons Who Inject Drugs in San Diego, California, and Tijuana, Baja California, Mexico.

PubMed

Meacham, Meredith C; Strathdee, Steffanie A; Rangel, Gudelia; Armenta, Richard F; Gaines, Tommi L; Garfein, Richard S

2016-09-01

Although persons who inject drugs (PWID) in the western United States-Mexico border region are known to inject both heroin and methamphetamine, little is known about the prevalence and risks associated with co-injection of this depressant-stimulant combination (also known as "goofball" and "Mexican speedball"). Baseline data from parallel cohort studies of PWID conducted concurrently in San Diego, CA, and Tijuana, Mexico, were used to estimate the prevalence and identify correlates of heroin-methamphetamine co-injection. PWID older than 18 years of age who reported injecting illicit drugs in the past month (N = 1,311; 32.7% female) were recruited in San Diego (n = 576) and Tijuana (n = 735) and completed interviewer-administered questionnaires. Bivariate and multivariable logistic regression analyses were used to identify correlates of heroin-meth-amphetamine co-injection. The prevalence of co-injection in the past 6 months was 39.9% overall and was higher in Tijuana (55.8%) than in San Diego (19.8%). In multivariable analyses adjusting for study cohort, distributive syringe sharing, purchasing syringes prefilled with drugs, finding it hard to get new syringes, reporting great or urgent need for treatment, and younger age were independently associated with co-injection. Past-6-month overdose was significantly associated with higher odds of co-injection in San Diego than in Tijuana. These findings indicate that heroin-methamphetamine co-injection is more common in Tijuana than in San Diego, yet this practice was only associated with overdose in San Diego. Heroin-methamphetamine coinjection was also independently associated with HIV-associated injection risk behaviors. Overdose-prevention interventions should address co-injection of depressants and stimulants.

Risk of neurobehavioral disinhibition in prenatal methamphetamine-exposed young children with positive hair toxicology results.

PubMed

Himes, Sarah K; LaGasse, Linda L; Derauf, Chris; Newman, Elana; Smith, Lynne M; Arria, Amelia M; Della Grotta, Sheri A; Dansereau, Lynne M; Abar, Beau; Neal, Charles R; Lester, Barry M; Huestis, Marilyn A

2014-08-01

The objective was to evaluate the effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age. Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa, and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child's neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared with child hair results. A total of 264 children were evaluated. Significantly more PME children (n = 133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n = 131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared with PME children without postnatal exposure. Child hair testing offered a noninvasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years.

Application of gas chromatography-tandem mass spectrometry for the determination of amphetamine-type stimulants in blood and urine.

PubMed

Woźniak, Mateusz Kacper; Wiergowski, Marek; Aszyk, Justyna; Kubica, Paweł; Namieśnik, Jacek; Biziuk, Marek

2018-01-30

Amphetamine, methamphetamine, phentermine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxy-N-ethylamphetamine (MDEA) are the most popular amphetamine-type stimulants. The use of these substances is a serious societal problem worldwide. In this study, a method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) with simple and rapid liquid-liquid extraction (LLE) and derivatization was developed and validated for the simultaneous determination of the six aforementioned amphetamine derivatives in blood and urine. The detection of all compounds was based on multiple reaction monitoring (MRM) transitions. The most important advantage of the method is the minimal sample volume (as low as 200μL) required for the extraction procedure. The validation parameters, i.e., the recovery (90.5-104%), inter-day accuracy (94.2-109.1%) and precision (0.5-5.8%), showed the repeatability and sensitivity of the method for both matrices and indicated that the proposed procedure fulfils internationally established acceptance criteria for bioanalytical methods The procedure was successfully applied to the analysis of real blood and urine samples examined in 22 forensic toxicological cases. To the best of our knowledge, this is the first work presenting the use of GC-MS/MS for the determination of amphetamine-type stimulants in blood and urine. In view of the low limits of detection (0.09-0.81ng/mL), limits of quantification (0.26-2.4ng/mL), and high selectivity, the procedure can be applied for drug monitoring in both fatal and non-fatal intoxication cases in routine toxicology analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13)

PubMed Central

Wardle, Margaret C.; Sokoloff, Greta; Stephens, Matthew; de Wit, Harriet; Palmer, Abraham A.

2012-01-01

Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8th intron of cadherin 13 (CDH13; P = 4.58×10−8), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1st intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10−7), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses. PMID:22952603

Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13).

PubMed

Hart, Amy B; Engelhardt, Barbara E; Wardle, Margaret C; Sokoloff, Greta; Stephens, Matthew; de Wit, Harriet; Palmer, Abraham A

2012-01-01

Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8(th) intron of cadherin 13 (CDH13; P = 4.58×10(-8)), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1(st) intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10(-7)), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.

Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells.

PubMed

Jiménez, Andrés; Jordà, Elvira G; Verdaguer, Ester; Pubill, David; Sureda, Francesc X; Canudas, Anna M; Escubedo, Elena; Camarasa, Jordi; Camins, Antoni; Pallàs, Mercè

2004-04-15

The neurotoxic action of the abuse drugs methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a higher decrease in viability than 24 h treatment. z.VAD.fmk (100 microM) but not MK-801 nor NBQX recovered control viability values. In both cases, cell death was characterised as apoptotic rather than necrotic by morphology cell observation. Apoptosis measured by flow cytometry indicated an increase in the hypodiploid population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the presence of z.VAD.fmk (100 microM) but not by 10 microM MK-801 or NBQX. Similar results were obtained by analysing nuclear chromatine condensation. These results ruled out excitotoxic participation in amphetamine derivative-induced neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was evaluated using alpha-tocopherol (1-15 microM) and cytometric studies. The co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action and apoptotic features, indicating ROS implication in CGNs death by amphetamine derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) release after 48-h treatment with METH and MDMA (4 mM). There was also indication of caspase-3-like activation, measured by immunoanalysis and biochemically. Finally, neurodegenerative action caused by amphetamine derivatives may be prevented by using caspase inhibitors.

A Study of the Prevalence of Psychiatric Disorders in Patients with Methamphetamine-Induced Psychosis

PubMed Central

Eslami-Shahrbabaki, Mahin; Fekrat, Alireza; Mazhari, Shahrzad

2015-01-01

Background The abuse of narcotic drugs and psychotropic substances such as amphetamines and ecstasy has had a growing trend. Tachycardia, increased blood pressure, hallucinations, panic attacks, and psychosis are the negative effects of methamphetamine abuse. The present study aimed to assess psychiatric disorders associated with methamphetamine-induced psychotic disorder. Methods This cross-sectional study was performed from October 2013 to March 2014 on 165 patients hospitalized at Shahid Beheshti Hospital in Kerman, Iran, and diagnosed with psychosis induced by methamphetamine abuse within the previous 6 months. Study subjects were selected via census method. Based on the exclusion criteria and due to the lack of cooperation of some patients, 121 patients were enrolled in the study. Research data were gathered using clinical interviews, the Yale-Brown obsessive compulsive scale (Y-BOCS), Hamilton anxiety scale (HAM-A) and Hamilton rating scale for depression (HRSD), Young mania rating scale (YMRS), substance dependence severity scale (SDSS), positive and negative syndrome scale (PANSS), and clinical global impression (CGI) scale. The data analysis was performed using SPSS software, descriptive statistics, and ANOVA. Findings Among the 121 patients of the sample group, 4 patients (3.3%) had anxiety, 58 patients (47.9%) depression, 30 patients (24.8%) obsessive-compulsive disorder (OCD), 20 patients (16.5%) bipolar mood disorder (BMD), 8 patients (6.6%) persistent psychotic symptoms, 85 patients (70.2%) personality disorder, and 36 patients (29.8%) had no personality disorders. The highest prevalence was related to borderline personality disorder (35.5%). However, 45 patients (37.2%) had no impairment associated with methamphetamine-induced psychosis. Conclusion It seems that there is comorbidity between psychiatric disorders, including mood disorders, especially depressive disorder, childhood history of attention deficit hyperactivity disorder (ADHD), bipolar disorder, and personality disorders such as borderline personality disorder, and antisocial personality disorders, and methamphetamine abuse. PMID:26322209

Using chiral liquid chromatography quadrupole time-of-flight mass spectrometry for the analysis of pharmaceuticals and illicit drugs in surface and wastewater at the enantiomeric level.

PubMed

Bagnall, J P; Evans, S E; Wort, M T; Lubben, A T; Kasprzyk-Hordern, B

2012-08-03

This paper presents and compares for the first time two chiral LC-QTOF-MS methodologies (utilising CBH and Chirobiotic V columns with cellobiohydrolase and vancomycin as chiral selectors) for the quantification of amphetamine, methamphetamine, MDA (methylenedioxyamphetamine), MDMA (methylenedioxymethamphetamine), propranolol, atenolol, metoprolol, fluoxetine and venlafaxine in river water and sewage effluent. The lowest MDLs (0.3-5.0 ng L(-1) and 1.3-15.1 ng L(-1) for river water and sewage effluent respectively) were observed using the chiral column Chirobiotic V. This is with the exception of methamphetamine and MDMA which had lower MDLs using the CBH column. However, the CBH column resulted in better resolution of enantiomers (R(s)=2.5 for amphetamine compared with R(s)=1.2 with Chirobiotic V). Method recovery rates were typically >80% for both methodologies. Pharmaceuticals and illicit drugs detected and quantified in environmental samples were successfully identified using MS/MS confirmation. In sewage effluent, the total beta-blocker concentrations of propranolol, atenolol and metoprolol were on average 77.0, 1091.0 and 3.6 ng L(-1) thus having EFs (Enantiomeric Fractions) of 0.43, 0.55 and 0.54 respectively. In river water, total propranolol and atenolol was quantified on average at <10.0 ng L(-1). Differences in EF between sewage and river water matrices were evident: venlafaxine was observed with respective EF of 0.43 ± 0.02 and 0.58 ± 0.02. Copyright © 2012 Elsevier B.V. All rights reserved.

Linking drugs of abuse in wastewater to contamination of surface and drinking water.

PubMed

Rodayan, Angela; Afana, Shadi; Segura, Pedro A; Sultana, Tamanna; Metcalfe, Chris D; Yargeau, Viviane

2016-04-01

The concentrations of 17 drugs of abuse, including cocaine, several amphetamines, opioid drugs, and 2 metabolites--benzoylecgonine, a metabolite of cocaine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, a metabolite of methadone--were investigated in an urban watershed that is heavily impacted by discharges of municipal wastewater. The artificial sweetener sucralose was also monitored as a persistent tracer of contamination from municipal wastewater. Monitoring was conducted in a municipal wastewater treatment plant (WWTP) and at sites upstream and downstream of the WWTP discharge, as well as in a drinking water treatment plant (DWTP) located 19 km downstream of the WWTP discharge that withdraws raw water from the river. Drug concentrations were monitored with polar organic chemical integrative samplers deployed for 2 wk in the river and in the WWTP and DWTP. Several of the investigated compounds exhibited a decrease in concentration with distance downstream from the wastewater discharge into the river, but there was little attenuation of sucralose, cocaine, benzoylecgonine, morphine, acetylmorphine, acetylcodeine, and oxycodone. Heroin and methadone were not detected at any sample locations. Amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were not detected in the samples collected at the drinking water intake. Many of the drugs of abuse were not removed effectively in the DWTP, including cocaine, benzoylecgonine, methylenedioxyamphetamine, ephedrine, and several prescription opioids, most probably because the DWTP was operating at or above its rated treatment capacity. These data indicate that there can be transport of drugs of abuse from wastewater sources into drinking water in urban watersheds. © 2015 SETAC.

Illicit drug consumption in school populations measured by wastewater analysis.

PubMed

Zuccato, Ettore; Gracia-Lor, Emma; Rousis, Nikolaos I; Parabiaghi, Alberto; Senta, Ivan; Riva, Francesco; Castiglioni, Sara

2017-09-01

Analysis of student consumption of illicit drugs (ID) by school population surveys (SPS) provides information useful for prevention, but the results may be influenced by subjective factors. We explored wastewater (WW) analysis to improve the information. We used WW analysis to measure ID consumption in eight secondary schools in Italy in 2010-13 (students aged 15-19). Samples were collected from the sewage pipes of the schools during lessons for one week each year. Samples were analysed by mass spectrometry to measure ID and consumption by students was compared to that of the general population. We found THCCOOH (human metabolite of THC) concentrations in 2010 indicating significant consumption of cannabis in all the schools and benzoylecgonine (human metabolite of cocaine) suggesting a limited consumption of cocaine in all but one school. Morphine was only found in traces, and amphetamine, methamphetamine, ecstasy, ketamine and mephedrone were not detectable. Repeated analysis showed cannabis stable until 2012 with increases in 2013, low cocaine and morphine levels, and none of the other ID. WW analysis suggested that students used amounts of cannabis comparable to the general population, with low, sporadic use of cocaine and opioids, but excluded the use of significant amounts of amphetamine, methamphetamine, ecstasy, ketamine and mephedrone. WW analysis was useful to confirm SPS figures and provides complementary findings for effective prevention strategies. This is the first time WW analysis has been used to investigate consumption of a large number of ID and new psychoactive substances (NPS) in schools. Copyright © 2017 Elsevier B.V. All rights reserved.

Amphetamine and Methamphetamine Differentially Affect Dopamine Transporters in Vitro and in Vivo*S⃞

PubMed Central

Goodwin, J. Shawn; Larson, Gaynor A.; Swant, Jarod; Sen, Namita; Javitch, Jonathan A.; Zahniser, Nancy R.; De Felice, Louis J.; Khoshbouei, Habibeh

2009-01-01

The psychostimulants d-amphetamine (AMPH) and methamphetamine (METH) release excess dopamine (DA) into the synaptic clefts of dopaminergic neurons. Abnormal DA release is thought to occur by reverse transport through the DA transporter (DAT), and it is believed to underlie the severe behavioral effects of these drugs. Here we compare structurally similar AMPH and METH on DAT function in a heterologous expression system and in an animal model. In the in vitro expression system, DAT-mediated whole-cell currents were greater for METH stimulation than for AMPH. At the same voltage and concentration, METH released five times more DA than AMPH and did so at physiological membrane potentials. At maximally effective concentrations, METH released twice as much [Ca2+]i from internal stores compared with AMPH. [Ca2+]i responses to both drugs were independent of membrane voltage but inhibited by DAT antagonists. Intact phosphorylation sites in the N-terminal domain of DAT were required for the AMPH- and METH-induced increase in [Ca2+]i and for the enhanced effects of METH on [Ca2+]i elevation. Calmodulin-dependent protein kinase II and protein kinase C inhibitors alone or in combination also blocked AMPH- or METH-induced Ca2+ responses. Finally, in the rat nucleus accumbens, in vivo voltammetry showed that systemic application of METH inhibited DAT-mediated DA clearance more efficiently than AMPH, resulting in excess external DA. Together these data demonstrate that METH has a stronger effect on DAT-mediated cell physiology than AMPH, which may contribute to the euphoric and addictive properties of METH compared with AMPH. PMID:19047053

Does random urine drug testing reduce illicit drug use in chronic pain patients receiving opioids?

PubMed

Manchikanti, Laxmaiah; Manchukonda, Rajeev; Pampati, Vidyasagar; Damron, Kim S; Brandon, Doris E; Cash, Kim A; McManus, Carla D

2006-04-01

Prescription drug abuse and illicit drug use are common in chronic pain patients. Adherence monitoring with screening tests, and urine drug testing, periodic monitoring with prescription monitoring programs, has become a common practice in recent years. Random drug testing for appropriate use of opioids and use of illicit drugs is often used in pain management practices. Thus, it is expected that random urine drug testing will deter use of illicit drugs, and also improve compliance. To study the prevalence of illicit drug use in patients receiving opioids for chronic pain management and to compare the results of illicit drug use with the results from a previous study. A prospective, consecutive study. Interventional pain management practice setting in the United States. A total of 500 consecutive patients on opioids, considered to be receiving stable doses of opioids supplemental to their interventional techniques, were studied by random drug testing. Testing was performed by rapid drug screen. Results were considered positive if one or more of the monitored illicit drugs including cocaine, marijuana (THC), methamphetamine or amphetamines were present. Illicit drug use was evident in 80 patients, or 16%, with marijuana in 11%, cocaine in 5%, and methamphetamine and/or amphetamines in 2%. When compared with previous data, the overall illicit drug use was significantly less. Illicit drug use in elderly patients was absent. The prevalence of illicit drug abuse in patients with chronic pain receiving opioids continues to be a common occurence. This study showed significant reductions in overall illicit drug use with adherence monitoring combined with random urine drug testing.

Probe Heating Method for the Analysis of Solid Samples Using a Portable Mass Spectrometer

PubMed Central

Kumano, Shun; Sugiyama, Masuyuki; Yamada, Masuyoshi; Nishimura, Kazushige; Hasegawa, Hideki; Morokuma, Hidetoshi; Inoue, Hiroyuki; Hashimoto, Yuichiro

2015-01-01

We previously reported on the development of a portable mass spectrometer for the onsite screening of illicit drugs, but our previous sampling system could only be used for liquid samples. In this study, we report on an attempt to develop a probe heating method that also permits solid samples to be analyzed using a portable mass spectrometer. An aluminum rod is used as the sampling probe. The powdered sample is affixed to the sampling probe or a droplet of sample solution is placed on the tip of the probe and dried. The probe is then placed on a heater to vaporize the sample. The vapor is then introduced into the portable mass spectrometer and analyzed. With the heater temperature set to 130°C, the developed system detected 1 ng of methamphetamine, 1 ng of amphetamine, 3 ng of 3,4-methylenedioxymethamphetamine, 1 ng of 3,4-methylenedioxyamphetamine, and 0.3 ng of cocaine. Even from mixtures consisting of clove powder and methamphetamine powder, methamphetamine ions were detected by tandem mass spectrometry. The developed probe heating method provides a simple method for the analysis of solid samples. A portable mass spectrometer incorporating this method would thus be useful for the onsite screening of illicit drugs. PMID:26819909

Mephedrone, an Abused Psychoactive Component of “Bath Salts” and Methamphetamine Congener, Does not Cause Neurotoxicity to Dopamine Nerve Endings of the Striatum

PubMed Central

Angoa-Pérez, Mariana; Kane, Michael J.; Francescutti, Dina M.; Sykes, Katherine E.; Shah, Mrudang M.; Mohammed, Abiy M.; Thomas, David M.; Kuhn, Donald M.

2012-01-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the US and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4X 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum. PMID:22191803

Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review.

PubMed

Shin, Eun-Joo; Tran, Hai-Quyen; Nguyen, Phuong-Tram; Jeong, Ji Hoon; Nah, Seung-Yeol; Jang, Choon-Gon; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2018-01-01

Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cδ has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA.

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

PubMed Central

KuKanich, Butch

2009-01-01

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after IV codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine IV and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were obtained at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after IV administration (T½ =1.22 hr; clearance=29.94 mL/min/kg; volume of distribution=3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (CMAX=735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (CMAX=1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (CMAX=6.74 μg/mL; TMAX=0.85 hr) and eliminated (T½=0.96 hr). In conclusion, the pharmacokinetics of codeine were similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after IV and oral administration. PMID:20444020

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs.

PubMed

KuKanich, B

2010-02-01

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration (T(1/2) = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (C(max) = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (C(max) = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C(max) = 6.74 microg/mL; T(max) = 0.85 h) and eliminated (T(1/2) = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after i.v. and oral administration.

Stability studies of amphetamine and ephedrine derivatives in urine.

PubMed

Jiménez, C; de la Torre, R; Ventura, M; Segura, J; Ventura, R

2006-10-20

Knowledge of the stability of drugs in biological specimens is a critical consideration for the interpretation of analytical results. Identification of proper storage conditions has been a matter of concern for most toxicology laboratories (both clinical and forensic), and the stability of drugs of abuse has been extensively studied. This concern should be extended to other areas of analytical chemistry like antidoping control. In this work, the stability of ephedrine derivatives (ephedrine, norephedrine, methylephedrine, pseudoephedrine, and norpseudoephedrine), and amphetamine derivatives (amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA)) in urine has been studied. Spiked urine samples were prepared for stability testing. Urine samples were quantified by GC/NPD or GC/MS. The homogeneity of each batch of sample was verified before starting the stability study. The stability of analytes was evaluated in sterilized and non-sterilized urine samples at different storage conditions. For long-term stability testing, analyte concentration in urine stored at 4 degrees C and -20 degrees C was determined at different time intervals for 24 months for sterile urine samples, and for 6 months for non-sterile samples. For short-term stability testing, analyte concentration was evaluated in liquid urine stored at 37 degrees C for 7 days. The effect of repeated freezing (at -20 degrees C) and thawing (at room temperature) was also studied in sterile urine for up to three cycles. No significant loss of the analytes under study was observed at any of the investigated conditions. These results show the feasibility of preparing reference materials containing ephedrine and amphetamine derivatives to be used for quality control purposes.

Surveillance of emerging drugs of abuse in Hong Kong: validation of an analytical tool.

PubMed

Tang, Magdalene H Y; Ching, C K; Tse, M L; Ng, Carol; Lee, Caroline; Chong, Y K; Wong, Watson; Mak, Tony W L

2015-04-01

To validate a locally developed chromatography-based method to monitor emerging drugs of abuse whilst performing regular drug testing in abusers. Cross-sectional study. Eleven regional hospitals, seven social service units, and a tertiary level clinical toxicology laboratory in Hong Kong. A total of 972 drug abusers and high-risk individuals were recruited from acute, rehabilitation, and high-risk settings between 1 November 2011 and 31 July 2013. A subset of the participants was of South Asian ethnicity. In total, 2000 urine or hair specimens were collected. Proof of concept that surveillance of emerging drugs of abuse can be performed whilst conducting routine drug of abuse testing in patients. The method was successfully applied to 2000 samples with three emerging drugs of abuse detected in five samples: PMMA (paramethoxymethamphetamine), TFMPP [1-(3-trifluoromethylphenyl)piperazine], and methcathinone. The method also detected conventional drugs of abuse, with codeine, methadone, heroin, methamphetamine, and ketamine being the most frequently detected drugs. Other findings included the observation that South Asians had significantly higher rates of using opiates such as heroin, methadone, and codeine; and that ketamine and cocaine had significantly higher detection rates in acute subjects compared with the rehabilitation population. This locally developed analytical method is a valid tool for simultaneous surveillance of emerging drugs of abuse and routine drug monitoring of patients at minimal additional cost and effort. Continued, proactive surveillance and early identification of emerging drugs will facilitate prompt clinical, social, and legislative management.

'Ecstasy' and the use of sleep medications in a general community sample: a 4-year follow-up.

PubMed

Tait, Robert J; George, Amanda; Olesen, Sarah

2013-09-01

Animal models show that a single dose of 3,4-methylenedioxymethamhetamine (MDMA; 'ecstasy') can result in long-term disruption of sleep. We evaluated the relationship between ecstasy consumption and the use of sleep medications in humans after controlling for key factors. The Personality and Total Health Through Life project uses a longitudinal cohort with follow-up every 4 years. This study reports data from waves 2 and 3. Participants were recruited from the electoral roll in the Australian Capital Territory and Queanbeyan, New South Wales, Australia. Participants were aged 20-24 years at wave 1 (1999-2000). The study collected self-reported data on ecstasy, meth/amphetamine, cannabis, alcohol, tobacco and use of sleeping medications (pharmaceutical or other substances). Depression was categorized using the Brief Patient Health Questionnaire (BPHQ). Other psychosocial measures included life-time traumas. We used generalized estimating equations to model outcomes. Ecstasy data were available from 2128 people at wave 2 and 1977 at wave 3: sleeping medication use was reported by 227 (10.7%) respondents at wave 2 and 239 (12.1%) at wave 3. Increased odds ratios (OR) for sleeping medication use was found for those with depression [OR = 1.88, 95% confidence interval (CI): 1.39, 2.53], women (OR = 1.44, 95% CI: 1.13, 1.84), and increased by 19% for each life-time trauma. Ecstasy use was not a significant predictor, but ≥monthly versus never meth/amphetamine use increased the odds (OR = 3.03, 95% CI 1.30, 7.03). The use of ecstasy appears to be associated with the use of sleeping medications but this association can be accounted for by other factors. © 2013 Society for the Study of Addiction.

New phenethylamines in Europe.

PubMed

King, L A

2014-01-01

Sixteen phenethylamines are now included in Schedules I and II of the United Nations 1971 Convention on Psychotropic Substances. Most of the ring-substituted compounds are in Schedule I, whereas 2C-B, amphetamine, and methamphetamine are listed in Schedule II. Substances in Schedule IV (e.g. benzphetamine) are now regarded as obsolete pharmaceutical products. They all represent the 'old phenethylamines'. By 2013, nearly 100 illicit phenethylamines had been found in the European Union (EU). Of these, nine (MBDB, 4-MTA, PMMA, 2C-I, 2C-T-2, 2C-T-7, TMA-2, 5-IT and 4-MA) were submitted for risk assessment by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). All except MBDB were recommended for EU-wide control. Of the 'new phenethylamines', 2C-B was the most commonly reported, but other 2C compounds were widespread. Many of the ring-substituted phenethylamines are described in the 1991 book PIHKAL. Many fused ring phenethylamines have appeared in the past few years; they include further benzofurans (e.g. 5-and 6-APB), indanylalkylamines (e.g. 5-IAP), dibenzofurans (e.g. 2C-B-FLY) and 2-aminopropylindoles (e.g.5-IT). The recent and rapid rise of phenethylamines with bulky N-substituents (e.g. 25I-NBOMe) has been particularly significant. Although not phenethylamines, it is notable that the thiophene bioisosteres of amphetamine and methamphetamine as well as certain conformationally-restricted variants (e.g. aminoindanes) have been found in recent drug seizures. In the United Kingdom Misuse of Drugs Act, most ring-substituted phenethylamines are either listed by name or are covered by generic definitions dating from 1977. In 2013, temporary generic legislation included a number of benzofurans, indanylalkylamines and certain 'NBOMe' compounds. Copyright © 2013 John Wiley & Sons, Ltd.

A universal harm-minimisation approach to preventing psychostimulant and cannabis use in adolescents: a cluster randomised controlled trial

PubMed Central

2014-01-01

Background Psychostimulants and cannabis are two of the three most commonly used illicit drugs by young Australians. As such, it is important to deliver prevention for these substances to prevent their misuse and to reduce associated harms. The present study aims to evaluate the feasibility and effectiveness of the universal computer-based Climate Schools: Psychostimulant and Cannabis Module. Methods A cluster randomised controlled trial was conducted with 1734 Year 10 students (mean age = 15.44 years; SD = 0.41) from 21 secondary schools in Australia. Schools were randomised to receive either the six lesson computer-based Climate Schools program or their usual health classes, including drug education, over the year. Results The Climate Schools program was shown to increase knowledge of cannabis and psychostimulants and decrease pro-drug attitudes. In the short-term the program was effective in subduing the uptake and plateauing the frequency of ecstasy use, however there were no changes in meth/amphetamine use. In addition, females who received the program used cannabis significantly less frequently than students who received drug education as usual. Finally, the Climate Schools program was related to decreasing students’ intentions to use meth/amphetamine and ecstasy in the future, however these effects did not last over time. Conclusions These findings provide support for the use of a harm-minimisation approach and computer technology as an innovative platform for the delivery of prevention education for illicit drugs in schools. The current study indicated that teachers and students enjoyed the program and that it is feasible to extend the successful Climate Schools model to the prevention of other drugs, namely cannabis and psychostimulants. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12613000492752. PMID:24943829

Prenatal Methamphetamine Exposure and Neonatal and Infant Neurobehavioral Outcome: Results from the IDEAL Study

PubMed Central

Kiblawi, Zeina N.; Smith, Lynne M.; Diaz, Sabrina D.; LaGasse, Linda L.; Derauf, Chris; Newman, Elana; Shah, Rizwan; Arria, Amelia; Huestis, Marilyn; Haning, William; Strauss, Arthur; DellaGrotta, Sheri; Dansereau, Lynne M.; Neal, Charles; Lester, Barry

2013-01-01

Background Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How MA use during pregnancy affects neonatal and infant neurobehavior is unknown. Methods The Infant Development, Environment, and Lifestyle (IDEAL) study screened 34,833 subjects at 4 clinical centers. 17,961 were eligible and 3,705 were consented, among which 412 were enrolled for longitudinal follow-up. Exposed subjects were identified by self-report and/or GC/MS confirmation of amphetamine and metabolites in meconium. Comparison subjects were matched (race, birth weight, maternal education, insurance), denied amphetamine use and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, or phencyclidine. The NICU Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life and again at one month to 380 enrollees (185 exposed, 195 comparison). ANOVA tested exposure effects on NNNS summary scores at birth and one month. GLM repeated measures analysis assessed the effect of MA exposure over time on the NNNS scores with and without covariates. Results By one month of age, both groups demonstrated higher quality of movement (P=.029), less lethargy (P=.001), and fewer asymmetric reflexes (P=.012), with no significant differences in NNNS scores between the exposed and comparison groups. Over the first month of life, arousal increased in exposed infants but decreased in comparison infants (p=.031) and total stress was decreased in exposed infants with no change in comparison infants (p=.026). Conclusions Improvement in total stress and arousal were observed in MA-exposed newborns by one month of age relative to the newborn period. PMID:24588296

What's the agreement between self-reported and biochemical verification of drug use? A look at permanent supportive housing residents.

PubMed

Rendon, Alexis; Livingston, Melvin; Suzuki, Sumihiro; Hill, Whitney; Walters, Scott

2017-07-01

Self-reported substance use is commonly used as an outcome measure in treatment research. We evaluated the validity of self-reported drug use in a sample of 334 adults with mental health problems who were residing in supportive housing programs. The primary analysis was the calculation of the positive predictive values (PPVs) of self-report compared to an oral fluid test taken at the same time. A sensitivity analysis compared the positive predictive values of two self-reported drug use histories: biological testing window (ranging between the past 96h to 30days depending on drug type) or the full past 90-day comparison window (maximum length recorded during interview). A multivariable logistic regression was used to predict discordance between self-report and the drug test for users. Self-reported drug use and oral fluid drug tests were compared to determine the positive predictive value for amphetamines/methamphetamines/PCP (47.1% agreement), cocaine (43.8% agreement), and marijuana (69.7% agreement) drug tests. Participants who misreported their drug use were more likely to be older, non-White, have no medical insurance, and not report any alcohol use. In general, amphetamine/methamphetamine/PCP and cocaine use was adequately captured by the biological test, while marijuana use was best captured by a combination of self-report and biological data. Using the full past 90day comparison window resulted in higher concordance with the oral fluid drug test, indicating that self-reported drug use in the past 90days may be a proxy for drug use within the biological testing window. Self-report has some disadvantages when used as the sole measure of drug use in this population. Copyright © 2017 Elsevier Ltd. All rights reserved.

Methamphetamine Facilitates Female Sexual Behavior and Enhances Neuronal Activation in the Medial Amygdala and Ventromedial Nucleus of the Hypothalamus

PubMed Central

Holder, Mary K; Hadjimarkou, Maria M.; Zup, Susan L.; Blutstein, Tamara; Benham, Rebecca S.; McCarthy, Margaret M.; Mong, Jessica A.

2009-01-01

Summary Methamphetamine (MA) abuse has reached epidemic proportions in the United States. Users of MA report dramatic increases in sexual drive that have been associated with increased engagement in risky sexual behavior leading to higher rates of sexually transmitted diseases and unplanned pregnancies. The ability of MA to enhance sexual drive in females is enigmatic since related psychostimulants like amphetamine and cocaine appear not to affect sexual drive in women, and in rodents models, amphetamine has been reported to be inhibitory to female sexual behavior. Examination of MA’s effects on female sexual behavior in an animal model is lacking. Here, using a rodent model, we have demonstrated that MA enhanced female sexual behavior. MA (5mg/kg) or saline vehicle was administered once daily for three days to adult ovariectomized rats primed with ovarian steroids. MA treatment significantly increased the number of proceptive events and the lordosis response compared to hormonally-primed, saline controls. The effect of MA on the neural circuitry underlying the motivation for sexual behavior was examined using Fos immunoreactivity. In the medial amygdala and the ventromedial nucleus of the hypothalamus, nuclei implicated in motivated behaviors, ovarian hormones and MA independently enhance the neuronal activation, but more striking was the significantly greater activation induced by their combined administration. Increases in dopamine neurotransmission may underlie the MA/hormone mediated increase in neuronal activation. In support of this possibility, ovarian hormones significantly increased tyrosine hyroxylase (the rate limiting enzyme in dopamine synthesis) immunoreactivity in the medial amygdala. Thus our present data suggest that the interactions of MA and ovarian hormones leads to changes in the neural substrate of key nuclei involved in mediating female sexual behaviors, and these changes may underlie MA’s ability to enhance these behaviors. PMID:19589643

Methamphetamine and amphetamine concentrations in survivors of body-packer syndrome in Japan.

PubMed

Uekusa, Kyoko; Hayashida, Makiko; Saito, Nobuyuki; Mashiko, Kunihiro; Hara, Kenji; Waters, Brian; Ohno, Youkichi

2013-04-10

There are few reports from Japan on the analysis of fluids in survivors of body-packer syndrome. We analyzed the concentrations of stimulants in the serum, plasma and urine collected from three patients suspected of being body packers at immigration that were referred to hospitals between 2010 and 2011. The drugs were extracted with solid-phase columns and analyzed by gas chromatography-mass spectrometry (GC-MS). In all cases, wrapped, cylindrical packets of foreign bodies were detected in the intestinal tract on plain X-ray (X-P) and computed tomography (CT), and they were eventually removed surgically. In case 1, the patient presented with convulsions and tachycardia at admission to the hospital and one of the packets was found to have ruptured. In case 2, although the subject appeared to have an intestinal obstruction caused by the packets on the third day, he exhibited no symptoms on arrival and the packets did not appear to have ruptured. In case 3, the patient exhibited restlessness on the first day and one of the removed packets had ruptured. In all cases, methamphetamine (MA) and amphetamine (AP) were detected in serum, plasma and urine. In this study, we report the variation in MA and AP concentrations in survivors of body-packer syndrome. The serum and plasma concentrations of MA were high in subjects that exhibited symptoms of MA intoxication. MA and AP were also detected in the case in which the patient exhibited no symptoms of intoxication and the packets had not ruptured. These results suggest either that the stimulants may have seeped through the wrap of the packets, or that the subject had been abusing the drugs. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Analysis of illicit drugs seized in the Province of Florence from 2006 to 2016.

PubMed

Bertol, Elisabetta; Bigagli, Laura; D'Errico, Stefano; Mari, Francesco; Palumbo, Diego; Pascali, Jennifer P; Vaiano, Fabio

2018-03-01

Comprehension of illicit drug market's features at local level is useful to plan and to correctly set-up specific informative and contrast activities. In this paper we report trends, purities and consumption estimations of illicit substances available on the Florentine territory from 2006 to 2016. These data were obtained by the analysis of 10,451 samples seized by the Law Enforcement Agencies in case of personal use offence. Analytical procedures consisted in targeted and untargeted analyses by gas chromatography-flame ionization detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. The most detected substances were: cannabis (78.0%; resin: 51.7%; herb: 26.3%), cocaine (10.4%), opiates (6.6%; heroin: 6.5%; morphine: 0.1%), ketamine (1.4%), amphetamines (1.3%; 3,4-methylenedioxymethamphetamine - MDMA -: 0.7%; methamphetamine: 0.6%; amphetamine: <0.1%) and methadone (1.3%). Cocaine, heroin and methamphetamine purities were higher than their mean values estimated for the Italian and European market, while THC content in cannabis seizures was unexpectedly below the European mean values. Starting from 2015, a total of 5 new psychoactive substances (NPS) were detected in seized material, mainly composed of white powders (pentedrone, 3-methylmethcathinone, 4-fluoroamphetamine, methoxethamine and AB-FUBINACA). Most of the seizures (75.5%) were from young male adults (14-34 years old). These data contribute to highlight new trends in the illicit drug market in the Tuscany area, but also to verify the persistence of old habits of drug consumption, confirming the need for more effective counteraction and prevention plans, especially among young people, where the diffusion of the legal highs is worrisome, also in consideration of the young age and the unconsciousness of the possible health effects. Copyright © 2018 Elsevier B.V. All rights reserved.

MATERNAL DEPRESSION AND PRENATAL EXPOSURE TO METHAMPHETAMINE: NEURODEVELOPMENTAL FINDINGS FROM THE INFANT DEVELOPMENT, ENVIRONMENT, AND LIFESTYLE (IDEAL) STUDY

PubMed Central

Smith, Lynne M.; Paz, Monica S.; LaGasse, Linda L.; Derauf, Chris; Newman, Elana; Shah, Rizwan; Arria, Amelia; Huestis, Marilyn A.; Haning, William; Strauss, Arthur; Grotta, Sheri Della; Dansereau, Lynne M.; Neal, Charles; Lester, Barry M.

2013-01-01

Background Maternal depression is associated with a higher incidence of behavioral problems in infants, but the effects of maternal depression as early as 1 month are not well characterized. The objective of this study is to determine the neurobehavioral effects of maternal depression on infants exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS). Methods Four hundred twelve mother–infant pairs were enrolled (MA = 204) and only biological mothers with custody of their child were included in the current analysis. At the 1-month visit (n = 126 MA-exposed; n = 193 MA-unexposed), the Beck Depression Inventory-II (BDI-II) was administered, and the NNNS was administered to the infant. Exposure was identified by self-report and/or gas chromatography/mass spectroscopy confirmation of amphetamine and metabolites in newborn meconium. Unexposed subjects were matched, denied amphetamine use, and had negative meconium screens. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS, with significance accepted at P < .05. Results The MA group had an increased incidence of depression-positive diagnosis and increased depression scores on the BDI-II. After adjusting for covariates, MA exposure was associated with increased arousal and handling scores, and a decreased ability to self-regulate. Maternal depression was associated with higher autonomic stress and poorer quality of movement. No additional differences were observed in infants whose mothers were both depressed and used MA during pregnancy. Conclusions Maternal depression is associated with neurodevelopmental patterns of increased stress and decreased quality of movement, suggesting maternal depression influences neurodevelopment in infants as young as 1 month. PMID:22555777

Comparison of (+)-methamphetamine, ±-methylenedioxymethamphetamine, (+)-amphetamine and ±-fenfluramine in rats on egocentric learning in the Cincinnati water maze.

PubMed

Vorhees, Charles V; He, Elizabeth; Skelton, Matthew R; Graham, Devon L; Schaefer, Tori L; Grace, Curtis E; Braun, Amanda A; Amos-Kroohs, Robyn; Williams, Michael T

2011-05-01

(+)-Methamphetamine (MA), (±)-3,4-methylenedioxymethamphetamine (MDMA), (+)-amphetamine (AMPH), and (±)-fenfluramine (FEN) are phenylethylamines with CNS effects. At higher doses, each induces protracted reductions in brain dopamine (DA) and/or serotonin. Chronic MA and MDMA users show persistent monoamine reductions and cognitive impairments. In rats, similar neurochemical effects can be induced, yet cognitive impairments have been difficult to demonstrate. We recently showed that rats treated on a single day with MA (10 mg/kg x 4 at 2 h intervals) exhibit impaired egocentric learning (Cincinnati water maze [CWM]) without affecting spatial learning (Morris water maze [MWM]) (Herring et al., [2008] Psychopharmacology (Berl) 199:637–650). Whether this effect is unique to MA or is a general characteristic of these drugs is unknown. Accordingly, this experiment compared these drugs on CWM performance. Drugs were given s.c. in four doses at 2 h intervals. MA doses were 10 or 12.5 mg/kg/dose, AMPH 25 mg/kg/dose (to match MA12.5-induced hyperthermia), MDMA 15 mg/kg/dose (previously established hyperthermia-inducing dose), and FEN 16.5 mg/kg/dose (equimolar to MA12.5). Two weeks later, rats were tested in the CWM (2 trials/day, 21 days). AMPH and MA (both doses) induced significant increases in CWM errors and latency to reach the goal with no differences in swim speed. MDMA and FEN did not significantly alter learning. Given that FEN selectively and MDMA preferentially affect serotonin whereas AMPH selectively and MA preferentially affect DA, the data suggest that egocentric learning may be predominantly dopaminergically mediated.

Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme.

PubMed

Siuciak, J A; McCarthy, S A; Chapin, D S; Reed, T M; Vorhees, C V; Repaske, D R

2007-07-01

PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.

Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

PubMed Central

Morgenthaler, Timothy I.; Kapur, Vishesh K.; Brown, Terry; Swick, Todd J.; Alessi, Cathy; Aurora, R. Nisha; Boehlecke, Brian; Chesson, Andrew L.; Friedman, Leah; Maganti, Rama; Owens, Judith; Pancer, Jeffrey; Zak, Rochelle

2007-01-01

These practice parameters pertain to the treatment of hypersomnias of central origin. They serve as both an update of previous practice parameters for the therapy of narcolepsy and as the first practice parameters to address treatment of other hypersomnias of central origin. They are based on evidence analyzed in the accompanying review paper. The specific disorders addressed by these parameters are narcolepsy (with cataplexy, without cataplexy, due to medical condition and unspecified), idiopathic hypersomnia (with long sleep time and without long sleep time), recurrent hypersomnia and hypersomnia due to medical condition. Successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce the fullest possible return of normal function, and regular follow-up to monitor response to treatment. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy, while tricyclic antidepressants and fluoxetine are effective treatments for cataplexy, sleep paralysis, and hypnagogic hallucinations; but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness in narcolepsy patients. Based on available evidence, modafinil is an effective therapy for sleepiness due to idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. Based on evidence and/or long history of use in the therapy of narcolepsy committee consensus was that modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are reasonable options for the therapy of hypersomnias of central origin. Citation: Morgenthaler TI; Kapur VK; Brown T; Swick TJ; Alessi C; Aurora RN; Boehlecke B; Chesson AL; Friedman L; Maganti R; Owens J; Pancer J; Zak R; Standards of Practice Committee of the AASM. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. SLEEP 2007;30(12):1705-1711. PMID:18246980

A universal harm-minimisation approach to preventing psychostimulant and cannabis use in adolescents: a cluster randomised controlled trial.

