Science.gov

Sample records for 9-tetrahydrocannabinol delta 9-thc

  1. Hormonal status and age differentially affect tolerance to the disruptive effects of delta-9-tetrahydrocannabinol9-THC) on learning in female rats

    PubMed Central

    Winsauer, Peter J.; Filipeanu, Catalin M.; Weed, Peter F.; Sutton, Jessie L.

    2015-01-01

    The effects of hormone status and age on the development of tolerance to Δ9-THC were assessed in sham-operated (intact) or ovariectomized (OVX) female rats that received either intraperitoneal saline or 5.6 mg/kg of Δ9-THC daily from postnatal day (PD) 75–180 (early adulthood onward) or PD 35–140 (adolescence onward). During this time, the four groups for each age (i.e., intact/saline, intact/THC, OVX/saline, and OVX/THC) were trained in a learning and performance procedure and dose-effect curves were established for Δ9-THC (0.56–56 mg/kg) and the cannabinoid type-1 receptor (CB1R) antagonist rimonabant (0.32–10 mg/kg). Despite the persistence of small rate-decreasing and error-increasing effects in intact and OVX females from both ages during chronic Δ9-THC, all of the Δ9-THC groups developed tolerance. However, the magnitude of tolerance, as well as the effect of hormone status, varied with the age at which chronic Δ9-THC was initiated. There was no evidence of dependence in any of the groups. Hippocampal protein expression of CB1R, AHA1 (a co-chaperone of CB1R) and HSP90β (a molecular chaperone modulated by AHA-1) was affected more by OVX than chronic Δ9-THC; striatal protein expression was not consistently affected by either manipulation. Hippocampal brain-derived neurotrophic factor expression varied with age, hormone status, and chronic treatment. Thus, hormonal status differentially affects the development of tolerance to the disruptive effects of delta-9-tetrahydrocannabinol9-THC) on learning and performance behavior in adolescent, but not adult, female rats. These factors and their interactions also differentially affect cannabinoid signaling proteins in the hippocampus and striatum, and ultimately, neural plasticity. PMID:26191005

  2. Radioimmunoanalysis of delta-9-THC in blood by means of an /sup 125/I tracer. [Delta-9-Tetrahydrocannabinol

    SciTech Connect

    Owens, S.M.; McBay, A.J.; Reisner, H.M.

    1982-01-01

    A radioimmunoassay for delta-9-THC in plasma, whole blood, or hemolyzed blood specimens has been presented. Samples and standards were diluted with methanol and centrifuged. An aliquot of the supernatant fluid was incubated with RIA buffer, /sup 125/I-labeled delta-8-THC and rabbit anti-THC serum. Solid phase goat anti-rabbit immunoglobulins were added to separate bound from free THC. After centrifugation the supernatant fluid was aspirated and the radioactivity of the precipitate was counted in a gamma counter. The concentration of THC was calculated from a standard curve using the logit-log transformation of the average counts of duplicate tubes. The assay had several advantages. Methanol dilution gave better results than direct analysis. The /sup 125/I-labeled THC had high specific activity and could be counted in a gamma counter. The immunological separation of antibody-bound THC from free THC was better than separation techniques using ammonium sulfate and activated charcoal. THC was determined in 0.1 ml of sample with a sensitivity of 1.5 ng/ml in plasma and 3.0 ng/ml in hemolyzed blood.

  3. Urinary excretion profiles of 11-nor-9-carboxy-Delta9-tetrahydrocannabinol. Study III. A Delta9-THC-COOH to creatinine ratio study.