PubMed

Vogl, Laura Elise; Newton, Nicola Clare; Champion, Katrina Elizabeth; Teesson, Maree

2014-06-18

Psychostimulants and cannabis are two of the three most commonly used illicit drugs by young Australians. As such, it is important to deliver prevention for these substances to prevent their misuse and to reduce associated harms. The present study aims to evaluate the feasibility and effectiveness of the universal computer-based Climate Schools: Psychostimulant and Cannabis Module. A cluster randomised controlled trial was conducted with 1734 Year 10 students (mean age = 15.44 years; SD = 0.41) from 21 secondary schools in Australia. Schools were randomised to receive either the six lesson computer-based Climate Schools program or their usual health classes, including drug education, over the year. The Climate Schools program was shown to increase knowledge of cannabis and psychostimulants and decrease pro-drug attitudes. In the short-term the program was effective in subduing the uptake and plateauing the frequency of ecstasy use, however there were no changes in meth/amphetamine use. In addition, females who received the program used cannabis significantly less frequently than students who received drug education as usual. Finally, the Climate Schools program was related to decreasing students' intentions to use meth/amphetamine and ecstasy in the future, however these effects did not last over time. These findings provide support for the use of a harm-minimisation approach and computer technology as an innovative platform for the delivery of prevention education for illicit drugs in schools. The current study indicated that teachers and students enjoyed the program and that it is feasible to extend the successful Climate Schools model to the prevention of other drugs, namely cannabis and psychostimulants. Australian and New Zealand Clinical Trials Registry ACTRN12613000492752.

National population size estimation of illicit drug users through the network scale-up method in 2013 in Iran.

PubMed

Nikfarjam, Ali; Shokoohi, Mostafa; Shahesmaeili, Armita; Haghdoost, Ali Akbar; Baneshi, Mohammad Reza; Haji-Maghsoudi, Saiedeh; Rastegari, Azam; Nasehi, Abbas Ali; Memaryan, Nadereh; Tarjoman, Termeh

2016-05-01

For a better understanding of the current situation of drug use in Iran, we utilized the network scale-up approach to estimate the prevalence of illicit drug use in the entire country. We implemented a self-administered, street-based questionnaire to 7535 passersby from the general public over 18 years of age by street based random walk quota sampling (based on gender, age and socio-economic status) from 31 provinces in Iran. The sample size in each province was approximately 400, ranging from 200 to 1000. In each province 75% of sample was recruited from the capital and the remaining 25% was recruited from one of the large cities of that province through stratified sampling. The questionnaire comprised questions on demographic information as well as questions to measure the total network size of participants as well as the network size in each of seven drug use groups including Opium, Shire (combination of Opium residue and pure opium), Crystal Methamphetamine, heroin/crack (which in Iranian context is a cocaine-free drug that mostly contains heroin, codeine, morphine and caffeine with or without other drugs), Hashish, Methamphetamine/LSD/ecstasy, and injecting drugs. The estimated size for each group was adjusted for transmission and barrier ratios. The most common type of illicit drug used was opium with the prevalence of 1500 per 100,000 population followed by shire (660), crystal methamphetamine (590), hashish (470), heroin/crack (350), methamphetamine, LSD and ecstasy (300) and injecting drugs (280). All types of substances were more common among men than women. The use of opium, shire and injecting drugs was more common in individuals over 30 whereas the use of stimulants and hashish was largest among individuals between 18 and 30 years of age. It seems that younger individuals and women are more desired to use new synthetic drugs such as crystal methamphetamine. Extending the preventive programs especially in youth as like as scaling up harm reduction services would be the main priorities in prevention and control of substance use in Iran. Because of poor service coverage and high stigma in women, more targeted programs in this affected population are needed. Copyright © 2016 Elsevier B.V. All rights reserved.

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

PubMed

Chen, Z R; Somogyi, A A; Reynolds, G; Bochner, F

1991-04-01

1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of drugs of abuse on the central neuropeptide Y system.

PubMed

Gonçalves, Joana; Martins, João; Baptista, Sofia; Ambrósio, António Francisco; Silva, Ana Paula

2016-07-01

Neuropeptide Y (NPY), which is widely expressed in the central nervous system is involved in several neuropathologies including addiction. Here we comprehensively and systematically review alterations on the central NPY system induced by several drugs. We report on the effects of psychostimulants [cocaine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and nicotine], ethanol, and opioids on NPY protein levels and expression of different NPY receptors. Overall, expression and function of NPY and its receptors are changed under conditions of drug exposure, thus affecting several physiologic behaviors, such as feeding, stress and anxiety. Drugs of abuse differentially affect the components of the NPY system. For example methamphetamine and nicotine lead to a consistent increase in NPY mRNA and protein levels in different brain sites whereas ethanol and opioids decrease NPY mRNA and protein expression. Drug-induced alterations on the different NPY receptors show more complex regulation pattern. Manipulation of the NPY system can have opposing effects on reinforcing and addictive properties of drugs of abuse. NPY can produce pro-addictive effects (nicotine and heroin), but can also exert inhibitory effects on addictive behavior (AMPH, ethanol). Furthermore, NPY can act as a neuroprotective agent in chronically methamphetamine and MDMA-treated rodents. In conclusion, manipulation of the NPY system seems to be a potential target to counteract neural alterations, addiction-related behaviors and cognitive deficits induced by these drugs. © 2015 Society for the Study of Addiction.

Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Francescutti, Dina M; Sykes, Katherine E; Shah, Mrudang M; Mohammed, Abiy M; Thomas, David M; Kuhn, Donald M

2012-03-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the United States and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4 × 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Multiple-dose safety study of ibuprofen/codeine and aspirin/codeine combinations.

PubMed

Friedman, H; Seckman, C; Stubbs, C; Oster, H; Royer, G

1990-01-01

This multiple-dose, double-blind, placebo-controlled, randomized, normal volunteer study compared formulations of ibuprofen/codeine and aspirin/codeine for systemic safety. Vital signs, hematologic, biochemical and urinary parameters, side effects, mood and mental alertness, were monitored. The placebo group had less gastrointestinal side effects and more frequent stools than the active treatment groups. There was statistical evidence for greater adverse effects of aspirin/codeine on mood and mental alertness in comparison to ibuprofen/codeine and placebo. Ibuprofen/codeine had a more favorable adverse effect profile than aspirin/codeine. A mild respiratory and cardiac depressant effect attributable to codeine was evident in all active treatment groups after 7 days of frequent therapy. More work needs to be done to elucidate the factors regulating the development of tolerance to the respiratory and cardiovascular depressant effects of opiates in general, and for codeine in particular.

Structural Characterization of a Therapeutic Anti-Methamphetamine Antibody Fragment: Oligomerization and Binding of Active Metabolites

PubMed Central

Gokulan, Kuppan; Varughese, Kottayil I.

2013-01-01

Vaccines and monoclonal antibodies (mAb) for treatment of (+)-methamphetamine (METH) abuse are in late stage preclinical and early clinical trial phases, respectively. These immunotherapies work as pharmacokinetic antagonists, sequestering METH and its metabolites away from sites of action in the brain and reduce the rewarding and toxic effects of the drug. A key aspect of these immunotherapy strategies is the understanding of the subtle molecular interactions important for generating antibodies with high affinity and specificity for METH. We previously determined crystal structures of a high affinity anti-METH therapeutic single chain antibody fragment (scFv6H4, KD = 10 nM) in complex with METH and the (+) stereoisomer of 3,4-methylenedioxymethamphetamine (MDMA, or “ecstasy”). Here we report the crystal structure of scFv6H4 in homo-trimeric unbound (apo) form (2.60Å), as well as monomeric forms in complex with two active metabolites; (+)-amphetamine (AMP, 2.38Å) and (+)-4-hydroxy methamphetamine (p-OH-METH, 2.33Å). The apo structure forms a trimer in the crystal lattice and it results in the formation of an intermolecular composite beta-sheet with a three-fold symmetry. We were also able to structurally characterize the coordination of the His-tags with Ni2+. Two of the histidine residues of each C-terminal His-tag interact with Ni2+ in an octahedral geometry. In the apo state the CDR loops of scFv6H4 form an open conformation of the binding pocket. Upon ligand binding, the CDR loops adopt a closed formation, encasing the drug almost completely. The structural information reported here elucidates key molecular interactions important in anti-methamphetamine abuse immunotherapy. PMID:24349338

Structural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites.

PubMed

Peterson, Eric C; Celikel, Reha; Gokulan, Kuppan; Varughese, Kottayil I

2013-01-01

Vaccines and monoclonal antibodies (mAb) for treatment of (+)-methamphetamine (METH) abuse are in late stage preclinical and early clinical trial phases, respectively. These immunotherapies work as pharmacokinetic antagonists, sequestering METH and its metabolites away from sites of action in the brain and reduce the rewarding and toxic effects of the drug. A key aspect of these immunotherapy strategies is the understanding of the subtle molecular interactions important for generating antibodies with high affinity and specificity for METH. We previously determined crystal structures of a high affinity anti-METH therapeutic single chain antibody fragment (scFv6H4, K(D) = 10 nM) in complex with METH and the (+) stereoisomer of 3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy"). Here we report the crystal structure of scFv6H4 in homo-trimeric unbound (apo) form (2.60Å), as well as monomeric forms in complex with two active metabolites; (+)-amphetamine (AMP, 2.38Å) and (+)-4-hydroxy methamphetamine (p-OH-METH, 2.33Å). The apo structure forms a trimer in the crystal lattice and it results in the formation of an intermolecular composite beta-sheet with a three-fold symmetry. We were also able to structurally characterize the coordination of the His-tags with Ni(2+). Two of the histidine residues of each C-terminal His-tag interact with Ni(2+) in an octahedral geometry. In the apo state the CDR loops of scFv6H4 form an open conformation of the binding pocket. Upon ligand binding, the CDR loops adopt a closed formation, encasing the drug almost completely. The structural information reported here elucidates key molecular interactions important in anti-methamphetamine abuse immunotherapy.

Prevalence of drug use among drivers based on mandatory, random tests in a roadside survey

PubMed Central

Alcañiz, Manuela; Guillen, Montserrat

2018-01-01

Background In the context of road safety, this study aims to examine the prevalence of drug use in a random sample of drivers. Methods A stratified probabilistic sample was designed to represent vehicles circulating on non-urban roads. Random drug tests were performed during autumn 2014 on 521 drivers in Catalonia (Spain). Participation was mandatory. The prevalence of drug driving for cannabis, methamphetamines, amphetamines, cocaine, opiates and benzodiazepines was assessed. Results The overall prevalence of drug use is 16.4% (95% CI: 13.9; 18.9) and affects primarily younger male drivers. Drug use is similarly prevalent during weekdays and on weekends, but increases with the number of occupants. The likelihood of being positive for methamphetamines is significantly higher for drivers of vans and lorries. Conclusions Different patterns of use are detected depending on the drug considered. Preventive drug tests should not only be conducted on weekends and at night-time, and need to be reinforced for drivers of commercial vehicles. Active educational campaigns should focus on the youngest age-group of male drivers. PMID:29920542

Pretreatment with nomifensine or nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline augments methamphetamine-induced stereotypical behavior in mice

PubMed Central

Hall, F. Scott; Uhl, George R.; Asano, Hiromi; Chatani, Ryuki; Hayata, Sachiko; Yokoyama, Hiroko; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Takemura, Motohiko

2014-01-01

Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10 mg/kg, i.p.) and nomifensine (3 mg/kg, i.p.) on METH (5 or 10 mg/kg ,i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice. PMID:22265332

Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: correlations between behavior and neurochemistry

PubMed Central

Murnane, Kevin Sean; Perrine, Shane Alan; Finton, Brendan James; Galloway, Matthew Peter; Howell, Leonard Lee; Fantegrossi, William Edward

2011-01-01

Rationale Considerable evidence indicates that amphetamine derivatives can deplete brain monoaminergic neurotransmitters. However, the behavioral and cognitive consequences of neurochemical depletions induced by amphetamines are not well established. Objectives In this study, mice were exposed to dosing regimens of 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH), or para-chloroamphetamine (PCA) known to deplete the monoamine neurotransmitters dopamine and serotonin, and the effects of these dosing regimens on learning and memory were assessed. Methods In the same animals, we determined deficits in learning and memory via passive avoidance (PA) behavior and changes in tissue content of monoamine neurotransmitters and their primary metabolites in the striatum, frontal cortex, cingulate, hippocampus, and amygdala via ex vivo high pressure liquid chromatography. Results Consistent with previous studies, significant reductions in tissue content of dopamine and serotonin were readily apparent. In addition, exposure to METH and PCA impaired PA performance and resulted in significant depletions of dopamine, serotonin, and their metabolites in several brain regions. Multiple linear regression analysis revealed that the tissue concentration of dopamine in the anterior striatum was the strongest predictor of PA performance, with an additional significant contribution by the tissue concentration of the serotonin metabolite 5-hydroxyindoleacetic acid in the cingulate. In contrast to the effects of METH and PCA, exposure to MDMA did not deplete anterior striatal dopamine levels or cingulate levels of 5-hydroxyindoleacetic acid, and it did not impair PA performance. Conclusions These studies demonstrate that certain amphetamines impair PA performance in mice and that these impairments may be attributable to specific neurochemical depletions. PMID:21993877

Male and Female Stimulant Use Among Rural Kentuckians: The Contribution of Spirituality and Religiosity

PubMed Central

Staton-Tindall, Michele; Oser, Carrie B.; Duvall, Jamieson L.; Havens, Jennifer R.; Webster, J. Matthew; Leukefeld, Carl; Booth, Brenda M.

2017-01-01

This study describes gender-specific patterns of drug use among active rural stimulant users and examines religiosity and spirituality as factors that may be related to stimulant use among males and females. The study includes a sample of 225 active rural stimulant users from Kentucky who were recruited using respondent driven sampling and completed face-to-face interviews. Findings suggest gender specific patterns among active rural stimulant users, with females reporting more amphetamine use. In addition, bivariate findings indicate that there is an inverse relationship between spirituality, religiosity, and stimulant use (specifically methamphetamine and amphetamine use), particularly for males. However, when further examining this relationship in multivariate models controlling for age and race, few significant findings were noted for spirituality and religiosity in predicting gender-specific stimulant use patterns. These findings suggest that treatment interventions that incorporate spirituality and religiosity should not only be gender specific, but should also target clients differentially. Findings on the degree of reported spirituality and religiosity also suggest that religious and/or faithbased organizations could be utilized for drug use interventions for rural stimulant users. PMID:29104311

Codeine use, dependence and help-seeking behaviour in the UK and Ireland: an online cross-sectional survey.

PubMed

Kimergård, A; Foley, M; Davey, Z; Dunne, J; Drummond, C; Deluca, P

2017-09-01

Codeine misuse and dependence poses a clinical and public health challenge. However, little is known about dependence and treatment needs in the UK and Ireland. To characterize codeine use, dependence and help-seeking behaviour. An online cross-sectional survey advertised on Facebook, Twitter, health and drug websites and e-mail circulars. The survey collected data on demographics and codeine use amongst adults from the UK and Ireland. The Severity of Dependence Scale measured the level of codeine dependence. The sample of 316 respondents had a mean age of 35.3 years (SD = 12.3) and 67% were women. Of the 316 respondents, 54 scored ≥5 on the Severity of Dependence Scale indicating codeine dependence (17.1%). Our study found that codeine dependence is a problem with both prescribed and 'over-the-counter' codeine. Codeine dependence was associated with daily use of codeine, faking or exaggerating symptoms to get a prescription for codeine and 'pharmacy shopping' ( P < 0.01). A higher number of respondents had sought advice on the Internet (12%) rather than from their general medical practitioner (GP) (5.4%). Less than 1% of respondents had sought advice from a pharmacist. Codeine dependent users were more likely to seek help on the Internet to control their use of codeine than from a GP, which may indicate a potential for greater specialized addiction treatment demand through increased identification and referrals in primary care. © The Author 2017. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Incorporation of methamphetamine and amphetamine in human hair following controlled oral methamphetamine administration

PubMed Central

Polettini, Aldo; Cone, Edward J.; Gorelick, David A.; Huestis, Marilyn A.

2012-01-01

Background Although hair testing is well established for the assessment of past drug exposure, uncertainties persist about mechanisms of drug incorporation into hair and interpretation of results. The aim of this study was to administer methamphetamine (MAMP) under controlled conditions as a model drug to investigate drug incorporation into human hair. Material and Methods Seven volunteers with a history of stimulant use received 4×10 mg (low) doses of sustained release S-(+)-MAMP HCl within one week, with weekly head hair samples collected by shaving. 3 weeks later, 4 of them received 4×20 mg (high) doses. After extensive isopropanol/phosphate buffer washing of the hair, MAMP and its metabolite amphetamine (AMP) concentrations were determined in all weekly hair samples by LC-MS-MS in selected reaction monitoring mode with the undeca- and deca-deuterated drugs, respectively, as internal standards (LLOQ, 0.005 ng/mg). Results MAMP Tmax occurred from 1 to 2 weeks after both doses, with Cmax ranging from 0.6–3.5 ng/mg after the low and 1.2–5.3 ng/mg after the high MAMP doses. AMP Cmax in hair was 0.1–0.3 ng/mg and 0.2–0.5 ng/mg, respectively, for low and high doses. Highly dose–related concentrations within subjects, but large variability between subjects were observed. MAMP concentrations were above the 0.2 ng/mg cutoff for at least two weeks following administration of both low and high doses. The overall AMP/MAMP ratio ranged from 0.07 to 0.37 with a mean value of 0.15±0.07, and a median of 0.13. The percentage of MAMP and AMP removed with the washing procedure decreased with time after administration. A strong correlation was found between area under the curve of MAMP (r2=0.90, p=0.00) and AMP (r2=0.94, p=0.00) concentrations calculated for the 3-week period following administration and the total melanin concentration in hair. Significant correlations were observed also between Cmax and melanin. Conclusions This study demonstrated that despite large inter-individual differences, the incorporation of MAMP and AMP into hair is dose-related with much of the observed scatter of MAMP and AMP concentrations explained by melanin concentration in hair. PMID:22541011

The impact of codeine re-scheduling on misuse: a retrospective review of calls to Australia's largest poisons centre.

PubMed

Cairns, Rose; Brown, Jared A; Buckley, Nicholas A

2016-10-01

Codeine is the most commonly used opioid in the world, and is available over the counter (OTC) in many countries, including Australia. Several countries are reconsidering codeine's OTC status due to concerns over addiction and misuse, with serious morbidity and mortality being reported. Australia's Therapeutic Goods Administration restricted codeine containing analgesics to 'Pharmacist Only' in 2010, and has recently been considering further up-scheduling to make codeine 'Prescription Only'. This paper estimated Australian trends of codeine misuse over the past 12 years, and examined whether trends changed following previous rescheduling efforts in 2010. A retrospective review of calls regarding codeine misuse made to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poisons centre), 2004-15. Joinpoint software was used to quantify the average annual change in calls, and whether there was a significant change in trend at any time, including following rescheduling. Australia. Four hundred patients about whom a call was made to the NSWPIC. Calls per year, patient age, gender, tablets taken per day, formulation used, symptom disposition. The NSWPIC database contained 400 cases of codeine combination analgesic misuse from 2004 to 2015. Joinpoint analysis showed that the frequency of cases increased significantly from 2004 to 2015, with an average annual percentage change (AAPC) of 19.5% [95% confidence interval (CI) = 13.8-25.5% P < 0.0001] for paracetamol/codeine and 17.9% (95% CI = 7.9-28.9%, P < 0.01) for ibuprofen/codeine. No significant change in trend was seen at any time, including following 2010 rescheduling. The median age of patients was 34 and 27 years for paracetamol/codeine and ibuprofen/codeine cases, respectively. Gender distribution was approximately equal. Clinical features reported were consistent with codeine, paracetamol and ibuprofen toxicity. Misuse of codeine combination products appears to be increasing in Australia. Limited rescheduling in 2010 failed to curb this increase. © 2016 Society for the Study of Addiction.

Identifying and treating codeine dependence: a systematic review.

PubMed

Nielsen, Suzanne; MacDonald, Tim; Johnson, Jacinta L

2018-06-04

Codeine dependence is a significant public health problem, motivating the recent rescheduling of codeine in Australia (1 February 2018). To provide information for informing clinical responses, we undertook a systematic review of what is known about identifying and treating codeine dependence. Articles published in English that described people who were codeine-dependent or a clinical approach to treating people who were codeine-dependent, without restriction on year of publication, were reviewed. Articles not including empirical data were excluded. One researcher screened each abstract; two researchers independently reviewed full text articles. Study quality was assessed, and data were extracted with standardised tools. MEDLINE and EMBASE were searched for relevant publications on 22 November 2016. The reference lists of eligible studies were searched to identify further relevant publications. 2150 articles were initially identified, of which 41 were eligible for inclusion in our analysis. Studies consistently reported specific characteristics associated with codeine dependence, including mental health comorbidity and escalation of codeine use attributed to psychiatric problems. Case reports and series described codeine dependence masked by complications associated with overusing simple analgesics and delayed detection. Ten studies described the treatment of codeine dependence. Three reports identified a role for behavioural therapy; the efficacy of CYP inhibitors in a small open label trial was not confirmed in a randomised controlled trial; four case series/chart reviews described opioid agonist therapy and medicated inpatient withdrawal; two qualitative studies identified barriers related to perceptions of codeine-dependent people and treatment providers, and confirmed positive perceptions and treatment outcomes achieved with opioid agonist treatments. Strategies for identifying problematic codeine use are needed. Identifying codeine dependence in clinical settings is often delayed, contributing to serious morbidity. Commonly described approaches for managing codeine dependence include opioid taper, opioid agonist treatment, and psychological therapies. These approaches are consistent with published evidence for pharmaceutical opioid dependence treatment and with broader frameworks for treating opioid dependence. PROSPERO registration: CRD42016052129.

New chlorinated amphetamine-type-stimulants disinfection-by-products formed during drinking water treatment.

PubMed

Huerta-Fontela, Maria; Pineda, Oriol; Ventura, Francesc; Galceran, Maria Teresa

2012-06-15

Previous studies have demonstrated high removal rates of amphetamine-type-stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3-dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L. Copyright © 2012 Elsevier Ltd. All rights reserved.

Psilocin identified in a DUID investigation.

PubMed

Tiscione, Nicholas B; Miller, Mattheu I

2006-06-01

Psilocin was identified in a urine specimen collected during a routine driving under the influence of drugs investigation, the first for this laboratory. The subject did not exhibit any response to an automobile crash, indicating the he may have been unaware of the severity of the situation or his immediate surroundings. The urine specimen gave a positive result on a fluorescence polarization immunoassay amphetamine/methamphetamine assay, and psilocin was determined to have 1.3% cross-reactivity at 50 mg/L. Psilocin was confirmed by gas chromatography-mass spectrometry following an extraction for acidic, neutral, and basic drugs. Hydrolysis and derivatization techniques were not employed. The urine concentration of psilocin decreased rapidly, although the specimen was maintained at 4 degrees C.

A re-examination of the mono-methoxy positional ring isomers of amphetamine, methamphetamine and phenyl-2-propanone.

PubMed

Dal Cason, T A

2001-06-15

Recently, tablets inscribed with the Mitsubishi 3-diamond logo, and sold as 3,4-methylenedioxymethamphetamine (MDMA), were found to contain p-methoxymethamphetamine (PMMA), a compound with MDMA-like effects. Shortly after this first submission, similarly inscribed tablets were encountered containing both PMMA and p-methoxyamphetamine (PMA). This second tablet composition has been implicated in several recent deaths in the US. Because two other positions are available for mono-methoxy substitution on the phenyl ring, it is essential that the correct identification be made for these compounds. Analytical data are supplied to enable differentiation of these ring isomers as well as the ketones that serve as their precursors.

Analysis of 44 drugs of abuse and metabolites in wastewater and river water using a hybrid quadrupole time-of-flight tandem mass spectrometry

NASA Astrophysics Data System (ADS)

Andres-Costa, M. Jesus; Andreu, Vicente; Picó, Yolanda

2016-04-01

The presence of drugs of abuse in the aquatic environment has been recognized as an important issue for the ecosystem due their possible negative effect on it (Richardson, 2011). Incomplete removal of these substances during wastewater treatment could be one of the causes of their release in the environment (Zuccato and Castiglioni, 2009). Pollution by illicit drug residues at very low concentrations is generalized in populated areas, with potential risks for human health and the environment (Zuccato, 2008; Castiglioni et al 2007).The aim of this study was to screen and quantify 44 drugs of abuse and metabolites of wastewater samples using a hybrid quadrupole time-of-flight tandem mass spectrometry and furthermore carry out a post-target screening to identify additional compounds present in the water samples. Wastewater samples were collected from the influent and effluent of three wastewater treatment plants (WWTPs) in Valencia and river water samples form Turia River Basin. Illicit drugs were extracted by solid-phase extraction (SPE). The chromatography was performed with an Agilent 1260 Infinity ultra high performance liquid chromatography (UHPLC). The UHPLC system was coupled to a hybrid quadrupole time-of-flight ABSciex Triple TOFTM 5600. All analytes were analyzed in positive mode. Acquiring full scan MS data was employed for quantification of drugs of abuse, and automatic data dependent information product ion spectra (IDA-MS/MS) was checked for identifying emerging illicit drugs and other compounds in water samples. The use of a database containing 1212 compounds achieved high confidence results for a wide number of contaminants. In the present study, the presence of compounds that belong to amphetamines group (amphetamine, methamphetamine, ephedrine, MDMA, MDA and MDEA), tryptamines (bufotenine), pirrolidinophenone group (α-PVP and 4'-MePHP), arylcyclohexylamines (ketamine), cocainics (cocaine, benzoylecgonine, cocaethylene and ecgonine methyl ester) and morphine derivatives (codeine, EDDP, morphine and methadone) and cannabinoids (THC) were detected in the influent, effluent or river water samples. These compounds were quantified, reaching cocainics and morphine derivates the highest values. Regarding post-target screening approach, more than 120 contaminants, mostly pharmaceuticals, but also mycotoxins and polyphenols were unambiguously identified. This new approach to data evaluation by non-target screening analyses opens the possibility of various other applications, for example in open and groundwater or for monitoring natural attenuation. Acknowledgements This work has been supported by the Spanish Ministry of Economy and Competitiveness trough the project CGL 2011-29703-C02-02. MJ Andrés Costa also acknowledges to this Ministry the FPI grant to perform her PhD. References Castiglioni S, Zuccato E. Chiabrando C., Faneli R., Bagnati R. Spectroscopy Europe (2007), 19, 7-9. Richardson SD. Anal Chem (2011), 84, 747-778. Zuccato E., Castiglioni S. Philos Trans R Soc A (2009), 367, 3965-3978. Zuccato E., Castiglioni S., Bagnati, R., Chiabrando C., Grassi P., Fanelli R. Water Res (2008), 42, 961-968.

Transformation of codeine and codeine-6-glucuronide to opioid analogues by urine adulteration with pyridinium chlorochromate: potential issue for urine drug testing.

PubMed

Luong, Susan; Ung, Alison T; Kalman, John; Fu, Shanlin

2014-07-30

Pyridinium chlorochromate (PCC) is the active ingredient of 'Urine Luck', a commercially available in vitro adulterating agent used to conceal the presence of drugs in a urine specimen. The exposure of codeine and its major glucuronide metabolite codeine-6-glucuronide (C6G) to PCC was investigated to determine whether PCC is an effective masking agent for these opiate compounds. Following the addition of PCC to both spiked and authentic codeine and C6G-positive urine specimens, the samples were monitored using liquid chromatography/mass spectrometry (LC/MS). Stable reaction products were identified and characterized using high-resolution MS analysis and, where possible, nuclear magnetic resonance (NMR) analysis. It was determined that PCC effectively oxidizes codeine and C6G, thus altering the original codeine-to-C6G ratio in the urine specimen. Four reaction products were identified for codeine: codeinone, 14-hydroxycodeinone, 6-O-methylcodeine and 8-hydroxy-7,8-dihydrocodeinone. Similarly, three reaction products were identified for C6G: codeinone, codeine and a lactone of C6G (tentative assignment). Besides addressing the complications added to interpretation, more investigation is warranted to further determine their potential for use as markers for monitoring the presence of codeine and C6G in urine specimens adulterated with PCC. Copyright © 2014 John Wiley & Sons, Ltd.

The challenge of complex drug use: Associated use of codeine-containing medicines and new psychoactive substances in a European cross-sectional online population.

PubMed

Kimergård, Andreas; Foley, Michelle; Davey, Zoe; Wadsworth, Elle; Drummond, Colin; Deluca, Paolo

2017-05-01

Misuse of codeine-containing medicines in combination with new psychoactive substances (NPS) is inadequately described. This study characterises codeine consumption amongst NPS users and non-NPS users to provide warning of health issues. Online survey conducted between July 2015 and March 2016. Out of 340 respondents, residing in a country in Europe and using codeine recently, 63.8% were female. Mean age: 34.9 years (SD = 12.4). Substance use included NPS (18.5%) and illicit controlled drugs (55.9%). Factors relating to codeine use found to significantly predict NPS use were consuming codeine extracted from combination tablets (OR = 16.79, 95% CI [8.67, 32.51]), obtaining codeine from friends, family, and acquaintances (OR = 3.98, 95% CI [1.82, 8.7]), use of illicit controlled drugs (OR = 34.99, 95% CI [8.39, 145.94]) and use of codeine to experience euphoria (OR = 6.41, 95% CI [3.42, 12.04]). Amongst NPS users, codeine is less likely to be used daily but more likely to be used for recreational purposes. Smaller populations engaging in high-risk use exist who take multiple drugs in high doses. Combinations of misused codeine and NPS highlight the need for policy to respond to a more complex drug situation. Copyright © 2017 John Wiley & Sons, Ltd.

Recent advances in Parkinson's disease therapy: use of monoamine oxidase inhibitors.

PubMed

Henchcliffe, Claire; Schumacher, H Christian; Burgut, F Tuna

2005-11-01

Monoamine oxidase inhibitors inhibit dopamine metabolism and are therefore effective in treating Parkinson's disease, a condition associated with progressive striatal dopamine deficiency secondary to degeneration of dopaminergic neurons in the substantia nigra. Selegiline is currently the most widely used monoamine oxidase-B inhibitor for Parkinson's disease, but has a low and variable bioavailability, and is metabolized to L-methamphetamine and L-amphetamine that carry a risk for potential neurotoxicity. There are two new approaches that circumvent these potential disadvantages. First, selegiline orally disintegrating tablets provide a novel delivery form of selegiline, avoiding first pass metabolism by rapid absorption through the oral mucosa, thus leading to significantly lower plasma concentrations of L-metamphetamine and L-amphetamine. Selegiline orally disintegrating tablets prove to be clinically effective and safe in patients with moderately advanced Parkinson's disease. Second, rasagiline is a new monoamine oxidase inhibitor, without known neurotoxic metabolites. In large clinical trials, rasagiline proves effective as monotherapy in early Parkinson's disease, as well as adjunctive therapy to levodopa in advanced disease. Clinical data suggest, in addition, a disease-modifying effect of rasagiline that may correlate with neuroprotective activity of monoamine oxidase-B inhibitors in animal models of Parkinson's disease.

Methamphetamine facilitates female sexual behavior and enhances neuronal activation in the medial amygdala and ventromedial nucleus of the hypothalamus.

PubMed

Holder, Mary K; Hadjimarkou, Maria M; Zup, Susan L; Blutstein, Tamara; Benham, Rebecca S; McCarthy, Margaret M; Mong, Jessica A

2010-02-01

Methamphetamine (MA) abuse has reached epidemic proportions in the United States. Users of MA report dramatic increases in sexual drive that have been associated with increased engagement in risky sexual behavior leading to higher rates of sexually transmitted diseases and unplanned pregnancies. The ability of MA to enhance sexual drive in females is enigmatic since related psychostimulants like amphetamine and cocaine appear not to affect sexual drive in women, and in rodents models, amphetamine has been reported to be inhibitory to female sexual behavior. Examination of MA's effects on female sexual behavior in an animal model is lacking. Here, using a rodent model, we have demonstrated that MA enhanced female sexual behavior. MA (5mg/kg) or saline vehicle was administered once daily for 3 days to adult ovariectomized rats primed with ovarian steroids. MA treatment significantly increased the number of proceptive events and the lordosis response compared to hormonally primed, saline controls. The effect of MA on the neural circuitry underlying the motivation for sexual behavior was examined using Fos immunoreactivity. In the medial amygdala and the ventromedial nucleus of the hypothalamus, nuclei implicated in motivated behaviors, ovarian hormones and MA independently enhance the neuronal activation, but more striking was the significantly greater activation induced by their combined administration. Increases in dopamine neurotransmission may underlie the MA/hormone mediated increase in neuronal activation. In support of this possibility, ovarian hormones significantly increased tyrosine hydroxylase (the rate limiting enzyme in dopamine synthesis) immunoreactivity in the medial amygdala. Thus our present data suggest that the interactions of MA and ovarian hormones leads to changes in the neural substrate of key nuclei involved in mediating female sexual behaviors, and these changes may underlie MA's ability to enhance these behaviors. 2009 Elsevier Ltd. All rights reserved.

Field Detection of Drugs of Abuse in Oral Fluid Using the Alere™ DDS®2 Mobile Test System with Confirmation by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS).

PubMed

Krotulski, Alex J; Mohr, Amanda L A; Friscia, Melissa; Logan, Barry K

2018-04-01

The collection and analysis of drugs in oral fluid (OF) at the roadside has become more feasible with the introduction of portable testing devices such as the Alere™ DDS®2 Mobile Test System (DDS®2). The objective of this study was to compare the on-site results for the DDS®2 to laboratory-based confirmatory assays with respect to detection of drugs of abuse in human subjects. As part of a larger Institutional Review Board approved study, two OF samples were collected from each participant at a music festival in Miami, FL, USA. One OF sample was field screened using the DDS®2, and a confirmatory OF sample was collected using the Quantisal™ OF collection device and submitted to the laboratory for testing. In total, 124 subjects participated in this study providing two contemporaneous OF samples. DDS®2 field screening yielded positive results for delta-9-tetrahydrocannabinol (THC) (n = 27), cocaine (n = 12), amphetamine (n = 3), methamphetamine (n = 3) and benzodiazepine (n = 1). No opiate-positive OF samples were detected. For cocaine, amphetamine, methamphetamine and benzodiazepines, the DDS®2 displayed sensitivity, specificity and accuracy of 100%. For THC, the DDS®2 displayed sensitivity of 90%, specificity of 100% and accuracy of 97.5%, when the threshold for confirmation matched that of the manufacturers advertised cut-off. When this confirmatory threshold was lowered to the analytical limit of detection (i.e., 1 ng/mL), apparent device performance for THC was poorer due to additional samples testing positive by confirmatory assay that had tested negative on the DDS®2, demonstrating a need for correlation between manufacturer cut-off and analytical reporting limit. These results from drug-using subjects demonstrate the value of field-based OF testing, and illustrate the significance of selecting an appropriate confirmation cut-off concentration with respect to performance evaluation and detection of drug use.

Enhanced Upregulation of CRH mRNA Expression in the Nucleus Accumbens of Male Rats after a Second Injection of Methamphetamine Given Thirty Days Later

PubMed Central

Cadet, Jean Lud; Brannock, Christie; Ladenheim, Bruce; McCoy, Michael T.; Krasnova, Irina N.; Lehrmann, Elin; Becker, Kevin G.; Jayanthi, Subramaniam

2014-01-01

Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; P<0.01) in the expression of 412 (352 upregulated, 60 down-regulated) transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (Crh), oxytocin (Oxt), and vasopressin (Avp) that were upregulated. Injection of METH (10 mg/kg) altered the expression of 503 (338 upregulated, 165 down-regulated) transcripts measured one month later (MS group). These genes also included Cart and Crh. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated) transcripts including Avp, Cart, and Crh. The METH-induced increased Crh expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crh, Cart, and Avp mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug. PMID:24475032

Tripling of Methamphetamine/Amphetamine Use among Homeless and Marginally Housed Persons, 1996–2003

PubMed Central

Colfax, Grant; Moss, Andrew R.; Bangsberg, David R.; Hahn, Judith A.

2007-01-01

Methamphetamine/amphetamine (MA)-related morbidity and mortality has been increasing in the United States. MA use is associated with high-risk sexual behavior and syringe-sharing practices. Homeless and marginalized housed persons (H/M) have high rates of substance use and mental health disorders. Little is known about trends of MA use among the H/M. The objective of this study was to quantify increases in MA use among H/M in San Francisco and to determine which demographic and behavioral subgroups have experienced the greatest increases in MA use. We conducted serial cross-sectional population-based studies in three waves: 1996–1997, 1999–2000, and 2003 and studied 2,348 H/M recruited at shelters and lunch lines. The main outcome was self-reported current (30-day) MA use. We found a tripling of current MA use among H/M persons from 1996 to 2003, with a sevenfold increase in smoked MA use. MA use doubled to tripled in most demographic and behavioral subgroups, whereas it quadrupled in those under age 35, and there was a fivefold increase among HIV-infected persons. The increase in MA use among H/M places a vulnerable population at additional increased risk for HIV infection and MA-use related morbidity and mortality. Among HIV-infected H/M, the increase in MA use has important public health implications for the development and secondary transmission of drug-resistant HIV caused by synergistic neurocognitive decline, poor adherence to HIV medications, and increased sexual risk behavior. Clinicians caring for H/M persons should inquire about MA use, refer interested MA users to MA dependence treatment programs and provide targeted HIV sexual risk reduction counseling. For HIV-infected H/M MA users, clinicians should closely monitor adherence to HIV or other chronic medications, to avoid unnecessary morbidity and mortality. Further research is needed to elucidate the most effective prevention and treatment for MA use and dependence among the H/M. PMID:18163214

Do prenatally methamphetamine-exposed adult male rats display general predisposition to drug abuse in the conditioned place preference test?

PubMed

Šlamberová, R; Pometlová, M; Schutová, B; Hrubá, L; Macúchová, E; Nová, E; Rokyta, R

2012-01-01

Drug abuse of pregnant women is a growing problem. The effect of prenatal drug exposure may have devastating effect on development of the offsprings that may be long-term or even permanent. One of the most common drug abused by pregnant women is methamphetamine (MA), which is also the most frequently abused illicit drug in the Czech Republic. Our previous studies demonstrated that prenatal MA exposure alters behavior, cognition, pain and seizures in adult rats in sex-specific manner. Our most recent studies demonstrate that prenatal MA exposure makes adult rats more sensitive to acute injection of the same or related drugs than their controls. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the Conditioned place preference (CPP). Adult male rats were divided to: prenatally MA-exposed (5 mg/kg daily for the entire prenatal period), prenatally saline-exposed (1 ml/kg of physiological saline) and controls (without maternal injections). The following drugs were used in the CPP test in adulthood: MA (5 mg/kg), amphetamine (5 mg/kg), cocaine (5 and 10 mg/kg), morphine (5 mg/kg), MDMA (5 mg/kg) and THC (2 mg/kg). Our data demonstrated that prenatally MA-exposed rats displayed higher amphetamine-seeking behavior than both controls. MA as well as morphine induced drug-seeking behavior of adult male rats, however this effect did not differ based on the prenatal MA exposure. In contrast, prenatal MA exposure induced rather tolerance to cocaine than sensitization after the conditioning in the CPP. MDMA and THC did not induce significant effects. Even though the present data did not fully confirmed our hypotheses, future studies are planned to test the drug-seeking behavior also in self-administration test.

A Clinical Tool for Reducing Central Nervous System Depression among Neonates Exposed to Codeine through Breast Milk

PubMed Central

Kelly, Lauren E.; Chaudhry, Shahnaz A.; Rieder, Michael J.; ‘t Jong, Geert; Moretti, Myla E.; Lausman, Andrea; Ross, Colin; Berger, Howard; Carleton, Bruce; Hayden, Michael R.; Madadi, Parvaz; Koren, Gideon

2013-01-01

Background Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety. Methods and Findings Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines. Conclusions The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity. PMID:23922910

Synthesis of novel sonocatalyst Er3+:YAlO3/Nb2O5 and its application for sonocatalytic degradation of methamphetamine hydrochloride.

PubMed

Wei, Chunsheng; Yi, Kuiyu; Sun, Guangsheng; Wang, Jun

2018-04-01

The composited sonocatalyst Er 3+ :YAlO 3 /Nb 2 O 5 was prepared by ultrasonic dispersion and high temperature calcinations method. The microstructure of Er 3+ :YAlO 3 was prepared via sol-gel method and Nb 2 O 5 was prepared by hydrothermal method. The samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectrometer (EDX), ultraviolet-visible (UV-vis) spectra and photoluminescence (PL) spectra, respectively. The sonocatalytic decomposition activity of composite sonocatalyst Er 3+ :YAlO 3 /Nb 2 O 5 was investigated by using ultrasound as sound source and methamphetamine hydrochloride as the target degradation product. The influences of composite sonocatalyst Er 3+ :YAlO 3 /Nb 2 O 5 with different ratios, calcination temperature, ultrasonic power, ultrasonic temperature and recycle times were investigated. The results showed that the sonocatalytic degradation rate was 82.17% after 5 h sonocatalytic decomposition under the condition of ultrasonic power of 700 W, frequency of 45 kHz and surrounding temperature of 30 °C. The sonocatalytic degradation ability of composite sonocatalyst for methamphetamine hydrochloride in aqueous solution was still good after recycled five times. The hydroxyl radicals (OH) and holes (h + ) are identified and hydroxyl radicals (OH) plays a major role during the oxidation process. The experimental results show that sonocatalytic is a new idea for the harmless treatment of amphetamine-type stimulants. Copyright © 2017 Elsevier B.V. All rights reserved.

History of the methamphetamine problem.

PubMed

Anglin, M D; Burke, C; Perrochet, B; Stamper, E; Dawud-Noursi, S

2000-01-01

Methamphetamine, called meth, crystal, or speed, is a central nervous system stimulant that can be injected, smoked, snorted, or ingested orally; prolonged use at high levels results in dependence. Methamphetamine (MA) is a derivative of amphetamine, which was widely prescribed in the 1950s and 1960s as a medication for depression and obesity, reaching a peak of 31 million prescriptions in the United States in 1967. Until the late 1980s, illicit use and manufacture of MA was endemic to California, but the MA user population has recently broadened in nature and in regional distribution, with increased use occurring in midwestern states. An estimated 4.7 million Americans (2.1% of the U.S. population) have tried MA at some time in their lives. Short- and long-term health effects of MA use include stroke, cardiac arrhythmia, stomach cramps, shaking, anxiety, insomnia, paranoia, hallucinations, and structural changes to the brain. Children of MA abusers are at risk of neglect and abuse, and the use of MA by pregnant women can cause growth retardation, premature birth, and developmental disorders in neonates and enduring cognitive deficits in children. MA-related deaths and admissions to hospital emergency rooms are increasing. Although inpatient hospitalization may be indicated to treat severe cases of long-term MA dependence, optimum treatment for MA abusers relies on an intensive outpatient setting with three to five visits per week of comprehensive counseling for at least the first three months. The burgeoning problems of increased MA use must be addressed by adequate treatment programs suitable for a variety of user types.

Kitchen chemistry: A scoping review of the diversionary use of pharmaceuticals for non-medicinal use and home production of drug solutions.

PubMed

Van Hout, Marie Claire

2014-01-01

Misuse of pharmaceuticals is of increasing drug policy and public health concern. A scoping review was conducted on the diversionary use of pharmaceuticals for non-medicinal use and home production of drug solutions. The research question was broad: What is known from the existing literature about the diversion of pharmaceuticals for non-medicinal use and for home production of drug solutions? The scoping process centred on the systematic selection, collection, and summarization of extant knowledge within this broad thematic remit. One hundred and thirty-four records were grouped into discrete thematic categories namely: non medicinal use and tampering with pharmaceuticals, oral misuse of codeine cough syrups, homemade drug solutions, and home-produced drug-related harms in the narrative review design. Forms of abuse of codeine cough syrup include mixtures with alcohol or soft drinks ('Purple Drank'), with kratom leaves ('Kratom cocktails'), or chemically altered to extract dextromorphan ('Lemon Drop'). Production of homemade opiates ('Cheornaya', 'Kolyosa', Himiya', 'Braun', 'Krokodil'), methamphetamine ('Vint', 'Pervitin'), methcathinone ('Jeff'), and cathinone ('Boltushka') are described. Displacement patterns between the non-medical use of pharmaceuticals, commercial, and homemade drugs appear dependent on availability of opiates, prescribing practices, supervision of substitution drug dosing, availability of cheap ingredients, policing, and awareness of harms. Adverse health and social consequences relate to the use of unknown and contaminated (end) substances, injecting practices, redosing, medical complications, and death. The review highlights a public health imperative requiring a multidisciplinary approach to quantify potential impact and required integrated policy responses incorporating international regulation, enforcement, health surveillance and service delivery. Copyright © 2014 John Wiley & Sons, Ltd.

Simultaneous determination of amphetamine-type stimulants and cannabinoids in fingernails by gas chromatography-mass spectrometry.

PubMed

Kim, Jin Young; Cheong, Jae Chul; Kim, Min Kyoung; Lee, Jae Il; In, Moon Kyo

2008-06-01

A gas chromatography-mass spectrometric (GC-MS) method was developed and validated for the simultaneous detection and quantification of four amphetamine-type stimulants (amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA)) and two cannabinoids (Delta9-tetrahydrocannabinol (Delta9-THC) and 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH)) in fingernails. Fingernail clippings (30 mg) were washed with distilled water and methanol, and then incubated in 1.0 M sodium hydroxide at 95 degrees C for 30 min. The compounds of interest were isolated by liquid-liquid extraction followed by derivatization with N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) at 70 degrees C for 15 min. The derivatized compounds were analyzed by GC-MS in the selective ion monitoring (SIM) mode. The linear ranges were 0.1-15.0 ng/mg for AP, 0.2-15.0 ng/mg for MDA, Delta9-THC and THCCOOH, and 0.2-30.0 ng/mg for MA and MDMA, with good correlation coefficients (r2 > 0.9991). The intra-day, inter-day, and inter-person precisions were within 10.6%, 6.3%, and 5.3%, respectively. The intra-day, inter-day and inter-person accuracies were between -6.1 and 5.0%, -6.2 and 5.7%, and -6.4 and 5.6%, respectively. The limits of detection (LODs) and quantification (LOQs) for each compound were lower than 0.056 and 0.2 ng/mg, respectively. The recoveries were in the range of 74.0-94.8%. Positive GC-MS results were obtained from specimens of nine suspected MA or cannabis abusers. The concentration ranges of MA, AP, and THCCOOH were 0.10-1.41, 0.12-2.64, and 0.20 ng/mg, respectively. Based on these results, the method proved to be effective for the simultaneous qualification and quantification of amphetamine-type stimulants and cannabinoids in fingernails.

A survey of nonmedical use of tranquilizers, stimulants, and pain relievers among college students: patterns of use among users and factors related to abstinence in non-users.

PubMed

Brandt, Sara A; Taverna, Elise C; Hallock, Robert M

2014-10-01

This study examined lifetime non-medical prescription drug use among college students at a small liberal arts college in the Northeast. We assessed the motives, frequency of use, sources, and perceived emotional/physical risks of nonmedical prescription drugs. Specifically, we examined the non-medical use of prescription pain relievers, stimulants, and anti-anxiety medication. We sent an internet-based survey to 1/3 of the student body and 303 students completed the survey. We found that 36.8% of the sample reported using prescription drugs for non-medical purposes. First-year students were less likely to have used the drugs than those in other class years. Of those reporting use, 48% reported non-medical use of pain relievers, 72.8% reported using stimulants, and 39.8% reported using anti-anxiety medication. The most commonly used pain relievers were Vicodin (hydrocodone/acetaminophen), OxyContin (oxycodone), and codeine (acetaminophen/codeine). The most commonly used stimulants were Adderall (amphetamine/dextroamphetamine) and Ritalin (methylphenidate), while the most commonly used anti-anxiety medication was Xanax (alprazolam). When non-users were asked what factors influenced their choice not to abuse prescription drugs, 82% cited a lack of interest, 61% responded it was due to a fear of damaging their physical health, and 60.1% responded fear of damaging their mental health. This study supports recent findings that show widespread non-medical use of prescription drugs among college students. Our report brings a more detailed understanding of the patterns of drug usage, and the factors influencing both drug use in those who use them and abstinence in those who choose not to use them. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Trace amine-associated receptor 1: a promising target for the treatment of psychostimulant addiction

PubMed Central

Jing, Li; Li, Jun-Xu

2015-01-01

Abuse of and addiction to psychostimulants remains a challenging clinical issue, yet no effective pharmacotherapy is available. Trace amine associated receptor 1 (TAAR 1) is increasingly recognized as a novel drug target that participates in the modulation of drug abuse. This review analyzed existing preclinical evidence from electrophysiological, biochemical to behavioral aspects regarding the functional interactions between TAAR 1 and dopaminergic system. TAAR 1 knockout mice demonstrate increased sensitivity to dopaminergic activation while TAAR 1 agonists reduce the neurochemical effects of cocaine and amphetamines, attenuate abuse- and addiction-related behavioral effects of cocaine and methamphetamine. It is concluded that TAAR 1 activation functionally modulate the dopaminergic activity and TAAR 1 agonists appear to be promising pharmacotherapies against psychostimulant addiction. PMID:26092759

A New Sensitive Sensor for Simultaneous Differential Pulse Voltammetric Determination of Codeine and Acetaminophen Using a Hydroquinone Derivative and Multiwall Carbon Nanotubes Carbon Paste Electrode

PubMed Central

Garazhian, Elahe; Shishehbore, M. Reza

2015-01-01

A new sensitive sensor was fabricated for simultaneous determination of codeine and acetaminophen based on 4-hydroxy-2-(triphenylphosphonio)phenolate (HTP) and multiwall carbon nanotubes paste electrode at trace levels. The sensitivity of codeine determination was deeply affected by spiking multiwall carbon nanotubes and a modifier in carbon paste. Electron transfer coefficient, α, catalytic electron rate constant, k, and the exchange current density, j 0, for oxidation of codeine at the HTP-MWCNT-CPE were calculated using cyclic voltammetry. The calibration curve was linear over the range 0.2–844.7 μM with two linear segments, and the detection limit of 0.063 μM of codeine was obtained using differential pulse voltammetry. The modified electrode was separated codeine and acetaminophen signals by differential pulse voltammetry. The modified electrode was applied for the determination of codeine and acetaminophen in biological and pharmaceutical samples with satisfactory results. PMID:25945094

Acetaminophen and codeine overdose

MedlinePlus

... this page: //medlineplus.gov/ency/article/002562.htm Acetaminophen and codeine overdose To use the sharing features on this page, please enable JavaScript. Acetaminophen (Tylenol) and codeine is a prescription pain medicine. ...

21 CFR 862.3270 - Codeine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862... in the diagnosis and treatment of codeine use or overdose and in monitoring levels of codeine to...

Abnormal white matter integrity in chronic users of codeine-containing cough syrups: a tract-based spatial statistics study.

PubMed

Qiu, Y-W; Su, H-H; Lv, X-F; Jiang, G-H

2015-01-01

Codeine-containing cough syrups have become one of the most popular drugs of abuse in young people in the world. Chronic codeine-containing cough syrup abuse is related to impairments in a broad range of cognitive functions. However, the potential brain white matter impairment caused by chronic codeine-containing cough syrup abuse has not been reported previously. Our aim was to investigate abnormalities in the microstructure of brain white matter in chronic users of codeine-containing syrups and to determine whether these WM abnormalities are related to the duration of the use these syrups and clinical impulsivity. Thirty chronic codeine-containing syrup users and 30 matched controls were evaluated. Diffusion tensor imaging was performed by using a single-shot spin-echo-planar sequence. Whole-brain voxelwise analysis of fractional anisotropy was performed by using tract-based spatial statistics to localize abnormal WM regions. The Barratt Impulsiveness Scale 11 was surveyed to assess participants' impulsivity. Volume-of-interest analysis was used to detect changes of diffusivity indices in regions with fractional anisotropy abnormalities. Abnormal fractional anisotropy was extracted and correlated with clinical impulsivity and the duration of codeine-containing syrup use. Chronic codeine-containing syrup users had significantly lower fractional anisotropy in the inferior fronto-occipital fasciculus of the bilateral temporo-occipital regions, right frontal region, and the right corona radiata WM than controls. There were significant negative correlations among fractional anisotropy values of the right frontal region of the inferior fronto-occipital fasciculus and the right superior corona radiata WM and Barratt Impulsiveness Scale total scores, and between the right frontal region of the inferior fronto-occipital fasciculus and nonplan impulsivity scores in chronic codeine-containing syrup users. There was also a significant negative correlation between fractional anisotropy values of the right frontal region of the inferior fronto-occipital fasciculus and the duration of codeine-containing syrup use in chronic users. Chronic codeine-containing syrup abuse may be associated with disruptions in brain WM integrity. These WM microstructural deficits may be linked to higher impulsivity in chronic codeine-containing syrup users. © 2015 by American Journal of Neuroradiology.

Impact of Safety-Related Regulations on Codeine Use in Children: A Quasi-Experimental Study Using Taiwan's National Health Insurance Research Database.

PubMed

Lin, Chih-Wan; Wang, Ching-Huan; Huang, Wei-I; Ke, Wei-Ming; Chao, Pi-Hui; Chen, Wen-Wen; Hsiao, Fei-Yuan

2017-07-01

Safety concerns regarding potential life-threatening adverse events associated with codeine have resulted in policy decisions to restrict its use in pediatrics. However, whether these drug safety communications have had an immediate and strong impact on codeine use remains in question. We aimed to investigate the impact of the two implemented safety-related regulations (label changes and reimbursement regulations) on the use of codeine for upper respiratory infection (URI) or cough. A quasi-experimental study was performed using Taiwan's National Health Insurance Research Database. Quarterly data of codeine prescription rates for URI/cough visits were reported, and an interrupted time series design was used to assess the impact of the safety regulations on the uses of codeine among children with URI/cough visits. Multivariable logistic regression models were used to explore patient and provider characteristics associated with the use of codeine. The safety-related regulations were associated with a significant reduction in codeine prescription rates of -4.24% (95% confidence interval [CI] -4.78 to -3.70), and the relative reduction compared with predicted rates based on preregulation projections was 60.4, 56.6, and 53.2% in the first, second, and third year after the regulations began, respectively. In the postregulation period, physicians specializing in otolaryngology (odds ratio [OR] 1.47, 95% CI 1.45-1.49), practicing in district hospitals (OR 6.84, 95% CI 5.82-8.04) or clinics (OR 6.50, 95% CI 5.54-7.62), and practicing in the least urbanized areas (OR 1.60, 95% CI 1.55-1.64) were more likely to prescribe codeine to children than their counterparts. Our study provides a successful example of how to effectively reduce the codeine prescriptions in children in the 'real-world' settings, and highlights areas where future effort could be made to improve the safety use of codeine. Future research is warranted to explore whether there was a simultaneous decrease in the incidence rates of codeine-related adverse events following the safety-related regulations.

Comparison of the postoperative analgesic effects of paracetamol-codeine phosphate and naproxen sodium-codeine phosphate for lumbar disk surgery.

PubMed

Polat, Reyhan; Peker, Kevser; Gülöksüz, Çiğdem Topçu; Ergil, Julide; Akkaya, Taylan

2015-09-01

The aim of this study was to compared the efficacy of paracetamol-codeine phosphate and naproxen sodium-codeine phosphate on postoperative pain and tramadol consumption during the first 24 hours after a lumbar disk surgery. After Ethics Committee approval and informed consent had been obtained, 64 patients were allocated into three groups. Patients received oral paracetamol-codeine (300 mg + 30 mg; Group P), naproxen sodium-codeine (550 mg + 30 mg; Group N), or placebo tablets (Group C) 30 minutes prior to induction of anesthesia. Patient-controlled analgesia was supplied postoperatively using tramadol. Pain intensity, tramadol consumption, and side effects were recorded every 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after surgery. Whole study period pain intensity (visual analogue scale scores) was lower in Group P (p = 0.007) and Group N (p = 0.001), compared with Group C, however, there was no statistically significant difference between Group P and Group N regarding pain intensity (p > 0.05). Tramadol consumption was lower in Group P and Group N, compared with Group C (p < 0.001), and in turn the lowest incidence of tramadol consumption was detected in Group P compared with Group N (p < 0.001) and Group C (p < 0.001). Side effects were similar between the groups. Preemptive administration of paracetamol-codeine and naproxen sodium-codeine combination significantly reduced tramadol consumption and provided more effective analgesia compared with placebo. The paracetamol-codeine combination was superior to naproxen sodium-codeine with regard to tramadol consumption. Copyright © 2015. Published by Elsevier Taiwan.

Codeine misuse and dependence in South Africa--learning from substance abuse treatment admissions.

PubMed

Dada, S; Harker Burnhams, N; Van Hout, M C; Parry, C D H

2015-09-14

Misuse of prescription and over-the-counter codeine-containing products is a global public health issue. To investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in South Africa (SA) and the profile of patients seeking treatment, so as to understand the nature and extent of the problem. Data were collected from centres participating in the South African Community Epidemiology Network on Drug Use in 2014. A total of 17 260 admissions were recorded. There were 435 recorded treatment admissions for codeine misuse or dependence as a primary or secondary substance of abuse (2.5% of all admissions). Of treatment admissions, 137 (0.8%) involved codeine as the primary substance of abuse; 74.9% of patients were males, with an even spread across population groups. Ages ranged from 11 to 70 years, with the highest proportion aged 20 - 29 years; >40% were referred by self, family and/or friends, and 26.7% by health professionals; and 36.8% had received treatment previously. The majority reported misuse of tablets/capsules, with 17.6% reporting misuse of syrups. Oral use comprised 96.6% and daily use 63.1%. Data from treatment admissions related to codeine misuse and dependence are informative, but provide an incomplete picture of the nature and extent of codeine-related problems in SA. Other data sources must be considered before further regulatory/policy changes regarding codeine are implemented.

Representations of Codeine Misuse on Instagram: Content Analysis

PubMed Central

Cherian, Roy; Westbrook, Marisa; Ramo, Danielle

2018-01-01

Background Prescription opioid misuse has doubled over the past 10 years and is now a public health epidemic. Analysis of social media data may provide additional insights into opioid misuse to supplement the traditional approaches of data collection (eg, self-report on surveys). Objective The aim of this study was to characterize representations of codeine misuse through analysis of public posts on Instagram to understand text phrases related to misuse. Methods We identified hashtags and searchable text phrases associated with codeine misuse by analyzing 1156 sequential Instagram posts over the course of 2 weeks from May 2016 to July 2016. Content analysis of posts associated with these hashtags identified the most common themes arising in images, as well as culture around misuse, including how misuse is happening and being perpetuated through social media. Results A majority of images (50/100; 50.0%) depicted codeine in its commonly misused form, combined with soda (lean). Codeine misuse was commonly represented with the ingestion of alcohol, cannabis, and benzodiazepines. Some images highlighted the previously noted affinity between codeine misuse and hip-hop culture or mainstream popular culture images. Conclusions The prevalence of codeine misuse images, glamorizing of ingestion with soda and alcohol, and their integration with mainstream, popular culture imagery holds the potential to normalize and increase codeine misuse and overdose. To reduce harm and prevent misuse, immediate public health efforts are needed to better understand the relationship between the potential normalization, ritualization, and commercialization of codeine misuse. PMID:29559422

A high-throughput urinalysis of abused drugs based on a SPE-LC-MS/MS method coupled with an in-house developed post-analysis data treatment system.

PubMed

Cheng, Wing-Chi; Yau, Tsan-Sang; Wong, Ming-Kei; Chan, Lai-Ping; Mok, Vincent King-Kuen

2006-10-16

A rapid urinalysis system based on SPE-LC-MS/MS with an in-house post-analysis data management system has been developed for the simultaneous identification and semi-quantitation of opiates (morphine, codeine), methadone, amphetamines (amphetamine, methylamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA)), 11-benzodiazepines or their metabolites and ketamine. The urine samples are subjected to automated solid phase extraction prior to analysis by LC-MS (Finnigan Surveyor LC connected to a Finnigan LCQ Advantage) fitted with an Alltech Rocket Platinum EPS C-18 column. With a single point calibration at the cut-off concentration for each analyte, simultaneous identification and semi-quantitation for the above mentioned drugs can be achieved in a 10 min run per urine sample. A computer macro-program package was developed to automatically retrieve appropriate data from the analytical data files, compare results with preset values (such as cut-off concentrations, MS matching scores) of each drug being analyzed and generate user-defined Excel reports to indicate all positive and negative results in batch-wise manner for ease of checking. The final analytical results are automatically copied into an Access database for report generation purposes. Through the use of automation in sample preparation, simultaneous identification and semi-quantitation by LC-MS/MS and a tailored made post-analysis data management system, this new urinalysis system significantly improves the quality of results, reduces the post-data treatment time, error due to data transfer and is suitable for high-throughput laboratory in batch-wise operation.

Pharmacokinetics and pharmacodynamics of oral acetaminophen in combination with codeine in healthy Greyhound dogs.

PubMed

KuKanich, B

2016-10-01

The purpose of this study was to determine the pharmacokinetic and antinociceptive effects of an acetaminophen/codeine combination administered orally to six healthy greyhounds. Antinociception was assessed using an electronic von Frey (vF) device as a mechanical/pressure model. Acetaminophen was administered at a dose of 600 mg (14.4-23.1 mg/kg) and codeine phosphate at 90 mg (2.1-3.3 mg/kg) equivalent to 67.5 mg codeine base (1.6-2.5 mg/kg). The geometric mean maximum plasma concentrations of acetaminophen, codeine, and codeine-6-glucuronide were 7.95 μg/mL, 11.0 ng/mL, and 3819 ng/mL, respectively. Morphine concentrations were <1 ng/mL. The terminal half-lives of acetaminophen, codeine, and codeine-6-glucuronide were 0.94, 1.71, and 3.12 h. There were no significant changes in vF thresholds, except at 12 h which decreased on average by 17% compared to baseline. The decrease in vF thresholds at 12 h could be due to aversion, hyperalgesia, or random variability. The lack of antinociception in this study could be due to a true lack of antinociception, lack of model sensitivity, or specificity. Further studies using different models (including clinical trials), different dog breeds, multiple dose regimens, and a range of dosages are needed prior to recommended use or concluding lack of efficacy for oral acetaminophen/codeine in dogs. © 2016 John Wiley & Sons Ltd.

Representations of Codeine Misuse on Instagram: Content Analysis.

PubMed

Cherian, Roy; Westbrook, Marisa; Ramo, Danielle; Sarkar, Urmimala

2018-03-20

Prescription opioid misuse has doubled over the past 10 years and is now a public health epidemic. Analysis of social media data may provide additional insights into opioid misuse to supplement the traditional approaches of data collection (eg, self-report on surveys). The aim of this study was to characterize representations of codeine misuse through analysis of public posts on Instagram to understand text phrases related to misuse. We identified hashtags and searchable text phrases associated with codeine misuse by analyzing 1156 sequential Instagram posts over the course of 2 weeks from May 2016 to July 2016. Content analysis of posts associated with these hashtags identified the most common themes arising in images, as well as culture around misuse, including how misuse is happening and being perpetuated through social media. A majority of images (50/100; 50.0%) depicted codeine in its commonly misused form, combined with soda (lean). Codeine misuse was commonly represented with the ingestion of alcohol, cannabis, and benzodiazepines. Some images highlighted the previously noted affinity between codeine misuse and hip-hop culture or mainstream popular culture images. The prevalence of codeine misuse images, glamorizing of ingestion with soda and alcohol, and their integration with mainstream, popular culture imagery holds the potential to normalize and increase codeine misuse and overdose. To reduce harm and prevent misuse, immediate public health efforts are needed to better understand the relationship between the potential normalization, ritualization, and commercialization of codeine misuse. ©Roy Cherian, Marisa Westbrook, Danielle Ramo, Urmimala Sarkar. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 20.03.2018.

Synthetic cathinones and their rewarding and reinforcing effects in rodents.

PubMed

Watterson, Lucas R; Olive, M Foster

2014-06-04

Synthetic cathinones, colloquially referred to as "bath salts", are derivatives of the psychoactive alkaloid cathinone found in Catha edulis (Khat). Since the mid-to-late 2000's, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death. However, scientific information regarding the abuse liability of these drugs has been relatively slower to materialize. Recently we have published several studies demonstrating that laboratory rodents will readily self-administer the "first generation" synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone via the intravenous route, in patterns similar to those of methamphetamine. Under progressive ratio schedules of reinforcement, the rank order of reinforcing efficacy of these compounds are MDPV ≥ methamphetamine > methylone. MDPV and methylone, as well as the "second generation" synthetic cathinones α-pyrrolidinovalerophenone (α-PVP) and 4-methylethcathinone (4-MEC), also dose-dependently increase brain reward function. Collectively, these findings indicate that synthetic cathinones have a high abuse and addiction potential and underscore the need for future assessment of the extent and duration of neurotoxicity induced by these emerging drugs of abuse.

Qualitative and quantitative temporal analysis of licit and illicit drugs in wastewater in Australia using liquid chromatography coupled to mass spectrometry.

PubMed

Bade, Richard; White, Jason M; Gerber, Cobus

2018-01-01

The combination of qualitative and quantitative bimonthly analysis of pharmaceuticals and illicit drugs using liquid chromatography coupled to mass spectrometry is presented. A liquid chromatography-quadrupole time of flight instrument equipped with Sequential Window Acquisition of all THeoretical fragment-ion spectra (SWATH) was used to qualitatively screen 346 compounds in influent wastewater from two wastewater treatment plants in South Australia over a 14-month period. A total of 100 compounds were confirmed and/or detected using this strategy, with 61 confirmed in all samples including antidepressants (amitriptyline, dothiepin, doxepin), antipsychotics (amisulpride, clozapine), illicit drugs (cocaine, methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA)), and known drug adulterants (lidocaine and tetramisole). A subset of these compounds was also included in a quantitative method, analyzed on a liquid chromatography-triple quadrupole mass spectrometer. The use of illicit stimulants (methamphetamine) showed a clear decrease, levels of opioid analgesics (morphine and methadone) remained relatively stable, while the use of new psychoactive substances (methylenedioxypyrovalerone (MDPV) and Alpha PVP) varied with no visible trend. This work demonstrates the value that high-frequency sampling combined with quantitative and qualitative analysis can deliver. Graphical abstract Temporal analysis of licit and illicit drugs in South Australia.

N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells.

PubMed

Zhang, Xinsheng; Banerjee, Atrayee; Banks, William A; Ercal, Nuran

2009-06-12

Oxidative stress plays an important role in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Methamphetamine (METH) is an amphetamine analog that causes degeneration of the dopaminergic system in mammals and subsequent oxidative stress. In our present study, we have used immortalized human brain microvascular endothelial (HBMVEC) cells to test whether N-acetylcysteine amide (NACA), a novel antioxidant, prevents METH-induced oxidative stress in vitro. Our studies showed that NACA protects against METH-induced oxidative stress in HBMVEC cells. NACA significantly protected the integrity of our blood brain barrier (BBB) model, as shown by permeability and trans-endothelial electrical resistance (TEER) studies. NACA also significantly increased the levels of intracellular glutathione (GSH) and glutathione peroxidase (GPx). Malondialdehyde (MDA) levels increased dramatically after METH exposure, but this increase was almost completely prevented when the cells were treated with NACA. Generation of reactive oxygen species (ROS) also increased after METH exposure, but was reduced to control levels with NACA treatment, as measured by dichlorofluorescin (DCF). These results suggest that NACA protects the BBB integrity in vitro, which could prevent oxidative stress-induced damage; therefore, the effectiveness of this antioxidant should be evaluated for the treatment of neurodegenerative diseases in the future.

Synthetic cathinones and their rewarding and reinforcing effects in rodents

PubMed Central

Watterson, Lucas R.; Olive, M. Foster

2014-01-01

Synthetic cathinones, colloquially referred to as “bath salts”, are derivatives of the psychoactive alkaloid cathinone found in Catha edulis (Khat). Since the mid-to-late 2000’s, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death. However, scientific information regarding the abuse liability of these drugs has been relatively slower to materialize. Recently we have published several studies demonstrating that laboratory rodents will readily self-administer the “first generation” synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone via the intravenous route, in patterns similar to those of methamphetamine. Under progressive ratio schedules of reinforcement, the rank order of reinforcing efficacy of these compounds are MDPV ≥ methamphetamine > methylone. MDPV and methylone, as well as the “second generation” synthetic cathinones α-pyrrolidinovalerophenone (α-PVP) and 4-methylethcathinone (4-MEC), also dose-dependently increase brain reward function. Collectively, these findings indicate that synthetic cathinones have a high abuse and addiction potential and underscore the need for future assessment of the extent and duration of neurotoxicity induced by these emerging drugs of abuse. PMID:25328910

Khat Use and Neurobehavioral Functions: Suggestions for Future Studies

PubMed Central

Hoffman, Richard; al’Absi, Mustafa

2010-01-01

Although there is a rich body of research available regarding the effect of acute and chronic khat dosing in animal models, research on the behavioral and cognitive effects of khat in human subjects is not extensive and several of the available studies have been done only in the context of observational and single-case studies. In light of the absence of a substantial literature on the neurobehavioral deficits associated with khat use and to provide a context that could be used to identify themes for future research we review previous research that has focused on other stimulant drugs. This review highlights multiple areas of neurocognitive deficit that have been identified in previous studies of individuals who have been chronic users of stimulants, such as amphetamines and methamphetamines. The review highlights a substantial body of evidence demonstrating a wide range of learning and memory impairments including deficits that persist during abstinence from active drug use. This review does not imply a similar khat effect, but due to some similarities pharmacologically between the active components of khat (cathinone and cathine) and amphetamines, future studies examining these same domains of cognitive functioning in chronic khat users and abstinent khat users appears to be warranted, if possible using some of the same or similar laboratory measures. PMID:20553832

Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

PubMed Central

Chen, Pin-I; Cao, Aiqin; Miyagawa, Kazuya; Tojais, Nancy F.; Hennigs, Jan K.; Li, Caiyun G.; Sweeney, Nathaly M.; Inglis, Audrey S.; Wang, Lingli; Li, Dan; Ye, Matthew; Feldman, Brian J.

2017-01-01

Amphetamine (AMPH) or methamphetamine (METH) abuse can cause oxidative damage and is a risk factor for diseases including pulmonary arterial hypertension (PAH). Pulmonary artery endothelial cells (PAECs) from AMPH-associated-PAH patients show DNA damage as judged by γH2AX foci and DNA comet tails. We therefore hypothesized that AMPH induces DNA damage and vascular pathology by interfering with normal adaptation to an environmental perturbation causing oxidative stress. Consistent with this, we found that AMPH alone does not cause DNA damage in normoxic PAECs, but greatly amplifies DNA damage in hypoxic PAECs. The mechanism involves AMPH activation of protein phosphatase 2A, which potentiates inhibition of Akt. This increases sirtuin 1, causing deacetylation and degradation of HIF1α, thereby impairing its transcriptional activity, resulting in a reduction in pyruvate dehydrogenase kinase 1 and impaired cytochrome c oxidase 4 isoform switch. Mitochondrial oxidative phosphorylation is inappropriately enhanced and, as a result of impaired electron transport and mitochondrial ROS increase, caspase-3 is activated and DNA damage is induced. In mice given binge doses of METH followed by hypoxia, HIF1α is suppressed and pulmonary artery DNA damage foci are associated with worse pulmonary vascular remodeling. Thus, chronic AMPH/METH can induce DNA damage associated with vascular disease by subverting the adaptive responses to oxidative stress. PMID:28138562

Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults

PubMed Central

Toms, Laurence; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

2014-01-01

Background This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly. Objectives Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events. Search methods We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update. Selection criteria Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults. Data collection and analysis Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo. Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups. Authors’ conclusions This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information. PMID:19160199

Acetaminophen and Codeine

MedlinePlus

The combination of acetaminophen and codeine is used to relieve mild to moderate pain. Acetaminophen is in a class of medications called analgesics ( ... The combination of acetaminophen and codeine comes as a tablet, capsule, and liquid to take by mouth. It usually is taken every 4 ...

Amphetamines and cannabinoids testing in hair: Evaluation of results from a two-year period.

PubMed

Burgueño, María José; Alonso, Amaya; Sánchez, Sergio

2016-08-01

This paper presents an overview of a set of amphetamines and cannabinoids tests performed on head hair samples from the Medico-Legal sector at the Madrid Department of the Spanish National Institute of Toxicology and Forensic Sciences during the years 2013 and 2014. The hair samples were tested for five stimulant phenylalkylamine derivatives -amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), and 3,4-methylenedioxy-N-ethylamphetamine (MDEA)- and/or two cannabinoids-Δ(9)-tetrahydrocannabinol (THC) and cannabinol (CBN)- by gas chromatography equipped with mass spectrometry detection in selected-ion monitoring mode, applying a method accredited to ISO/IEC 17025 standards. The test results were interpreted according to the confirmation cut-offs proposed by the Society of Hair Testing (SoHT) to identify chronic drug use. The ratios of positive results were studied in relation to gender, age, hair colour, dyeing and length of the tested samples to assess the independence from these variables or the association with them. Low, medium and high ranges of concentration were also estimated for each drug. 21.94% of the 2954 hair samples tested for phenylalkylamine derivatives were positive for one or more substances. 16.38% of the samples were positive for AP, 12.09% for MDMA and only 0.44% for MA. 6.60% of the tested samples were positive for AP/MDMA combination. A total of 3178 samples were tested for cannabinoids, resulting in 53.40% positive for THC and CBN. Simultaneous tests for phenylalkylamine derivatives and cannabinoids were performed in 2931 of the samples; 14.94% of them were positive for THC, CBN, and one or more amphetamines. According to the results from the statistical analysis, the use of THC and MDMA vary with age and gender among the Medico-Legal sector in an extended area of Spain, while the use of AP appears to be independent of these variables. On the other hand, the results of THC in hair could be influenced by the length of the tested segment; therefore, a consensus regarding the hair length between 3.0 and 5.5cm for THC testing should be reached. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Identification of prenatal amphetamines exposure by maternal interview and meconium toxicology in the Infant Development, Environment and Lifestyle (IDEAL) study.

PubMed

Gray, Teresa R; LaGasse, Linda L; Smith, Lynne M; Derauf, Chris; Grant, Penny; Shah, Rizwan; Arria, Amelia M; Della Grotta, Sheri A; Strauss, Arthur; Haning, William F; Lester, Barry M; Huestis, Marilyn A

2009-12-01

The Infant Development Environment and Lifestyle study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development; potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration, and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis, and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry. The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by gas chromatography mass spectrometry. Tobacco exposure was equally detected by immunoassay cotinine screening and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use or frequency or route of MAMP use. Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women stopped MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers.

The external gate of the human and Drosophila serotonin transporters requires a basic/acidic amino acid pair for 3,4-methylenedioxymethamphetamine (MDMA) translocation and the induction of substrate efflux.

PubMed

Sealover, Natalie R; Felts, Bruce; Kuntz, Charles P; Jarrard, Rachel E; Hockerman, Gregory H; Lamb, Patrick W; Barker, Eric L; Henry, L Keith

2016-11-15

The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters. The resulting dramatic increase in volume transmission and signal duration of neurotransmitters leads to psychotropic, stimulant, and entactogenic effects. The mechanism by which amphetamines drive reverse transport of the monoamines remains largely enigmatic, however, promising outcomes for the therapeutic utility of MDMA for post-traumatic stress disorder and the long-time use of the dopaminergic and noradrenergic-directed amphetamines in treatment of attention-deficit hyperactivity disorder and narcolepsy increases the importance of understanding this phenomenon. Previously, we identified functional differences between the human and Drosophila melanogaster serotonin transporters (hSERT and dSERT, respectively) revealing that MDMA is an effective substrate for hSERT but not dSERT even though serotonin is a potent substrate for both transporters. Chimeric dSERT/hSERT transporters revealed that the molecular components necessary for recognition of MDMA as a substrate was linked to regions of the protein flanking transmembrane domains (TM) V through IX. Here, we performed species-scanning mutagenesis of hSERT, dSERT and C. elegans SERT (ceSERT) along with biochemical and electrophysiological analysis and identified a single amino acid in TM10 (Glu394, hSERT; Asn484, dSERT, Asp517, ceSERT) that is primarily responsible for the differences in MDMA recognition. Our findings reveal that an acidic residue is necessary at this position for MDMA recognition as a substrate and serotonin releaser. Copyright © 2016 Elsevier Inc. All rights reserved.

Monoamine transporter and receptor interaction profiles of a new series of designer cathinones.

PubMed

Simmler, L D; Rickli, A; Hoener, M C; Liechti, M E

2014-04-01

Psychoactive β-keto amphetamines (cathinones) are sold as "bath salts" or "legal highs" and recreationally abused. We characterized the pharmacology of a new series of cathinones, including methedrone, 4-methylethcathinone (4-MEC), 3-fluoromethcathinone (3-FMC), pentylone, ethcathinone, buphedrone, pentedrone, and N,N-dimethylcathinone. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-HT) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporter, the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells, and binding affinity to monoamine transporters and receptors. All of the cathinones were potent NE uptake inhibitors but differed in their DA vs. 5-HT transporter inhibition profiles and monoamine release effects. Methedrone was a more potent 5-HT than DA transporter inhibitor and released NE and 5-HT similar to para-methoxymethamphetamine (PMMA), para-methoxyamphetamine (PMA), 4-methylthioamphetamine (4-MTA), and 3,4-methylenedioxymethamphetamine (MDMA). 4-MEC and pentylone equipotently inhibited all of the monoamine transporters and released 5-HT. Ethcathinone and 3-FMC inhibited NE and DA uptake and released NE, and 3-FMC also released DA similar to N-ethylamphetamine and methamphetamine. Pentedrone and N,N-dimethylcathinone were non-releasing NE and DA uptake inhibitors as previously shown for pyrovalerone cathinones. Buphedrone preferentially inhibited NE and DA uptake and also released NE. None of the cathinones bound to rodent trace amine-associated receptor 1, in contrast to the non-β-keto-amphetamines. None of the cathinones exhibited relevant binding to other monoamine receptors. In summary, we found considerable differences in the monoamine transporter interaction profiles among different cathinones and compared with related amphetamines. Copyright © 2013 Elsevier Ltd. All rights reserved.

Abuse of Medications Employed for the Treatment of ADHD: Results From a Large-Scale Community Survey

PubMed Central

Bright, George M.

2008-01-01

Objective The objective is to assess abuse of prescription and illicit stimulants among individuals being treated for attention-deficit/hyperactivity disorder (ADHD). Methods A survey was distributed to patients enrolled in an ADHD treatment center. It included questions designed to gain information about demographics; ADHD treatment history; illicit drug use; and misuse of prescribed stimulant medications, including type of stimulant medication most frequently misused or abused, and how the stimulant was prepared and administered. Results A total of 545 subjects (89.2% with ADHD) were included in the survey. Results indicated that 14.3% of respondents abused prescription stimulants. Of these, 79.8% abused short-acting agents; 17.2% abused long-acting stimulants; 2.0% abused both short- and long-acting agents; and 1.0% abused other agents. The specific medications abused most often were mixed amphetamine salts (Adderall; 40.0%), mixed amphetamine salts extended release (Adderall XR; 14.2%), and methylphenidate (Ritalin; 15.0%), and the most common manner of stimulant abuse was crushing pills and snorting (75.0%). Survey results also showed that 39.1% of respondents used nonprescription stimulants, most often cocaine (62.2%), methamphetamine (4.8%), and both cocaine and amphetamine (31.1%). Choice of illicit drug was based on rapidity of high onset (43.5%), ease of acquisition (40.7%), ease of use (10.2%), and cost (5.5%). Conclusions The risks for abuse of prescription and illicit stimulants are elevated among individuals being treated in an ADHD clinic. Prescription agents used most often are those with pharmacologic and pharmacokinetic characteristics that provide a rapid high. This suggests that long-acting stimulant preparations that have been developed for the treatment of ADHD may have lower abuse potential than short-acting formulations. PMID:18596945

One-Step Derivatization-Extraction Method for Rapid Analysis of Eleven Amphetamines and Cathinones in Oral Fluid by GC-MS.

PubMed

Mohamed, Khaled

2017-09-01

A simple analytical method was developed for in-matrix derivatization of 11 amphetamine-like molecules. Ethyl chloroformate as the derivatization reagent and ethyl acetate as the extraction solvent were added directly to oral fluid samples at alkaline pH. Samples were analyzed by gas chromatography-mass spectrometry. Ions monitored for quantification were m/z 44, 91 and 116 for amphetamine (AMP); m/z 58, 91 and 130 for methamphetamine (MA); m/z 44, 105 and 116 for 4-methylamphetamine; m/z 44, 116 and 251 for 3,4-methylenedioxyamphetamine; m/z 58, 130 and 265 for 3,4-methylenedioxymethamphetamine (MDMA); m/z 72, 116 and 144 for 3,4-methylenedioxyethylamphetamine; m/z 44, 105 and 116 for cathinone; m/z 58, 105 and 130 for methcathinone; m/z 58, 119 and 130 for mephedrone; m/z 58, 107 and 130 for ephedrine (EPH); m/z 207, 250 and 322 for fenethylline; m/z 48, 92 and 120 for AMP-D5; m/z 62, 92 and 134 for MA-D5; m/z 48, 120 and 256 for MDA-D5; and m/z 62, 134 and 270 for MDMA-D5. The underlined ions were used as quantifier ions. Calibration curves were linear in the concentration range of 2.5-1,000 ng/mL for all analytes except for EPH, which was linear within 5-1,000 ng/mL. Precision and accuracy were less than 12.9% (relative standard deviation) and ±12.8% (bias), respectively, for all analytes. The method was tested in the analysis of oral fluid specimens collected from users. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

PubMed Central

Quiding, H; Olsson, G L; Boreus, L O; Bondesson, U

1992-01-01

1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine. PMID:1540490

Determination of morphine and codeine in urine using poly(dimethylsiloxane) microchip electrophoresis with electrochemical detection.

PubMed

Zhang, Qian-Li; Xu, Jing-Juan; Li, Xiang-Yun; Lian, Hong-Zhen; Chen, Hong-Yuan

2007-01-04

In this paper, a poly(dimethylsiloxane) (PDMS) microchip with electrochemical (EC) detection was developed for rapid separation and detection of morphine and codeine. It was found that morphine and codeine were well separated within 140 s in phosphate buffer solution (PBS) (pH 6.6, 40 mM)-beta-cyclodextrin (beta-CD) (20 mM)-acetonitrile (30%, v/v). The detection limit was 0.2 microM for morphine and 1 microM for codeine. The protocol was successfully applied to monitoring the amount of morphine and codeine in human urine. Compared with the conventional methods, the presented method had many advantages such as lower instrument cost, less reagent consumption and shorter analysis time.

To prescribe codeine or not to prescribe codeine?

PubMed

Fleming, Marc L; Wanat, Matthew A

2014-09-01

A recently published study in Pediatrics by Kaiser et al. (2014; Epub April 21, DOI: 10.1542/peds.2013-3171) reported that on average, over the past decade, children aged 3 to 17 were prescribed approximately 700,000 prescriptions for codeine-containing products each year in association with emergency department (ED) visits. Although, guidelines from the American Academy of Pediatrics issued warnings in 1997 and reaffirmed their concerns regarding the safety and effectiveness of codeine in 2006, it is still often prescribed for pain and cough associated with upper respiratory infection. With the impending rescheduling of hydrocodone combination products to Schedule II, physicians and mid-level prescribers may be compelled to prescribe codeine-containing products (e.g., with acetaminophen) due to reduced administrative burden and limits on Schedule II prescriptive authority for nurse practitioners and physician assistants in some states. This commentary expounds on the safety and effectiveness concerns of codeine, with a primary focus on patients in the ED setting.

"Tampering to Death": A Fatal Codeine Intoxication Due to a Homemade Purification of a Medical Formulation.

PubMed

Fais, Paolo; Pigaiani, Nicola; Cecchetto, Giovanni; Montisci, Massimo; Gottardo, Rossella; Viel, Guido; Pascali, Jennifer Paola; Tagliaro, Franco

2017-11-01

Many homemade tamper processes of medical codeine formulations are available on selected "forums" on the Internet, where recreational codeine users claim to be able to purify codeine by removing additives, such as acetaminophen, to avoid or limit adverse effects. In this work, it is reported and discussed a fatal case of codeine intoxication. The findings of objects such as jars, filters, and tablets, and amounts of unknown liquid material at the death scene investigation suggested a fatal codeine intoxication after the tampering procedure called "cold water extraction." Toxicological results obtained from the analysis of both the nonbiological material and the body fluids of the decedent integrated with the information collected at the death scene investigation confirmed the above-mentioned hypothesis. This report underlines the importance of a tight interconnection between criminalistics and legal medicine to strengthen the identification of the cause of death and the reconstruction of the event. © 2017 American Academy of Forensic Sciences.

CHANGING PRESCRIBING CULTURE - A FOCUS ON CODEINE POSTPARTUM.