    PubMed

    Fraser, Albert D; Worth, David

    2003-11-26

    Huestis and Cone reported in [J. Anal. Toxicol. 22 (1998) 445] that serial monitoring of Delta9-THC-COOH/creatinine ratios in paired urine specimens collected at least 24h apart could differentiate new drug use from residual Delta(9)-THC-COOH excretion following acute marijuana use in a controlled setting. The best accuracy (85.4%) for predicting new marijuana use was for a Delta(9)-THC-COOH/creatinine ratio > or = 0.5 (dividing the Delta9-THC-COOH/creatinine ratio of specimen no. 2 by the specimen no. 1 ratio). In previous studies in this laboratory [J. Anal. Toxicol. 23 (1999) 531 and Forensic Sci. Int. 133 (2003) 26], urine specimens were collected from chronic marijuana users > or = 24 h or > = 48 h apart in an uncontrolled setting. Subjects with a history of chronic marijuana use were screened for cannabinoids with the EMIT II Plus cannabinoids assay (cut-off 50 ng/ml) followed by confirmation for Delta9-THC-COOH by GC-MS (cut-off 15 ng/ml). Creatinine was analyzed as an index of dilution. The objective of the present study was to evaluate whether creatinine corrected specimens could differentiate new marijuana or hashish use from the excretion of residual Delta(9)-THC-COOH in chronic marijuana users based on the Huestis 0.5 ratio. Urine specimens (N=376) were collected from 29 individuals > or = 96 h between urine collections. The mean urinary Delta9-THC-COOH concentration was 464.4 ng/ml, mean Delta9-THC-COOH/creatinine ratio (ng/(ml Delta9-THC-COOH mmoll creatinine)) was 36.8 and the overall mean Delta9-THC-COOH/creatinine ratio of specimen 2/mean Delta9-THC-COOH/creatinine ratio of specimen 1 was 1.37. The Huestis ratio calculation indicated new drug use in 83% of all sequentially paired urine specimens. The data were sub-divided into three groups (Groups A-C) based on mean Delta9-THC-COOH/creatinine values. Interindividual mean Delta9-THC-COOH/creatinine values ranged from 4.7 to 13.4 in Group A where 80% of paired specimens indicated new drug use (N=10

  4. Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol9-THC) on complex behavior in female rats.

    PubMed

    Winsauer, Peter J; Sutton, Jessie L

    2014-02-01

    This study examined whether chronic Δ(9)-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ(9)-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6 mg/kg of Δ(9)-THC i.p. for 40 days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ(9)-THC (0.56-10 mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ(9)-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ(9)-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ(9)-THC than the OVX groups irrespective of chronic Δ(9)-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ(9)-THC) and the dose of Δ(9)-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ(9)-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we

  5. Susceptibility of Naegleria fowleri to delta 9-tetrahydrocannabinol.

    PubMed Central

    Pringle, H L; Bradley, S G; Harris, L S

    1979-01-01

    Growth of the pathogenic amoeboflagellate Naegleria fowleri is inhibited by delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC is amoebostatic at 5 to 50 micrograms/ml. delta 9-THC prevents enflagellation and encystment, but does not impair amoeboid movement. Calf serum at 10 and 20% (vol/vol) reduces the antiamoeba activity of delta 9-THC. Only 1-methoxy delta 8-tetrahydrocannabinol, of 17 cannabinoids tested, failed to inhibit growth of N. fowleri. Antinaeglerial activity was not markedly altered by opening the pyran ring, by converting the cyclohexyl ring to an aromatic ring, or by reversing the hydroxyl and pentyl groups on the benzene ring. delta 9-THC prevented the cytopathic effect of N. fowleri on African green monkey (Vero) cells and human epithelioma (HEp-2) cells in culture. delta 9-THC afforded modest protection to mice infected with N. fowleri. Images PMID:526010

  6. Antinociceptive activity of Delta9-tetrahydrocannabinol non-ionic microemulsions.

    PubMed

    Lazzari, P; Fadda, P; Marchese, G; Casu, G L; Pani, L

    2010-06-30

    Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of Cannabis sativa L., has been widely studied for its potential pharmaceutical application in the treatment of various diseases and disturbs. This sparingly soluble terpeno-phenolic compound is not easy to handle and to be formulated in pharmaceutical preparations. The aim of this work was to develop a stable aqueous Delta(9)-THC formulation acceptable for different ways of administration, and to evaluate the therapeutic properties of the new Delta(9)-THC based preparation for pain treatment. Due to the thermodynamic stability and advantages of microemulsion based systems, the study was focused on the identification of aqueous microemulsion based systems containing Delta(9)-THC. Oil in water Delta(9)-THC microemulsions were individuated through phase diagrams construction, using the non-ionic surfactant Solutol HS15, being this surfactant acceptable for parenteral administration in human. A selected microemulsion samples containing 0.2 wt% of Delta(9)-THC, stable up to 52 degrees C, was successfully assayed on animal models of pain. Significant antinociceptive activity has been detected by both intraperitoneal and intragastric administration of the new Delta(9)-THC pharmaceutical preparation. The effect has been highlighted in shorter time if compared to a preparation of the same active principle based on previously reported conventional preparation. PMID:20399844