PubMed

Al-Adhami, Noor; Whitfield, Karen; North, Angela

2016-09-01

To eliminate the prescribing of codeine and codeine combination products postpartum to improve safety in breast fed infants.Concerns have been raised over the use of codeine and codeine combination products during breast feeding after the death of a neonate whose mother had been prescribed codeine postpartum. High concentrations of morphine were found in the infant's blood and this was attributed to the mother being a CYP2D6 ultrafast metaboliser.1 METHODS: The evidence surrounding the safety of codeine and codeine combination products in children, during the postpartum period and specifically for breast fed infants was collated. The evidence was presented to key stakeholders including obstetricians, midwives, safety and quality representatives, nurse unit managers and acute pain team representatives. Postpartum analgesia was discussed and an agreed protocol developed. Training and education sessions were undertaken to obstetric medical and nursing staff. The evidence that was presented to key stakeholders included:▸ Reports over the safety concerns surrounding the use of codeine and codeine combination products during breast feeding▸ Guidelines and contraindications about the use of codeine in children that had been issued by international regulatory bodies (US Food and Drug Administration and European Medicines Agency).▸ Recommendations from the Australian Medicines Handbook to avoid in breast feeding2 ▸ Recommendations from Hale's Medications and Mothers Milk that reported limited data and had made a recent re-classification from L3 (limited data-probably compatible) to L4 (limited data-possibly hazardous).3 Before presenting the evidence to key stakeholders and undertaking training to nursing and medical staff, more than 90% of postpartum women were prescribed a codeine containing product as part of their 'as required' analgesic regimen.Since the intervention, codeine combination products have now been almost completely eliminated on medication charts for postpartum women (less than 5%). Those that are prescribed are ceased once highlighted to medical staff. The obstetric pharmacist now presents a session on postpartum analgesia at every new resident medical officer orientation outlining suitable medications to prescribe. In addition all new pharmacists to the women's and new born's team receive training about postpartum analgesia. This study highlights the impact that can be achieved when health care professionals work together to change the culture and prescribing habits in a hospital setting, to enhance patient safety. Evaluating the evidence and presenting to stakeholders as well as providing ongoing training and education to medical, nursing and pharmacy staff are all essential to a successful outcome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The complexity of intestinal permeability: Assigning the correct BCS classification through careful data interpretation.

PubMed

Zur, Moran; Hanson, Allison S; Dahan, Arik

2014-09-30

While the solubility parameter is fairly straightforward when assigning BCS classification, the intestinal permeability (Peff) is more complex than generally recognized. In this paper we emphasize this complexity through the analysis of codeine, a commonly used antitussive/analgesic drug. Codeine was previously classified as a low-permeability compound, based on its lower LogP compared to metoprolol, a marker for the low-high permeability class boundary. In contrast, high fraction of dose absorbed (Fabs) was reported for codeine, which challenges the generally recognized Peff-Fabs correlation. The purpose of this study was to clarify this ambiguity through elucidation of codeine's BCS solubility/permeability class membership. Codeine's BCS solubility class was determined, and its intestinal permeability throughout the small intestine was investigated, both in vitro and in vivo in rats. Codeine was found to be unequivocally a high-solubility compound. All in vitro studies indicated that codeine's permeability is higher than metoprolol's. In vivo studies in rats showed similar permeability for both drugs throughout the entire small-intestine. In conclusion, codeine was found to be a BCS Class I compound. No Peff-Fabs discrepancy is involved in its absorption; rather, it reflects the risk of assigning BCS classification based on merely limited physicochemical characteristics. A thorough investigation using multiple experimental methods is prudent before assigning a BCS classification, to avoid misjudgment in various settings, e.g., drug discovery, formulation design, drug development and regulation. Copyright © 2013 Elsevier B.V. All rights reserved.

Paracetamol-codeine compared to ketorolac for pain control in the Emergency Department.

PubMed

Buccelletti, F; Marsiliani, D; Zuccalà, G; Iacomini, P; Proietti, L; Pola, E; Zirio, G; Genitiempo, M; Marrocco, R; Conti, C; Brunetti, C; Rocchi, L; Merendi, G; D'Aurizio, G; Gilardi, E; Franceschi, F

2014-10-01

Paracetamol /codeine has shown a strong analgesic activity in several studies conducted among different kind of subjects, including those with trauma. Nevertheless, its efficacy in patients accessing the Emergency Department (ED) for different kind of pain has never been tested. This is a cross-sectional, observational, prospective, cohort study. Inclusion criteria were patients > 18 year old presenting to the ED for localized traumatic or inflammatory pain involving only extremities. Numeric scale (NRS) was recorded thirty minutes and two hours after the administration of the analgesic therapy, consisting of 15 mg of ketorolac or 1000 mg/60 mg of paracetamol/ codeine, both orally. Two-hundred patients were consecutively enrolled; 87 were treated with paracetamol/codeine and 113 with ketorolac. The combination paracetamol/codeine resulted to be not inferior to ketorolac in non-traumatic pain group and trauma group (p = 0.635 and p = 0.482, respectively). Compared to ketorolac, the combination paracetamol/codeine exerted a significantly higher analgesic activity in patients with fractures and muscular pain (p = 0.044) and was more effective in acute pain (p = 0.002), with a significant effect two hours after the administration (p = 0.029). Paracetamol/codeine is equivalent to ketorolac in non-traumatic pain and post-traumatic pain, but is superior in acute pain and in patients with fractures and muscular pain. Those results play in favor of the use of the combination paracetamol/codeine in patients accessing the ED for non-traumatic or traumatic pain of the extremities.

Quantitative detection of codeine in human plasma using surface-enhanced Raman scattering via adaptation of the isotopic labelling principle.

PubMed

Subaihi, Abdu; Muhamadali, Howbeer; Mutter, Shaun T; Blanch, Ewan; Ellis, David I; Goodacre, Royston

2017-03-27

In this study surface enhanced Raman scattering (SERS) combined with the isotopic labelling (IL) principle has been used for the quantification of codeine spiked into both water and human plasma. Multivariate statistical approaches were employed for the analysis of these SERS spectral data, particularly partial least squares regression (PLSR) which was used to generate models using the full SERS spectral data for quantification of codeine with, and without, an internal isotopic labelled standard. The PLSR models provided accurate codeine quantification in water and human plasma with high prediction accuracy (Q 2 ). In addition, the employment of codeine-d 6 as the internal standard further improved the accuracy of the model, by increasing the Q 2 from 0.89 to 0.94 and decreasing the low root-mean-square error of predictions (RMSEP) from 11.36 to 8.44. Using the peak area at 1281 cm -1 assigned to C-N stretching, C-H wagging and ring breathing, the limit of detection was calculated in both water and human plasma to be 0.7 μM (209.55 ng mL -1 ) and 1.39 μM (416.12 ng mL -1 ), respectively. Due to a lack of definitive codeine vibrational assignments, density functional theory (DFT) calculations have also been used to assign the spectral bands with their corresponding vibrational modes, which were in excellent agreement with our experimental Raman and SERS findings. Thus, we have successfully demonstrated the application of SERS with isotope labelling for the absolute quantification of codeine in human plasma for the first time with a high degree of accuracy and reproducibility. The use of the IL principle which employs an isotopolog (that is to say, a molecule which is only different by the substitution of atoms by isotopes) improves quantification and reproducibility because the competition of the codeine and codeine-d 6 for the metal surface used for SERS is equal and this will offset any difference in the number of particles under analysis or any fluctuations in laser fluence. It is our belief that this may open up new exciting opportunities for testing SERS in real-world samples and applications which would be an area of potential future studies.

Drugs in hair. Part I. Metabolisms of major drug classes.

PubMed

White, R M

2017-01-01

Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered. Copyright © 2017 Central Police University.

Lack of respiratory depression in paracetamol-codeine combination overdoses.

PubMed

Heppell, Simon P E; Isbister, Geoffrey K

2017-06-01

Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987-2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; absolute difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group. Paracetamol-codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression. © 2016 The British Pharmacological Society.

Simultaneous screening and quantification of 29 drugs of abuse in oral fluid by solid-phase extraction and ultraperformance LC-MS/MS.

PubMed

Badawi, Nora; Simonsen, Kirsten Wiese; Steentoft, Anni; Bernhoft, Inger Marie; Linnet, Kristian

2009-11-01

The European DRUID (Driving under the Influence of Drugs, Alcohol And Medicines) project calls for analysis of oral fluid (OF) samples, collected randomly and anonymously at the roadside from drivers in Denmark throughout 2008-2009. To analyze these samples we developed an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for detection of 29 drugs and illicit compounds in OF. The drugs detected were opioids, amphetamines, cocaine, benzodiazepines, and Delta-9-tetrahydrocannabinol. Solid-phase extraction was performed with a Gilson ASPEC XL4 system equipped with Bond Elut Certify sample cartridges. OF samples (200 mg) diluted with 5 mL of ammonium acetate/methanol (vol/vol 90:10) buffer were applied to the columns and eluted with 3 mL of acetonitrile with aqueous ammonium hydroxide. Target drugs were quantified by use of a Waters ACQUITY UPLC system coupled to a Waters Quattro Premier XE triple quadrupole (positive electrospray ionization mode, multiple reaction monitoring mode). Extraction recoveries were 36%-114% for all analytes, including Delta-9-tetrahydrocannabinol and benzoylecgonine. The lower limit of quantification was 0.5 mug/kg for all analytes. Total imprecision (CV) was 5.9%-19.4%. With the use of deuterated internal standards for most compounds, the performance of the method was not influenced by matrix effects. A preliminary account of OF samples collected at the roadside showed the presence of amphetamine, cocaine, codeine, Delta-9-tetrahydrocannabinol, tramadol, and zopiclone. The UPLC-MS/MS method makes it possible to detect all 29 analytes in 1 chromatographic run (15 min), including Delta-9-tetrahydrocannabinol and benzoylecgonine, which previously have been difficult to incorporate into multicomponent methods.

Evaluating a switch from meconium to umbilical cord tissue for newborn drug testing: A retrospective study at an academic medical center.

PubMed

Palmer, Kendra L; Wood, Kelly E; Krasowski, Matthew D

2017-04-01

The objective of this study was to compare detection rates of newborn drug exposure at an academic medical center transitioning from meconium to umbilical cord tissue toxicology testing. We performed an Institutional Review Board-approved retrospective chart review on all newborns (n=2072) for whom newborn drug testing was ordered at our academic medical center between June 2012 and August 2015 (in August 2013, umbilical cord tissue became the preferred specimen). Meconium toxicology testing was positive for at least one compound in 221 cases (21.3% of 1037 total specimens), with non-medical drug use identified in 85 cases (8.2%). Umbilical cord tissue toxicology testing was positive for at least one compound in 302 cases (29.2%), with non-medical drug use identified in 107 cases (10.3%). Of the cases involving non-medical drug use, the most common compounds detected were tetrahydrocannabinol and amphetamines. Non-medical drug use did not differ significantly between meconium and umbilical cord tissue, either as a total or for classes of drugs such as amphetamines, cannabinoids, and opiates. Maternal non-medical use of tramadol (not tested for in meconium) was identified in 5 cases (0.4%). There were significant differences in rate of detection of iatrogenic medications. Specifically, morphine, lorazepam, phenobarbital, and codeine were more commonly detected in meconium, while oxycodone was more commonly detected in umbilical cord tissue. Umbilical cord tissue toxicology testing yielded a similar detection rate compared to meconium testing. The use of umbilical cord tissue avoids detection of medications given to the neonate prior to meconium collection. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response.

PubMed

McMillan, Douglas M; Tyndale, Rachel F

2017-12-01

Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Nicotine induction of rat brain CYP2D increases acute codeine conversion to morphine, and analgesia, however the role of brain CYP2D on the effects of repeated codeine exposure and tolerance is unknown. Rats were pretreated with nicotine (brain CYP2D inducer; 1mg/kg subcutaneously) or vehicle (saline; 1ml/kg subcutaneously). Codeine (40-60mg/kg oral-gavage) or morphine (20-30mg/kg oral-gavage) was administered daily and analgesia was assessed daily using the tail-flick reflex assay. Nicotine (versus saline) pretreatment increased acute codeine analgesia (1.32-fold change in AUC 0-60 min ; p<0.05) and the rate of loss of peak analgesia (11.42%/day versus 4.20%; p<0.006) across the first four days of codeine administration (time to negligible analgesia). Inducing brain CYP2D with nicotine did not alter acute morphine analgesia (1.03-fold; p>0.8), or the rate of morphine tolerance (8.1%/day versus 7.6%; p>0.9). The rate of both codeine and morphine tolerance (loss in peak analgesia from day 1 to day 4) correlated with initial analgesic response on day 1 (R=0.97, p<001). Increasing brain CYP2D altered initial analgesia and subsequent rate of tolerance. Variation in an individual's initial response to analgesic (e.g. high initial dose, smoking) may affect the rate of tolerance, and thereby the risk for dose escalation and/or opioid dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

Codeine Shopping Behavior in a Retrospective Cohort of Chronic Noncancer Pain Patients: Incidence and Risk Factors.

PubMed

Chenaf, Chouki; Kabore, Jean-Luc; Delorme, Jessica; Pereira, Bruno; Mulliez, Aurélien; Roche, Lucie; Eschalier, Alain; Delage, Noémie; Authier, Nicolas

2016-12-01

Codeine is a widely used opioid analgesic but studies on its misuse in chronic noncancer pain (CNCP) are still lacking. The aim of this study was to assess the incidence of codeine shopping behavior in CNCP patients and to identify the associated risk factors. This was a population-based retrospective cohort study from the French health insurance claims database from 2004 to 2014. The main outcome was the one-year incidence of codeine shopping behavior defined as ≥1 day of overlapping prescriptions written by ≥2 different prescribers and filled in ≥3 different pharmacies. A total of 1,958 CNCP patients treated with codeine were included, with a mean age of 62.7 ± 16.1 years, 36.8% men. The 1-year incidence rate of codeine shopping behavior was 4.03% (95% confidence interval [CI], 3.07-5.28). In multivariate analysis, risk factors associated with shopping behavior were younger age (≤40 years) (hazard ratio [HR] = 7.29; 95% CI, 4.28-12.42), mental health disorders (HR = 2.25; 95% CI, 1.08-4.67), concurrent use of anxiolytic benzodiazepines (HR = 3.12; 95% CI, 1.55-6.26), and previous use of strong opioids (HR = 2.94; 95% CI, 1.24-6.98). The incidence of codeine shopping behavior in CNCP patients was 4% and risk factors identified were shared with those of opioid abuse. Shopping behavior for codeine was not infrequent in CNCP patients. The risk factors identified in this study are similar to those identified for opioid abuse in other studies. Appropriate use of codeine from the perspectives of patients and healthcare providers should be encouraged. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Spatial differences and temporal changes in illicit drug use in Europe quantified by wastewater analysis.

PubMed

Ort, Christoph; van Nuijs, Alexander L N; Berset, Jean-Daniel; Bijlsma, Lubertus; Castiglioni, Sara; Covaci, Adrian; de Voogt, Pim; Emke, Erik; Fatta-Kassinos, Despo; Griffiths, Paul; Hernández, Félix; González-Mariño, Iria; Grabic, Roman; Kasprzyk-Hordern, Barbara; Mastroianni, Nicola; Meierjohann, Axel; Nefau, Thomas; Ostman, Marcus; Pico, Yolanda; Racamonde, Ines; Reid, Malcolm; Slobodnik, Jaroslav; Terzic, Senka; Thomaidis, Nikolaos; Thomas, Kevin V

2014-08-01

To perform wastewater analyses to assess spatial differences and temporal changes of illicit drug use in a large European population. Analyses of raw wastewater over a 1-week period in 2012 and 2013. Catchment areas of wastewater treatment plants (WWTPs) across Europe, as follows: 2012: 25 WWTPs in 11 countries (23 cities, total population 11.50 million); 2013: 47 WWTPs in 21 countries (42 cities, total population 24.74 million). Excretion products of five illicit drugs (cocaine, amphetamine, ecstasy, methamphetamine, cannabis) were quantified in wastewater samples using methods based on liquid chromatography coupled to mass spectrometry. Spatial differences were assessed and confirmed to vary greatly across European metropolitan areas. In general, results were in agreement with traditional surveillance data, where available. While temporal changes were substantial in individual cities and years (P ranging from insignificant to <10(-3) ), overall means were relatively stable. The overall mean of methamphetamine was an exception (apparent decline in 2012), as it was influenced mainly by four cities. Wastewater analysis performed across Europe provides complementary evidence on illicit drug consumption and generally concurs with traditional surveillance data. Wastewater analysis can measure total illicit drug use more quickly and regularly than is the current norm for national surveys, and creates estimates where such data does not exist. © 2014 Society for the Study of Addiction.

Differential action of methamphetamine on tyrosine hydroxylase and dopamine transport in the nigrostriatal pathway of μ-opioid receptor knockout mice.

PubMed

Park, Sang Won; He, Zhi; Shen, Xine; Roman, Richard J; Ma, Tangeng

2012-06-01

Extensive anatomical and functional interactions exist between central dopaminergic and opioidergic systems and both systems are proposed to be targets for amphetamine-like drugs. We have previously reported that μ-opioid receptor (μ-OR) knockout mice are resistant to the loss of dopamine in the striatum and the development of behavioral sensitization induced by repeated methamphetamine (METH) treatment. The present study assessed whether METH-treated μ-OR knockout mice exhibit a differential response of the expression of dopamine transporter and tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis and maintaining dopamine levels. Mice daily received intraperitoneal injection of METH (0, 0.6, 2.5, or 10 mg/kg) for 7 days and sacrificed on day 11 (4 days after the last injection). The expression of TH protein in the striatum and the levels of TH mRNA and number of TH positive neurons in the substantia nigra were reduced in wild-type mice treated with METH (2.5 and 10 mg/kg), but not in the μ-OR knockout mice. In contrast, METH exposure at the highest dose (10 mg/kg) reduced dopamine transporter levels in both strains of mice. These results suggest that the μ-OR contributes to METH-induced loss of dopamine and behavioral sensitization by decreasing the expression of TH.

Spatial differences and temporal changes in illicit drug use in Europe quantified by wastewater analysis

PubMed Central

Ort, Christoph; van Nuijs, Alexander L N; Berset, Jean-Daniel; Bijlsma, Lubertus; Castiglioni, Sara; Covaci, Adrian; de Voogt, Pim; Emke, Erik; Fatta-Kassinos, Despo; Griffiths, Paul; Hernández, Félix; González-Mariño, Iria; Grabic, Roman; Kasprzyk-Hordern, Barbara; Mastroianni, Nicola; Meierjohann, Axel; Nefau, Thomas; Östman, Marcus; Pico, Yolanda; Racamonde, Ines; Reid, Malcolm; Slobodnik, Jaroslav; Terzic, Senka; Thomaidis, Nikolaos; Thomas, Kevin V

2014-01-01

Aims To perform wastewater analyses to assess spatial differences and temporal changes of illicit drug use in a large European population. Design Analyses of raw wastewater over a 1-week period in 2012 and 2013. Setting and Participants Catchment areas of wastewater treatment plants (WWTPs) across Europe, as follows: 2012: 25 WWTPs in 11 countries (23 cities, total population 11.50 million); 2013: 47 WWTPs in 21 countries (42 cities, total population 24.74 million). Measurements Excretion products of five illicit drugs (cocaine, amphetamine, ecstasy, methamphetamine, cannabis) were quantified in wastewater samples using methods based on liquid chromatography coupled to mass spectrometry. Findings Spatial differences were assessed and confirmed to vary greatly across European metropolitan areas. In general, results were in agreement with traditional surveillance data, where available. While temporal changes were substantial in individual cities and years (P ranging from insignificant to <10−3), overall means were relatively stable. The overall mean of methamphetamine was an exception (apparent decline in 2012), as it was influenced mainly by four cities. Conclusions Wastewater analysis performed across Europe provides complementary evidence on illicit drug consumption and generally concurs with traditional surveillance data. Wastewater analysis can measure total illicit drug use more quickly and regularly than is the current norm for national surveys, and creates estimates where such data does not exist. PMID:24861844

MDMA, methamphetamine and their combination: possible lessons for party drug users from recent preclinical research.

PubMed

Clemens, Kelly J; McGregor, Iain S; Hunt, Glenn E; Cornish, Jennifer L

2007-01-01

The substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and methamphetamine (METH, 'ice', 'speed') are increasingly popular drugs amongst party-drug users. Studies with humans have investigated the acute and possible long-term adverse effects of these drugs, yet outcomes of such studies are often ambiguous due to a variety of confounding factors. Studies employing animal models have value in determining the acute and long-term effects of MDMA and METH on brain and behaviour. Self-administration studies show that intravenous METH is a particularly potent reinforcer in rats and other species. In contrast, MDMA appears to have powerful effects in enhancing social behaviour in laboratory animals. Brief exposure to MDMA or METH may produce long-term reductions in dopamine, serotonin and noradrenaline in the brain and alterations in the density of various receptor and transporter proteins. However it is still unclear, particularly in the case of MDMA, whether this reflects a 'neurotoxic' effect of the drug. Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies. Recent laboratory studies suggest that MDMA/METH combinations may produce greater adverse neurochemical and behavioural effects than either drug alone. This is of some concern given recent evidence that party drug users may be frequently exposed to this combination of drugs.

Anticodeine aptamer immobilized on a Whatman cellulose paper for thin-film microextraction of codeine from urine followed by electrospray ionization ion mobility spectrometry.

PubMed

Hashemian, Zahra; Khayamian, Taghi; Saraji, Mohammad

2015-02-01

A combination of thin-film microextaction based on an aptamer immobilized on modified Whatman cellulose paper followed by electrospray ionization ion mobility spectrometry has been developed for the analysis of codeine in urine samples. The immobilization is based on the covalent linking of an amino-modified anticodeine aptamer to aldehyde groups of the oxidized cellulose paper. The covalent bonds were examined by infrared spectroscopy and elemental analysis. The effect of the extraction parameters, including the elution conditions (solvent type and volume), extraction time, and extraction temperature, on the extraction efficiency were investigated. Under the optimized conditions, the linear dynamic range was found to be 10-300 ng/mL with a detection limit of 3.4 ng/mL for codeine in urine. The relative standard deviation was 6.8% for three replicate measurements of codeine at 100 ng/mL in urine. Furthermore, the samples were analyzed with a standard method for the analysis of codeine using high-performance liquid chromatography with ultraviolet detection. The comparison of the results validates the accuracy of the proposed method as an alternative method for the analysis of codeine in urine samples.

The occurrence of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs in surface water in South Wales, UK.

PubMed

Kasprzyk-Hordern, Barbara; Dinsdale, Richard M; Guwy, Alan J

2008-07-01

The presence and fate of 56 pharmaceuticals, personal care products, endocrine disruptors and illicit drugs (PPCPs) were investigated in the South Wales region of the UK. Two contrasting rivers: River Taff and River Ely were chosen for this investigation and were monitored for a period of 10 months. The impact of the factors affecting the levels of concentration of PPCPs and illicit drugs in surface water such as surrounding area, proximity to wastewater effluent and weather conditions, mainly rainfall was also investigated. Most PPCPs were frequently found in river water at concentrations reaching single microgL(-1) and their levels depended mainly on the extent of water dilution resulting from rainfall. Discharge of treated wastewater effluent into the river course was found to be the main cause of water contamination with PPCPs. The most frequently detected PPCPs represent the group of pharmaceuticals dispensed at the highest levels in the Welsh community. These were antibacterial drugs (trimethoprim, erythromycin-H(2)O and amoxicillin), anti-inflammatories/analgesics (paracetamol, tramadol, codeine, naproxen, ibuprofen and diclofenac) and antiepileptic drugs (carbamazepine and gabapentin). Only four PPCPs out of 56 (simvastatin, pravastatin, digoxin and digoxigenin) were not quantified over the course of the study. Several PPCPs were found to be both ubiquitous and persistent in the aqueous environment (e.g. erythromycin-H(2)O, codeine, carbamazepine, gabapentin and valsartan). The calculated average daily loads of PPCPs indicated that in total almost 6 kg of studied PPCPs are discharged daily into the studied rivers. The illicit drugs studied were found in rivers at low levels of ng L(-1). Average daily loads of amphetamine, cocaine and its main metabolite benzoylecgonine were as follows: 8, 1.2 and 39 gday(-1), respectively. Their frequent occurrence in surface water is primarily associated with their high illegal usage and is strongly associated with the discharge of insufficiently treated wastewater effluent.

Codeine and its alternates for pain and cough relief*

PubMed Central

Eddy, Nathan B.; Friebel, Hans; Hahn, Klaus-Jürgen; Halbach, Hans

1969-01-01

This report—the third of a series on codeine and its alternates for pain and cough relief—presents a detailed review of the physiology and pathophysiology of cough, the methods for the experimental and clinical measurement of the antitussive action of drugs, possible mechanisms of action of antitussive agents, and includes a compilation of experimental results and clinical experience with codeine as an antitussive. PMID:4896168

"Codeine Is My Helper": Misuse of and Dependence on Codeine-Containing Medicines in South Africa.

PubMed

Van Hout, Marie Claire; Rich, Eileen; Dada, Siphokazi; Bergin, Michael

2017-02-01

Misuse of codeine-containing medicines is an emerging global public health concern. The majority of research has been conducted in developed countries (European Members States, Australia, the United States). This study aimed to gain an understanding of unique individual and collective experiences of trajectories of codeine misuse and dependence in South Africa. In-depth interviews were conducted with a purposive sample of adult codeine misusers and dependents ( n = 25). Narratives were analyzed using the empirical phenomenological psychological five-step method. Nine themes with 63 categories emerged, with two additional high levels of abstraction. Findings are illustrated: participant profile and product preferences, motives for use, transitioning to misuse and dependence, pharmacy purchasing and alternative sourcing routes, effects and withdrawal experiences, help-seeking and treatment experiences, and strategies for prevention. The study underscores the need for continued support for enhanced patient awareness of risk of habit forming use and related health consequences and professional pharmacovigilance.

Codeine and its alternates for pain and cough relief*

PubMed Central

Eddy, Nathan B.; Friebel, Hans; Hahn, Klaus-Jürgen; Halbach, Hans

1968-01-01

This report—the first of a series on codeine and its alternates for pain and cough relief—presents a detailed evaluation of experimental and clinical data concerning the analgesic action of codeine (the antitussive action will be assessed separately). The authors discuss the pharmacology of the drug, including side-effects and toxicity; effects on the respiratory, circulatory, digestive and urinary systems; tolerance, dependence and liability to abuse; metabolic effects; and mechanism of action. Though codeine is generally more toxic than morphine to animals on account of its convulsant action, it is less toxic to man, possibly because it produces less respiratory depression. Again, tolerance to its analgesic effects has been demonstrated in several animal species, but dependence in man is observed far less frequently than it is with morphine, and the abstinence syndrome is less intense. From their extensive review of the evidence available, the authors conclude that codeine is a good analgesic and that little risk to public health is likely to arise from its clinical use to relieve pain. PMID:4972938

Codeine and its alternates for pain and cough relief*

PubMed Central

Eddy, Nathan B.; Friebel, Hans; Hahn, Klaus-Jürgen; Halbach, Hans

1969-01-01

This report—the second of a series on codeine and its alternates for pain and cough relief—contains a detailed evaluation of experimental and clinical data on newer substances having analgesic properties comparable to and in approximately the same range as those of codeine. The data are discussed under the headings: analgesic effects in animals; clinical usefulness; side-effects with particular reference to dependence and abuse liability. PMID:4894737

Long-term stability of morphine, codeine, and 6-acetylmorphine in real-life whole blood samples, stored at -20°C.

PubMed

Høiseth, Gudrun; Fjeld, Bente; Burns, Margrete Larsen; Strand, Dag Helge; Vindenes, Vigdis

2014-06-01

Stability of drugs during storage is important in forensic toxicology. For the analytes detected after intake of heroin (6-acetylmorphine (6-AM), morphine and codeine), long-time stability in real life whole blood samples are studied in only a small number of cases. Whole blood post mortem (n=37) and whole blood samples from living persons (n=22) containing morphine and codeine as well as 6-AM in blood or urine were selected. All cases represented intake of heroin. All samples contained fluoride and were initially analysed and stored in normal conditions (-20°C) for 4-9 years. All samples were then reanalysed using the same analytical methods and the results were compared. For samples from living persons, the median change in concentration was -3.7% for morphine and -5.3% for codeine. For post mortem samples, the median change in concentration was -12% for morphine and -11% for codeine. Both for samples from living persons and post mortem samples, the decrease in the concentrations from the original analysis to reanalysis were statistically significant for morphine and codeine. Regarding 6-AM, all living samples were negative at reanalysis. For post mortem samples, four cases still tested positive for 6-AM at reanalysis with a median change in the concentrations of -81%. There was no significant change in the morphine to codeine concentration ratios neither for living nor post mortem samples. This study showed that in real life whole blood samples, the concentrations of morphine and codeine are relatively stable during long-term storage at -20°C. 6-AM on the other hand, shows a considerable decrease in concentrations that is important to consider when interpreting results from reanalyses of forensic cases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Fenton-like reaction: a possible way to efficiently remove illicit drugs and pharmaceuticals from wastewater.

PubMed

Mackuľak, Tomáš; Mosný, Michal; Grabic, Roman; Golovko, Oksana; Koba, Olga; Birošová, Lucia

2015-03-01

We analyzed 13 psychoactive pharmaceuticals, illicit drugs and their metabolites in wastewater treatment plant influent and effluent and the possibility of their degradation by biological and chemical processes. Tramadol (413-853 ng/L) and methamphetamine (460-682 ng/L) were the most concentrated compounds in the wastewater in winter and summer, respectively. A significant decrease in the concentration of tramadol in wastewater was measured during the summer. The lowest efficiency was observed for tramadol, venlafaxine, citalopram and oxazepam (∼ 10%) and the highest efficiency was observed for amphetamine and THC-COOH (∼ 80%). The efficiency of compound degradation via the Fenton reaction, a modified Fenton reaction and different degradation (by algae, wood-rotting fungi and enzymes at influent versus effluent) was determined. The Fenton reaction and its modification were efficient at eliminating these substances in comparison with the tested biological processes. Copyright © 2015 Elsevier B.V. All rights reserved.

The variability of ecstasy tablets composition in Brazil.

PubMed

Togni, Loraine R; Lanaro, Rafael; Resende, Rodrigo R; Costa, Jose L

2015-01-01

The content of ecstasy tablets has been changing over the years, and nowadays 3,4-methylenedioxymethamphetamine (MDMA) is not always present in the tablets. The aim of this study was to investigate the chemical composition in the seized tablets labeled as ecstasy. We analyzed samples from 150 different seizures made by Sao Paulo's State Police by gas chromatography-mass spectrometry. MDMA was present in 44.7% of the analyzed samples, and another twenty different active substances were identified in these tablets, such as caffeine, 2C-B, piperazines, amphetamines, phencyclidine, and others. Methamphetamine was present in 22% of these samples. The results demonstrate a huge shift in the pattern of trafficking of synthetic drugs, where MDMA has been replaced in tablets mostly by illicit psychoactive substances, in a clear attempt to bypass the law. The great variability in the tablets composition may lead to an increased risk of drug poisoning. © 2014 American Academy of Forensic Sciences.

Micro-solid phase extraction coupled with high-performance liquid chromatography-tandem mass spectrometry for the determination of stimulants, hallucinogens, ketamine and phencyclidine in oral fluids.

PubMed

Sergi, Manuel; Compagnone, Dario; Curini, Roberta; D'Ascenzo, Giuseppe; Del Carlo, Michele; Napoletano, Sabino; Risoluti, Roberta

2010-08-24

A confirmatory method for the determination of illicit drugs based on micro-solid phase extraction with modified tips, made of a functionalized fiberglass with apolar chains of octadecylsilane into monolithic structure, has been developed in this study. Drugs belonging to different chemical classes, such as amphetamine, methamphetamine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethylamphetamine, cocaine, benzoylecgonine, ketamine, mescaline, phencyclidine and psilocybine were analyzed. The quantitation was performed by liquid chromatography-tandem mass spectrometry and the analytes were detected in positive ionization by means of an electrospray source. The limits of quantification ranged between 0.3 ng mL(-1) for cocaine and 4.9 ng mL(-1) for psilocybine, with coefficients of determination (r(2)) >0.99 for all the analytes as recommended in the guidelines of Society of Forensic Toxicologists-American Association Forensic Sciences. 2010 Elsevier B.V. All rights reserved.

Impact of Pharmaceutical Impurities in Ecstasy Tablets: Gas Chromatography-Mass Spectrometry Study

PubMed Central

Jalali, Amir; Hatamie, Amir; Saferpour, Tahere; Khajeamiri, Alireza; Safa, Tahere; Buazar, Foad

2016-01-01

In this study, a simple and reliable method by gas chromatograph–mass spectrometry (GC–MS) was developed for the fast and regular identification of 3, 4-MDMA impurities in ecstasy tablets. In so doing, 8 samples of impurities were extracted by diethyl ether under alkaline condition and then analyzed by GC–MS. The results revealed high MDMA levels ranging from 37.6% to 57.7%. The GC-MS method showed that unambiguous identification can be achieved for MDMA from 3, 4-methylenedioxyamphetamine (MDA), Amphetamine (AM), methamphetamine (MA) and ketamine (Keta) compounds, respectively. The experimental results indicated the acceptable time window without interfering peaks. It is found that GC-MS was provided a suitable and rapid identification approach for MDMA (Ecstacy) tablets, particularly in the Forensic labs. Consequently, the intense MDMA levels would support the police to develop a simple quantification of impurity in Ecstasy tablets. PMID:27610162

Contamination profiles, mass loadings, and sewage epidemiology of neuropsychiatric and illicit drugs in wastewater and river waters from a community in the Midwestern United States.

PubMed

Skees, Allie J; Foppe, Katelyn S; Loganathan, Bommanna; Subedi, Bikram

2018-08-01

In this study, residues of the neuropsychiatric and illicit drugs including stimulants, opioids, hallucinogens, antischizophrenics, sedatives, and antidepressants were determined in influent and effluent samples from a small wastewater treatment plant, a receiving creek, and river waters in the Four Rivers region of the Midwestern United States. Nineteen neuropsychiatric drugs, eight illicit drugs, and three metabolites of illicit drugs were detected and quantitated in the water samples using HPLC-MS/MS. Residual concentrations of the drugs varied from below the detection limit to sub-μg/L levels. The source of residual cocaine and benzoylecgonine in wastewater is primarily from human consumption of cocaine rather than direct disposal. Wastewater based epidemiology is utilized to estimate the community usage of drugs based on the concentration of drug residues in wastewater, wastewater inflow, and the population served by the centralized wastewater treatment plant. The per-capita consumption rate of methamphetamine (1740 mg/d/1000 people) and amphetamine (970 mg/d/1000 people) found in this study were the highest reported per-capita consumption rates in the USA. Antidepressant venlafaxine found to have the highest environmental emission from the WWTP (333 ± 160 mg/d/1000 people) followed by citalopram (132 ± 60.2 mg/d/1000 people), methamphetamine (111 ± 43.6 mg/d/1000 people), and hydrocodone (108 ± 90.1 mg/d/1000 people). Bee Creek, an immediate receiving water body, is found to be a source of several neuropsychiatric and illicit drugs including methamphetamine, methadone, alprazolam, oxazepam, temazepam, carbamazepine, venlafaxine, citalopram, sertraline, oxycodone, and hydrocodone (p < 0.036) in the Clarks River. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification and analysis of damaged or porous hair.

PubMed

Hill, Virginia; Loni, Elvan; Cairns, Thomas; Sommer, Jonathan; Schaffer, Michael

2014-06-01

Cosmetic hair treatments have been referred to as 'the pitfall' of hair analysis. However, most cosmetic treatments, when applied to the hair as instructed by the product vendors, do not interfere with analysis, provided such treatments can be identified by the laboratory and the samples analyzed and reported appropriately for the condition of the hair. This paper provides methods for identifying damaged or porous hair samples using digestion rates of hair in dithiothreitol with and without proteinase K, as well as a protein measurement method applied to dithiothreitol-digested samples. Extremely damaged samples may be unsuitable for analysis. Aggressive and extended aqueous washing of hair samples is a proven method for removing or identifying externally derived drug contamination of hair. In addition to this wash procedure, we have developed an alternative wash procedure using 90% ethanol for washing damaged or porous hair. The procedure, like the aqueous wash procedure, requires analysis of the last of five washes to evaluate the effectiveness of the washing procedure. This evaluation, termed the Wash Criterion, is derived from studies of the kinetics of washing of hair samples that have been experimentally contaminated and of hair from drug users. To study decontamination methods, in vitro contaminated drug-negative hair samples were washed by both the aqueous buffer method and a 90% ethanol method. Analysis of cocaine and methamphetamine was by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Porous hair samples from drug users, when washed in 90% ethanol, pass the wash criterion although they may fail the aqueous wash criterion. Those samples that fail both the ethanolic and aqueous wash criterion are not reported as positive for ingestion. Similar ratios of the metabolite amphetamine relative to methamphetamine in the last wash and the hair is an additional criterion for assessing contamination vs. ingestion of methamphetamine. Copyright © 2014 John Wiley & Sons, Ltd.

Codeine and its alternates for pain and cough relief*

PubMed Central

Eddy, Nathan B.; Friebel, Hans; Hahn, Klaus-Jürgen; Halbach, Hans

1969-01-01

In this report—the fourth of a series on codeine and its alternates for pain and cough relief—an attempt is made to evaluate, on the basis of experimental and clinical data, and wherever possible in comparison with codeine, the effectiveness of a number of antitussive substances currently in clinical use. In the discussion of the undesired side-effects particular attention is paid to the risk of dependence and abuse. PMID:4390406

Dispositional study of opioids in mice pretreated with sympathomimetic agents.

PubMed

Dambisya, Y M; Chan, K; Wong, C L

1992-08-01

Brain and plasma levels of morphine and codeine were determined by an assay method involving solid-phase extraction and ion-pair reversed phase HPLC. Detection was by a variable wavelength UV-detector (for codeine) and an amperometric electro-chemical detector (for morphine) coupled in series. Ephedrine or phenylpropanolamine pretreatment did not interfere with the plasma disposition of morphine, evidenced by overlapping plasma concentration-time profiles. Brain opioid levels were equally unaffected by sympathomimetic pretreatment. The relative ratios of brain to plasma concentrations at the time corresponding to the respective peak anti-nociceptive activity for morphine and codeine revealed no significant differences. It is concluded that single doses of ephedrine and phenylpropanolamine do not affect the disposition of morphine and codeine in mice.

Boltushka: A Homemade Amphetamine-Type Stimulant and HIV Risk in Odessa, Ukraine

PubMed Central

Chintalova-Dallas, Repsina; Case, Patricia; Kitsenko, Nataliya; Lazzarini, Zita

2009-01-01

Background Homemade amphetamine-type stimulants (ATSs) have been reported in Russia and Eastern Europe for decades. Recipes differ geographically and over time producing differing active ingredients. Vint and jeff (active ingredients methamphetamine and methcathinone, respectively) are two such homemade ATSs originally produced from over-the-counter cold medications and household chemicals. Methods During a Rapid Policy Assessment and Responses (RPAR) project in Odessa, Ukraine, researchers found use of boltushka, a novel homemade ATS. Fourteen supplemental qualitative interviews were conducted, including ten interviews with boltushka injectors and four interviews with pharmacists. We report patterns of boltushka use among local injection drug users (IDUs) as well as the role of laws, regulations, and current pharmacy practices. Results Legal restrictions on over-the-counter cold medicines in Ukraine led to products containing phenypropanolamine (PPA), which oxidized with KMnO4 (potassium permanganate), produces a weak ATS, cathinone, called boltushka. Boltushka’s ingredients are easily available in pharmacies or on the black market. IDUs reported a mean age at first use of 16 years old (range 12–21). While published data are scant, anecdotal evidence reported here include amphetamine-like effects on energy and appetite, binging patterns of use, and some reports of shaking and other neurological damage consistent with earlier reports from exposure to KMnO4. Users reported sharing syringes and other non-sterile injection practices. No users reported specific treatment or prevention programs for boltushka users. Conclusions Although Ukrainian government regulations have limited access to precursor chemicals, IDUs have continued to make and use boltushka. The actual extent and demographics of boltushka use are unknown. Besides risk of bloodborne disease, the health effects of injected homemade ATSs and their constituent chemicals are poorly documented. Interventions beyond available harm reduction efforts may be required. Education/treatment specific to boltushka users and screening for other physical harms are critical interventions. PMID:18976896

Muscle pain perception and sympathetic nerve activity to exercise during opioid modulation

NASA Technical Reports Server (NTRS)

Cook, D. B.; O'Connor, P. J.; Ray, C. A.

2000-01-01

The purpose of this experiment was to examine the effects of the endogenous opioid system on forearm muscle pain and muscle sympathetic nerve activity (MSNA) during dynamic fatiguing exercise. Twelve college-age men (24 +/- 4 yr) performed graded (1-min stages; 30 contractions/min) handgrip to fatigue 1 h after the ingestion of either 60 mg codeine, 50 mg naltrexone, or placebo. Pain (0-10 scale) and exertion (0-10 and 6-20 scales) intensities were measured during the last 15 s of each minute of exercise and every 15 s during recovery. MSNA was measured continuously from the peroneal nerve in the left leg. Pain threshold occurred earlier [1.8 +/- 1, 2. 2 +/- 1, 2.2 +/- 1 J: codeine, naltrexone, and placebo, respectively] and was associated with a lower rating of perceived exertion (RPE) (2.7 +/- 2, 3.6 +/- 2, 3.8 +/- 2: codeine, naltrexone, and placebo, respectively) in the codeine condition compared with either the naltrexone or placebo conditions. There were no main effects (i.e., drugs) or interaction (i.e., drugs x time) for either forearm muscle pain or RPE during exercise [pain: F (2, 22) = 0.69, P = 0.51]. There was no effect of drug on MSNA, heart rate, or blood pressure during baseline, exercise, or recovery. Peak exercise MSNA responses were 21 +/- 1, 21 +/- 2.0, and 21 +/- 2.0 bursts/30 s for codeine, naltrexone, and placebo conditions, respectively. Peak mean arterial pressure responses were 135 +/- 4, 131 +/- 3, and 132 +/- 4 mmHg for codeine, naltrexone, and placebo conditions, respectively. It is concluded that neither 60 mg codeine nor 50 mg naltrexone has an effect on forearm muscle pain, exertion, or MSNA during high- intensity handgrip to fatigue.

Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects

PubMed Central

Gelston, Eloise A; Coller, Janet K; Lopatko, Olga V; James, Heather M; Schmidt, Helmut; White, Jason M; Somogyi, Andrew A

2012-01-01

AIMS To compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODS Ten methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide. RESULTS The urinary metabolic ratio for O-demethylation was significantly higher (P = 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P < 0.0002), but there was no significant difference (P = 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P = 0.72) and lower morphine-3- and -6- and codeine-6-glucuronide concentrations (P < 0.008). CONCLUSION Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6. PMID:22092298

Codeine

MedlinePlus

... with other medications, to reduce coughing. Codeine will help relieve symptoms but will not treat the cause ... granisetron (Kytril), ondansetron (Zofran, Zuplenz), or palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram ( ...

Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: the role of mu opioid receptor activation.

PubMed

Horner, Kristen A; Noble, Erika S; Gilbert, Yamiece E

2010-06-01

Amphetamines induce stereotypy, which correlates with patch-enhanced c-Fos expression the patch compartment of caudate putamen (CPu). Methamphetamine (METH) treatment also induces patch-enhanced expression of prodynorphin (PD), arc and zif/268 in the CPu. Whether patch-enhanced activation of any of these genes correlates with METH-induced stereotypy is unknown, and the factors that contribute to this pattern of expression are poorly understood. Activation of mu opioid receptors, which are expressed by the neurons of the patch compartment, may underlie METH-induced patch-enhanced gene expression and stereotypy. The current study examined whether striatal mu opioid receptor blockade altered METH-induced stereotypy and patch-enhanced gene expression, and if there was a correlation between the two responses. Animals were intrastriatally infused with the mu antagonist CTAP (10 microg/microl), treated with METH (7.5 mg/kg, s.c.), placed in activity chambers for 3h, and then sacrificed. CTAP pretreatment attenuated METH-induced increases in PD, arc and zif/268 mRNA expression and significantly reduced METH-induced stereotypy. Patch-enhanced PD and arc mRNA expression in the dorsolateral CPu correlated negatively with METH-induced stereotypy. These data indicate that mu opioid receptor activation contributes to METH-induced gene expression in the CPu and stereotypy, and that patch-enhanced PD and arc expression may be a homeostatic response to METH treatment. Copyright 2010 Elsevier Inc. All rights reserved.

Analysis of stimulant drugs in the wastewater of five Nordic capitals.

PubMed

Löve, Arndís Sue Ching; Baz-Lomba, Jose Antonio; Reid, Malcolm J; Kankaanpää, Aino; Gunnar, Teemu; Dam, Maria; Ólafsdóttir, Kristín; Thomas, Kevin V

2018-06-15

Wastewater-based epidemiology is an efficient way to assess illicit drug use, complementing currently used methods retrieved from different data sources. The aim of this study is to compare stimulant drug use in five Nordic capital cities that include for the first time wastewater samples from Torshavn in the Faroe Islands. Currently there are no published reports that compare stimulant drug use in these Nordic capitals. All wastewater samples were analyzed using solid phase extraction and ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The results were compared with data published by the European Monitoring Centre for Drugs and Drug Addiction based on illicit drugs in wastewater from over 50 European cities. Confirming previous reports, the results showed high amphetamine loads compared with other European countries. Very little apparent abuse of stimulant drugs was detected in Torshavn. Methamphetamine loads were the highest from Helsinki of the Nordic countries, indicating substantial fluctuations in the availability of the drug compared with previous studies. Methamphetamine loads from Oslo confirmed that the use continues to be high. Estimated cocaine use was found to be in the lower range compared with other cities in the southern and western part of Europe. Ecstasy and cocaine showed clear variations between weekdays and weekends, indicating recreational use. This study further demonstrates geographical trends in the stimulant drug market in five Nordic capitals, which enables a better comparison with other areas of the continent. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Methamphetamine-Induced Stereotypy Correlates Negatively with Patch-Enhanced Prodynorphin and ARC mRNA Expression in the Rat Caudate Putamen: The Role of Mu Opioid Receptor Activation

PubMed Central

Horner, Kristen A.; Noble, Erika S.; Gilbert, Yamiece E.

2010-01-01

Amphetamines induce stereotypy, which correlates with patch-enhanced c-Fos expression the patch compartment of caudate putamen (CPu). Methamphetamine (METH) treatment also induces patch-enhanced expression of prodynorphin (PD), arc and zif/268 in the CPu. Whether patch-enhanced activation of any of these genes correlates with METH-induced stereotypy is unknown, and the factors that contribute to this pattern of expression are poorly understood. Activation of mu opioid receptors, which are expressed by the neurons of the patch compartment, may underlie METH-induced patch-enhanced gene expression and stereotypy. The current study examined whether striatal mu opioid receptor blockade altered METH-induced stereotypy and patch-enhanced gene expression, and if there was a correlation between the two responses. Animals were intrastriatally infused with the mu antagonist CTAP (10 μg/μl), treated with METH (7.5 mg/kg, s.c.), placed in activity chambers for 3h, and then sacrificed. CTAP pretreatment attenuated METH-induced increases in PD, arc and zif/268 mRNA expression and significantly reduced METH-induced stereotypy. Patch-enhanced PD and arc mRNA expression in the dorsolateral CPu correlated negatively with METH-induced stereotypy. These data indicate that mu opioid receptor activation contributes to METH-induced gene expression in the CPu and stereotypy, and that patch-enhanced PD and arc expression may be a homeostatic response to METH treatment. PMID:20298714

Current trends in Finnish drug abuse: Wastewater based epidemiology combined with other national indicators.

PubMed

Kankaanpää, Aino; Ariniemi, Kari; Heinonen, Mari; Kuoppasalmi, Kimmo; Gunnar, Teemu

2016-10-15

No single measure is able to provide a complete picture of population- or community-level drug abuse and its current trends. Therefore, a multi-indicator approach is needed. The aim of this study was to combine wastewater-based epidemiology (WBE) with data from other national indicators, namely driving under the influence of drugs (DUID) statistics, drug seizures, and drug use surveys. Furthermore, drug market size estimates and a comparison of confiscated drugs to drugs actually consumed by users were performed using the WBE approach. Samples for wastewater analysis were collected during one-week sampling periods in 2012, 2014 and 2015, with a maximum of 14 cities participating. The samples were analysed with a validated ultra-high-performance liquid chromatography-mass spectrometric (UHPLC-MS/MS) methodology for various common drugs of abuse. The results were then compared with data from other national indicators available. Joint interpretation of the data shows that the use of amphetamine and MDMA has increased in Finland from 2012 to 2014. A similar trend was also observed for cocaine, although its use remains at a very low level compared to many other European countries. Heroin was practically absent from the Finnish drug market during the study period. The retail market for the most common stimulant drugs were estimated to have been worth EUR 70 million for amphetamine and around EUR 10 million for both methamphetamine and cocaine, in 2014 in Finland. Copyright © 2016 Elsevier B.V. All rights reserved.

Sensitivity, specificity, and efficiency in detecting opiates in oral fluid with the Cozart Opiate Microplate EIA and GC-MS following controlled codeine administration.

PubMed

Barnes, Allan J; Kim, Insook; Schepers, Raf; Moolchan, Eric T; Wilson, Lisa; Cooper, Gail; Reid, Claire; Hand, Chris; Huestis, Marilyn A

2003-10-01

Oral fluid specimens (N = 1406) were collected from 19 subjects prior to and up to 72 h following controlled administration of oral codeine. Volunteers provided informed consent to participate in this National Institute on Drug Abuse Institutional Review Board-approved protocol. A modification of Cozart Microplate Opiate EIA Oral Fluid Kit (Opiate ELISA), employing codeine calibrators, was used for semiquantitative analysis of opiates, followed by gas chromatography-mass spectrometry (GC-MS) for the confirmation and quantitation of codeine, norcodeine, morphine, and normorphine in oral fluid. GC-MS limits of detection and quantitation were 2.5 microg/L for all analytes. The Substance Abuse and Mental Health Services Administration (SAMHSA) has proposed a 40-microg/L opiate screening and a 40-microg/L morphine or codeine confirmation cutoff for the detection of opiate use. Oral fluid opiate screening and confirmation cutoffs of 30 micro g/L are in use in the U.K. Utilizing 2.5-, 20-, 30-, and 40-microg/L GC-MS cutoffs, 26%, 20%, 19%, and 18% of the oral fluid specimens were positive for codeine or one of its metabolites. Six Opiate ELISA/confirmation cutoff criteria (2.5/2.5, 10/2.5, 20/20, 30/20, 30/30, and 40/40 microg/L) were evaluated. Calculations for Opiate ELISA sensitivity, specificity, and efficiency were determined from the number of true-positive, true-negative, false-positive, and false-negative results at each screening/confirmation cutoff. Sensitivity, specificity, and efficiency for the lowest cutoff were 91.5%, 88.6%, and 89.3%. Application of the cutoff currently used in the U.K. yielded sensitivity, specificity, and efficiency results of 79.7%, 99.0%, and 95.4% and similar results of 76.7%, 99.1%, and 95.1% when applying the SAMHSA criteria. These data indicate that the Opiate ELISA efficiently detects oral codeine use. In addition, the data, collected following controlled oral codeine administration, may aid in the interpretation of opiate oral fluid test results and in the selection of appropriate oral fluid screening and confirmation cutoffs.

Assessment of the efficacy and safety profiles of aspirin and acetaminophen with codeine: results from 2 randomized, controlled trials in individuals with tension-type headache and postoperative dental pain.

PubMed

Gatoulis, Sergio C; Voelker, Michael; Fisher, Matt

2012-01-01

Aspirin is a widely used NSAID that has been extensively studied in numerous conditions. Nonprescription analgesics, such as aspirin, are frequently used for a wide variety of common ailments, including conditions such as dental pain and tension-type headache. We sought to compare the efficacy and safety profiles of aspirin, acetaminophen with codeine, and placebo in the treatment of post-operative dental pain and tension-type headache. These were 2 randomized, double-blind, placebo-controlled, single-dose clinical trials that assigned participants (2:2:1) to receive either aspirin (1000 mg), acetaminophen (300 mg) with codeine (30 mg), or placebo. The primary efficacy end point was the sum of pain intensity differences from baseline (SPID) over 6 hours for the dental pain study and over 4 hours for the tension-type headache study. Other common analgesic measures, in addition to safety, were also evaluated. The results of the dental pain study for aspirin and acetaminophen with codeine suggest statistically significant efficacy for all measures compared with placebo at all time points. Aspirin provided statistically significant efficacy compared with acetaminophen with codeine for SPID(0-4) (P = 0.028). In the tension-type headache study, aspirin and acetaminophen with codeine provided statistically significant efficacy compared with placebo for SPID(0-4) and SPID(0-6) (P < 0.001) and for total pain relief (P < 0.001). There were no significant differences between aspirin and acetaminophen with codeine at any evaluation of SPID (P ≥ 0.070), complete relief (P ≥ 0.179), or time to meaningful relief (P ≥ 0.245). Regarding safety, there were no statistically significant differences between treatment groups in the incidence of adverse events in the dental pain and tension-type headache studies. These 2 randomized, double-blind, placebo-controlled studies demonstrate that treatment with aspirin (1000 mg) provides statistically significant analgesic efficacy compared with placebo use and comparable efficacy with acetaminophen (300 mg) with codeine (30 mg) therapy after impacted third molar extraction and in tension- type headache. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Hair analysis for opiates: hydromorphone and hydrocodone as indicators of heroin use.

PubMed

Madry, Milena M; Bosshard, Mona M; Kraemer, Thomas; Baumgartner, Markus R

2016-05-01

Identification of external contamination is a challenge in hair analysis. This study investigates metabolite ratios of hydromorphone to morphine and hydrocodone to codeine as indicators to distinguish contamination from heroin use provided that hydromorphone/hydrocodone intake is excluded. Hair samples after external contamination with street heroin proved to be negative for hydromorphone/hydrocodone. Hair samples from individuals with suspected street heroin use/contamination or opiate medication were analyzed for 6-monoacetylmorphine, morphine, acetylcodeine, codeine, hydromorphone and hydrocodone, and metabolite ratios of hydromorphone to morphine and hydrocodone to codeine were assessed. Hair samples from individuals with medicinal heroin/morphine/codeine use displayed significantly higher metabolite ratios than those with suspected street heroin use/contamination. Hydromorphone/hydrocodone are solely formed during body passage. Thus, metabolite ratios can be used to distinguish morphine/heroin use from external contamination.

Extracorporeal elimination of butalbital in acute aspirin-butalbital-caffeine-codeine (Fiorinal with Codeine) poisoning.

PubMed

Poyant, Janelle O; Albright, Robert; Clain, Jeremy; Pandompatam, Govind; Barreto, Erin F

2017-11-10

Butalbital is a small molecule (approximately 220 Da), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325 mg-butalbital 50 mg-caffeine 40 mg with codeine 30 mg (Fiorinal with Codeine). This is a case report of a single patient. A 67-year-old female was admitted to the medical intensive care unit approximately 3 h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4 mg/dL (3.4 mmol/L). Approximately 8 h after ingestion of 2000 mg of butalbital, our patient's serum concentration was 26.9 mg/L (normal <10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233-300 mL/min. The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose.

Separation and determination of impurities in paracetamol, codeine and pitophenone in the presence of fenpiverinium in combined suppository dosage form.

PubMed

Vojta, Jiří; Hanzlík, Pavel; Jedlička, Aleš; Coufal, Pavel

2015-01-01

A new HPLC method for separation and determination of impurities in paracetamol, codeine phosphate hemihydrate and pitophenone hydrochloride in the presence of fenpiverinium bromide in combined suppository dosage form was developed and validated. The separation of paracetamol and its impurities 4-aminophenol, 4-nitrophenol, 4-chloracetanilid; codeine and its impurities methylcodeine, morphine, codeine dimer and 10-hydroxycodeine; pitophenone and its impurities 2-[4-[2-(1-piperidinyl)ethoxy]benzoyl] benzoic acid, 2-[4-[2-(1-piperidinyl)ethoxy]benzoyl]benzoic acid 2-(1-piperidinyl)-ethyl ester, methyl ester of 2-(4-hydroxybenzoyl) benzoic acid and fenpiverinium was achieved by using ion-pair reversed phase liquid chromatography with UV detection. Validation parameters such as the precision, accuracy, linearity, limit of detection (LOD), limit of quantification (LOQ) and robustness were verified for all the mentioned impurities of codeine phosphate hemihydrate and 4-aminophenol and 2-[4-[2-(1-piperidinyl)ethoxy]benzoyl] benzoic acid as the main degradation products of paracetamol and pitophenone hydrochloride, respectively. The described method was found to be useful for analysis of the stability samples and therefore suitable for routine purity testing of the drug product. Copyright © 2014 Elsevier B.V. All rights reserved.

Tramadol can selectively manage moderate pain in children following European advice limiting codeine use.

PubMed

Marzuillo, Pierluigi; Calligaris, Lorenzo; Barbi, Egidio

2014-11-01

The European Medicine Agency recommendations limiting codeine use in children have created a void in managing moderate pain. We review the evidence on the pharmacokinetic, pharmacodynamic and safety profile of tramadol, a possible substitute for codeine. Tramadol appears to be safe in both paediatric inpatients and outpatients. It may be appropriate to limit the current use of tramadol to monitored settings in children with risk factors for respiratory depression, subject to further safety evidence. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Codeine and its alternates for pain and cough relief*

PubMed Central

Eddy, Nathan B.; Friebel, Hans; Hahn, Klaus-Jürgen; Halbach, Hans

1969-01-01

This chapter concludes the survey of experimental and clinical data on the analgesic and antitussive properties of codeine and its potential therapeutic alternates. From an evaluation of their effectiveness on the one hand and the side-effects, including tolerance, dependence and abuse liability on the other, it would appear that the therapeutic goals of codeine could be achieved by other substances, except perhaps where analgesia, cough relief, and sedation are required simultaneously. The use of these other substances would, however, result in no particular gain and probably no particular loss. PMID:4898386

Direct and efficient liquid chromatographic-tandem mass spectrometric method for opiates in urine drug testing - importance of 6-acetylmorphine and reduction of analytes.

PubMed

Andersson, Maria; Stephanson, Nikolai; Ohman, Inger; Terzuoli, Tommy; Lindh, Jonatan D; Beck, Olof

2014-04-01

Opiates comprise a class of abused drugs that is of primary interest in clinical and forensic urine drug testing. Determination of heroin, codeine, or a multi-drug ingestion is complicated since both heroin and codeine can lead to urinary excretion of free and conjugated morphine. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers advantage over gas chromatography-mass spectrometry by simplifying sample preparation but increases the number of analytes. A method based on direct injection of five-fold diluted urine for confirmation of morphine, morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide and 6-acetylmorphine was validated using LC-MS/MS in positive electrospray mode monitoring two transitions using selected reaction monitoring. The method was applied for the analysis of 3155 unknown urine samples which were positive for opiates in immunochemical screening. A linear response was observed for all compounds in the calibration curves covering more than three orders of magnitude. Cut off was set to 2 ng/ml for 6-acetylmorphine and 150 ng/ml for the other analytes. 6-Acetylmorphine was found to be effective (sensitivity 82%) in detecting samples as heroin intake. Morphine-3-glucuronide and codeine-6-glucuronide was the predominant components of total morphine and codeine, 84% and 93%, respectively. The authors have validated a robust LC-MS/MS method for rapid qualitative and quantitative analysis of opiates in urine. 6-Acetylmorphine has been demonstrated as a sensitive and important parameter for a heroin intake. A possible interpretation strategy to conclude the source of detected analytes was proposed. The method might be further developed by reducing the number of analytes to morphine-3-glucuronide, codeine-6-glucuronide and 6-acetylmorphine without compromising test performance. Copyright © 2013 John Wiley & Sons, Ltd.

Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration

PubMed Central

Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.

2014-01-01

Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine and 3.1mg codeine, 8h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography tandem mass spectrometry (1μg/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32h after the first dose. All specimens screened positive 0.5h after dosing and remained positive for 0.5-13h at Draeger 20μg/L morphine cutoff. Maximum OF morphine and codeine concentrations (Cmax) were 177 and 32.6μg/L, with times to Cmax (Tmax) of 0.5-1h and 0.5-2.5h post-dose, respectively. Windows of detection after the second dose extended at least 24h for morphine and to 18h for codeine. After both doses, the last morphine positive OF result was 1h with 40μg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cutoff, and 0.5h with 95μg/L cutoff, recently recommended by the Driving Under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1h after ingestion of 15.7mg of morphine in raw poppy seeds, depending upon the cutoff employed. PMID:25345619

Ibuprofen with acetaminophen for postoperative pain control following tonsillectomy does not increase emergency department utilization.

PubMed

Bedwell, Joshua R; Pierce, Matthew; Levy, Michelle; Shah, Rahul K

2014-12-01

To compare the performance of ibuprofen vs codeine for postoperative pain management after tonsillectomy as measured by need for emergency department (ED) treatment for pain and/or dehydration. Retrospective case series with chart review. Tertiary children's hospital. Consecutive series of patients who underwent tonsillectomy with or without adenoidectomy at a tertiary children's hospital. Patients were categorized based on the type of postoperative pain management (acetaminophen with codeine vs acetaminophen and ibuprofen). The main outcome measure was the proportion of patients requiring ED visits or inpatient admissions for inadequate pain control or dehydration. Secondary measures included antibiotic use, postoperative hemorrhage, need for return to the operating room, vomiting, and oral diet tolerance. Patients in the ibuprofen/acetaminophen group were younger than those in the codeine/acetaminophen group (6.2 vs 8.1 years, P < .05). Patients in the codeine/acetaminophen group were more likely to use antibiotics in the postoperative period (50.3% vs 5.9%, P < .05). The proportion of patients requiring ED visits or inpatient admission for dehydration was not significantly different between the groups (5.1% for codeine, 2.7% for ibuprofen, P = .12). Multivariable analysis controlling for age and antibiotic use showed no difference in ED visits or admission for dehydration (P = .09). There was no difference between the groups for any of the secondary measures. Ibuprofen with acetaminophen represents a safe and acceptable analgesic alternative to codeine and acetaminophen in patients undergoing pediatric tonsillectomy. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

[The knowledge of students and teachers of selected groups about the OTC drugs containing codeine and pseudoephedrine--an alternative to "legal highs"?].

PubMed

Sliwińska-Mossoń, Mariola; Marcinkiewicz, Marcin; Marciniak, Katarzyna; Milnerowicz, Halina

2015-01-01

Currently the youth to intoxication increasingly used drugs generally available over the counter (OTC, Over-The-Counter drug) containing psychotropic substances. The knowledge on the subject among parents and teachers is inadequate. The aim of the study is to assess the knowledge of students and teachers about OTC drugs containing codeine or pseudoephedrine and their consequences on the use and popularity of these drugs. The study was conducted from December 2014 to March 2015 of 93 respondents. In conducting the study used research tool in the form of an anonymous questionnaire consisting of 21 questions for the students and teachers of 16 questions, the questions relate knowledge of the studied group persons on the OTC drugs containing codeine or pseudoephedrine and the effects of their use. Among the students participating in the study, the majority of respondents are aware that using drugs containing codeine or pseudoephedrine can be addicted to them. Higher knowledge on this subject have demonstrated high school students, but less teachers. Most of the respondents had knowledge about the health effects that result from an overdose of these drugs. Among the students most frequently reported sources of knowledge about OTC drugs containing codeine or pseudoephedrine were friends and the Internet. The general knowledge of high school students and teachers on the effects of OTC medications containing codeine or pseudoephedrine is not sufficient. There is a need to conduct preventive and educational action aimed at increasing knowledge among youth and adults on the health effects of these drugs.

77 FR 59980 - Established Aggregate Production Quotas for Schedule I and II Controlled Substances and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-01

... certain established aggregate production quotas will mitigate adverse public effects if an unforeseen... Cocaine 240,000 g Codeine (for conversion) 81,250,000 g Codeine (for sale) 49,506,250 g Dextropropoxyphene...

Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults.

PubMed

Wiffen, Philip J; Knaggs, Roger; Derry, Sheena; Cole, Peter; Phillips, Tudor; Moore, R Andrew

2016-12-27

Paracetamol, either alone or in combination with codeine or dihydrocodeine, is commonly used to treat chronic neuropathic pain. This review sought evidence for efficacy and harm from randomised double-blind studies. To assess the analgesic efficacy and adverse events of paracetamol with or without codeine or dihydrocodeine for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to July 2016, together with reference lists of retrieved papers and reviews, and two online study registries. We included randomised, double-blind studies of two weeks' duration or longer, comparing paracetamol, alone or in combination with codeine or dihydrocodeine, with placebo or another active treatment in chronic neuropathic pain. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE. No study satisfied the inclusion criteria. Effects of interventions were not assessed as there were no included studies. We have only very low quality evidence and have no reliable indication of the likely effect. There is insufficient evidence to support or refute the suggestion that paracetamol alone, or in combination with codeine or dihydrocodeine, works in any neuropathic pain condition.

Meth math: modeling temperature responses to methamphetamine.

PubMed

Molkov, Yaroslav I; Zaretskaia, Maria V; Zaretsky, Dmitry V

2014-04-15

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.

Sex differences in methamphetamine pharmacokinetics in adult rats and its transfer to pups through the placental membrane and breast milk.

PubMed

Rambousek, Lukas; Kacer, Petr; Syslova, Kamila; Bumba, Jakub; Bubenikova-Valesova, Vera; Slamberova, Romana

2014-06-01

Methamphetamine (METH) abuse is a growing health problem worldwide, and METH use during pregnancy not only endangers the mother's health but also the developing fetus. To provide better insight into these risks, we performed the following experiments. First, we investigated how sex influences the pharmacokinetics of METH and amphetamine (AMP) in male and female rats. Subsequently, we simulated chronic exposure of prenatal infants to METH abuse by investigating brain and plasma levels of METH and AMP in dams and pups. Finally, we modeled chronic exposure of infants to METH via breast milk and investigated sex differences in pups with regard to drug levels and possible sensitization effect of chronic prenatal METH co-treatment. We observed significantly higher levels of METH and AMP in the plasma and brain of female rats compared to males. Additionally, brain concentrations of METH and AMP in pups exposed to METH prenatally were equivalent to 62.13% and 37.78% relative to dam, respectively. Plasma concentrations of AMP where equivalent to 100% of the concentration in dams, while METH was equivalent to only 36.98%. Finally, we did not observe a significant effect relative to sex with regard to METH/AMP levels or sensitization effects linked to prenatal METH exposure. We demonstrated that female rats display higher levels of METH and AMP, thus indicating a greater risk of addiction and toxicity. Furthermore, our data show that pups are exposed to both METH and AMP following dam exposure. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Meth math: modeling temperature responses to methamphetamine

PubMed Central

Molkov, Yaroslav I.; Zaretskaia, Maria V.

2014-01-01

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants. PMID:24500434

Toward development of an in vitro model of methamphetamine-induced dopamine nerve terminal toxicity.

PubMed

Kim, S; Westphalen, R; Callahan, B; Hatzidimitriou, G; Yuan, J; Ricaurte, G A

2000-05-01

To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA) neurotoxicity, striatal synaptosomes were incubated at 37 degrees C with METH for different periods of time (10-80 min), washed once, then tested for DA transporter function at 37 degrees C. METH produced time- and dose-dependent reductions in the V(max) of DA uptake, without producing any change in K(m). Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium ion, 6-hydroxydopamine, and amphetamine under similar conditions produced comparable effects. In contrast, incubation with fenfluramine, a serotonin neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar as striatal glutamate uptake was unaffected. Various DA transporter blockers (cocaine, methylphenidate, and bupropion) afforded complete protection against METH-induced decreases in DA uptake, without producing any effect themselves. METH's effects were also temperature dependent, with greater decreases in DA uptake occurring at higher temperatures. Tests for residual drug revealed small amounts (0.1-0.2 microM) of remaining METH, but kinetic studies indicated that decreases in DA uptake were not likely to be due to METH acting as a competitive inhibitor of DA uptake. Decreases in the V(max) of DA uptake were not accompanied by decreases in B(max) of [(3)H]WIN 35,428 binding, possibly because there is no mechanism for removing damaged DA nerve endings from the in vitro preparation Collectively, these results give good support to the development of a valid in vitro model that may prove helpful for elucidating the mechanisms underlying METH-induced DA neurotoxicity.

Association between cytochrome P450 2D6 polymorphisms and body fluid methamphetamine concentrations in Japanese forensic autopsy cases.

PubMed

Matsusue, Aya; Ikeda, Tomoya; Tani, Naoto; Waters, Brian; Hara, Kenji; Kashiwagi, Masayuki; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin-Ichi; Ishikawa, Takaki

2018-05-18

Methamphetamine (MA) is an illicit stimulant that affects the central nervous system. Cytochrome P450 2D6 (CYP2D6) plays an important role in MA metabolism. Numerous allelic variants confer substantial variation in CYP2D6 activity among individuals. In the present study, we examined the frequencies of CYP2D6 alleles, including CYP2D6*1, *2, *4, *5, *10, *14A, *14B, *18, and *36, and multiplication, in 82 forensic autopsy cases of MA abusers and 567 autopsy cases in which MA was not detected (controls). Ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) phenotypes were predicted from CYP2D6 genotypes. Of MA abusers, 64 subjects were predicted to be EM, 17 were IM, and 1 was UM. No MA abuser had the predicted PM phenotype. No significant differences in CYP2D6 phenotype frequencies were found between MA abusers and controls. MA and amphetamine (AMP) concentrations were measured in the right heart blood, left heart blood, peripheral external iliac blood, urine, pericardial fluid, and bone marrow of MA abusers. MA concentrations in urine and bone marrow were significantly higher in IM than in EM. AMP concentration was not associated with CYP2D6 phenotype in any body fluid. These results suggest that the MA concentration in body fluids is influenced by CYP2D6 phenotypes in the Japanese population. Copyright © 2018 Elsevier B.V. All rights reserved.

Emergence of cocaine and methamphetamine injection among HIV-positive injection drug users in Northern and Western India

PubMed Central

Mehta, Shruti H.; Srikrishnan, Aylur K; Noble, Eva; Vasudevan, Canjeevaram K; Solomon, Suniti; Kumar, M Suresh; Solomon, Sunil S

2014-01-01

Background Little is known regarding the epidemiology of drug injection and risk behaviors among injection drug users (IDUs) across India. In particular, there is limited data on the prevalence of stimulant injection. Methods We sampled 801 HIV positive IDUs from 14 locations throughout India to represent the geography of India as well as the diversity in IDU epidemic stage (established epidemics, emerging epidemics and large cities). All participants underwent a behavioral survey and blood draw. Given prior associations with stimulant injection and HIV risk, we compared stimulant injectors (cocaine and/or methamphetamine) to those who injected opiates and/or pharmaceuticals only. Results The median age was 33; 86% were male. The primary drugs injected were heroin, buprenorphine and other pharmaceuticals. In all but four sites, >50% of those actively injecting reported needle sharing. Stimulant injection was most common in emerging epidemics. Compared to exclusive opiate injectors, stimulant injectors were significantly younger, more likely to be educated and employed, more likely to report non-injection use of heroin, crack/cocaine and amphetamines, heavy alcohol use, recent needle sharing (71% vs. 57%), sex with a casual partner (57% vs. 31%) and men having sex with other men (33% vs. 9%; p<0.01 for all). Conclusions Emerging IDU epidemics have a drug/sexual risk profile not previously been observed in India. Given the high prevalence of stimulant injection in these populations, HIV prevention/treatment programs may need to be redesigned to maximize effectiveness. The high levels of injection sharing overall reinforce the need to ensure access to harm-reduction services for all. PMID:24382362

Drug interactions between common illicit drugs and prescription therapies.

PubMed

Lindsey, Wesley T; Stewart, David; Childress, Darrell

2012-07-01

The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug-drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

Treatment of addiction and addiction-related behavior

DOEpatents

Dewey, Stephen L.; Brodie, Jonathan D.; Ashby, Jr., Charles R.

2003-01-01

The present invention provides a highly efficient method for treating substance addiction and for changing addiction-related behavior of a mammal suffering from substance addiction. The method includes administering to a mammal an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof. The present invention also provides a method of treatment of cocaine, morphine, heroin, nicotine, amphetamine, methamphetamine, or ethanol addiction by treating a mammal with an effective amount of gamma vinylGABA or a pharmaceutically acceptable salt thereof. In one embodiment, the method of the present invention includes administering to the mammal an effective amount of a composition which increases central nervous system GABA levels wherein the effective amount is sufficient to diminish, inhibit or eliminate behavior associated with craving or use of drugs of abuse. The composition includes GVG, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fengabine, cetylGABA, topiramate or tiagabine or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

Cognitive rehabilitation for individuals with opioid use disorder: A randomized controlled trial.

PubMed

Rezapour, Tara; Hatami, Javad; Farhoudian, Ali; Sofuoglu, Mehmet; Noroozi, Alireza; Daneshmand, Reza; Samiei, Ahmadreza; Ekhtiari, Hamed

2017-11-21

To examine the efficacy of cognitive rehabilitation treatment (CRT) for people with opioid use disorder who were recruited into a methadone maintenance treatment (MMT) programme. 120 male subjects were randomly assigned to (1) MMT plus CRT in two months or (2) MMT plus a control intervention. Subjects were assessed at the beginning, mid-point and post-intervention as well as at 1-, 3- and 6-month follow-up time points. Analysis with repeated measure ANOVA showed that the CRT group performed significantly better in tests of learning, switching, processing speed, working memory and memory span. Moreover, the CRT group had significantly lower opiate use over the control group during 3-months follow-up. Analysis including only those with a history of methamphetamine use showed that the CRT group had significantly lower amphetamine use. No group differences were observed for treatment retention. Our findings provide evidence that adding CRT as an adjunct intervention to MMT can improve cognitive performance as well as abstinence from both opiates and stimulants.

Profiles in drug metabolism and toxicology: Richard Tecwyn Williams (1909-1979).

PubMed

Jones, Alan Wayne

2015-01-01

This article pays homage to the life and work of a veritable pioneer in toxicology and drug metabolism, namely a Welshman, Richard Tecwyn Williams, FRS. Professor Williams, or RT as he was known, made major contributions to knowledge about the metabolism and toxicology of drugs and xenobiotics during a scientific career spanning nearly 50 years. Author or coauthor of close to 400 research articles and reviews, including a classic book, entitled Detoxication Mechanisms, Williams and his research school investigated virtually all aspects of drug metabolism, especially conjugations. In particular, the concepts of phase 1 and phase II metabolic pathways were introduced by Williams; the biliary excretion of drugs was extensively studied as were species differences in drug metabolism and detoxication. Besides investigating the metabolism of many pharmaceutical drugs, such as sulfonamides and thalidomide, Williams and his group investigated the disposition and fate in the body of organic pesticides and recreational drugs of abuse, such as amphetamine, methamphetamine and lysergic acid diethylamide (LSD).

The Health Effect of Psychostimulants: A Literature Review.

PubMed

Favrod-Coune, Thierry; Broers, Barbara

2010-07-22

Prevalence of psychostimulant use is high, and raising in several countries. Nicotine is the legal stimulant causing the most important public health impact. Cocaine ranks among the most used illicit substances after cannabis. Stimulant medications are frequently misused. Psychostimulants can lead to addiction, have physical, psychological and social health consequences and can induce a great disease burden. The aim of the present article is to provide a literature review on the health effects of stimulants as potential drugs of abuse. It will cover essentially cocaine, amphetamines and its derivatives (including methamphetamines and 3-4-methylenedioxymethamphetamine, ecstasy), nicotine, caffeine and khat, and touch upon the issues of prescribed substances (anti-depressants, weight control medications, attention-deficit hyperactivity disorder medications, hypersomniac disorder). Their pharmacology, addictive potential, health consequences and treatment will be discussed. We used Medline for the literature review from 1990 to the date of this review, and mention the findings of human and animal studies (the latter only if they are of clinical relevance).

Clinical update on benefit versus risks of oral paracetamol alone or with codeine: still a good option?

PubMed

Kress, Hans Georg; Untersteiner, Gerald

2017-02-01

After decades of worldwide use of paracetamol/acetaminophen as a popular and apparently safe prescription and over-the-counter medicine, the future role of this poorly understood analgesic has been seriously questioned by recent concerns about prenatal, cardiovascular (CV) and hepatic safety, and also about its analgesic efficacy. At the same time the usefulness of codeine in combination products has come under debate. Based on a PubMed database literature search on the terms efficacy, safety, paracetamol, acetaminophen, codeine and their combinations up to and including June 2016, this clinical update reviews the current evidence of the benefit and risks of oral paracetamol alone and with codeine for mild-to-moderate pain in adults, and compares the respective efficacy and safety profiles with those of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas there is a clear strong association of NSAID use and gastrointestinal (GI) and CV morbidity and mortality, evidence for paracetamol with and without codeine supports the recommended use even in most vulnerable individuals, such as the elderly, pregnant women, alcoholics, and compromised GI and CV patients. The controversies and widespread misconceptions about the complex hepatic metabolism and potential hepatotoxicity have been corrected by recent reviews, and paracetamol remains the first-line nonopioid analgesic in patients with liver diseases if notes of caution are applied. Due to its safety and tolerability profile paracetamol remained a first-line treatment in many international guidelines. Alone and with codeine it is a safe and effective option in adults, whilst NSAIDs are obviously less safe as alternatives, given the risk of potentially fatal GI and CV adverse effects.

Tramadol for noncancer pain and the risk of hyponatremia.

PubMed

Fournier, Jean-Pascal; Yin, Hui; Nessim, Sharon J; Montastruc, Jean-Louis; Azoulay, Laurent

2015-04-01

Case reports have signaled a possible association between tramadol, a weak opioid analgesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine. Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles. The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54). In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparative Analgesic Efficacy of Oxycodone/Acetaminophen vs Codeine/Acetaminophen for Short-Term Pain Management Following ED Discharge.

PubMed

Chang, Andrew K; Bijur, Polly E; Lupow, Jason B; Gallagher, E John

2015-12-01

To test the hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen following emergency department (ED) discharge. Prospective, randomized, double-blind, trial. Adult inner city ED. ED patients with acute extremity pain who were discharged home. Patients randomized to oxycodone/acetaminophen (5 mg/325 mg) or codeine/acetaminophen (30 mg/300 mg). The primary outcome, obtained via telephone one day after ED discharge, was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug. Secondary outcomes included proportion of patients with >50% pain reduction, side-effect profile, and patient satisfaction. Two hundred and forty patients were enrolled. Mean baseline NRS scores were 7.9 in both groups. Mean decrease over 2 hours was 4.5 NRS units in the oxycodone/acetaminophen group vs 4.2 NRS units in the codeine/acetaminophen group, for a clinically and statistically nonsignificant difference of 0.2 NRS units (95% CI -0.4-0.9 NRS units). Similarly, 66% vs 61% achieved >50% pain relief for a nonsignificant difference of 5% (95% CI -8% to 17%). Side-effect profile and patient satisfaction were similar. Our hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen was rejected. Although pain within each group was reduced by more than half, the between-group difference was not significant. Pending independent validation, these unexpected findings suggest that codeine/acetaminophen, a Schedule III agent, may be a clinically reasonable outpatient opioid alternative to oxycodone/acetaminophen, a more tightly restricted Schedule II agent thought to be more prone to misuse. Wiley Periodicals, Inc.

Best Practices and Innovations for Managing Codeine Misuse and Dependence.

PubMed

Norman, Ian J; Bergin, Michael; Parry, Charles D; Van Hout, Marie Claire

Promoting and ensuring safe use of codeine containing medicines remains a public health issue given the rise in reporting of misuse and dependence particularly in countries where available over-the-counter (OTC). The aim of this unique study was to identify best practices in management of opioid abuse and dependence, particularly codeine, and innovations to meet challenges surrounding safe and compliant use, patient awareness-raising, reducing health harms and enhancing successful treatment of dependence. A mixed methods approach using three data points was used that included : (1) analysis of data from existing scoping reviews to identify potential areas for innovation (2) interviews with key national stakeholders from public health, pharmaceutical, regulatory, primary care and addiction practice in three distinct regulatory regimes (Ireland, United Kingdom and South Africa); and (3) a circular email request for information on potential innovations to members of the European Medicine's Agency European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). Data from these three sources were analysed to identify best practices and opportunities for innovation. Best practices and potential innovations were identified under the nine headings: (1) manufacture; (2) product information and public education; (3) responsible prescribing; (4) monitoring and surveillance; (5) dispensing, screening and brief interventions in community pharmacies; (6) safety in the workplace and on the road; (7) internet supply of codeine and online support; (8) treatment of codeine dependence; and (9) learning resources and training for health professionals. Challenges ensuring availability of codeine containing medicines for legitimate therapeutic use, while minimising misuse, dependence and related health harms warrant consideration of new innovations. Most promising innovative potential lies across the products' retail lifecycle from manufacture to prescriber and community pharmacy practitioner.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Comparison of fatal poisonings by prescription opioids.

PubMed

Häkkinen, Margareeta; Launiainen, Terhi; Vuori, Erkki; Ojanperä, Ilkka

2012-10-10

There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14-44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5 mg/l, respectively) than in other causes of death (0.09 and 5.9 mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8 mg/l, respectively) than in other causes of death (0.6 and 0.2 mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35 mg/l) was not different from that in other causes of death (0.30 mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The detection of drugs of abuse in fingerprints using Raman spectroscopy I: latent fingerprints

NASA Astrophysics Data System (ADS)

Day, Joanna S.; Edwards, Howell G. M.; Dobrowski, Steven A.; Voice, Alison M.

2004-02-01

This paper describes the application of Raman spectroscopy to the detection of exogenous substances in latent fingerprints. The scenario considered was that of an individual handling a substance and subsequently depositing a contaminated fingerprint. Five drugs of abuse (codeine phosphate, cocaine hydrochloride, amphetamine sulphate, barbital and nitrazepam) and five non-controlled substances of similar appearance, which may be used in the adulteration of drugs of abuse (caffeine, aspirin, paracetamol, starch and talc), were studied in both sweat-rich and sebum-rich latent fingerprints. The substances studied could be clearly distinguished using their Raman spectra and were all successfully detected in latent fingerprints. Photobleaching was necessary to reduce the fluorescence background in the spectra of some substances. Raman spectra obtained from the substances in sweat-rich latent fingerprints were of a similar quality to spectra that obtained from the substances under normal sampling conditions. Interfering Raman bands arising from latent fingerprint material were present in the spectra obtained from the substances in sebum-rich fingerprints. These bands did not prevent identification of the substances and could be successfully removed by spectral subtraction. The most difficult aspect of the detection of these substances in latent fingerprints was visually locating the substance in the fingerprint in order to obtain a Raman spectrum.

Chronic treatment of (+)-methamphetamine-induced locomotor effects in rats using one or a combination of two high affinity anti-methamphetamine monoclonal antibodies

PubMed Central

Hambuchen, Michael D.; Rüedi-Bettschen, Daniela; Gunnell, Melinda G.; Hendrickson, Howard; Owens, S. Michael

2016-01-01

ABSTRACT We hypothesized that treatment of methamphetamine (METH) effects with a mixture of 2 high affinity anti-METH monoclonal antibodies (mAb) with differing molecular recognition for METH-like structures could increase efficacy compared to treatment with a single mAb. The antibodies studied were mAb7F9 (METH and amphetamine [AMP] KD = 7.7 and 270 nM) and mAb4G9 (16 nM and 110 nM, respectively) in a 50:50 mixture. Adult male Sprague Dawley Rats were treated with iv saline or a loading dose of mAb7F9-mAb4G9 (141 mg/kg of each mAb) followed by 2 weekly doses (70.5 mg/kg total) on days 7 and 14. METH challenge doses (0.56 mg/kg) were administered 4 hrs and 3 days after each mAb7F9-mAb4G9 treatment, and 7 days after the final treatment (day 21). Locomotor activity (0–4 hrs) and serum METH and AMP concentrations (at 5 hrs) were measured after each METH challenge. MAb7F9-mAb4G9 treatment significantly reduced the duration of locomotor activity after 6 of the 7 METH doses (P < 0.05) and significantly increased serum METH and AMP concentrations. Administering three-fold higher METH doses (1.68 mg/kg) on days 24 and 28 showed mAb7F9-mAb4G9 treatment had negligible effects on the duration of METH-induced locomotor activity. These data were then compared to previous monotherapy data. While mAb7F9-mAb4G9 therapy inhibited the effects of multiple METH challenge doses, the inhibition was not as profound or as long lasting as the effects of mAb7F9 treatment alone. These data demonstrate the importance of both mAb affinity and specificity in the production of effective, long-lasting anti-METH mAb therapies. PMID:27163775

High-throughput analysis of amphetamines in blood and urine with online solid-phase extraction-liquid chromatography-tandem mass spectrometry.