  7. Oxidative and genetic responses induced by Δ-9-tetrahydrocannabinol (Δ-9-THC) to Dreissena polymorpha.

    PubMed

    Parolini, Marco; Binelli, Andrea

    2014-01-15

    Cannabis is the most used illicit substance worldwide and its main psychoactive compound, the Δ-9-tetrahydrocannabinol (Δ-9-THC), is detected in aquatic environments at measurable concentrations. Even though its occurrence is well documented, no information is available on its hazard to aquatic organisms. The aim of this study was to assess the adverse effects induced to zebra mussel (Dreissena polymorpha) specimens by 14 day exposures to environmentally relevant Δ-9-THC concentrations (0.05 μg/L and 0.5 μg/L) by means of the application of a biomarker suite. Catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities, as well as the lipid peroxidation (LPO) and protein carbonyl content (PCC), were measured as oxidative stress indices. The single cell gel electrophoresis (SCGE) assay, the DNA diffusion assay and the micronucleus test (MN test) were applied to investigate DNA injuries, while the neutral red retention assay (NRRA) was used to assess Δ-9-THC cytotoxicity. The lowest treatment induced negligible adverse effects to bivalves, while 0.5 μg/L Δ-9-THC exposure caused remarkable alterations in D. polymorpha oxidative status, which lead to significant increase of lipid peroxidation, protein carbonylation and DNA damage. PMID:24008074

  8. Oxidative and genetic responses induced by Δ-9-tetrahydrocannabinol (Δ-9-THC) to Dreissena polymorpha.

    PubMed

    Parolini, Marco; Binelli, Andrea

    2014-01-15

    Cannabis is the most used illicit substance worldwide and its main psychoactive compound, the Δ-9-tetrahydrocannabinol (Δ-9-THC), is detected in aquatic environments at measurable concentrations. Even though its occurrence is well documented, no information is available on its hazard to aquatic organisms. The aim of this study was to assess the adverse effects induced to zebra mussel (Dreissena polymorpha) specimens by 14 day exposures to environmentally relevant Δ-9-THC concentrations (0.05 μg/L and 0.5 μg/L) by means of the application of a biomarker suite. Catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities, as well as the lipid peroxidation (LPO) and protein carbonyl content (PCC), were measured as oxidative stress indices. The single cell gel electrophoresis (SCGE) assay, the DNA diffusion assay and the micronucleus test (MN test) were applied to investigate DNA injuries, while the neutral red retention assay (NRRA) was used to assess Δ-9-THC cytotoxicity. The lowest treatment induced negligible adverse effects to bivalves, while 0.5 μg/L Δ-9-THC exposure caused remarkable alterations in D. polymorpha oxidative status, which lead to significant increase of lipid peroxidation, protein carbonylation and DNA damage.

  9. Delta9-THC as a discriminative cue in pigeons: effects of delta8-THC, CBD, and CBN.

    PubMed

    Järbe, T U; Henriksson, B G; Ohlin, G C

    1977-07-01

    Pigeons, trained to discriminate the effects of i.m. injections of delta9-tetrahydrocannabinol (delta9-THC, 0.25 mg/kg) from the effects of the vehicle in a drug discrimination paradigm, were tested for generalization with the isomeric delta8-THC, cannabidiol (CBD) and cannabinol (CBN). When given in sufficient doses, delta8-THC and CBN were found to substitute for delta9-THC whereas CBD did not. CBD and CBN did not antagonize the stimulus effect of delta9-THC. The combination of CBN and delta9-THC rather appeared to accentuate the drug response.

  10. Hair analysis for delta(9)-THC, delta(9)-THC-COOH, CBN and CBD, by GC/MS-EI. Comparison with GC/MS-NCI for delta(9)-THC-COOH.

    PubMed

    Baptista, Maria João; Monsanto, Paula Verâncio; Pinho Marques, Estela Gouveia; Bermejo, Ana; Avila, Sofia; Castanheira, Alice Martelo; Margalho, Cláudia; Barroso, Mário; Vieira, Duarte Nuno

    2002-08-14

    A sensitive analytical method was developed for quantitative analysis of delta(9)-tetrahydrocannabinol (delta(9)-THC), 11-nor-delta(9)-tetrahydrocannabinol-carboxylic acid (delta(9)-THC-COOH), cannabinol (CBN) and cannabidiol (CBD) in human hair. The identification of delta(9)-THC-COOH in hair would document Cannabis use more effectively than the detection of parent drug (delta(9)-THC) which might have come from environmental exposure. Ketamine was added to hair samples as internal standard for CBN and CBD. Ketoprofen was added to hair samples as internal standard for the other compounds. Samples were hydrolyzed with beta-glucuronidase/arylsulfatase for 2h at 40 degrees C. After cooling, samples were extracted with a liquid-liquid extraction procedure (with chloroform/isopropyl alcohol, after alkalinization, and n-hexane/ethyl acetate, after acidification), which was developed in our laboratory. The extracts were analysed before and after derivatization with pentafluoropropionic anhydride (PFPA) and pentafluoropropanol (PFPOH) using a Hewlett Packard gas chromatographer/mass spectrometer detector, in electron impact mode (GC/MS-EI). Derivatized delta(9)-THC-COOH was also analysed using a Hewlett Packard gas chromatographer/mass spectrometer detector, in negative ion chemical ionization mode (GC/MS-NCI) using methane as the reagent gas. Responses were linear ranging from 0.10 to 5.00 ng/mg hair for delta(9)-THC and CBN, 0.10-10.00 ng/mg hair for CBD, 0.01-5.00 ng/mg for delta(9)-THC-COOH (r(2)>0.99). The intra-assay precisions ranged from <0.01 to 12.40%. Extraction recoveries ranged from 80.9 to 104.0% for delta(9)-THC, 85.9-100.0% for delta(9)-THC-COOH, 76.7-95.8% for CBN and 71.0-94.0% for CBD. The analytical method was applied to 87 human hair samples, obtained from individuals who testified in court of having committed drug related crimes. Quantification of delta(9)-THC-COOH using GC/MS-NCI was found to be more convenient than GC/MS-EI. The latter may give rise