PubMed

Fernández, María del Mar Ramírez; Wille, Sarah M R; Samyn, Nele; Wood, Michelle; López-Rivadulla, Manuel; De Boeck, Gert

2009-01-01

An automated online solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS-MS) method for the analysis of amphetamines in blood and urine was developed and validated. Chromatographic separation was achieved on a Nucleodur Sphinx RP column with an LC gradient (a mixture of 10 mM ammonium formate buffer and acetonitrile), ensuring the elution of amphetamine, methamphetamine, MDMA, MDA, MDEA, PMA, and ephedrine within 11 min. The method was fully validated, according to international guidelines, using only 100 and 50 microL of blood and urine, respectively. The method showed an excellent intra- and interassay precision (relative standard deviation < 11.2% and bias < 13%) for two external quality control samples (QC) for both matrices and three and two 'in house' QCs for blood and urine, respectively. Responses were linear over the investigated range (r(2) > 0.99, 2.5-400 microg/L for blood and 25-1000 microg/L for urine). Limits of quantification were determined to be 2.5 and 25 microg/L for blood and urine, respectively. Limits of detection ranged from 0.05 to 0.5 microg/L for blood and 0.25 to 2.5 microg/L for urine, depending on the compound. Furthermore, the analytes and the processed samples were demonstrated to be stable (in the autosampler for at least 72 h and after three freeze/thaw cycles), and no disturbing matrix effects were observed for all compounds. Moreover, no carryover was observed after the analysis of high concentration samples (15,000 microg/L). The method was subsequently applied to authentic blood and urine samples obtained from forensic cases, which covered a broad range of concentrations. The validation results and actual sample analyses demonstrated that this method is rugged, precise, accurate, and well-suited for routine analysis as more than 72 samples are analyzed non-stop in 24 h with minimum sample handling. The combination of the high-throughput online SPE and the well-known sensitivity and selectivity assured by MS-MS resulted in the elimination of the bottleneck associated with the sample preparation requirements and provided increased sensitivity, accuracy, and precision.

21 CFR 862.3270 - Codeine test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Codeine test system. 862.3270 Section 862.3270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3270 - Codeine test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Codeine test system. 862.3270 Section 862.3270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3270 - Codeine test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Codeine test system. 862.3270 Section 862.3270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3270 - Codeine test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Codeine test system. 862.3270 Section 862.3270 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

Systemic synergism between codeine and morphine in three pain models in mice.

PubMed

Miranda, Hugo F; Noriega, Viviana; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

2013-01-01

The combination of two analgesic agents offers advantages in pain treatment. Codeine and morphine analgesia is due to activation of opioid receptor subtypes. This study, performed in mice using isobolographic analysis, evaluated the type of interaction in intraperitoneal (ip) or intrathecal (it) coadministration of codeine and morphine, in three nociceptive behavioral models. Intrathecal morphine resulted to be 7.5 times more potent than ip morphine in the writhing test, 55.6 times in the tail flick test and 1.7 times in phase II of the orofacial formalin test; however, in phase I of the same test ip was 1.2 times more potent than it morphine. Intrathecal codeine resulted being 3.4 times more potent than ip codeine in the writhing test, 1.6 times in the tail flick test, 2.5 times in phase I and 6.7 times in phase II of the orofacial formalin test. Opioid coadministration had a synergistic effect in the acute tonic pain (acetic acid writhing test), acute phasic pain (tail flick test) and inflammatory pain (orofacial formalin test). The interaction index ranged between 0.284 (writhing ip) and 0.440 (orofacial formalin phase II ip). This synergy may relate to the different pathways of pain transmission and to the different intracellular signal transduction. The present findings also raise the possibility of potential clinical advantages in combining opioids in pain management.

Motor and Cognitive Outcomes Through Three Years Of Age In Children Exposed To Prenatal Methamphetamine

PubMed Central

Smith, Lynne M.; LaGasse, Linda L.; Derauf, Chris; Newman, Elana; Shah, Rizwan; Haning, William; Arria, Amelia; Huestis, Marilyn; Strauss, Arthur; Grotta, Sheri Della; Dansereau, Lynne M.; Lin, Hai; Lester, Barry M.

2010-01-01

Background Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown. Objective To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age. Design/Methods IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self-report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n= 330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n= 331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time. Results Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P = 0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age. Conclusions There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years. PMID:21256431

Motor and cognitive outcomes through three years of age in children exposed to prenatal methamphetamine.

PubMed

Smith, Lynne M; LaGasse, Linda L; Derauf, Chris; Newman, Elana; Shah, Rizwan; Haning, William; Arria, Amelia; Huestis, Marilyn; Strauss, Arthur; Della Grotta, Sheri; Dansereau, Lynne M; Lin, Hai; Lester, Barry M

2011-01-01

Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown. To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age. IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, and type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n=330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n=331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time. Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P=0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age. There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years. Copyright © 2010 Elsevier Inc. All rights reserved.

Codeine, alone and with paracetamol (acetaminophen), for cancer pain.

PubMed

Straube, Carmen; Derry, Sheena; Jackson, Kenneth C; Wiffen, Philip J; Bell, Rae F; Strassels, Scott; Straube, Sebastian

2014-09-19

Pain is very common in patients with cancer. Opioid analgesics, including codeine, play a significant role in major guidelines on the management of cancer pain, particularly for mild to moderate pain. Codeine is widely available and inexpensive, which may make it a good choice, especially in low-resource settings. Its use is controversial, in part because codeine is not effective in a minority of patients who cannot convert it to its active metabolite (morphine), and also because of concerns about potential abuse, and safety in children. To determine the efficacy and safety of codeine used alone or in combination with paracetamol for relieving cancer pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2014, Issue 2), MEDLINE and EMBASE from inception to 5 March 2014, supplemented by searches of clinical trial registries and screening of the reference lists of the identified studies and reviews in the field. We sought randomised, double-blind, controlled trials using single or multiple doses of codeine, with or without paracetamol, for the treatment of cancer pain. Trials could have either parallel or cross-over design, with at least 10 participants per treatment group. Studies in children or adults reporting on any type, grade, and stage of cancer were eligible. We accepted any formulation, dosage regimen, and route of administration of codeine, and both placebo and active controls. Two review authors independently read the titles and abstracts of all studies identified by the searches and excluded those that clearly did not meet the inclusion criteria. For the remaining studies, two authors read the full manuscripts and assessed them for inclusion. We resolved discrepancies between review authors by discussion. Included studies were described qualitatively, since no meta-analysis was possible because of the small amount of data identified, and clinical and methodological between-study heterogeneity. We included 15 studies including 721 participants with cancer pain due to diverse types of malignancy. All studies were performed on adults; there were no studies on children. The included studies were of adequate methodological quality, but all except for one were judged to be at a high risk of bias because of small study size, and six because of methods used to deal with missing data or high withdrawal rates. Three studies used a parallel group design; the remainder were cross-over trials in which there was an adequate washout period, but only one reported results for treatment periods separately.Twelve studies used codeine as a single agent and three combined it with paracetamol. Ten studies included a placebo arm, and 14 included one or more of 16 different active drug comparators or compared different routes of administration. Most studies investigated the effect of a single dose of medication, while five used treatment periods of one, seven or 21 days. Most studies used codeine at doses of 30 mg to 120 mg.There were insufficient data for any pooled analysis. Only two studies reported our preferred responder outcome of 'participants with at least 50% reduction in pain' and two reported 'participants with no worse than mild pain'. Eleven studies reported treatment group mean measures of pain intensity or pain relief; overall for these outcome measures, codeine or codeine plus paracetamol was numerically superior to placebo and equivalent to the active comparators.Adverse event reporting was poor: only two studies reported the number of participants with any adverse event specified by treatment group and only one reported the number of participants with any serious adverse event. In multiple-dose studies nausea, vomiting and constipation were common, with somnolence and dizziness frequent in the 21-day study. Withdrawal from the studies, where reported, was less than 10% except in two studies. There were three deaths, in all cases due to the underlying cancer. We identified only a small amount of data in studies that were both randomised and double-blind. Studies were small, of short duration, and most had significant shortcomings in reporting. The available evidence indicates that codeine is more effective against cancer pain than placebo, but with increased risk of nausea, vomiting, and constipation. Uncertainty remains as to the magnitude and time-course of the analgesic effect and the safety and tolerability in longer-term use. There were no data for children.

The relationship between crystalline methamphetamine use and methamphetamine dependence.

PubMed

McKetin, Rebecca; Kelly, Erin; McLaren, Jennifer

2006-12-01

The aim of the current study was to determine whether crystalline methamphetamine users are more dependent on methamphetamine than people who use other forms of the drug, and if so, whether this could be accounted for by their methamphetamine use history. A structured face-to-face interview was used to assess drug use patterns and demographics among a convenience sample of 309 regular methamphetamine users from Sydney, Australia. Dependence on methamphetamine in the past year was measured using the Severity of Dependence Scale. The use of crystalline methamphetamine in the past year was confirmed using a photographic identification sheet. Participants who had used crystalline methamphetamine in the past year were significantly more likely to be dependent on methamphetamine than participants who took only other forms of methamphetamine during this time (61% versus 39%). Methamphetamine dependence was also associated with injecting or smoking methamphetamine (67% and 58%, respectively versus 30% for intranasal or oral use), using methamphetamine more than weekly (68% versus 34%), having used the drug for more than 5 years (61% versus 36%), and having used 'base' methamphetamine in the past year (59% versus 39%). Crystalline methamphetamine use remained significantly associated with methamphetamine dependence after adjusting for these patterns of methamphetamine use. Methamphetamine users who took crystalline methamphetamine in the past year were more likely to be dependent than methamphetamine users who had not taken the crystalline form of the drug during this time.

Regular use of acetaminophen or acetaminophen-codeine combinations and prescription of rescue therapy with non-steroidal anti-inflammatory drugs: a population-based study in primary care.

PubMed

Vannacci, Alfredo; Lombardi, Niccolò; Simonetti, Monica; Fornasari, Diego; Fanelli, Andrea; Cricelli, Iacopo; Cricelli, Claudio; Lora Aprile, Pierangelo; Lapi, Francesco

2017-06-01

There are contrasting positions concerning the benefit-risk ratio of acetaminophen use for osteoarthritis (OA)-related pain. To clarify the effectiveness of acetaminophen or acetaminophen-codeine combinations according to their regimen of use, we evaluated whether being a regular user (adherent) of these medications decreased the occurrence of rescue therapy with non-steroidal anti-inflammatory drugs (NSAIDs). Using the Health Search IMS Health Longitudinal Patient Database, we formed a cohort of patients aged ≥18 years and newly treated with acetaminophen or acetaminophen-codeine combinations for OA between 1 January 2001 and 31 December 2013. These patients were followed up for one year in which they were categorized as regular or irregular users of these medications according to a variable medication possession ratio (VMPR) ≥ 50% or lower. We operationally defined the rescue therapy as the use of any NSAIDs prescribed for OA-related pain. Overall, 40,029 patients (69.5% females; mean age: 68 ± 13.57) treated with acetaminophen or acetaminophen-codeine combinations formed the cohort. After the first year of treatment, regular users showed a statistically significantly lower risk of being prescribed with rescue therapy with NSAIDs (OR = 0.89; 95% CI 0.84-0.96). These findings show that regular use of acetaminophen or acetaminophen-codeine combinations may reduce the need for NSAIDs to treat OA-related pain.

"TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference.

PubMed

Grandy, David K; Miller, Gregory M; Li, Jun-Xu

2016-02-01

In keeping with the free-thinking tradition San Antonians are known for, the Scientific Program Committee of the Behavior, Biology and Chemistry: Translational Research in Addiction Conference chose trace amine-associated receptor 1 (TAAR1) as the focus of the plenary symposium for its 7th annual meeting held at the University of Texas Health Science Center at San Antonio on March 14 and 15, 2015. The timing of the meeting's plenary session on TAAR1 coincided with the Ides of March, an apt concurrence given the long association of this date with the overthrow of the status quo. And whether aware of the coincidence or not, those in attendance witnessed the plunging of the metaphorical dagger into the heart of the dopamine (DA) transporter (DAT)-centric view of psychostimulant action. The symposium's four plenary presentations focused on the molecular and cellular biology, genetics, medicinal chemistry and behavioral pharmacology of the TAAR1 system and the experimental use of newly developed selective TAAR1 ligands. The consensus was that TAAR1 is a DA and methamphetamine receptor, interacts with DAT and DA D2 receptors, and is essential in modulating addiction-related effects of psychostimulants. Collectively the findings presented during the symposium constitute a significant challenge to the current view that psychostimulants such as methamphetamine and amphetamine solely target DAT to interfere with normal DA signaling and provide a novel conceptual framework from which a more complete understanding of the molecular mechanisms underlying the actions of DA and METH is likely to emerge. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study

PubMed Central

Ray, Lara A; Bujarski, Spencer; Courtney, Kelly E; Moallem, Nathasha R; Lunny, Katy; Roche, Daniel; Leventhal, Adam M; Shoptaw, Steve; Heinzerling, Keith; London, Edythe D; Miotto, Karen

2015-01-01

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of ‘crave drug,' ‘stimulated,' and ‘would like drug access,' decreased the the post-MA administration timecourse of ‘anxious' and increased ratings of ‘bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA. PMID:25801501

Toll-Like Receptor 4 Mediates Methamphetamine-Induced Neuroinflammation through Caspase-11 Signaling Pathway in Astrocytes

PubMed Central

Du, Si-Hao; Qiao, Dong-Fang; Chen, Chuan-Xiang; Chen, Si; Liu, Chao; Lin, Zhoumeng; Wang, Huijun; Xie, Wei-Bing

2017-01-01

Methamphetamine (METH) is an amphetamine-typed stimulant drug that is increasingly being abused worldwide. Previous studies have shown that METH toxicity is systemic, especially targeting dopaminergic neurons in the central nervous system (CNS). However, the role of neuroinflammation in METH neurotoxicity remains unclear. We hypothesized that Toll-like receptor 4 (TLR4) and Caspase-11 are involved in METH-induced astrocyte-related neuroinflammation. We tested our hypothesis by examining the changes of TLR4 and Caspase-11 protein expression in primary cultured C57BL/6 mouse astrocytes and in the midbrain and striatum of mice exposed to METH with western blot and double immunofluorescence labeling. We also determined the effects of blocking Caspase-11 expression with wedelolactone (a specific inhibitor of Caspase-11) or siRNA on METH-induced neuroinflammation in astrocytes. Furthermore, we determined the effects of blocking TLR4 expression with TAK-242 (a specific inhibitor of TLR4) or siRNA on METH-induced neuroinflammation in astrocytes. METH exposure increased Caspase-11 and TLR4 expression both in vitro and in vivo, with the effects in vitro being dose-dependent. Inhibition of Caspase-11 expression with either wedelolactone or siRNAs reduced the expression of inflammasome NLRP3 and pro-inflammatory cytokines. In addition, blocking TLR4 expression inhibited METH-induced activation of NF-κB and Caspase-11 in vitro and in vivo, suggesting that TLR4-Caspase-11 pathway is involved in METH-induced neuroinflammation. These results indicate that Caspase-11 and TLR4 play an important role in METH-induced neuroinflammation and may be potential gene targets for therapeutics in METH-caused neurotoxicity. PMID:29311802

Forensic drug intelligence and the rise of cryptomarkets. Part I: Studying the Australian virtual market.

PubMed

Broséus, Julian; Morelato, Marie; Tahtouh, Mark; Roux, Claude

2017-10-01

Analysing and understanding cryptomarkets is essential to become proactive in the fight against the illicit drug trade. Such a research seeks to combine a diversity of indicators related to the virtual (darknet markets) and physical (the traditional "offline" market) aspects of the illicit drug trade to provide information on the distribution and consumption as well as to assess similarities/differences between the virtual and physical markets. This study analysed data that had previously been collected on cryptomarkets from December 2013 to March 2015. In this article, the data was extracted from two marketplaces, Evolution and Silk Road 2, and analysed to evaluate the illicit drug trade of the Australian virtual market (e.g. information about the supply and demand, trafficking flows, prices of illicit drugs and market share) and highlight its specificities. The results revealed the domestic nature of the virtual Australian illicit drug trade (i.e. Australian sellers essentially ship their products to local customers). This may explain the coherence between supply and demand. Particularly, the virtual Australian illicit drug trade is dominated by amphetamine-type substances (ATS), mainly methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), and cannabis. Australia, as a shipping country, accounts for half of the methamphetamine offered and purchased on Silk Road 2. Moreover, it was observed that the online price fixed by Australian sellers for the considered illicit drugs is higher than for any other shipping countries, which is in line with previous studies. Understanding the virtual and physical drug market necessitates the integration and fusion of different perspectives to capture the dynamic nature of drug trafficking, monitor its evolution and finally improve our understanding of the phenomenon so policy makers can make informed decisions. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibiting effects of rhynchophylline on zebrafish methamphetamine dependence are associated with amelioration of neurotransmitters content and down-regulation of TH and NR2B expression.

PubMed

Jiang, Mingjin; Chen, Yifei; Li, Chan; Peng, Qiuxian; Fang, Miao; Liu, Wei; Kang, Qunzhao; Lin, Yingbo; Yung, Ken Kin Lam; Mo, Zhixian

2016-07-04

Others and we have reported that rhynchophylline reverses amphetamine-induced conditioned place preference (CPP) effect which may be partly mediated by amelioration of central neurotransmitters and N-methyl-d-aspartate receptor 2B (NR2B) levels in the rat brains. The current study investigated the inhibiting effects of rhynchophylline on methamphetamine-induced (METH-induced) CPP in adult zebrafish and METH-induced locomotor activity in tyrosine hydroxylase-green fluorescent protein (TH-GFP) transgenic zebrafish larvae and attempted to confirm the hypothesis that these effects were mediated via regulation of neurotransmitters and dopaminergic and glutamatergic systems. After baseline preference test (on days 1-3), zebrafish were injected intraperitoneally METH (on days 4, 6 and 8) or the same volume of fish physiological saline (on days 5 and 7) and were immediately conditioned. Rhynchophylline was administered at 12h after injection of METH. On day 9, zebrafish were tested for METH-induced CPP. Results revealed that rhynchophylline (100mg/kg) significantly inhibited the acquisition of METH-induced CPP, reduced the content of dopamine and glutamate and down-regulated the expression of TH and NR2B in the CPP zebrafish brains. Furthermore, the influence of rhynchophylline on METH-induced locomotor activity was also observed in TH-GFP transgenic zebrafish larvae. Results showed that rhynchophylline (50mg/L) treatment led to a significant reduction on the locomotor activity and TH expression in TH-GFP transgenic zebrafish larvae. Taken together, these data indicate that the inhibition of the formation of METH dependence by rhynchophylline in zebrafish is associated with amelioration of the neurotransmitters dopamine and glutamate content and down-regulation of TH and NR2B expression. Copyright © 2016 Elsevier Inc. All rights reserved.

Correlates and subgroups of injecting drug use in UK gay and bisexual men: Findings from the 2014 Gay Men's Sex Survey.

PubMed

Melendez-Torres, G J; Bourne, Adam; Hickson, Ford; Reid, David; Weatherburn, Peter

2018-04-16

Evidence to understand which gay and bisexual men (GBM) inject drugs remains scant, especially in the UK. We describe correlates of last-year injecting in UK GBM, and characterise subgroups of GBM who inject drugs by types of drugs used. Using data from the 2014 Gay Men's Sex Survey, an opportunistic internet-based survey conducted of GBM living in the UK, we examined via logistic regression correlates with any injecting of six drugs (amphetamine/speed, crystal methamphetamine, heroin, mephedrone, GHB/GBL, and ketamine) in the last year. We estimated latent class models to understand underlying subgroups of injecting drug use among GBM reporting injecting drug use in the last year. Injecting was most common in GBM who were of middle age, who were HIV seropositive, and who lived in London, and was significantly associated with sexual risk with multiple partners in the last year, whether steady or non-steady. Most GBM who engaged in injecting either injected crystal methamphetamine, mephedrone or both (class 1, chemsex, 88.6% of injectors), whereas a smaller group had a focus on opiates (class 2, opiate, 7.9%). A small but identifiable subgroup (class 3, eclectic, 3.5%) engaged in injecting across the range of drugs examined. This is the first epidemiological analysis to describe subgroups of injecting, and to describe correlates of injecting drug use, in UK GBM. Implications for design of harm reduction services include a need to focus on injecting drug use beyond opiates, currently the focus of most harm reduction services. Copyright © 2018 Elsevier B.V. All rights reserved.

Rapid Morphological Brain Abnormalities during Acute Methamphetamine Intoxication in the Rat. An Experimental study using Light and Electron Microscopy

PubMed Central

Sharma, Hari S.; Kiyatkin, Eugene A.

2009-01-01

This study describes morphological abnormalities of brain cells during acute methamphetamine (METH) intoxication in the rat and demonstrates the role of hyperthermia, disruption of the blood-brain barrier (BBB) and edema in their development. Rats with chronically implanted brain, muscle and skin temperature probes and an intravenous (iv) catheter were exposed to METH (9 mg/kg) at standard (23°C) and warm (29°C) ambient temperatures, allowing for the observation of hyperthermia ranging from mild to pathological levels (38–42°C). When brain temperature peaked or reached a level suggestive of possible lethality (>41.5°C), rats were injected with Evans blue (EB), rapidly anesthetized, perfused, and their brains were taken for further analyses. Four brain areas (cortex, hippocampus, thalamus and hypothalamus) were analyzed for EB extravasation, water and electrolyte (Na+, K+, Cl−) contents, immunostained for albumin and glial fibrillary acidic protein, and examined for neuronal, glial and axonal alterations using standard light and electron microscopy. These examinations revealed profound abnormalities in neuronal, glial, and endothelial cells, which were stronger with METH administered at 29°C than 23°C and tightly correlated with brain and body hyperthermia. These changes had some structural specificity, but in each structure they tightly correlated with increases in EB levels, the numbers of albumin-positive cells, and water and ion contents, suggesting leakage of the BBB, acutely developing brain edema, and serious shifts in brain ion homeostasis as leading factors underlying brain abnormalities. While most of these acute structural and functional abnormalities appear to be reversible, they could trigger subsequent cellular alterations in the brain and accelerate neurodegeneration—the most dangerous complication of chronic amphetamine-like drug abuse. PMID:18773954

Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation.

PubMed

Onaivi, Emmanuel S; Ali, Syed F; Chirwa, Sanika S; Zwiller, Jean; Thiriet, Nathalie; Akinshola, B Emmanuel; Ishiguro, Hiroki

2002-06-01

The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a "threshold" beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.

Illicit stimulant use in humans is associated with a long-term increase in tremor.

PubMed

Flavel, Stanley C; Koch, Jenna D; White, Jason M; Todd, Gabrielle

2012-01-01

Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is a significant health problem. The United Nations Office on Drugs and Crime estimates that 14-57 million people use stimulants each year. Chronic use of illicit stimulants can cause neurotoxicity in animals and humans but the long-term functional consequences are not well understood. Stimulant users self-report problems with tremor whilst abstinent. Thus, the aim of the current study was to investigate the long-term effect of stimulant use on human tremor during rest and movement. We hypothesized that individuals with a history of stimulant use would exhibit abnormally large tremor during rest and movement. Tremor was assessed in abstinent ecstasy users (n = 9; 22 ± 3 yrs) and abstinent users of amphetamine-like drugs (n = 7; 33 ± 9 yrs) and in two control groups: non-drug users (n = 23; 27 ± 8 yrs) and cannabis users (n = 12; 24 ± 7 yrs). Tremor was measured with an accelerometer attached to the index finger at rest (30 s) and during flexion and extension of the index finger (30 s). Acceleration traces were analyzed with fast-Fourier transform. During movement, tremor amplitude was significantly greater in ecstasy users than in non-drug users (frequency range 3.9-13.3 Hz; P<0.05), but was unaffected in cannabis users or users of amphetamine-like drugs. The peak frequency of tremor did not significantly differ between groups nor did resting tremor. In conclusion, abstinent ecstasy users exhibit an abnormally large tremor during movement. Further work is required to determine if the abnormality translates to increased risk of movement disorders in this population.

Detecting alcohol and illicit drugs in oral fluid samples collected from truck drivers in the state of São Paulo, Brazil.

PubMed

Yonamine, Mauricio; Sanches, Livia Rentas; Paranhos, Beatriz Aparecida Passos Bismara; de Almeida, Rafael Menck; Andreuccetti, Gabriel; Leyton, Vilma

2013-01-01

Alcohol and drug use by truck drivers is a current problem in Brazil. Though there is evidence that alcohol consumption is occurring in higher proportions, the use of stimulant drugs to avoid fatigue and to maintain the work schedule has also been reported. The purpose of this study was to estimate the incidence of alcohol and illicit drug use among truck drivers on São Paulo state roads. São Paulo is the most populous state in Brazil and has the largest industrial park and economic production in the country. Data were assessed not only using a questionnaire but also, and more reliably, through toxicological analysis of oral fluid samples. Between the years 2002 and 2008, 1250 oral fluid samples were collected from truck drivers on the roads during morning hours. The samples were tested for the presence of alcohol, cocaine, tetrahydrocannabinol (THC), and amphetamine/methamphetamine. A previously published, validated gas chromatographic (gas chromatography-flame ionization detection and gas chromatography-mass spectrometry) method was applied to the samples for alcohol and drug detection. Of the total analyzed samples, 3.1 percent (n = 39) were positive: 1.44 percent (n = 18) were positive for alcohol, 0.64 percent (n = 8) for amphetamines, 0.56 percent (n = 7) for cocaine, and 0.40 percent (n = 5) for THC. In one case, cocaine and THC were detected. The results are indicative of the extent of alcohol and drug use by truck drivers in the state of São Paulo, Brazil. This research provides evidence that not only alcohol but also illicit drug use is a real problem among professional drivers. The use of these substances should be controlled to better promote safe driving conditions on Brazilian roads.

Evaluation of commercial enzyme-linked immunosorbent assays to identify psychedelic phenethylamines.

PubMed

Kerrigan, Sarah; Mellon, Monica Brady; Banuelos, Stephanie; Arndt, Crystal

2011-09-01

The 2C, 2C-T, and DO series of designer drugs pose a number of challenges to forensic toxicology laboratories. Although these drugs are seized by law enforcement agencies throughout the United States, they are not readily detected in forensic toxicology laboratories. A systematic evaluation of the cross-reactivity of 9 commercial enzyme-linked immunosorbent assays (ELISAs) was conducted using 11 designer drugs. Cross-reactivity was measured towards 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2,5-dimethoxyphenethylamine (2C-H), 2,5-dimethoxy4-iodophenethylamine (2C-I), 2,5-dimethoxy-4ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4isopropylthiophenethylamine (2C-T-4), 2,5-dimethoxy-4propylthiophenethylamine (2C-T-7), 2,5-dimethoxy-4bromoamphetamine (DOB), 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), and 4methylthioamphetamine (4-MTA). Cross-reactivity towards the 2C, 2C-T, and DO series of psychedelic amphetamines was < 0.4%. Concentrations as high as 50,000 ng/mL in urine, which greatly exceed those expected in forensic case samples, were not sufficient to produce a positive result. The only substance to produce any measurable cross-reactivity was 4-MTA. Cross-reactivities of 5 and 7% were obtained using four methamphetamine/MDMA directed assays, 25 and 200% using two amphetamine-directed assays. The absence of any measurable cross-reactivity towards the 10 2C, 2C-T, and DO psychedelic phenethylamines makes it harder to detect these drugs using routine screening. As a consequence, laboratories that rely upon immunoassay rather than more broad spectrum chromatographic screening techniques, may fail to detect these powerful psychedelic substances.

Portable kit for identification and detection of drugs in human urine using surface-enhanced Raman spectroscopy.

PubMed

Han, Zhenzhen; Liu, Honglin; Meng, Juan; Yang, Liangbao; Liu, Jing; Liu, Jinhuai

2015-09-15

A portable kit was demonstrated for rapid and reliable surface-enhanced Raman scattering (SERS) detection of drugs in human urine. This kit contains two sealed reagent tubes, a packet of standardized SERS substrates, and a mini Raman device. A 3 min pretreatment for separating amphetamines from human urine was developed with an extraction rate of >80% examined by ultraperformance liquid chromatography (UPLC). Simultaneously, highly reproducible two-dimensional (2D) gold nanorod (GNR) arrays were assembled by the use of methoxymercaptopoly(ethylene glycol) (mPEG-SH) capping. Thirty batches of GNR arrays produced the 1001 cm(-1) intensity of methamphetamine (MA) molecules with a relative standard deviation (RSD) of 7.9%, and a 21 × 21 μm(2) area mapping on a 2D GNR array produced a statistical RSD of <10%, implying an excellent reproducibility and uniformity. The detection limit of amphetamines in human urine was at least 0.1 ppm. Moreover, the portable kit was successfully used for detecting MA, 3,4-methylenedioxymethamphetamine (MDMA), and methcathinone (MC) in 30 volunteers' urine samples with various clinical natures, and the dual-analyte detection of MA and MDMA implied a good capability of multiplex analysis. UPLC examination and the SERS recovery test clearly indicated that our pretreatment procedure was sufficient to lower the high background signals caused by complex components in urine and demonstrated the practicability and the resistance to false positives, which is a vital problem for law enforcement applications. The excellent performance of our portable kit promises a great prospective toward a rapid, reliable, and on-spot analyzer, especially for public safety and healthcare.

Illicit Stimulant Use in Humans Is Associated with a Long-Term Increase in Tremor

PubMed Central

Flavel, Stanley C.; Koch, Jenna D.; White, Jason M.; Todd, Gabrielle

2012-01-01

Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is a significant health problem. The United Nations Office on Drugs and Crime estimates that 14–57 million people use stimulants each year. Chronic use of illicit stimulants can cause neurotoxicity in animals and humans but the long-term functional consequences are not well understood. Stimulant users self-report problems with tremor whilst abstinent. Thus, the aim of the current study was to investigate the long-term effect of stimulant use on human tremor during rest and movement. We hypothesized that individuals with a history of stimulant use would exhibit abnormally large tremor during rest and movement. Tremor was assessed in abstinent ecstasy users (n = 9; 22±3 yrs) and abstinent users of amphetamine-like drugs (n = 7; 33±9 yrs) and in two control groups: non-drug users (n = 23; 27±8 yrs) and cannabis users (n = 12; 24±7 yrs). Tremor was measured with an accelerometer attached to the index finger at rest (30 s) and during flexion and extension of the index finger (30 s). Acceleration traces were analyzed with fast-Fourier transform. During movement, tremor amplitude was significantly greater in ecstasy users than in non-drug users (frequency range 3.9–13.3 Hz; P<0.05), but was unaffected in cannabis users or users of amphetamine-like drugs. The peak frequency of tremor did not significantly differ between groups nor did resting tremor. In conclusion, abstinent ecstasy users exhibit an abnormally large tremor during movement. Further work is required to determine if the abnormality translates to increased risk of movement disorders in this population. PMID:23272201

Acute health problems due to recreational drug use in patients presenting to an urban emergency department in Switzerland.

PubMed

Liakoni, Evangelia; Dolder, Patrick C; Rentsch, Katharina; Liechti, Matthias E

2015-01-01

To describe acute toxicity of recreational drugs including novel psychoactive substances. We included all cases presenting at the emergency department (ED) of the University Hospital of Basel, Switzerland, between October 2013 and September 2014 with acute toxicity due to self-reported recreational drug use or with symptoms/signs consistent with acute toxicity. Isolated ethanol intoxications were excluded. Intoxications were confirmed with immunoassays and liquid chromatography coupled with mass spectrometry (LC-MS/MS), which also detected novel psychoactive substances. Among the 47,767 attendances at the ED, 216 were directly related to acute toxicity of recreational drugs. The mean patient age was 31 years and 69% were male. Analytical drug confirmation was available in 180 cases. Most presentations were related to cocaine (36%), cannabis (31%), opioids (13%), 3,4-methylenedioxy-methamphetamine (MDMA, 9%), other amphetamines (7%), benzodiazepines (7%), and lysergic acid diethylamide (LSD, 5%). The substances most commonly detected analytically were cannabis (37%), cocaine (33%), opioids (29%), benzodiazepines (21%), and amphetamines including MDMA (13%). Notably, there were only two cases of novel psychoactive substances (2,5-dimethoxy-4-bromophenethylamine [2C-B] and pentylone). The most frequent symptoms were tachycardia (31%), anxiety (27%), nausea or vomiting (23%), and agitation (22%). Severe complications included myocardial infarction (2), psychosis (10), seizures (10), and 1 fatality. Most patients were discharged home (68%), 8% were admitted to intensive care and 9% were referred to psychiatric care. Medical problems related to illicit drugs mostly concerned cocaine and cannabis and mainly involved sympathomimetic toxicity and/or psychiatric disorders. ED presentations associated with novel psychoactive substances appeared to be relatively rare.

Amphetamine-type stimulant use and HIV/STI risk behaviour among young female sex workers in Phnom Penh, Cambodia

PubMed Central

Maher, L; Phlong, P; Mooney-Somers, J; Keo, S; Stein, E; Page, K

2011-01-01

Background Use of amphetamine-type substances (ATS) has been linked to increased risk of HIV and other sexually transmitted infections (STI) worldwide. In Cambodia, recent ATS use is independently associated with incident STI infection among young female sex workers (FSW). Methods We conducted 33 in-depth interviews with women (15–29 years old) engaged in sex work to explore ATS use and vulnerability to HIV/STI. Results Participants reported that ATS, primarily methamphetamine in pill and crystalline forms (yama), were cheap, widely available and commonly used. Yama was described as a “power drug” (thnam kamlang) which enabled women to work long hours and serve more customers. Use of ATS by clients was also common, with some providing drugs for women and/or encouraging their use, often resulting in prolonged sexual activity. Requests for unprotected sex were also more common among intoxicated clients and strategies typically employed to negotiate condom use were less effective. Conclusion ATS use was highly functional for young women engaged in sex work, facilitating a sense of power and agency and highlighting the occupational significance and normalization of ATS in this setting. This highly gendered dynamic supports the limited but emerging literature on women’s use of ATS, which to date has been heavily focused on men. Results indicate an urgent need to increase awareness of the risks associated with ATS use, to provide women with alternative and sustainable options for income generation, to better regulate the conditions of sex work, and to work with FSWs and their clients to develop and promote culturally appropriate harm reduction interventions. PMID:21316935

Amphetamine-Type-Stimulants (ATS) Use and Homosexuality-Related Enacted Stigma Are Associated With Depression Among Men Who Have Sex With Men (MSM) in Two Major Cities in Vietnam in 2014.

PubMed

Vu, Nga Thi Thu; Holt, Martin; Phan, Huong Thi Thu; La, Lan Thi; Tran, Gioi Minh; Doan, Tung Thanh; Nguyen, Trang Nguyen Nhu; de Wit, John

2017-09-19

Men who have sex with men (MSM) are disproportionately affected by mental health concerns, including depression. Amphetamine-type-stimulants (ATS) use and homosexuality-related stigma and discrimination have been found associated with depression among MSM. To assess the prevalence of depression and its associations with ATS use and homosexuality-related stigma and discrimination among MSM in Vietnam. 622 MSM were conveniently recruited in Hanoi and Ho Chi Minh city, Vietnam, from September to December 2014. We collected information on demographic characteristics, ATS, alcohol and other drug use, sexual behaviors, homosexuality-related and discrimination stigma, and sexual sensation-seeking. Depression and suicidal thoughts were assessed by the Patient Health Questionnaire (PHQ-9). We assessed associations of depression with ATS use and homosexuality-related stigma and discrimination using logistic regression. Of 622 sampled MSM, 11.3% were classified as having major depression, 9.8% reported any suicidal thoughts in the last two weeks, 30.4% ever had used any ATS, 88.8% ever ad drank alcohol and 21.5% had ever used any other drugs. In multivariate analysis, depression was significantly associated with ATS use (Adjusted Odds Ratio [AOR: 2.20; (95% Confidence Interval (CI): 1.32-3.67], younger age of sexual debut with another man (AOR: 0.09; 95% CI: 0.02-0.50), and greater enacted homosexuality-related stigma (AOR: 1.97; 95% CI: 1.19-3.26). We found a moderate prevalence of depression among sampled MSM, which was associated with ATS use and enacted homosexuality-related stigma. We recommend integrating assessment and interventions regarding depression and methamphetamine use into gay-friendly, culturally adapted holistic HIV prevention for MSM in Vietnam.

Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review

PubMed Central

2012-01-01

Background There is increasing concern that prescription stimulants may be associated with adverse cardiovascular events such as stroke, myocardial infarction, and sudden death. Public health concerns are amplified by increasing use of prescription stimulants among adults. Methods The objective of this study was to conduct a systematic review of the evidence of an association between prescription stimulant use and adverse cardiovascular outcomes. PUBMED, MEDLINE, EMBASE and Google Scholar searches were conducted using key words related to these topics (MESH): ADHD; Adults; Amphetamine; Amphetamines; Arrhythmias, Cardiac; Cardiovascular Diseases; Cardiovascular System; Central Nervous Stimulants; Cerebrovascular; Cohort Studies; Case–control Studies; Death; Death, Sudden, Cardiac; Dextroamphetamine; Drug Toxicity; Methamphetamine; Methylphenidate; Myocardial Infarction; Stimulant; Stroke; Safety. Eligible studies were population-based studies of children, adolescents, or adults using prescription stimulant use as the independent variable and a hard cardiovascular outcome as the dependent variable. Results Ten population-based observational studies which evaluated prescription stimulant use with cardiovascular outcomes were reviewed. Six out of seven studies in children and adolescents did not show an association between stimulant use and adverse cardiovascular outcomes. In contrast, two out of three studies in adults found an association. Conclusions Findings of an association between prescription stimulant use and adverse cardiovascular outcomes are mixed. Studies of children and adolescents suggest that statistical power is limited in available study populations, and the absolute risk of an event is low. More suggestive of a safety signal, studies of adults found an increased risk for transient ischemic attack and sudden death/ventricular arrhythmia. Interpretation was limited due to differences in population, cardiovascular outcome selection/ascertainment, and methodology. Accounting for confounding and selection biases in these studies is of particular concern. Future studies should address this and other methodological issues. PMID:22682429

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning.

PubMed

King, C P; Militello, L; Hart, A; St Pierre, C L; Leung, E; Versaggi, C L; Roberson, N; Catlin, J; Palmer, A A; Richards, J B; Meyer, P J

2017-09-01

Genome-wide association studies in humans have suggested that variants of the cadherin-13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction-related behaviors, we assessed Cdh13 knockout (KO) rats and AdipoQ KO mice using intravenous cocaine self-administration and conditioned place preference (CPP) paradigms. During intravenous cocaine self-administration, male Cdh13 heterozygous (+/-) and KO (-/-) rats showed increased cue-induced reinstatement compared with wild-type (WT) rats when presented with a cocaine-paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 -/- rats showed higher responding for a saccharin reinforcer and learned the choice reaction time (RT) task more slowly than WTs. However, we found no differences between Cdh13 -/- and +/+ rats in responding for sensory reinforcement, number of premature responses in the RT task, tendency to approach a Pavlovian food cue, CPP and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ -/- mice, there was a significant increase in CPP to methamphetamine (1 mg/kg) but not to a range of d-amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Could piracetam potentiate behavioural effects of psychostimulants?

PubMed

Slais, Karel; Machalova, Alena; Landa, Leos; Vrskova, Dagmar; Sulcova, Alexandra

2012-08-01

Press and internet reports mention abuse of nootropic drug piracetam (PIR) in combination with psychostimulants methamphetamine (MET) or 4-methylenedioxymethamphetamine (MDMA). These combinations are believed to produce more profound desirable effects, while decreasing hangover. However, there is a lack of valid experimental studies on such drug-drug interactions in the scientific literature available. Our hypothesis proposes that a functional interaction exists between PIR and amphetamine psychostimulants (MET and MDMA) which can potentiate psychostimulant behavioural effects. Our hypothesis is supported by the results of our pilot experiment testing acute effects of drugs given to mice intraperitoneally (Vehicle, n=12; MET 2.5mg/kg, n=10; MDMA 2.5mg/kg, n=11; PIR 300 mg/kg, n=12; PIR+MET, n=12; PIR+MDMA, n=11) in the Open Field Test (Actitrack, Panlab, Spain). PIR given alone caused no significant changes in mouse locomotor/exploratory behaviour, whereas the same dose combined with either MET or MDMA significantly enhanced their stimulatory effects. Different possible neurobiological mechanism underlying drug-drug interaction of PIR with MET or MDMA are discussed, as modulation of dopaminergic, glutamatergic or cholinergic brain systems. However, the interaction with membrane phospholipids seems as the most plausible mechanism explaining PIR action on activities of neurotransmitter systems. Despite that our behavioural experiment cannot serve for explanation of the pharmacological mechanisms of these functional interactions, it shows that PIR effects can increase behavioural stimulation of amphetamine drugs. Thus, the reported combining of PIR with MET or MDMA by human abusers is not perhaps a coincidental phenomenon and may be based on existing PIR potential to intensify acute psychostimulant effects of these drugs of abuse. Copyright © 2012 Elsevier Ltd. All rights reserved.

Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse.

PubMed

Miller, D B; O'Callaghan, J P

1994-08-01

In the companion paper we demonstrated that d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA) and d-methylenedioxymethamephetamine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopaminergic projections to the striatum of the mouse. An elevation in core temperature also was associated with exposure to d-METH, d-MDA and d-MDMA, whereas exposure to d-FEN lowered core temperature. Given these findings, we examined the effects of temperature on substituted amphetamine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of striatal dopamine (DA) and glial fibrillary acidic protein (GFAP) were taken as indicators of neurotoxicity. Alterations in ambient temperature, pretreatment with drugs reported to cause hypothermia in the mouse and hypothermia induced by restraint stress were used to affect AMP-induced neurotoxicity. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg) or d-MDMA (20 mg/kg) every 2 hr for a total of four s.c. injections. All three AMPs increased core temperature and caused large (> 75%) decreases in striatal dopamine and large (> 300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering ambient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment with MK-801 lowered core temperature and blocked AMP-induced neurotoxicity; elevation of ambient temperature during this regimen elevated core temperature and markedly attenuated the neuroprotective effects of MK-801. Pretreatment with MK-801 also lowered core temperature in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

75 FR 55828 - Controlled Substances: Final Revised Aggregate Production Quotas for 2010

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-14

...) 18,600,000 g Carfentanil 200 g Cocaine 247,000 g Codeine (for conversion) 65,000,000 g Codeine (for... effect on the economy of $100,000,000 or more; a major increase in costs or prices; or significant adverse effects on competition, employment, investment, productivity, innovation, or on the ability of...

Psychomotor effect differences between l-methamphetamine and d-methamphetamine are independent of murine plasma and brain pharmacokinetics profiles.

PubMed

Nishimura, Tetsuya; Takahata, Kazue; Kosugi, Yuri; Tanabe, Takaaki; Muraoka, Shizuko

2017-05-01

l-Methamphetamine has been occasionally referred to as a stimulant similar to d-methamphetamine, probably owing to insufficient comparative studies. Here, we directly compared psychomotor efficacies and pharmacokinetics of methamphetamine enantiomers in mice. Only d-methamphetamine, but not l-methamphetamine, induced stereotypy and sensitization at 1-10 mg/kg. However, plasma pharmacokinetic parameters of 10 mg/kg l-methamphetamine were ≥tenfold those of 1 mg/kg d-methamphetamine. These results clearly indicate that differential psychomotor efficacies of methamphetamine enantiomers are independent of their pharmacokinetic profiles.

Simultaneous determination of morphine, codeine and 6-acetyl morphine in human urine and blood samples using direct aqueous derivatisation: validation and application to real cases.

PubMed

Chericoni, S; Stefanelli, F; Iannella, V; Giusiani, M

2014-02-15

Opiates play a relevant role in forensic toxicology and their assay in urine or blood is usually performed for example in workplace drug-testing or toxicological investigation of drug impaired driving. The present work describes two new methods for detecting morphine, codeine and 6-monoacethyl morphine in human urine or blood using a single step derivatisation in aqueous phase. Propyl chloroformate is used as the dramatizing agent followed by liquid-liquid extraction and gas-chromatography-mass spectroscopy to detect the derivatives. The methods have been validated both for hydrolysed and unhydrolysed urine. For hydrolysed urine, the LOD and LOQ were 2.5ng/ml and 8.5ng/ml for codeine, and 5.2ng/ml and 15.1ng/ml for morphine, respectively. For unhydrolysed urine, the LOD and LOQ were 3.0ng/ml and 10.1ng/ml for codeine, 2.7ng/ml and 8.1ng/ml for morphine, 0.8ng/ml and 1.5ng/ml for 6-monoacetyl morphine, respectively. In blood, the LOD and LOQ were 0.44ng/ml and 1.46ng/ml for codeine, 0.29ng/ml and 0.98ng/ml for morphine, 0.15ng/ml and 0.51ng/ml for 6-monoacetyl morphine, respectively. The validated methods have been applied to 50 urine samples and 40 blood samples (both positive and negative) and they can be used in routine analyses. Copyright © 2013 Elsevier B.V. All rights reserved.

Comparison of Clinical Efficacies of Preoperatively Initiated Naproxen Sodium-Codeine Phosphate in Combination, Diclofenac Potassium, and Benzydamine Hydrochloride for Pain, Edema, and Trismus After Extraction of Impacted Lower Third Molar: A Randomized Double-Blind Study.

PubMed

Cigerim, Levent; Eroglu, Cennet Neslihan

2018-03-01

The aim of this study was to compare the clinical efficacies of naproxen sodium-codeine phosphate in combination, benzydamine hydrochloride, and diclofenac potassium for pain, edema, and trismus after lower third molar extraction. Ninety healthy volunteers in whom impacted third molar extraction was indicated were randomly distributed into 3 groups. One hour before the tooth-extraction process, patients were administered one of the following drugs: naproxen sodium, 550 mg, and codeine phosphate, 30 mg, in a tablet; diclofenac potassium, 50 mg, in a coated pill; or benzydamine hydrochloride, 50 mg, in a coated pill. Pain assessment was conducted via a visual analog scale; edema assessment, by measuring the distances between predetermined facial landmarks; and trismus assessment, by measuring interincisal distance. Regarding rescue analgesics (paracetamol, 500 mg), the number and time of use by patients were recorded. Naproxen sodium-codeine phosphate was more effective for pain, edema, and trismus than diclofenac potassium and benzydamine hydrochloride (P < .05). Benzydamine hydrochloride yielded similar clinical responses to diclofenac potassium (P > .05). No drug-related side effects were observed. Naproxen sodium-codeine phosphate constitutes the drug of choice after the extraction of a patient's impacted lower third molar. Benzydamine hydrochloride has similar efficacy to diclofenac potassium, and it can be used as a nonsteroidal anti-inflammatory analgesic drug. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( --)-cocaine.

PubMed

Fowler, Joanna S; Kroll, Carsten; Ferrieri, Richard; Alexoff, David; Logan, Jean; Dewey, Stephen L; Schiffer, Wynne; Schlyer, David; Carter, Pauline; King, Payton; Shea, Colleen; Xu, Youwen; Muench, Lisa; Benveniste, Helene; Vaska, Paul; Volkow, Nora D

2007-10-01

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (-)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. d- and l-methamphetamine and (-)-cocaine were labeled with (11)C via alkylation of the norprecursors with (11)C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2-3 h apart to determine the distribution and kinetics of (11)C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. (11)C-d-Methamphetamine pharmacokinetics were compared with (11)C-l-methamphetamine and (11)C-(-)-cocaine in both brain and peripheral organs in the same animal. (11)C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. (11)C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of (11)C-d-methamphetamine and (11)C-(-)-cocaine showed that (11)C-d-methamphetamine peaked later in the brain than did (11)C-(-)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for (11)C-d-methamphetamine. Brain pharmacokinetics did not differ between d-and l-methamphetamine and thus cannot account for the more intense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade by methamphetamine indicates that the PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of (11)C-d-methamphetamine and (11)C-(-)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (-)-cocaine. High kidney uptake of d-methamphetamine or its labeled metabolites may account for the reported renal toxicity of d-methamphetamine in humans.

Component analysis of Iranian crack; a newly abused narcotic substance in iran.

PubMed

Farhoudian, Ali; Sadeghi, Mandana; Khoddami Vishteh, Hamid Reza; Moazen, Babak; Fekri, Monir; Rahimi Movaghar, Afarin

2014-01-01

Iranian crack is a new form of narcotic substance that has found widespread prevalence in Iran in the past years. Crack only nominally resembles crack cocaine as it is widely different in its clinical signs. Thus the present study aims to quantify the chemical combination of this drug. The samples included 18 specimen of Crack collected from different zones of Tehran, Iran. All specimens were in the form of inodorous cream solid powdery substance. TLC and HPLC methods were used to perform semi-quantitative and quantitative analysis of the components, respectively. The TLC analysis showed no cocaine compound in the specimens while they all revealed to contain heroin, codeine, morphine and caffeine. All but two specimens contained thebaine. None of the specimens contained amphetamine, benzodiazepines, tricyclic antidepressants, aspirin, barbiturates, tramadol and buprenorphine. Acetaminophen was found in four specimens. HPLC revealed heroin to be the foundation substance in all specimens and most of them contained a significant amount of acetylcodeine. The present analysis of the chemical combination of Crack showed that this substance is a heroin-based narcotic which is basically different from the cocaine-based crack used in Western countries. Studies like the present one at different time points, especially when abnormal clinical signs are detected, can reveal the chemical combination of the target substance and contribute to the clinical management of its acute or chronic poisoning.

Dioxygenases Catalyze O-Demethylation and O,O-Demethylenation with Widespread Roles in Benzylisoquinoline Alkaloid Metabolism in Opium Poppy*

PubMed Central

Farrow, Scott C.; Facchini, Peter J.

2013-01-01

In opium poppy, the antepenultimate and final steps in morphine biosynthesis are catalyzed by the 2-oxoglutarate/Fe(II)-dependent dioxygenases, thebaine 6-O-demethylase (T6ODM) and codeine O-demethylase (CODM). Further investigation into the biochemical functions of CODM and T6ODM revealed extensive and unexpected roles for such enzymes in the metabolism of protopine, benzo[c]phenanthridine, and rhoeadine alkaloids. When assayed with a wide range of benzylisoquinoline alkaloids, CODM, T6ODM, and the functionally unassigned paralog DIOX2, renamed protopine O-dealkylase, showed novel and efficient dealkylation activities, including regio- and substrate-specific O-demethylation and O,O-demethylenation. Enzymes catalyzing O,O-demethylenation, which cleave a methylenedioxy bridge leaving two hydroxyl groups, have previously not been reported in plants. Similar cleavage of methylenedioxy bridges on substituted amphetamines is catalyzed by heme-dependent cytochromes P450 in mammals. Preferred substrates for O,O-demethylenation by CODM and protopine O-dealkylase were protopine alkaloids that serve as intermediates in the biosynthesis of benzo[c]phenanthridine and rhoeadine derivatives. Virus-induced gene silencing used to suppress the abundance of CODM and/or T6ODM transcripts indicated a direct physiological role for these enzymes in the metabolism of protopine alkaloids, and they revealed their indirect involvement in the formation of the antimicrobial benzo[c]phenanthridine sanguinarine and certain rhoeadine alkaloids in opium poppy. PMID:23928311

Dioxygenases catalyze O-demethylation and O,O-demethylenation with widespread roles in benzylisoquinoline alkaloid metabolism in opium poppy.

PubMed

Farrow, Scott C; Facchini, Peter J

2013-10-04

In opium poppy, the antepenultimate and final steps in morphine biosynthesis are catalyzed by the 2-oxoglutarate/Fe(II)-dependent dioxygenases, thebaine 6-O-demethylase (T6ODM) and codeine O-demethylase (CODM). Further investigation into the biochemical functions of CODM and T6ODM revealed extensive and unexpected roles for such enzymes in the metabolism of protopine, benzo[c]phenanthridine, and rhoeadine alkaloids. When assayed with a wide range of benzylisoquinoline alkaloids, CODM, T6ODM, and the functionally unassigned paralog DIOX2, renamed protopine O-dealkylase, showed novel and efficient dealkylation activities, including regio- and substrate-specific O-demethylation and O,O-demethylenation. Enzymes catalyzing O,O-demethylenation, which cleave a methylenedioxy bridge leaving two hydroxyl groups, have previously not been reported in plants. Similar cleavage of methylenedioxy bridges on substituted amphetamines is catalyzed by heme-dependent cytochromes P450 in mammals. Preferred substrates for O,O-demethylenation by CODM and protopine O-dealkylase were protopine alkaloids that serve as intermediates in the biosynthesis of benzo[c]phenanthridine and rhoeadine derivatives. Virus-induced gene silencing used to suppress the abundance of CODM and/or T6ODM transcripts indicated a direct physiological role for these enzymes in the metabolism of protopine alkaloids, and they revealed their indirect involvement in the formation of the antimicrobial benzo[c]phenanthridine sanguinarine and certain rhoeadine alkaloids in opium poppy.

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its congeners.

PubMed

Huether, G; Zhou, D; Rüther, E

1997-01-01

The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromise the ability of 5-HT terminals to maintain their functional and structural integrity. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromised all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca(++)-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto "buffered" personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.

Method of simultaneous stir bar sorptive extraction of phenethylamines and THC metabolite from urine.

PubMed

Goto, Yoshiyuki; Takeda, Shiho; Araki, Toshinori; Fuchigami, Takayuki

2011-10-01

Stir bar sorptive extraction is a technique used for extracting target substances from various aqueous matrixes such as environmental water, food, and biological samples. This type of extraction is carried out by rotating a coated stir bar is rotated in the sample solution. In particular, Twister bar is a commercial stir bar that is coated with polydimethylsiloxane (PDMS) and used to perform sorptive extraction. In this study, we developed a method for simultaneous detection of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, and a Δ(9)-tetrahydrocannabiniol (THC) metabolite in human urine. For extracting the target analytes, the Twister bar was simply stirred in the sample in the presence of a derivatizing agent. Using this technique, phenethylamines and the acidic THC metabolite can be simultaneously extracted from human urine. This method also enables the extraction of trace amounts of these substances with good reproducibility and high selectivity. The proposed method offers many advantages over other extraction-based approaches and is therefore well suited for screening psychoactive substances in urine specimens.

Psychostimulants and Movement Disorders

PubMed Central

Asser, Andres; Taba, Pille

2015-01-01

Psychostimulants are a diverse group of substances with their main psychomotor effects resembling those of amphetamine, methamphetamine, cocaine, or cathinone. Due to their potential as drugs of abuse, recreational use of most of these substances is illegal since 1971 Convention on Psychotropic Substances. In recent years, new psychoactive substances have emerged mainly as synthetic cathinones with new molecules frequently complementing the list. Psychostimulant related movement disorders are a known entity often seen in emergency rooms around the world. These admissions are becoming more frequent as are fatalities associated with drug abuse. Still the legal constraints of the novel synthetic molecules are bypassed. At the same time, chronic and permanent movement disorders are much less frequently encountered. These disorders frequently manifest as a combination of movement disorders. The more common symptoms include agitation, tremor, hyperkinetic and stereotypical movements, cognitive impairment, and also hyperthermia and cardiovascular dysfunction. The pathophysiological mechanisms behind the clinical manifestations have been researched for decades. The common denominator is the monoaminergic signaling. Dopamine has received the most attention but further research has demonstrated involvement of other pathways. Common mechanisms linking psychostimulant use and several movement disorders exist. PMID:25941511

Illicit drug use and treatment in South Africa: a review.

PubMed

Peltzer, Karl; Ramlagan, Shandir; Johnson, Bruce D; Phaswana-Mafuya, Nancy

2010-11-01

This review synthesizes available epidemiological data on current drug use and substance user treatment admissions in South Africa since 1994, and how changes in the political, economic, and social structures within South Africa, both before and after Apartheid, has made the country more vulnerable to drug use. Based on national surveys, current use of cannabis ranged among adolescents from 2% to 9% and among adults it was 2%, cocaine/crack (0.3%), mandrax/sedatives (0.3%), club drugs/amphetamine-type stimulants (0.2%), opiates (0.1%), and hallucinogens (0.1%). The use of primary illicit substance at admission to South African drug user treatment centers was cannabis 16.9%, methamphetamine (tik) 12.8%, crack/cocaine 9.6%, cannabis and mandrax 3.4%, heroin/opiates 9.2%, and prescription and OTC drugs 2.6%. An increase in substance user treatment admissions has increased. While the prevalence of illicit drug use in South Africa is relatively low compared to the United States and Australia, prevention and intervention policies need to be designed to reduce these levels by targeting the more risky subpopulations identified from this review.

Illicit Drug Use and Treatment in South Africa

PubMed Central

Peltzer, Karl; Ramlagan, Shandir; Johnson, Bruce D.; Phaswana-Mafuya, Nancy

2008-01-01

This review synthesizes available epidemiological data on current drug use and substance abuse treatment admissions in south africa since 1994, and how changes in the political, economic and social structures within south africa both before and after apartheid make the country more vulnerable to drug use. based on national surveys current use of cannabis ranged among adolescents from 2% to 9% and among adults 2%, cocaine/crack (0.3%), mandrax/sedatives (0.3%), club drugs/amphetamine-type stimulants (0.2%), opiates (0.1%) and hallucinogens (0.1%). The primary illicit substance at admission to South African drug treatment centers was cannabis 16.9%, methamphetamine (Tik) 12.8%, crack/cocaine 9.6%, cannabis and mandrax 3.4%, heroin/opiates 9.2%, and prescription and OTC 2.6%. An increase in substance abuse treatment admissions has occurred. While the prevalence of illicit drug use in South Africa is relatively low compared to the USA and Australia, prevention and intervention policies need to be designed to reduce these levels by targeting the more risky subpopulations identified from this review. PMID:21039113

Psychostimulants and movement disorders.

PubMed

Asser, Andres; Taba, Pille

2015-01-01

Psychostimulants are a diverse group of substances with their main psychomotor effects resembling those of amphetamine, methamphetamine, cocaine, or cathinone. Due to their potential as drugs of abuse, recreational use of most of these substances is illegal since 1971 Convention on Psychotropic Substances. In recent years, new psychoactive substances have emerged mainly as synthetic cathinones with new molecules frequently complementing the list. Psychostimulant related movement disorders are a known entity often seen in emergency rooms around the world. These admissions are becoming more frequent as are fatalities associated with drug abuse. Still the legal constraints of the novel synthetic molecules are bypassed. At the same time, chronic and permanent movement disorders are much less frequently encountered. These disorders frequently manifest as a combination of movement disorders. The more common symptoms include agitation, tremor, hyperkinetic and stereotypical movements, cognitive impairment, and also hyperthermia and cardiovascular dysfunction. The pathophysiological mechanisms behind the clinical manifestations have been researched for decades. The common denominator is the monoaminergic signaling. Dopamine has received the most attention but further research has demonstrated involvement of other pathways. Common mechanisms linking psychostimulant use and several movement disorders exist.

Interval timing in genetically modified mice: a simple paradigm

PubMed Central

Balci, F.; Papachristos, E. B.; Gallistel, C. R.; Brunner, D.; Gibson, J.; Shumyatsky, G. P.

2009-01-01

We describe a behavioral screen for the quantitative study of interval timing and interval memory in mice. Mice learn to switch from a short-latency feeding station to a long-latency station when the short latency has passed without a feeding. The psychometric function is the cumulative distribution of switch latencies. Its median measures timing accuracy and its interquartile interval measures timing precision. Next, using this behavioral paradigm, we have examined mice with a gene knockout of the receptor for gastrin-releasing peptide that show enhanced (i.e. prolonged) freezing in fear conditioning. We have tested the hypothesis that the mutants freeze longer because they are more uncertain than wild types about when to expect the electric shock. The knockouts however show normal accuracy and precision in timing, so we have rejected this alternative hypothesis. Last, we conduct the pharmacological validation of our behavioral screen using D-amphetamine and methamphetamine. We suggest including the analysis of interval timing and temporal memory in tests of genetically modified mice for learning and memory and argue that our paradigm allows this to be done simply and efficiently. PMID:17696995

Interval timing in genetically modified mice: a simple paradigm.

PubMed

Balci, F; Papachristos, E B; Gallistel, C R; Brunner, D; Gibson, J; Shumyatsky, G P

2008-04-01

We describe a behavioral screen for the quantitative study of interval timing and interval memory in mice. Mice learn to switch from a short-latency feeding station to a long-latency station when the short latency has passed without a feeding. The psychometric function is the cumulative distribution of switch latencies. Its median measures timing accuracy and its interquartile interval measures timing precision. Next, using this behavioral paradigm, we have examined mice with a gene knockout of the receptor for gastrin-releasing peptide that show enhanced (i.e. prolonged) freezing in fear conditioning. We have tested the hypothesis that the mutants freeze longer because they are more uncertain than wild types about when to expect the electric shock. The knockouts however show normal accuracy and precision in timing, so we have rejected this alternative hypothesis. Last, we conduct the pharmacological validation of our behavioral screen using d-amphetamine and methamphetamine. We suggest including the analysis of interval timing and temporal memory in tests of genetically modified mice for learning and memory and argue that our paradigm allows this to be done simply and efficiently.

PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (—)-Cocaine

PubMed Central

Fowler, Joanna S.; Kroll, Carsten; Ferrieri, Richard; Alexoff, David; Logan, Jean; Dewey, Stephen L.; Schiffer, Wynne; Schlyer, David; Carter, Pauline; King, Payton; Shea, Colleen; Xu, Youwen; Muench, Lisa; Benveniste, Helene; Vaska, Paul; Volkow, Nora D.

2009-01-01

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (—)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods d- and l-methamphetamine and (—)-cocaine were labeled with 11C via alkylation of the norprecursors with 11C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2–3 h apart to determine the distribution and kinetics of 11C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11C-d-Methamphetamine pharmacokinetics were compared with 11C-l-methamphetamine and 11C-(—)-cocaine in both brain and peripheral organs in the same animal. Results 11C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11C-d-methamphetamine and 11C-(—)-cocaine showed that 11C-d-methamphetamine peaked later in the brain than did 11C-(—)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for 11C-d-methamphetamine. Conclusion Brain pharmacokinetics did not differ between d-and l-methamphetamine and thus cannot account for the more intense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade by methamphetamine indicates that the PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of 11C-d-methamphetamine and 11C-(—)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (—)-cocaine. High kidney uptake of d-methamphetamine or its labeled metabolites may account for the reported renal toxicity of d-methamphetamine in humans. PMID:17873134

Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behavior in rats.

PubMed

Miszkiel, Joanna; Przegaliński, Edmund

2013-01-01

Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs. To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior. The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1B receptor antagonist. Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation.

Morphine and codeine concentrations in human urine following controlled poppy seeds administration of known opiate content.

PubMed

Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; LoDico, Charles; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

2014-08-01

Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45 g oral poppy seed doses 8 h apart, each containing 15.7 mg morphine and 3mg codeine. Urine was collected ad libitum up to 32 h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2000 and 300 μg/L cutoffs, and the ThermoFisher CEDIA(®) heroin metabolite (6-acetylmorphine, 6-AM) and Lin-Zhi 6-AM immunoassays with 10 μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32 h following dosing; 26.6% and 83.4% were positive for morphine at 2000 and 300 μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7522 μg/L with a median peak concentration of 5239 μg/L. The median first morphine-positive urine sample at 2000 μg/L cutoff concentration occurred at 6.6 h (1.2-12.1), with the last positive from 2.6 to 18 h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2000 μg/L, but 20.2% exceeded 300 μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300 μg/L cutoffs. The CEDIA 6-AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. Copyright © 2014. Published by Elsevier Ireland Ltd.

Morphine and Codeine Concentrations in Human Urine following Controlled Poppy Seeds Administration of Known Opiate Content

PubMed Central

Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; LoDico, Charles; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

2014-01-01

Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45g oral poppy seed doses 8h apart, each containing 15.7mg morphine and 3mg codeine. Urine was collected ad libitum up to 32h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2,000 and 300μg/L cutoffs, and the ThermoFisher CEDIA® Heroin Metabolite (6-acetylmorphine, 6AM) and Lin-Zhi 6AM immunoassays with 10μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32h following dosing; 26.6% and 83.4% were positive for morphine at 2,000 and 300μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7,522μg/L with a median peak concentration of 5,239μg/L. The median first morphine-positive urine sample at 2,000μg/L cutoff concentration occurred at 6.6h (1.2-12.1), with the last positive from 2.6 to 18h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2,000μg/L, but 20.2% exceeded 300μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300μg/L cutoffs. The CEDIA 6AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. PMID:24887324

Codeine Plus Acetaminophen for Pain After Photorefractive Keratectomy: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial.

PubMed

Pereira, Vinicius B P; Garcia, Renato; Torricelli, Andre A M; Mukai, Adriana; Bechara, Samir J

2017-10-01

Pain after photorefractive keratectomy (PRK) is significant, and the analgesic efficacy and safety of oral opioids in combination with acetaminophen has not been fully investigated in PRK trials. To assess the efficacy and safety of the combination of codeine plus acetaminophen (paracetamol) versus placebo as an add-on therapy for pain control after PRK. Randomized, double-blind, placebo-controlled trial. Single tertiary center. One eye was randomly allocated to the intervention, whereas the fellow eye was treated with a placebo. Eyes were operated 2 weeks apart. The participants were adults older than 20 years with refractive stability for ≥1 year, who underwent PRK for correction of myopia or myopic astigmatism. Codeine (30 mg) plus acetaminophen (500 mg) was given orally 4 times per day for 4 days after PRK. The follow-up duration was 4 months. The study outcomes included pain scores at 1 to 72 hours, as measured by the visual analog scale, McGill Pain Questionnaire, and Brief Pain Inventory, as well as adverse events and corneal wound healing. Of the initial 82 eyes, 80 completed the trial (40 intervention, 40 placebo). Median (interquartile range) pain scores as measured by the visual analog scale were statistically and clinically lower during treatment with codeine/acetaminophen compared with the placebo: 1 hour: 4 (2-4) versus 6 (3-6), P < 0.001; 24 hours: 4 (3-6) versus 7 (6-9), P < 0.001; 48 hours: 1 (0-2) versus 3 (2-5), P < 0.001; and 72 hours: 0 (0-0) versus 0 (0-2), P = 0.001. Virtually identical results were obtained by the McGill Pain Questionnaire and Brief Pain Inventory scales. The most common adverse events with codeine/acetaminophen were drowsiness (42%), nausea (18%), and constipation (5%). No case of delayed epithelial healing was observed in both treatment arms. When added to the usual care therapy, the oral combination of codeine/acetaminophen was safe and significantly superior to the placebo for pain control after PRK. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02625753.

Methamphetamine Use and Violent Behavior: User Perceptions and Predictors

PubMed Central

Brecht, Mary-Lynn; Herbeck, Diane

2015-01-01

This study describes the extent to which methamphetamine users perceive that their methamphetamine use has resulted in violent behavior, and describes the level of self-reported prevalence of specific violent criminal behaviors irrespective of methamphetamine use. Predictors of these two violence-related indicators, in terms of potential correlates from substance use history, criminal history, and health risk domains are examined. Data are from extensive interviews of 350 methamphetamine users who received substance use treatment in a large California county. A majority (56%) perceived that their methamphetamine use resulted in violent behavior; 59% reported specific violent criminal behaviors. For more than half of those reporting violent criminal behavior, this behavior pattern began before methamphetamine initiation. Thus, for a subsample of methamphetamine users, violence may be related to factors other than methamphetamine use. Users' perceptions that their methamphetamine use resulted in violence appears strongest for those with the most severe methamphetamine-related problems, particularly paranoia. PMID:26594058

Dextromethorphan differentially affects opioid antinociception in rats

PubMed Central

Chen, Shiou-Lan; Huang, Eagle Yi-Kung; Chow, Lok-Hi; Tao, Pao-Luh

2005-01-01

Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the μ-opioid receptor agonists morphine (5 mg kg−1, s.c.), meperidine (25 mg kg−1, s.c.) and codeine (25 mg kg−1, s.c.), and the κ-opioid agonists nalbuphine (8 mg kg−1, s.c.) and U-50,488H (20 mg kg−1, s.c.) were studied using the tail-flick test in male Sprague–Dawley rats. Coadministration of DM (20 mg kg−1, i.p.) with these opioids was also performed and investigated. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC. It was found that DM potentiated the antinociceptive effects of some μ-opioid agonists but not codeine or κ-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine). The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids. PMID:15655510

Comparison of the postoperative analgesic effects of naproxen sodium and naproxen sodium-codeine phosphate for arthroscopic meniscus surgery.

PubMed

Bali, Cagla; Ergenoglu, Pinar; Ozmete, Ozlem; Akin, Sule; Ozyilkan, Nesrin Bozdogan; Cok, Oya Yalcin; Aribogan, Anis

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to control arthroscopic pain. Addition of oral effective opioid "codeine" to NSAIDs may be more effective and decrease parenteral opioid consumption in the postoperative period. The aim of this study was to compare the efficacy and side effects of naproxen sodium and a new preparation naproxen sodium-codeine phosphate when administered preemptively for arthroscopic meniscectomy. Sixty-one patients were randomized into two groups to receive either oral naproxen sodium (Group N) or naproxen sodium-codeine phosphate (Group NC) before surgery. The surgery was carried out under general anesthesia. Intravenous meperidine was initiated by patient-controlled analgesia (PCA) for all patients. The primary outcome measure was pain score at the first postoperative hour assessed by the Visual Analogue Scale (VAS). Sedation assessed by Ramsey Sedation Scale, first demand time of PCA, postoperative meperidine consumption, side effects and hemodynamic data were also recorded. The groups were demographically comparable. Median VAS scores both at rest and on movement were significantly lower in Group NC compared with Group N, except 18(th) hour on movement (p<0.05). The median time to the first demand of PCA was shorter in Group N compared with Group NC (p<0.001). Meperidine consumption was higher in Group N compared with Group NC (p<0.001). There was no difference between groups with respect to side effects (p>0.05). The combination of naproxen sodium-codeine phosphate provided more effective analgesia than naproxen sodium and did not increase side effects. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

[Comparison of the postoperative analgesic effects of naproxen sodium and naproxen sodium-codeine phosphate for arthroscopic meniscus surgery].

PubMed

Bali, Cagla; Ergenoglu, Pinar; Ozmete, Ozlem; Akin, Sule; Ozyilkan, Nesrin Bozdogan; Cok, Oya Yalcin; Aribogan, Anis

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to control arthroscopic pain. Addition of oral effective opioid "codeine" to NSAIDs may be more effective and decrease parenteral opioid consumption in the postoperative period. The aim of this study was to compare the efficacy and side effects of naproxen sodium and a new preparation naproxen sodium-codeine phosphate when administered preemptively for arthroscopic meniscectomy. Sixty-one patients were randomized into two groups to receive either oral naproxen sodium (Group N) or naproxen sodium-codeine phosphate (Group NC) before surgery. The surgery was carried out under general anesthesia. Intravenous meperidine was initiated by patient-controlled analgesia (PCA) for all patients. The primary outcome measure was pain score at the first postoperative hour assessed by the Visual Analogue Scale (VAS). Sedation assessed by Ramsey Sedation Scale, first demand time of PCA, postoperative meperidine consumption, side effects and hemodynamic data were also recorded. The groups were demographically comparable. Median VAS scores both at rest and on movement were significantly lower in Group NC compared with Group N, except 18(th) hour on movement (p<0.05). The median time to the first demand of PCA was shorter in Group N compared with Group NC (p<0.001). Meperidine consumption was higher in Group N compared with Group NC (p<0.001). There was no difference between groups with respect to side effects (p>0.05). The combination of naproxen sodium-codeine phosphate provided more effective analgesia than naproxen sodium and did not increase side effects. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants

PubMed Central

Miliano, Cristina; Serpelloni, Giovanni; Rimondo, Claudia; Mereu, Maddalena; Marti, Matteo; De Luca, Maria Antonietta

2016-01-01

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds. PMID:27147945

Substance use - amphetamines

MedlinePlus

Substance abuse - amphetamines; Drug abuse - amphetamines; Drug use - amphetamines ... Amphetamine: goey, louee, speed, uppers, whiz Dextroamphetamine (ADHD medicine used illegally): dexies, kiddie-speed, pep pills, uppers; ...

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E

2015-08-01

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.

Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats.

PubMed

Thorn, David A; Li, Jiuzhou; Qiu, Yanyan; Li, Jun-Xu

2016-09-01

Methamphetamine abuse remains an alarming public heath challenge, with no approved pharmacotherapies available. Agmatine is a naturally occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose dependently increased drug-associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10-100 mg/kg) did not substitute for methamphetamine, but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of a 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96±0.17°C. Agmatine (10-32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for the treatment of methamphetamine abuse and overdose.

Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats

PubMed Central

Thorn, David A.; Li, Jiuzhou; Qiu, Yanyan; Li, Jun-Xu

2016-01-01

Methamphetamine abuse remains an alarming public heath challenge with no approved pharmacotherapies available. Agmatine is a naturally-occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose-dependently increased drug-associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10 –100 mg/kg) did not substitute for methamphetamine but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96 ± 0.17 °C. Agmatine (10 – 32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for treating methamphetamine abuse and overdose. PMID:27232669

Increased self-reported impulsivity in methamphetamine users maintaining drug abstinence.

PubMed

Jones, Hannah W; Dean, Andy C; Price, Kimberly A; London, Edythe D

2016-09-01

Impulsivity has been proposed as an important factor in the initiation and maintenance of addiction. Indirect evidence suggests that some methamphetamine users report less impulsivity when they are using methamphetamine compared to when abstaining from drug use, but this hypothesis has not been directly tested. In this study, self-reports of impulsivity were obtained from 32 methamphetamine-dependent (DSM-IV) research participants and 41 healthy control subjects, using the Barratt Impulsiveness Scale-11. The methamphetamine users were assessed during an active period of methamphetamine use, as determined through urinalysis, and again after approximately 1 week of confirmed abstinence. Control subjects likewise completed two assessments. A subset of participants also completed serial assessments of the Beck Depression Inventory (Methamphetamine Group, N = 17, Control Group, N = 38) and the Methamphetamine Withdrawal Questionnaire (Methamphetamine Group, N = 12). There was a significant interaction of group with time on impulsivity (p = 0.044), reflecting a significant increase from the first to the second assessment in the methamphetamine users (p = 0.013), but no change among healthy control subjects. In contrast, depressive and withdrawal symptoms significantly decreased between the first and second assessments in the methamphetamine users (ps ≤0.01). Change in impulsivity in methamphetamine users was not significantly correlated with change in withdrawal or depression (ps >0.05). These findings suggest that methamphetamine users report more impulsivity when abstaining from drug use, an effect that is not significantly related to methamphetamine withdrawal. Attenuation of impulsivity may reinforce continued methamphetamine use in these individuals.

[Use of Emerging Drugs in Medellín, Colombia].

PubMed

Castaño Pérez, Guillermo A; Calderón Vallejo, Gustavo A; Berbesi Fernández, Dedsy Yajaira

2013-09-01

The ongoing emergence of new synthetic substances that are used as drugs is a constant challenge to public health. Emerging drugs is the concept used in this research project to define the emergence of new psychoactive substances at a given time, a specific context and group, the reemergence of others that some epidemiologists considered had lost their prevalence, and the sudden prevalence of drugs that had low levels of consumption. This research project was carried out using an empirical-analytical approach using a mixed methods study. The convenience sample was made up of 510 drug dependents institutionalized in treatment centers in Medellin in the year 2011. The examination was carried out related to the consumption of emerging drugs. An ad hoc tool was applied to all the drug users in order to identify which of the drugs of this study they considered to be emergent. Once the consumers were identified and selected based on the frequency of consumption, and the prevalence in the last year and last month, a semi-structured interview was carried out to find out details on the substances and their consumption characteristics. Based on the new drug consumers in Medellin, 82.2% were male and 17.8% female. As regards education levels, 58.2% were in high school, 26.8% hold higher technical or college degrees, and 1.4% had no schooling. Only 27.8% held a steady job, occasional employment, or were independent business owners, 40.7% were students and 8.9% were housewives. More than three-quarters (76.3%) were single, and 17.8% had a steady partner. The sample represented all social classes. Of all the emerging drugs found in this study, the prevalence of benzodiazepines stands out (flunitrazepam and clonazepam), life prevalence (LP), 97.5%; last year prevalence (LYP), 67.9%, and last month prevalence (LMP), 46.7%. These were followed by the synthetic drugs (LSD, Ecstasies, amphetamines, GHB, Vegetable Ecstasies, Phencyclidine; Methamphetamine, Ketamine, 2CB), with LP, 96.5%; LYP, 44.5%, and LMP, 23.5%. Then there was smokable cocaine (Crack and Free-Base), with LP, 80%, LYP, 52.1%, and LYP=31.7%. The opiate derivatives (heroine, morphine, opium, codeine, dextromethorphan, meperidine, fentanyl) had an LP, 61.4%; LYP, 26.7% and LMP, 16%. The consumption statistics of the hallucinogens such as mushrooms, scopolamine and "yague", had an LP, 73.5%; LYP, 23.2% and LMP, 12.2%. Finally, use of inhalants such as popper and dichloromethane (Dick) had an LP, 87.9%; LYP, 37.6% and LMP, 21.6%. These results are an alert to the need to track the development of these so called emergent drugs due to the risks they pose for public health. Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Beliefs and Social Norms about Codeine and Promethazine Hydrochloride Cough Syrup (CPHCS) Onset and Perceived Addiction among Urban Houstonian Adolescents: An Addiction Trend in the City of Lean

ERIC Educational Resources Information Center

Peters, Ronald J., Jr.; Kelder, Steven H.; Markham, Christine M.; Yacoubian, George S., Jr.; Peters, LeCresha A.; Ellis, Artist

2003-01-01

In the current study, we used a qualitative approach to investigate relevant beliefs and norms associated with codeine and promethazine hydrochloride cough syrup (CPHCS) consumption, initiation, and perceived addiction among 48 alternative school students who identified themselves as current CPHCS users. In general, both boys and girls believed…

Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice

PubMed Central

Kesby, James P.; Hubbard, David T.; Markou, Athina; Semenova, Svetlana

2012-01-01

Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID:23252824

Single nucleotide polymorphism near CREB1, rs7591784, is associated with pretreatment methamphetamine use frequency and outcome of outpatient treatment for methamphetamine use disorder

PubMed Central

Heinzerling, Keith G.; Demirdjian, Levon; Wu, Yingnian; Shoptaw, Steven

2016-01-01

Although stimulant dependence is highly heritable, few studies have examined genetic influences on methamphetamine dependence. We performed a candidate gene study of 52 SNPs and pretreatment methamphetamine use frequency among 263 methamphetamine dependent Hispanic and Non-Hispanic White participants of several methamphetamine outpatient clinical trials in Los Angeles. One SNP, rs7591784 was significantly associated with pretreatment methamphetamine use frequency following Bonferroni correction (p < 0.001) in males but not females. We then examined rs7591784 and methamphetamine urine drug screen results during 12 weeks of outpatient treatment among males with treatment outcome data available (N = 94) and found rs7591784 was significantly associated with methamphetamine use during treatment controlling for pretreatment methamphetamine use. rs7591784 is near CREB1 and in a linkage disequilibrium block with rs2952768, previously shown to influence CREB1 expression. The CREB signaling pathway is involved in gene expression changes related to chronic use of multiple drugs of abuse including methamphetamine and these results suggest that variability in CREB signaling may influence pretreatment frequency of methamphetamine use as well as outcomes of outpatient treatment. Medications targeting the CREB pathway, including phosphodiesterase inhibitors, warrant investigation as pharmacotherapies for methamphetamine use disorders. PMID:26736037

A comparison of economic demand and conditioned-cued reinstatement of methamphetamine- or food-seeking in rats

PubMed Central

Galuska, Chad M.; Banna, Kelly M.; Willse, Lena Vaughn; Yahyavi-Firouz-Abadi, Noushin; See, Ronald E.

2011-01-01

The present study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long-Evans rats lever-pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 μg/50 μl infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-hr sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. We conclude that continued access to methamphetamine – but not food – alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity and reinstatement measures appear to be related indices of drug-seeking. PMID:21597363

Identifying cases of heroin toxicity where 6-acetylmorphine (6-AM) is not detected by toxicological analyses.

PubMed

Ellis, Ashley D; McGwin, Gerald; Davis, Gregory G; Dye, Daniel W

2016-09-01

Heroin has a half-life of 2-6 min and is metabolized too quickly to be detected in autopsy samples. The presence of 6-acetylmophine (6-AM) in urine, blood, or other samples is convincing evidence of heroin use by a decedent, but 6-AM itself has a half-life of 6-25 min before it is hydrolyzed to morphine, so 6-AM may not be present in sufficient concentration to detect in postmortem samples. Codeine is often present in heroin preparations as an impurity and is not a metabolite of heroin. Studies report that a ratio of morphine to codeine greater than one indicates heroin use. We hypothesize that the ratio of morphine to codeine in our decedents abusing drugs intravenously will be no different in individuals with 6-AM present than in individuals where no 6-AM is detected, and we report our study of this hypothesis. All accidental deaths investigated by the Jefferson County Coroner/Medical Examiner Office from 2010 to 2013 with morphine detected in blood samples collected at autopsy were reviewed. Five deaths where trauma caused or contributed to death were excluded from the review. The presence or absence of 6-AM and the concentrations of morphine and codeine were recorded for each case. The ratio of morphine to codeine was calculated for all decedents. Any individual in whom no morphine or codeine was detected in a postmortem sample was excluded from further study. Absence or presence of drug paraphernalia or evidence of intravascular (IV) drug use was documented in each case to identify IV drug users. The proportion of the IV drug users with and without 6-AM present in a postmortem sample was compared to the M/C ratio for the individuals. Of the 230 deaths included in the analysis, 103 IV drug users with quantifiable morphine and codeine in a postmortem sample were identified allowing for calculation of an M/C ratio. In these IV drug users, the M/C ratio was greater than 1 in 98 % of decedents. When controlling for the absence or presence of 6-AM there was no statistically significant difference in the proportion of IV drug users when compared to non IV drug users with an M/C ratio of greater than 1 (p = 1.000). The M/C ratio in IV drug users, if greater than 1, is seen in deaths due to heroin toxicity where 6-AM is detected in a postmortem sample. This study provides evidence that a M/C ratio greater than one in an IV drug user is evidence of a death due to heroin toxicity even if 6-AM is not detected in the blood. Using the M/C ratio, in addition to scene and autopsy findings, provides sufficient evidence to show heroin is the source of the morphine and codeine. Listing heroin as a cause or contributing factor in deaths with evidence of IV drug abuse and where the M/C ratio exceeds 1 will improve identification of heroin fatalities, which will allow better allocation of resources for public health initiatives.

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys

PubMed Central

Banks, Matthew L; Blough, Bruce E

2015-01-01

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0–0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32–1.8 mg/kg/h) and risperidone (0.001–0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01–0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model. PMID:25742872

The Impact of Age, HIV Serostatus and Seroconversion on Methamphetamine Use

PubMed Central

Montoya, Jessica L.; Cattie, Jordan; Morgan, Erin; Woods, Steven Paul; Cherner, Mariana; Moore, David J.; Atkinson, J. Hampton; Grant, Igor

2016-01-01

Background Characterizing methamphetamine use in relation to age, HIV serostatus and seroconversion is pertinent given the increasingly older age of the population with HIV and the intertwined epidemics of methamphetamine use and HIV. Objectives Study aims were to investigate whether 1) methamphetamine use differs by age and HIV serostatus and 2) receiving an HIV diagnosis impacts methamphetamine use among younger and older persons with HIV. Methods This study examined methamphetamine use characteristics among 217 individuals with a lifetime methamphetamine dependence diagnosis who completed an in-person study assessment. Results Multivariable regressions revealed that HIV serostatus uniquely attenuates methamphetamine use, such that persons with HIV report a smaller cumulative quantity (β = −.16, p = .01) and a fewer number of days (β = −.18, p = .004) of methamphetamine use than persons without HIV. Among the HIV+ sample, all participants persisted in methamphetamine use after receiving an HIV diagnosis, with about 20% initiating use after seroconversion. Repeated measures analysis of variance indicated that density of methamphetamine use (i.e., grams per day used) was greater among the younger, relative to the older, HIV+ group (p = .02), and increased for both age groups following seroconversion (p < .001). Conclusion These analyses indicate that although HIV serostatus may attenuate methamphetamine use behaviors, many people with HIV initiate, or persist in, methamphetamine use after receiving an HIV diagnosis. These findings raise the question of whether tailoring of prevention and intervention strategies might reduce the impact of methamphetamine and HIV across the age continuum. PMID:26837461

The impact of age, HIV serostatus and seroconversion on methamphetamine use.