  11. delta-9-Tetrahydrocannabinol: effect on macromolecular synthesis in human and other mammalian cells.

    PubMed

    Blevins, R D; Regan, J D

    1976-03-11

    The principal psychoactive component of marihuana is delta-9-tetrahydrocannabinol. This compound at 10(-5) molar concentration in the medium of human cell cultures appeared to inhibit DNA, RNA, and protein synthesis by 50, 40, and 30% respectively, as measured by incorporation of radioactive precursors into acid-insoluble cell fractions in human diploid fibroblasts, human neuroblastoma cells, and mouse neuroblastoma cells. While delta-9-tetrahydrocannabinol inhibited semiconservative DNA synthesis, it had no effect on DNA repair synthesis in human cells as assayed by the photolysis of 5-bromodeoxyuridine incorporation into DNA during repair after ultraviolet radiation damage. Delta-9-tetrahydrocannabinol also had no effect on rejoining of DNA single-strand breaks induced by gamma-rays. The nonspecificity of the inhibition of macromolecular synthesis by delta-9-THC suggested a possible interference with uptake of radioactive precursors. However, experimentation has shown that this depression of macromolecular synthesis cannot be accounted for by reduced transport of radioactive precursors into the cell because the rate of transport of these precursors into the cell is essentially the same in the presence or absence of delta-9-THC. Pool sizes of macromolecular precursors as measured radioisotopically (3H-thymidine, 3H-uridine, 14C-leucine) appear to be reduced about 50%, and this reduced pool size could fully account for the reduced macromolecular synthesis seen in the presence of delta-9-THC. We do not know what causes this apparent reduction of pool sizes in the presence of delta-9-THC.

  12. Actions of delta-9-tetrahydrocannabinol in cannabis

    PubMed Central

    COOPER, ZIVA D.; HANEY, MARGARET

    2009-01-01

    Cannabis use disorders have been recently identified as a relevant clinical issue: a subset of cannabis smokers seeks treatment for their cannabis use, yet few succeed in maintaining long-term abstinence. The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis, delta-9-tetrahydrocannabinol (THC) are mediated by the cannabinoid CB1 receptor. The CB1 receptor has also been shown to mediate cannabinoid dependence and expression of withdrawal upon cessation of drug administration, a phenomenon verified across species. This paper will review findings implicating the CB1 receptor in the behavioural effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement, factors that contribute to the maintenance of chronic cannabis smoking despite negative consequences. Opioidergic modulation of these effects is also discussed. PMID:19367504

  13. Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis.

    PubMed

    D'Souza, Deepak Cyril; Ranganathan, Mohini; Braley, Gabriel; Gueorguieva, Ralitza; Zimolo, Zoran; Cooper, Thomas; Perry, Edward; Krystal, John

    2008-09-01

    Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Delta-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Delta-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Delta-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Delta-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of 'high'; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Delta-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.

  14. Involvement of hindbrain and peripheral prostanoids in gastric motor and cardiovascular responses to delta-9-tetrahydrocannabinol in the rat.