PubMed

Montoya, Jessica L; Cattie, Jordan; Morgan, Erin; Woods, Steven Paul; Cherner, Mariana; Moore, David J; Atkinson, J Hampton; Grant, Igor

2016-03-01

Characterizing methamphetamine use in relation to age, HIV serostatus and seroconversion is pertinent given the increasingly older age of the population with HIV and the intertwined epidemics of methamphetamine use and HIV. Study aims were to investigate whether (i) methamphetamine use differs by age and HIV serostatus, and (ii) receiving an HIV diagnosis impacts methamphetamine use among younger and older persons with HIV. This study examined methamphetamine use characteristics among 217 individuals with a lifetime methamphetamine dependence diagnosis who completed an in-person study assessment. Multivariable regressions revealed that HIV serostatus uniquely attenuates methamphetamine use, such that persons with HIV report a smaller cumulative quantity (β = -0.16, p = 0.01) and a fewer number of days (β = -0.18, p = 0.004) of methamphetamine use than persons without HIV. Among the HIV+ sample, all participants persisted in methamphetamine use after receiving an HIV diagnosis, with about 20% initiating use after seroconversion. Repeated measures analysis of variance indicated that density of methamphetamine use (i.e. grams per day used) was greater among the younger, relative to the older, HIV+ group (p = 0.02), and increased for both age groups following seroconversion (p < 0.001). These analyses indicate that although HIV serostatus may attenuate methamphetamine use behaviors, many people with HIV initiate, or persist in, methamphetamine use after receiving an HIV diagnosis. These findings raise the question of whether tailoring of prevention and intervention strategies might reduce the impact of methamphetamine and HIV across the age continuum.

Crystal methamphetamine smoking among regular ecstasy users in Australia: increases in use and associations with harm.

PubMed

Kinner, Stuart A; Degenhardt, Louisa

2008-05-01

This study examined (a) changes in crystal methamphetamine use among regular ecstasy users (REU) in Australia and (b) associations of crystal use and smoking with demographics, drug use and harm. Cross-sectional surveys (2000-06) of REU in three Australian capital cities, and in 2006, 750 REU in all Australian capital cities. The interview included: demographics, drug use, risk behaviour, recent criminal activity and methamphetamine dependence using Severity of Dependence Scale. There was little change in overall methamphetamine use, but a marked increase in crystal methamphetamine smoking. Among recent methamphetamine users in 2006 (n = 606), crystal methamphetamine users (n = 364) reported more frequent methamphetamine use and higher levels of dependence. Compared with those who had used only other forms of methamphetamine, recent crystal methamphetamine users were more likely to 'binge' on drugs for > or = 48 hours, engage in crime and experience financial and legal problems related to drug use. Non-smoking crystal methamphetamine users (n = 78) more often reported recent injecting and heroin use. Recent smokers were more likely to have: greater polydrug use, recently overdosed on a 'party drug', and accessed medical services for their drug use. Many of these associations were accounted for by their injecting and heavier methamphetamine use, rather than smoking per se. Crystal methamphetamine smoking among REU has increased markedly and is associated with significant harm. This appears related to smokers' heavier levels of methamphetamine use. Effective harm reduction strategies should be tailored to these specific risks.

Evaluating Exercise as a Therapeutic Intervention for Methamphetamine Addiction-Like Behavior1

PubMed Central

Somkuwar, Sucharita S.; Staples, Miranda C.; Fannon, McKenzie J.; Ghofranian, Atoosa; Mandyam, Chitra D.

2015-01-01

Abstract The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction. PMID:29765835

Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

PubMed

Thomas, David M; Kuhn, Donald M

2005-02-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

Simultaneous HPLC analysis of pseudophedrine hydrochloride, codeine phosphate, and triprolidine hydrochloride in liquid dosage forms.

PubMed

Manassra, Adnan; Khamis, Mustafa; El-Dakiky, Magdy; Abdel-Qader, Zuhair; Al-Rimawi, Fuad

2010-03-11

An HPLC method using UV detection is proposed for the simultaneous determination of pseudophedrine hydrochloride, codeine phosphate, and triprolidine hydrochloride in liquid formulation. C18 column (250mmx4.0mm) is used as the stationary phase with a mixture of methanol:acetate buffer:acetonitrile (85:5:10, v/v) as the mobile phase. The factors affecting column separation of the analytes were studied. The calibration graphs exhibited a linear concentration range of 0.06-1.0mg/ml for pseudophedrine hydrochloride, 0.02-1.0mg/ml for codeine phosphate, and 0.0025-1.0mg/ml for triprolidine hydrochloride for a sample size of 5microl with correlation coefficients of better than 0.999 for all active ingredients studied. The results demonstrate that this method is reliable, reproducible and suitable for routine use with analysis time of less than 4min. Copyright 2009 Elsevier B.V. All rights reserved.

Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.

PubMed

Armstrong, Scott C; Cozza, Kelly L

2003-01-01

Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. This understanding is important so that clinicians can choose the proper dosages for analgesia and anticipate potential drug-drug interactions.

On the Role of Imitation on Adolescence Methamphetamine Abuse Dynamics.

PubMed

Mushanyu, J; Nyabadza, F; Muchatibaya, G; Stewart, A G R

2017-03-01

Adolescence methamphetamine use is an issue of considerable concern due to its correlation with later delinquency, divorce, unemployment and health problems. Understanding how adolescents initiate methamphetamine abuse is important in developing effective prevention programs. We formulate a mathematical model for the spread of methamphetamine abuse using nonlinear ordinary differential equations. It is assumed that susceptibles are recruited into methamphetamine use through imitation. An epidemic threshold value, [Formula: see text], termed the abuse reproduction number, is proposed and defined herein in the drug-using context. The model is shown to exhibit the phenomenon of backward bifurcation. This means that methamphetamine problems may persist in the population even if [Formula: see text] is less than one. Sensitivity analysis of [Formula: see text] was performed to determine the relative importance of different parameters in methamphetamine abuse initiation. The model is then fitted to data on methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse in the treatment centres of Cape Town and parameter values that give the best fit are chosen. Results show that the proportion of methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse will continue to decrease in Cape Town of South Africa. The results suggest that intervention programs targeted at reducing adolescence methamphetamine abuse, are positively impacting methamphetamine abuse.

A comparison of economic demand and conditioned-cued reinstatement of methamphetamine-seeking or food-seeking in rats.

PubMed

Galuska, Chad M; Banna, Kelly M; Willse, Lena Vaughn; Yahyavi-Firouz-Abadi, Noushin; See, Ronald E

2011-08-01

This study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long-Evans rats were lever pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 μg/50 μl infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-h sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. Continued access to methamphetamine, but not food, alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity thus provides a useful measure of abuse liability that may predict future relapse to renewed drug-seeking and drug use.

N-Acetyl and Glutamatergic Neurometabolites in Perisylvian Brain Regions of Methamphetamine Users.

PubMed

Tang, Jinsong; O'Neill, Joseph; Alger, Jeffry R; Shen, Zhiwei; Johnson, Maritza C; London, Edythe D

2018-05-21

Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms. Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety. In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47). The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.

Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.

PubMed

Lin, Yin Chiu; Kuo, Yu-Min; Liao, Pao-Chi; Cherng, Chianfang G; Su, Su-Wen; Yu, Lung

2007-04-30

Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.

Dopamine D3 receptor antagonist SB-277011A inhibits methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking in rats

PubMed Central

Higley, Amanda E.; Kiefer, Stephen W.; Li, Xia; Gaál, József; Xi, Zheng-Xiong; Gardner, Eliot L.

2013-01-01

We have previously reported that selective blockade of brain dopamine D3 receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long–Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D3 receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D3 antagonists for the treatment of methamphetamine addiction. PMID:21466803

Acute Modafinil Effects on Attention and Inhibitory Control in Methamphetamine-Dependent Humans*

PubMed Central

Dean, Andy C.; Sevak, Rajkumar J.; Monterosso, John R.; Hellemann, Gerhard; Sugar, Catherine A.; London, Edythe D.

2011-01-01

Objective: Individuals who are methamphetamine dependent exhibit higher rates of cognitive dysfunction than healthy people who do not use methamphetamine, and this dysfunction may have a negative effect on the success of behavioral treatments for the disorder. Therefore, a medication that improves cognition, such as modafinil (Provigil), may serve as a useful adjunct to behavioral treatments for methamphetamine dependence. Although cognitive-enhancing effects of modafinil have been reported in several populations, little is known about the effects of modafinil in methamphetamine-dependent individuals. We thus sought to evaluate the effects of modafinil on the cognitive performance of methamphetamine-dependent and healthy individuals. Method: Seventeen healthy subjects and 24 methamphetamine-dependent subjects participated in this randomized, double-blind, placebo-controlled, crossover study. Effects of modafinil (200 mg, single oral dose) were assessed on participants’ performance on tests of inhibitory control, working memory, and processing speed/attention. Results: Across subjects, modafinil improved performance on a test of sustained attention, with no significant improvement on any other cognitive tests. However, within the methamphetamine-dependent group only, participants with a high baseline frequency of methamphetamine use demonstrated a greater effect of modafinil on tests of inhibitory control and processing speed than those participants with low baseline use of methamphetamine. Conclusions: Although modafinil produced limited effects across all participants, methamphetamine-dependent participants with a high baseline use of methamphetamine demonstrated significant cognitive improvement on modafinil relative to those with low baseline methamphetamine use. These results add to the findings from a clinical trial that suggested that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently. PMID:22051208

Delayed emergence of methamphetamine's enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence.

PubMed

Vaupel, D B; Schindler, C W; Chefer, S; Belcher, A M; Ahmet, I; Scheidweiler, K B; Huestis, M A; Stein, E A

2016-02-01

Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. Eight male rhesus monkeys with long histories of intravenous methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naïve monkeys. Cardiovascular responses to methamphetamine were followed for 2.5h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals. No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events. Published by Elsevier Ireland Ltd.

Determinants of cue-elicited craving and physiologic reactivity in methamphetamine-dependent subjects in the laboratory.

PubMed

Tolliver, Bryan K; McRae-Clark, Aimee L; Saladin, Michael; Price, Kimber L; Simpson, Annie N; DeSantis, Stacia M; Baker, Nathaniel L; Brady, Kathleen T

2010-03-01

Craving for methamphetamine is commonly reported by heavy users of the drug and may increase the risk of relapse in newly abstinent individuals. Exposure to methamphetamine-associated cues in the laboratory can elicit measureable craving and autonomic reactivity in some individuals with methamphetamine dependence. In this study, clinical and demographic correlates of methamphetamine craving and the optimal conditions for its measurement in the laboratory are explored. Subjective (craving) and physiologic (heart rate and skin conductance) reactivity to presentation of methamphetamine-associated photo, video, and paraphernalia cues were evaluated in 43 subjects with methamphetamine dependence. Association of cue reactivity with demographic and clinical characteristics including duration, frequency, amount, and recency of methamphetamine use were assessed. Craving was reported by fewer than half of subjects at baseline and by approximately 70% of subjects after methamphetamine cue exposure. Relative to baseline, subjective craving was increased by all three cue modalities to a similar extent. In general, physiological cue reactivity correlated poorly with cue-induced craving. Craving at baseline was strongly predictive of cue-induced craving. Differences in cue-induced craving were not associated with age, sex, education, employment, treatment status, or number of days using methamphetamine in the 60 days prior to study entry. In contrast, the degree of baseline craving was strongly associated with employment status and the number of days using methamphetamine in the past 60 days. Cue-induced craving for methamphetamine may be reliably measured in methamphetamine-dependent individuals in the laboratory. Further studies employing the cue reactivity paradigm in methamphetamine dependence are warranted.

Increased blood 8-hydroxy-2-deoxyguanosine levels in methamphetamine users during early abstinence.

PubMed

Huang, Ming-Chyi; Lai, Ying-Ching; Lin, Shih-Ku; Chen, Chun-Hsin

2018-01-01

Reactive oxygen species (ROS) are thought to play a role in the adverse physical and mental consequences of methamphetamine usage. The oxidative DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a well-known biomarker of ROS-induced DNA damage. Currently, there is insufficient clinical information about methamphetamine-induced oxidative DNA damage. This study examined differences in blood levels of 8-OHdG between methamphetamine users and non-users as well as alterations in 8-OHdG levels after 2 weeks of methamphetamine abstinence. We recruited 182 methamphetamine users (78.6% of male) and 71 healthy controls (95.8% of male). Baseline serum 8-OHdG levels were measured in both groups using a competitive enzyme-linked immunosorbent assay. In methamphetamine users, 8-OHdG levels were measured again 2 weeks after baseline measurement. The results showed that methamphetamine users had significantly higher 8-OHdG levels (0.34 ± 0.13 ng/mL) than healthy controls (0.30 ± 0.08 ng/mL) (p < 0.001). The 8-OHdG levels did not alter after 2 weeks of methamphetamine abstinence (0.32 ± 0.12 ng/mL, p = 0.051 compared to baseline measurement; p = 0.12 compared to healthy controls). No significant correlations were observed between baseline 8-OHdG levels in methamphetamine users and post-abstinence interval, age of the first methamphetamine use, duration of methamphetamine use, or history of frequent methamphetamine use. Our findings suggest that methamphetamine users had an enhanced level of oxidative damage, which did not normalize during early abstinence. Future studies are required to determine the effects of long-term methamphetamine abstinence and potential confounders on 8-OHdG levels in methamphetamine users.

Efficacy and tolerance of lysine clonixinate versus paracetamol/codeine following inguinal hernioplasty.

PubMed

de los Santos, A R; Di Girolamo, G; Martí, M L

1998-01-01

In this study lysine clonixinate, a nonsteroidal antiinflammatory agent with selective inhibition of cyclooxygenase-2 and 5-lipooxygenase in in vitro and in vivo pharmacodynamic studies, was evaluated in a prospective, randomized, double-blind, double-dummy clinical study versus paracetamol/codeine, in 151 patients with pain following inguinal hernioplasty. Patients were treated with one 125 mg tablet of lysine clonixinate or paracetamol/codeine (500 mg + 30 mg) administered at fixed doses every 4 h during 2 days. Controls were carried out 1, 2 and 4 h after the first intake of day 1 and day 2. Each control included assessment of pain at rest, when coughing, sitting and upon moderate pressure. Both treatment groups (lysine clonixinate, 77 patients and paracetamol/codeine, 74 patients) were comparable in terms of demographic and baseline pain intensities. Spontaneous pain was reduced significantly in both treatment groups from the 1st-h control. The following values were recorded in the lysine clonixinate group during day 1: baseline: 6.86 +/- 1.24; 1st h: 4.49 +/- 1.77; 2nd h: 2.96 +/- 1.74; 4th h: 2.23 +/- 1.51. The following values for the same group during day 2 were: predose: 1.70 +/- 1.64; 1st h: 1.16 +/- 1.17; 2nd h: 0.78 +/- 1.06; 4th h: 0.63 +/- 1.05. The paracetamol/codeine group revealed the following values: day 1: baseline: 6.72 +/- 1.22; 1st h: 4.57 +/- 1.72; 2nd h: 2.97 +/- 1.68; 4th h: 2.47 +/- 1.68 and day 2: predose: 2.02 +/- 1.57; 1st h: 1.32 +/- 1.23; 2nd h: 0.82 +/- 0.99; 4th h: 0.66 +/- 0.89. Reduction of pain induced by coughing, sitting and pressure showed similar behavior patterns. No significant differences between both treatment groups were encountered in terms of analgesic efficacy. Incidence of adverse effects was significantly higher in the paracetamol/codeine group (X2: p < 0.05): 11 out of 74 patients; three patients had to discontinue treatment. In the lysine clonixinate group four out of 77 patients showed side effects but these did not require treatment discontinuation.

Randomized clinical trial of hydrocodone/acetaminophen versus codeine/acetaminophen in the treatment of acute extremity pain after emergency department discharge.

PubMed

Chang, Andrew K; Bijur, Polly E; Munjal, Kevin G; John Gallagher, E

2014-03-01

The objective was to test the hypothesis that hydrocodone/acetaminophen (Vicodin [5/500]) provides more efficacious analgesia than codeine/acetaminophen (Tylenol #3 [30/300]) in patients discharged from the emergency department (ED). Both are currently Drug Enforcement Administration (DEA) Schedule III narcotics. This was a prospective, randomized, double-blind, clinical trial of patients with acute extremity pain who were discharged home from the ED, comparing a 3-day supply of oral hydrocodone/acetaminophen (5 mg/500 mg) to oral codeine/acetaminophen (30 mg/300 mg). Pain was measured on a valid and reproducible verbal numeric rating scale (NRS) ranging from 0 to 10, and patients were contacted by telephone approximately 24 hours after being discharged. The primary outcome was the between-group difference in improvement in pain at 2 hours following the most recent ingestion of the study drug, relative to the time of phone contact after ED discharge. Secondary outcomes compared side-effect profiles and patient satisfaction. The median time from ED discharge to follow-up was 26 hours (interquartile range [IQR] = 24 to 39 hours). The mean NRS pain score before the most recent dose of pain medication after ED discharge was 7.6 NRS units for both groups. The mean decrease in pain scores 2 hours after pain medications were taken were 3.9 NRS units in the hydrocodone/acetaminophen group versus 3.5 NRS units in the codeine/acetaminophen group, for a difference of 0.4 NRS units (95% confidence interval [CI] = -0.3 to 1.2 NRS units). No differences were found in side effects or patient satisfaction. Both medications decreased NRS pain scores by approximately 50%. However, the oral hydrocodone/acetaminophen failed to provide clinically or statistically superior pain relief compared to oral codeine/acetaminophen when prescribed to patients discharged from the ED with acute extremity pain. Similarly, there were no clinically or statistically important differences in side-effect profiles or patient satisfaction. If the DEA reclassifies hydrocodone as a Schedule II narcotic, as recently recommended by its advisory board, our data suggest that the codeine/acetaminophen may be a clinically reasonable Schedule III substitute for hydrocodone/acetaminophen at ED discharge. These findings should be regarded as tentative and require independent validation in similar and other acute pain models. © 2014 by the Society for Academic Emergency Medicine.

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

PubMed Central

Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

2014-01-01

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Methamphetamine induces the release of endothelin.

PubMed

Seo, Jeong-Woo; Jones, Susan M; Hostetter, Trisha A; Iliff, Jeffrey J; West, G Alexander

2016-02-01

Methamphetamine is a potent psychostimulant drug of abuse that increases release and blocks reuptake of dopamine, producing intense euphoria, factors that may contribute to its widespread abuse. It also produces severe neurotoxicity resulting from oxidative stress, DNA damage, blood-brain barrier disruption, microgliosis, and mitochondrial dysfunction. Intracerebral hemorrhagic and ischemic stroke have been reported after intravenous and oral abuse of methamphetamine. Several studies have shown that methamphetamine causes vasoconstriction of vessels. This study investigates the effect of methamphetamine on endothelin-1 (ET-1) release in mouse brain endothelial cells by ELISA. ET-1 transcription as well as endothelial nitric oxide synthase (eNOS) activation and transcription were measured following methamphetamine treatment. We also examine the effect of methamphetamine on isolated cerebral arteriolar vessels from C57BL/6 mice. Penetrating middle cerebral arterioles were cannulated at both ends with a micropipette system. Methamphetamine was applied extraluminally, and the vascular response was investigated. Methamphetamine treatment of mouse brain endothelial cells resulted in ET-1 release and a transient increase in ET-1 message. The activity and transcription of eNOS were only slightly enhanced after 24 hr of treatment with methamphetamine. In addition, methamphetamine caused significant vasoconstriction of isolated mouse intracerebral arterioles. The vasoconstrictive effect of methamphetamine was attenuated by coapplication of the endothelin receptor antagonist PD145065. These findings suggest that vasoconstriction induced by methamphetamine is mediated through the endothelin receptor and may involve an endothelin-dependent pathway. © 2015 Wiley Periodicals, Inc.

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

PubMed

Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-05

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

Regulatory responses to over-the-counter codeine analgesic misuse in Australia, New Zealand and the United Kingdom.

PubMed

Tobin, Claire L; Dobbin, Malcolm; McAvoy, Brian

2013-10-01

Analysis of the policy response by Australia's National Drugs and Poisons Schedule Committee (NDPSC) and comparison with recommendations by expert advisory committees in New Zealand and the United Kingdom. Analysis of public policy documents of relevant regulatory authorities was conducted. Data were extracted regarding changes to over-the-counter (OTC) codeine analgesic scheduling, indications, maximum unit dose, maximum daily dose, maximum pack size, warning labels, consumer medicine information and advertising. Where available, public submissions and other issues considered by the committees and rationale for their recommendations were recorded and thematically analysed. Expert advisory committees in Australia, NZ and the UK defined the policy problem of OTC codeine misuse and harm as small relative to total use and responded by restricting availability. Pharmacist supervision was required at the point-of-sale and pack sizes were reduced to short-term use. Comparison with recommendations by expert advisory committees in NZ and the UK suggests the NDPSC's actions in response to OTC codeine misuse were appropriate given the available evidence of misuse and harm, but highlights opportunities to utilise additional regulatory levers. Framing policy problems as matters of public health in the context of limited evidence may support decision makers to implement cautionary incremental policy change. © 2013 The Authors. ANZJPH © 2013 Public Health Association of Australia.

The Central Amygdala Nucleus is Critical for Incubation of Methamphetamine Craving

PubMed Central

Li, Xuan; Zeric, Tamara; Kambhampati, Sarita; Bossert, Jennifer M; Shaham, Yavin

2015-01-01

Cue-induced methamphetamine seeking progressively increases after withdrawal but mechanisms underlying this ‘incubation of methamphetamine craving' are unknown. Here we studied the role of central amygdala (CeA), ventral medial prefrontal cortex (vmPFC), and orbitofrontal cortex (OFC), brain regions implicated in incubation of cocaine and heroin craving, in incubation of methamphetamine craving. We also assessed the role of basolateral amygdala (BLA) and dorsal medial prefrontal cortex (dmPFC). We trained rats to self-administer methamphetamine (10 days; 9 h/day, 0.1 mg/kg/infusion) and tested them for cue-induced methamphetamine seeking under extinction conditions during early (2 days) or late (4–5 weeks) withdrawal. We first confirmed that ‘incubation of methamphetamine craving' occurs under our experimental conditions. Next, we assessed the effect of reversible inactivation of CeA or BLA by GABAA+GABAB receptor agonists (muscimol+baclofen, 0.03+0.3 nmol) on cue-induced methamphetamine seeking during early and late withdrawal. We also assessed the effect of muscimol+baclofen reversible inactivation of vmPFC, dmPFC, and OFC on ‘incubated' cue-induced methamphetamine seeking during late withdrawal. Lever presses in the cue-induced methamphetamine extinction tests were higher during late withdrawal than during early withdrawal (incubation of methamphetamine craving). Muscimol+baclofen injections into CeA but not BLA decreased cue-induced methamphetamine seeking during late but not early withdrawal. Muscimol+baclofen injections into dmPFC, vmPFC, or OFC during late withdrawal had no effect on incubated cue-induced methamphetamine seeking. Together with previous studies, results indicate that the CeA has a critical role in incubation of both drug and non-drug reward craving and demonstrate an unexpected dissociation in mechanisms of incubation of methamphetamine vs cocaine craving. PMID:25475163

The differential effects of alprazolam and oxazepam on methamphetamine self-administration in rats.

PubMed

Spence, Allyson L; Guerin, Glenn F; Goeders, Nicholas E

2016-09-01

Methamphetamine is the second most commonly used illicit drug in the world, and despite recent attempts by the Drug Enforcement Administration to combat this epidemic, methamphetamine use is still on the rise. As methamphetamine use increases so does polydrug use, particularly that involving methamphetamine and benzodiazepines. The present study was designed to examine the effects of two benzodiazepines on methamphetamine self-administration. Five doses of methamphetamine (0.0075, 0.015, 0.03, 0.09, and 0.12mg/kg/infusion) were tested, producing an inverted U-shaped dose-response curve. Rats were then pretreated with oxazepam, alprazolam, or vehicle prior to methamphetamine self-administration. To determine if the effects of these drugs were due to the GABAA receptor and/or translocator protein (TSPO), we also pretreated rats with an antagonist for the benzodiazepine-binding site on the GABAA receptor (i.e., flumazenil) and a TSPO antagonist (i.e., PK11195) prior to alprazolam or oxazepam administration. Oxazepam significantly reduced methamphetamine self-administration as demonstrated by a downward shift of the dose-response curve. In contrast, alprazolam significantly enhanced methamphetamine self-administration as evidenced by a leftward shift of the dose-response curve. Flumazenil completely blocked the effects of alprazolam on methamphetamine self-administration. When administered individually, both flumazenil and PK11195 partially reversed the effects of oxazepam on methamphetamine self-administration. However, when these two antagonists were combined, the effects of oxazepam were completely reversed. The GABAA receptor is responsible for the alprazolam-induced enhancement of methamphetamine self-administration, while the activation of both the GABAA receptor and TSPO are responsible for the oxazepam-induced reduction of methamphetamine self-administration. Published by Elsevier Ireland Ltd.

Methamphetamine decreases CD4 T cell frequency and alters pro-inflammatory cytokine production in a model of drug abuse

PubMed Central

Mata, Mariana M.; Napier, T. Celeste; Graves, Steven M.; Mahmood, Fareeha; Raeisi, Shohreh; Baum, Linda L.

2015-01-01

The reason co-morbid methamphetamine use and HIV infection lead to more rapid progression to AIDS is unclear. We used a model of methamphetamine self-administration to measure the effect of methamphetamine on the systemic immune system to better understand the comorbidity of methamphetamine and HIV. Catheters were implanted into the jugular veins of male, Sprague Dawley rats so they could self-administer methamphetamine (n = 18) or be given saline (control; n = 16) for 14 days. One day after the last self-administration session, blood and spleens were collected. We measured serum levels of pro-inflammatory cytokines, intracellular IFN-γand TNF-α, and frequencies of CD4+, CD8+, CD200+ and CD11b/c+ lymphocytes in the spleen. Rats that self-administer methamphetamine had a lower frequency of CD4+ T cells, but more of these cells produced IFN-γ. Methamphetamine did not alter the frequency of TNF-α-producing CD4+ T cells. Methamphetamine using rats had a higher frequency of CD8+ T cells, but fewer of them produced TNF-α. CD11b/c and CD200 expression were unchanged. Serum cytokine levels of IFN-γ, TNF-α and IL-6 in methamphetamine rats were unchanged. Methamphetamine lifetime dose inversely correlated with serum TNF-α levels. Or data suggest that methamphetamine abuse may exacerbate HIV disease progression by activating CD4 T cells, making them more susceptible to HIV infection, and contributing to their premature demise. Methamphetamine may also increase susceptibility to HIV infection, explaining why African American men who have sex with men (MSM) and frequently use methamphetamine are at the highest risk of HIV infection. PMID:25678251

Methamphetamine decreases CD4 T cell frequency and alters pro-inflammatory cytokine production in a model of drug abuse.

PubMed

Mata, Mariana M; Napier, T Celeste; Graves, Steven M; Mahmood, Fareeha; Raeisi, Shohreh; Baum, Linda L

2015-04-05

The reason co-morbid methamphetamine use and HIV infection lead to more rapid progression to AIDS is unclear. We used a model of methamphetamine self-administration to measure the effect of methamphetamine on the systemic immune system to better understand the co-morbidity of methamphetamine and HIV. Catheters were implanted into the jugular veins of male, Sprague Dawley rats so they could self-administer methamphetamine (n=18) or be given saline (control; n=16) for 14 days. One day after the last operant session, blood and spleens were collected. We measured serum levels of pro-inflammatory cytokines, intracellular IFN-γ and TNF-α, and frequencies of CD4(+), CD8(+), CD200(+) and CD11b/c(+) lymphocytes in the spleen. Rats that self-administered methamphetamine had a lower frequency of CD4(+) T cells, but more of these cells produced IFN-γ. Methamphetamine did not alter the frequency of TNF-α-producing CD4(+) T cells. Methamphetamine using rats had a higher frequency of CD8(+) T cells, but fewer of them produced TNF-α. CD11b/c and CD200 expression were unchanged. Serum cytokine levels of IFN-γ, TNF-α and IL-6 in methamphetamine rats were unchanged. Methamphetamine lifetime dose inversely correlated with serum TNF-α levels. Our data suggest that methamphetamine abuse may exacerbate HIV disease progression by activating CD4 T cells, making them more susceptible to HIV infection, and contributing to their premature demise. Methamphetamine may also increase susceptibility to HIV infection, explaining why men who have sex with men (MSM) and frequently use methamphetamine are at the highest risk of HIV infection. Copyright © 2015 Elsevier B.V. All rights reserved.

Aggregate versus day level association between methamphetamine use and HIV medication non-adherence among gay and bisexual men

PubMed Central

Parsons, Jeffrey T.; Kowalczyk, William; Botsko, Michael; Tomassilli, Julia; Golub, Sarit A.

2013-01-01

Methamphetamine use is associated with HIV infection, especially among gay and bisexual men. Methamphetamine use contributes to disease progression both directly, by increasing viral load and damaging the immune system, and indirectly, by decreasing medication adherence. Research examining the association of methamphetamine use and non-adherence has traditionally compared groups of users and nonusers on adherence, compared methamphetamine use between participants above or below some threshold level of adherence (e.g. >90% dose adherence), or examined aggregate relationships. Using Timeline Follow-back procedures, the present study examined aggregate, threshold, and day-level associations of methamphetamine use with non-adherence in 210 HIV-positive gay and bisexual methamphetamine-using men. Methamphetamine use was not associated with adherence behavior at the aggregate-level, but methamphetamine use on a given day was associated with 2.3 times the odds of non-adherence on that day. Threshold results were equivocal. These data suggest that the methamphetamine and non-adherence relationship is complicated: non-adherence is more likely to occur on days in which methamphetamine is used, but participants reported more non-adherence days in which methamphetamine was not used. This seeming paradox generates questions about the selection of analytical techniques and has important implications for behavioral interventions targeting substance use and adherence among HIV-positive individuals. PMID:23553345

Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET.

PubMed

Sekine, Y; Iyo, M; Ouchi, Y; Matsunaga, T; Tsukada, H; Okada, H; Yoshikawa, E; Futatsubashi, M; Takei, N; Mori, N

2001-08-01

A positron emission tomography (PET) study has suggested that dopamine transporter density of the caudate/putamen is reduced in methamphetamine users. The authors measured nucleus accumbens and prefrontal cortex density, in addition to caudate/putamen density, in methamphetamine users and assessed the relation of these measures to the subjects' clinical characteristics. PET and 2-beta-carbomethoxy-3beta-(4-[(11)C] fluorophenyl)tropane, a dopamine transporter ligand, were used to measure dopamine transporter density in 11 male methamphetamine users and nine male comparison subjects who did not use methamphetamine. Psychiatric symptoms in methamphetamine users were evaluated by using the Brief Psychiatric Rating Scale and applying a craving score. The dopamine transporter density in all three of the regions observed was significantly lower in the methamphetamine users than the comparison subjects. The severity of psychiatric symptoms was significantly correlated with the duration of methamphetamine use. The dopamine transporter reduction in the caudate/putamen and nucleus accumbens was significantly associated with the duration of methamphetamine use and closely related to the severity of persistent psychiatric symptoms. These findings suggest that longer use of methamphetamine may cause more severe psychiatric symptoms and greater reduction of dopamine transporter density in the brain. They also show that the dopamine transporter reduction may be long-lasting, even if methamphetamine use ceases. Further, persistent psychiatric symptoms in methamphetamine users, including psychotic symptoms, may be attributable to the reduction of dopamine transporter density.

Methamphetamine functions as a positive and negative drug feature in a Pavlovian appetitive discrimination task.

PubMed

Reichel, Carmela M; Wilkinson, Jamie L; Bevins, Rick A

2007-12-01

This research determined the ability of methamphetamine to serve as a positive or negative feature, and assessed the ability of bupropion, cocaine, and naloxone to substitute for the methamphetamine features. Rats received methamphetamine (0.5 mg/kg, intraperitoneally) or saline 15 min before a conditioning session. For the feature positive (FP) group, offset of 15-s cue lights was followed by access to sucrose on methamphetamine sessions; sucrose was withheld during saline sessions. For the feature negative (FN) group, the light offset was followed by sucrose on saline sessions; sucrose was withheld during methamphetamine sessions. During acquisition, the FP group had higher responding on methamphetamine sessions than on saline sessions. For the FN group, responding was higher on saline sessions than on methamphetamine sessions. Conditioned responding was sensitive to methamphetamine dose. For the FP group, bupropion and cocaine fully and partially substituted for methamphetamine, respectively. In contrast, both drugs fully substituted for methamphetamine in the FN group. Naloxone did not substitute in either set of rats. FP-trained rats were more sensitive to the locomotor stimulating effects of the test drugs than FN-trained rats. This research demonstrates that the pharmacological effects of methamphetamine function as a FP or FN in this Pavlovian discrimination task and that training history can affect conditioned responding and locomotor effects evoked by a drug.

Methamphetamine enhances Hepatitis C virus replication in human hepatocytes

PubMed Central

Ye, L.; Peng, J. S.; Wang, X.; Wang, Y. J.; Luo, G. X.; Ho, W. Z.

2009-01-01

SUMMARY Very little is known about the interactions between hepatitis C virus (HCV) and methamphetamine, which is a highly abused psychostimulant and a known risk factor for human immunodeficiency virus (HIV)/HCV infection. This study examined whether methamphetamine has the ability to inhibit innate immunity in the host cells, facilitating HCV replication in human hepatocytes. Methamphetamine inhibited intracellular interferon alpha expression in human hepatocytes, which was associated with the increase in HCV replication. In addition, methamphetamine also compromised the anti-HCV effect of recombinant interferon alpha. Further investigation of mechanism(s) responsible for the methamphetamine action revealed that methamphetamine was able to inhibit the expression of the signal transducer and activator of transcription 1, a key modulator in interferon-mediated immune and biological responses. Methamphetamine also down-regulated the expression of interferon regulatory factor-5, a crucial transcriptional factor that activates the interferon pathway. These in vitro findings that methamphetamine compromises interferon alpha-mediated innate immunity against HCV infection indicate that methamphetamine may have a cofactor role in the immunopathogenesis of HCV disease. PMID:18307590

Methamphetamine Use in Club Subcultures

PubMed Central

Kelly, Brian C.; LeClair, Amy; Parsons, Jeffrey T.

2014-01-01

In recent decades, methamphetamine developed a peculiar geographic distribution in the United States, with limited diffusion in the Northeast. While use within gay clubs received attention, methamphetamine in club subcultures more broadly remains less clear. Using quantitative and qualitative data, we provide a descriptive assessment of methamphetamine use in club subcultures. Methamphetamine use in club subcultures often has instrumental purposes. The context of initiation into methamphetamine use and its close connection to cocaine shape later patterns of use. Viewing meth solely as a gay party drug misses a significant part of the population and may misguide public health strategies to reduce methamphetamine use in the Northeast. PMID:23848380

The role of hyperthermia and metabolism as mechanisms of tolerance to methamphetamine neurotoxicity.

PubMed

Johnson-Davis, Kamisha L; Fleckenstein, Annette E; Wilkins, Diana G

2003-12-15

Pretreatment with multiple methamphetamine injections prior to a high-dose methamphetamine challenge administration can attenuate long-term deficits in striatal and hippocampal serotonin content caused by the stimulant. The present data extend previous findings by demonstrating that rats pretreated with escalating doses methamphetamine did not exhibit dopamine deficits in the striatum, nor serotonin deficits in striatal, frontal cortical, or hippocampal tissues, 7 days after a challenge methamphetamine administration. This protection was not due to attenuation of methamphetamine-induced hyperthermia or altered brain methamphetamine concentrations. These data differ from previous findings thereby highlighting that different mechanisms contribute to the tolerance of the neurotoxic effects.

Delayed emergence of methamphetamine’s enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence

PubMed Central

Vaupel, DB; Schindler, CW; Chefer, S; Belcher, AM; Ahmet, I; Scheidweiler, KB; Huestis, MA; Stein, EA

2015-01-01

Background Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. Methods Eight male rhesus monkeys with long histories of intravenous methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naïve monkeys. Cardiovascular responses to methamphetamine were followed for 2.5 h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals. Results No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. Conclusions Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events. PMID:26775284

Increased prevalence of self-reported psychotic illness predicted by crystal methamphetamine use: Evidence from a high-risk population.

PubMed

Lappin, Julia M; Roxburgh, Amanda; Kaye, Sharlene; Chalmers, Jenny; Sara, Grant; Dobbins, Timothy; Burns, Lucinda; Farrell, Michael

2016-12-01

The potential of methamphetamine, and high-potency crystal methamphetamine in particular, to precipitate psychotic symptoms and psychotic illness is the subject of much speculation internationally. Established psychotic illness is disabling for individuals and costly to society. The aim of this study was to investigate whether use of crystal methamphetamine was associated with greater prevalence of self-reported psychotic illness, compared to use of other forms of methamphetamine. The sample comprised participants interviewed as part of an annual cross-sectional survey of Australian people who inject drugs. Comparisons were made between groups according to the nature of their methamphetamine use: crystal methamphetamine or other forms of methamphetamine. Self-reported diagnoses of psychotic illness and other mental health problems were compared between groups. Predictors of self-reported psychotic illness were examined using multivariable logistic regression analyses. Self-reported psychotic illness was highly prevalent among users of crystal methamphetamine (12.0%), and significantly more so than among users of other forms of methamphetamine (3.9%) (OR=3.36; CI: 1.03-10.97). Significant predictors of self-reported psychosis in the cohort were: use of crystal methamphetamine; dependent use; lack of education beyond high school; and younger age. Highly increased prevalence of self-reported psychotic illness is associated with use of high-potency crystal methamphetamine in people who inject drugs, particularly where there is dependent use. There is an urgent need to develop effective interventions for dependent crystal methamphetamine use; and a need to monitor for symptoms of psychotic illness in drug-using populations. Copyright © 2016 Elsevier B.V. All rights reserved.

Managing acute pain in patients who report lactose intolerance: the safety of an old excipient re-examined.

PubMed

Mill, Deanna; Dawson, Jessica; Johnson, Jacinta Lee

2018-05-01

Lactose intolerance is exceedingly common, reportedly affecting up to 70% of the world's population, leading to both abdominal and systemic symptoms. Current treatment focuses predominantly on restricting dietary consumption of lactose. Given lactose is one of the most commonly used excipients in the pharmaceutical industry, consideration must be given to the lactose content and therefore safety of pharmaceutical preparations prescribed for patients with lactose intolerance. This article summarizes the current literature examining the likelihood of inducing adverse effects through the administration of lactose-containing pharmaceutical preparations in patients reporting lactose intolerance, describes how to assess this risk on an individual patient basis and reviews suitable analgesic options for this population. A case study is presented detailing a patient reporting lactose intolerance who insists on treatment with the lactose-free product codeine/ibuprofen (Nurofen Plus) rather than other codeine-free analgesics. It is important to assess the likelihood of lactose as an excipient inducing symptoms in this scenario, as reluctance to cease codeine could suggest codeine dependence, an issue that is becoming increasingly common in countries such as Australia and Canada. Given codeine dependence is associated with serious sequelae including hospitalization and death, the patient must either be reassured the lactose component in their prescribed analgesics will not induce symptoms or an alternative treatment strategy must be confirmed. General recommendations applying theory from the literature to the management of acute pain in lactose-intolerant patients are discussed and specific treatment options are outlined. Although large inter-individual variability is reported, most lactose-intolerant patients can tolerate the small quantities of lactose found in pharmaceutical preparations. Cumulative lactose exposure can be assessed in patients taking multiple medications while also consuming lactose in the diet. In those sensitive to small quantities of lactose, lactase supplements can be trailed. Additionally, for the analgesic drug classes employed for the management of acute pain, lactose-free formulations, including most oral liquids and dispersible tablets and some oral tablets and capsules, are available.

Misuse and dependence on non-prescription codeine analgesics or sedative H1 antihistamines by adults: a cross-sectional investigation in France.

PubMed

Roussin, Anne; Bouyssi, Annabelle; Pouché, Lucie; Pourcel, Laure; Lapeyre-Mestre, Maryse

2013-01-01

Given the growing worldwide market of non-prescription drugs, monitoring their misuse in the context of self-medication represents a particular challenge in Public Health. The aim of this study was to investigate the prevalence of misuse, abuse, and dependence on non-prescription psychoactive drugs. During one month, in randomly solicited community pharmacies, an anonymous questionnaire was offered to adults requesting paracetamol (control group), codeine combined with paracetamol in analgesics, or sedative H1 antihistamines. Responses about misuse (drug use not in agreement with the Patient Information Leaflet) abuse (excessive drug use having detrimental consequences), and dependence (established according to questions adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria) on psychoactive drugs were compared to those of the paracetamol control group. 295 patients (mean age 48.5 years, 68.5% of women) having used one of the studied drugs during the previous month were included. Misuse and dependence to codeine analgesics concerned 6.8% and 17.8% of the patients exposed to these drugs, respectively, (n = 118), which was significantly higher than for paracetamol. 19.5% had used codeine analgesics daily for more than six months. Headache was the most frequent reason for persistent daily use. A high prevalence of persistent daily users of sedative H1 antihistamines was also observed. Whereas these drugs are recommended only for short treatment courses of occasional insomnia, 72.2% of the participants having taken doxylamine (n = 36) were daily users, predominantly for more than six months. Results on misuse and dependence on non-prescription codeine analgesics suggest that chronic pain, in particular chronic cephalalgia, requires better medical care. In addition, as for hypnotics on prescription, persistent use of doxylamine for self-medication is not justified until an acceptable benefit-risk ratio for chronic sleep disturbance is shown by clinical data.

Perceived Risk of Methamphetamine among Chinese Methamphetamine Users

PubMed Central

Kelly, Brian C; Liu, Tieqiao; Yang, Xiaozhao Yosef; Zhang, Guanbai; Hao, Wei; Wang, Jichuan

2014-01-01

Background Methamphetamine use has grown considerably in China in recent years. Information about perceptions of risk on methamphetamine is important to facilitate health promotion efforts. Methods Using both survey data and qualitative interview data, the authors evaluate the perceived risk of methamphetamine use among Chinese users using a mixed-methods approach. Through Respondent Driven Sampling, the authors recruited a sample of 303 methamphetamine users in Changsha, China. Results A majority (59.1%) perceive that infrequent methamphetamine use poses no risk to the user, while 11.2% perceive at least moderate risk for light use. A majority (56.7%) perceived at least moderate risk associated with regular methamphetamine use. Most (82.2%) also perceive methamphetamine to be easily obtainable. A path model indicates that perceived risk shapes intentions to use and expectations of future use, as does perceived availability. Qualitatively, while addiction was the most common risk discussed by users, they differed on whether they perceived the drug addictive. Other concerns raised by interviewees included impaired cognition, mental health problems, physical harm, and social dysfunction. Discussion While some users identify significant risks with methamphetamine, others do not perceive its use to be problematic. Collectively, these findings indicate that intervening upon perceptions of risk among Chinese methamphetamine users may be a means to influence intentions to use. PMID:24925820