    PubMed

    Krowicki, Z K

    2012-12-01

    We previously reported that delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of Cannabis sativa, inhibited gastric motor activity and evoked bradycardia and hypotension upon its parenteral administration in the rat. As prostanoids are important mediators of the actions of cannabinoids, we hypothesized that the inhibitory gastric motor and cardiovascular effects of delta-9-THC could depend on cyclooxygenase (COX) activation in the hindbrain and/or in the periphery. To test this hypothesis, vehicle or delta-9-THC (0.2 mg/kg, i.v.) were administered before and 15-min after the COX inhibitor tolmetin (50 mg/kg, i.v.) or 15 min after topical application of tolmetin to the surface of the dorsal medulla (0.5 mg/rat) in chloralose-anesthetized rats. Delta-9-THC-evoked gastric motor inhibition and bradycardia were abolished by parenteral and were attenuated by hindbrain administration of tolmetin. Moreover, administration of delta-9-THC after parenteral tolmetin evoked marked and long-lasting hypertension. We concluded that the inhibitory gastric motor and cardiovascular effects of systemically administered delta-9-THC depend on the hindbrain and peripheral activation of COX. PMID:23388474

  15. A cannabinoid analogue of Delta9-tetrahydrocannabinol disrupts neural development in chick.

    PubMed

    Psychoyos, Delphine; Hungund, Basalingappa; Cooper, Thomas; Finnell, Richard H

    2008-10-01

    Marijuana is the most commonly abused illicit drug by pregnant women. Its major psychoactive constituent, Delta(9)-THC (Delta(9)-tetrahydrocannabinol), crosses the placenta and accumulates in the foetus, potentially harming its development. In humans, marijuana use in early pregnancy is associated with miscarriage, a fetal alcohol-like syndrome, as well as learning disabilities, memory impairment, and ADHD in the offspring. Classical studies in the 1970 s have reached disparate conclusions as to the teratogenic effects of cannabinoids in animal models. Further, there is very little known about the immediate effects of Delta(9)-THC on early embryogenesis. We have used the chick embryo as a model in order to characterize the effects of a water-soluble Delta(9)-THC analogue, O-2545, on early development. Embryos were exposed to the drug (0.035 to 0.35 mg/ml) at gastrulation and assessed for morphological defects at stages equivalent to 9-14 somites. We report that O-2545 impairs the formation of brain, heart, somite, and spinal cord primordia. Shorter incubation times following exposure to the drug show that O-2545 interferes with the initial steps of head process and neural plate formation. Our results indicate that the administration of the cannabinoid O-2545 during early embryogenesis results in embryotoxic effects and serves to illuminate the risks of marijuana exposure during the second week of pregnancy, a time point at which most women are unaware of their pregnancies. PMID:19040278

  16. A cannabinoid analogue of Delta9-tetrahydrocannabinol disrupts neural development in chick.

    PubMed

    Psychoyos, Delphine; Hungund, Basalingappa; Cooper, Thomas; Finnell, Richard H

    2008-10-01

    Marijuana is the most commonly abused illicit drug by pregnant women. Its major psychoactive constituent, Delta(9)-THC (Delta(9)-tetrahydrocannabinol), crosses the placenta and accumulates in the foetus, potentially harming its development. In humans, marijuana use in early pregnancy is associated with miscarriage, a fetal alcohol-like syndrome, as well as learning disabilities, memory impairment, and ADHD in the offspring. Classical studies in the 1970 s have reached disparate conclusions as to the teratogenic effects of cannabinoids in animal models. Further, there is very little known about the immediate effects of Delta(9)-THC on early embryogenesis. We have used the chick embryo as a model in order to characterize the effects of a water-soluble Delta(9)-THC analogue, O-2545, on early development. Embryos were exposed to the drug (0.035 to 0.35 mg/ml) at gastrulation and assessed for morphological defects at stages equivalent to 9-14 somites. We report that O-2545 impairs the formation of brain, heart, somite, and spinal cord primordia. Shorter incubation times following exposure to the drug show that O-2545 interferes with the initial steps of head process and neural plate formation. Our results indicate that the administration of the cannabinoid O-2545 during early embryogenesis results in embryotoxic effects and serves to illuminate the risks of marijuana exposure during the second week of pregnancy, a time point at which most women are unaware of their pregnancies.

  17. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice.

    PubMed

    Long, Leonora E; Chesworth, Rose; Huang, Xu-Feng; McGregor, Iain S; Arnold, Jonathon C; Karl, Tim

    2010-08-01

    Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.

  18. Delta(9) -tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: A critical examination of the preclinical literature.

    PubMed

    Fowler, C J

    2015-06-01

    An Internet search with search words "cannabis cures cancer" produce a wealth of sites claiming that cannabis has this effect. These sites are freely accessible to the general public and thus contribute to public opinion. But do delta(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD) cure cancer? In the absence of clinical data other than a safety study and case reports, preclinical data should be evaluated in terms of its predictive value. Using a strict approach where only concentrations and/or models relevant to the clinical situation are considered, the current preclinical data do not yet provide robust evidence that systemically administered Δ(9) -THC will be useful for the curative treatment of cancer. There is more support for an intratumoral route of administration of higher doses of Δ(9) -THC. CBD produces effects in relevant concentrations and models, although more data are needed concerning its use in conjunction with other treatment strategies.

  19. Failure of acute and chronic administration of delta 9-tetrahydrocannabinol to affect the repeated acquisition of serial position response in pigeons.

    PubMed

    McMillan, D E

    1988-01-01

    Pigeons were trained to acquire a new four-response position sequence each day by pecking three response keys in a predetermined order. The key color varied after each correct response prior to food delivery. Acute administration of delta 9-tetrahydrocannabinol (delta 9-THC) up to a dose that completely eliminated responding, had no effect on total acquisition errors, or on within session patterns of error elimination. Chronic administration of delta 9-THC (3-10 mg/kg/day), either before or after the session for 4-7 weeks, also did not affect these error measures, although rates of responding were markedly suppressed and at times no responding occurred. Discontinuation of delta 9-THC administration for periods of 4-6 weeks also was without effect on errors. These experiments suggest that neither acute nor chronic delta 9-THC produce specific effects on the repeated acquisition of serial position responses in pigeons.

  20. Emotional response to intravenous delta9tetrahydrocannabinol during oral surgery.

    PubMed

    Gregg, J M; Small, E W; Moore, R; Raft, D; Toomey, T C

    1976-04-01

    The administration of delta9THC intravenously as a premedicant to oral surgery resulted in acute pronounced elevations in anxiety states, a predominance of dysphoria over euphoria, and varying degrees of psychotic-like paranoiac thought. Neural effects that appeared to promote these effects included distortions of perception with sensory delusions, and heightened sensory receptiveness including antalgesic impressions of surgery; autonomic and visceral arousal greater than control or placebo levels; lack of overt behavioral signals of distress due to depersonalization; and time disintegration leading to fear-inducing misinformation about real surgical events. Introverted subjects who generally were inclined to rely on drug solutions to their problems tended to respond poorly to surgical pain and anxiety with delta9THC. These results, obtained from subjects considered to have levels of presurgical apprehension that were average or below average, suggest that the environment in which high doses of cannabinols are experienced is a potent factor in determining the quality of the emotional response. A surgical environment containing even the mild stress of outpatient oral surgery appears to have the potential to precipitate undesirable emotional responses among cannabinol-intoxicated patients. There is continued high-level social use of cannabinols inour society, with an estimate of 40% to 55% among the college-age group seen frequently by oral surgeons. Results of this study suggest that clinicians should be prepared to detect the subtle signs of marijuana intoxication to protect their patients from further psychophysiologic complications during surgery.

  1. Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.

    PubMed

    Stewart, Jennifer L; McMahon, Lance R

    2010-07-01

    Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Delta(9)-tetrahydrocannabinol (Delta(9)-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receiving chronic Delta(9)-THC (1 mg/kg/12 h s.c.) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) under a fixed ratio schedule of stimulus-shock termination. The discriminative stimulus effects of rimonabant were dose-dependent (ED(50) = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Delta(9)-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Delta(9)-THC treatment resulted in increased responding on the rimonabant lever, head shaking, and activity during the dark cycle. The rimonabant discriminative stimulus was attenuated fully by Delta(9)-THC (at doses larger than mg/kg/12 h) and the cannabinoid agonist CP 55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and partially by the cannabinoid agonist WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the alpha(2)-adrenergic agonist clonidine. In contrast, a benzodiazepine (diazepam) and monoamine agonist (cocaine) did not attenuate the rimonabant discriminative stimulus. Head shaking was attenuated by all test compounds. These results show that the discriminative stimulus effects of rimonabant in Delta(9)-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest

  2. Differential role of the nitric oxide pathway on delta(9)-THC-induced central nervous system effects in the mouse.

    PubMed

    Azad, S C; Marsicano, G; Eberlein, I; Putzke, J; Zieglgänsberger, W; Spanagel, R; Lutz, B

    2001-02-01

    This study investigated whether the nitric oxide pathway was involved in the central effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of cannabis sativa. Body temperature, nociception and locomotion were measured in neuronal nitric oxide synthase (nNOS) knock-out (KO) mice and wild-type (WT) controls after intraperitoneal application of Delta(9)-THC. These Delta(9)-THC-induced effects are known to be mediated through the brain-type cannabinoid receptor 1 (CB1). Therefore, in situ hybridization (ISH) experiments were performed in the adult murine brain to determine possible changes in CB1 mRNA levels in nNOS-KO, compared with WT mice, and to reveal brain areas where CB1 and nNOS were coexpressed in the same neurons. We found that an intraperitoneal injection of 10 mg/kg Delta(9)-THC led to the same increase in the hot plate latencies in both genotypes, suggesting that Delta(9)-THC-mediated antinociception does not involve nNOS. In contrast, a significant Delta(9)-THC-induced decrease of body temperature and locomotor activity was only observed in WT, but not in nNOS-KO mice. ISH revealed significantly lower levels of CB1 mRNA in the ventromedial hypothalamus (VMH) and the caudate putamen (Cpu) of the nNOS-KO animals, compared with WT mice. Both areas are known to be among the regions involved in cannabinoid-induced thermoregulation and decrease of locomotion. A numerical evaluation of nNOS/CB1 coexpression showed that approximately half of the nNOS-positive cells in the dorsolateral Cpu also express low levels of CB1. ISH of adjacent serial sections with CB1 and nNOS, revealed expression of both transcripts in VMH, suggesting that numerous nNOS-positive cells of VMH coexpress CB1. Our findings indicate that the nitric oxide pathway is involved in some, but not all of the central effects of Delta(9)-THC.

  3. Tissue glutathione levels in mice treated with delta-9-tetrahydrocannabinol.

    PubMed

    Husain, S; Ahmed, K M

    1991-11-01

    Glutathione (GSH) is widely distributed among living cells and is involved in many biological functions. It provides the sulfhydryl groups for conjugation of toxic metabolites of several xenobiotica. Acetaminophen (Tylenol) toxicity is a classical example of this property. For this purpose, we studied the effects of delta-9-tetrahydrocannabinol (THC) on tissue levels of GSH in the mice. Groups of male Swiss Webster mice weighing 25 +/- 5 g were treated with 50 mg/kg, PO THC at 1300 h. Control mice were given equal volume of sesame oil (5 ml/kg, PO) which was the vehicle for THC. Ninety minutes following THC administration, mice were sacrificed, their plasma, brain, heart, liver, kidney and testis were collected. All tissues were homogenized in 5% TCA/EDTA solution and supernatant solutions of these homogenates were diluted. In these diluted samples, levels of GSH were determined by a modified spectrophotometric procedure and the GSH levels were expressed as micromoles of GSH/g tissue. In this study, THC caused no effects on GSH levels in brain, heart, testis and plasma. However, GSH levels in liver and kidney were decreased by 14% and 7% respectively. Although the decrease in kidney GSH levels were insignificant, these changes in liver and kidney could be indicative of a possible metabolic and/or dispositional interaction between THC and different commonly available drugs such as acetaminophen. PMID:1666916

  4. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana.

    PubMed

    Voth, E A; Schwartz, R H

    1997-05-15

    The use of crude marijuana for herbal medicinal applications is now being widely discussed in both the medical and lay literature. Ballot initiatives in California and Arizona have recently made crude marijuana accessible to patients under certain circumstances. As medicinal applications of pure forms of delta-9-tetrahydrocannabinol (THC) and crude marijuana are being considered, the most promising uses of any form of THC are to counteract the nausea associated with cancer chemotherapy and to stimulate appetite. We evaluated the relevant research published between 1975 and 1996 on the medical applications, physical complications, and legal precedents for the use of pure THC or crude marijuana. Our review focused on the medical use of THC derivatives for nausea associated with cancer chemotherapy, glaucoma, stimulation of appetite, and spinal cord spasticity. Despite the toxicity of THC delivered in any form, evidence supports the selective use of pure THC preparations to treat nausea associated with cancer chemotherapy and to stimulate appetite. The evidence does not support the reclassification of crude marijuana as a prescribable medicine.

  5. Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum.

    PubMed

    Bossong, Matthijs G; van Berckel, Bart N M; Boellaard, Ronald; Zuurman, Lineke; Schuit, Robert C; Windhorst, Albert D; van Gerven, Joop M A; Ramsey, Nick F; Lammertsma, Adriaan A; Kahn, René S

    2009-02-01

    The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Delta 9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D(2)/D(3) receptor tracer [(11)C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [(11)C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia. PMID:18754005

  6. Delta-9-Tetrahydrocannabinol-Induced Dopamine Release as a Function of Psychosis Risk: 18F-Fallypride Positron Emission Tomography Study

    PubMed Central

    Kuepper, Rebecca; Ceccarini, Jenny; Lataster, Johan; van Os, Jim; van Kroonenburgh, Marinus; van Gerven, Joop M. A.; Marcelis, Machteld; Van Laere, Koen; Henquet, Cécile

    2013-01-01

    Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis. PMID:23936196

  7. Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Delta9-tetrahydrocannabinol.

    PubMed

    McMahon, Lance R

    2006-12-01

    Cannabinoid CB(1) receptors are hypothesized to mediate the discriminative stimulus effects of cannabinoids. This study characterized a Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.1 mg/kg i.v.) discriminative stimulus and examined antagonism of cannabinoid agonists in rhesus monkeys. High levels of responding on the Delta(9)-THC lever were produced by cannabinoid agonists with the following rank order potency: CP 55940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol] > Delta(9)-THC = WIN 55212-2 [(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt] > arachidonylcyclopropylamide = (R)-methanandamide. A CB(2)-selective agonist, AM 1241 [(R)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole], and noncannabinoids (cocaine, ketamine, midazolam, and morphine) did not produce high levels of Delta(9)-THC lever responding. The CB(1)-selective antagonist SR 141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] surmountably antagonized the discriminative stimulus effects of Delta(9)-THC and CP 55940, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.1 and 6.7, respectively). SR 141716A surmountably antagonized WIN 55212-2; however, larger doses disrupted responding, precluding Schild analysis. The CB(1)-selective antagonist AM 251 surmountably antagonized Delta(9)-THC, CP 55940, and WIN 55212-2, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.3, 6.1, and 6.2, respectively). The CB(2)-selective antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] did not modify the Delta(9)-THC discriminative stimulus. These results demonstrate that the discriminative stimulus effects of Delta(9)-THC are

  8. Delta(9)-tetrahydrocannabinol increases endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons: involvement of CB(1) receptors.

    PubMed

    Tomasini, Maria Cristina; Ferraro, Luca; Bebe, Berta Wonjie; Tanganelli, Sergio; Cassano, Tommaso; Cuomo, Vincenzo; Antonelli, Tiziana

    2002-05-15

    The effects of the principal psychoactive component of marijuana, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), on endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons were investigated. Locally applied Delta(9)-THC (0.03, 3, 300, and 1,000 nM) concentration-dependently increased basal extracellular glutamate levels (+18% +/- 11%, +54% +/- 10%, +90% +/- 14%, +149% +/- 33% vs. basal). The facilitatory effects of Delta(9)-THC (3 and 300 nM) on cortical glutamate were fully counteracted in the presence of the selective CB(1) receptor antagonist SR141716A (10 nM) and by replacement of the normal Krebs-Ringer bicarbonate buffer with a low-Ca(2+) (0.2 mM) medium. Delta(9)-THC application also induced an enhancement in K(+)-evoked glutamate levels. These findings suggest that an increase in cortical glutamatergic transmission mediated by local CB(1) receptor activation may underlie some of the psychoactive and behavioral effects of acute marijuana consumption.

  9. [Allergenic character of tetrahydrocannabinol (delta 9 THC), active principle of Indian hemp (Cannabis saliva var. indica)].

    PubMed

    Lecorsier, A; Hoellinger, H; Nguyen-Hoang-Nam; Fournier, E

    1977-11-28

    The maximization test applied on the Hartley Guinea Pig and the mast cell degranulation test performed on the sensibilised Guinea Pig serum resulted in: 1, extreme allergenicity; 2, the formation of circulating antibodies anti delta9 THC. PMID:414851

  10. Comparison of the discriminative stimulus properties of delta9-THC and psilocybin in rats.

    PubMed

    Greenberg, I; Kuhn, D; Appel, J B

    1975-01-01

    Male albino rats were trained to respond differentially on the left or right lever in a 2-lever chamber on the basis of which drug had been given intra-peritoneally (IP) 30 min before experimentation. In 1 group 1.9 mg/kg of delta9-THC and control injections (vehicle) served as the discriminative stimuli associated with each lever and in another group the drug stimuli were 1.0 mg/kg of delta9-THC and 1.0 mg/kg of psilocybin. The results confirmed those of other experiments using different procedures; that delta9-THC can acquire discriminative control over responding. The fact that delta9-THC and psilocybin were also found to differentially control lever choice demonstrates that these 2 drugs probably produce discriminably different states in rats. PMID:1208637

  11. Blunting of the HPA-axis underlies the lack of preventive efficacy of early post-stressor single-dose Delta-9-tetrahydrocannabinol (THC).

    PubMed

    Mayer, Tzur Alexander; Matar, Michael Alex; Kaplan, Zeev; Zohar, Joseph; Cohen, Hagit

    2014-07-01

    The therapeutic value of Delta-9-tetrahydrocannabinol9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Δ9-THC administered intraperitoneally following exposure to psychogenic stress. Animals were exposed to predator scent stress and treated 1h later with Δ9-THC (1, 5 and 10mg/kg) or vehicle. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 1, 6 and 24 h or 7 days after exposure and freezing behavior upon exposure to a trauma cue on day 8. Pre-set cut-off behavioral criteria classified exposed animals as those with "extreme," "minimal" or "intermediate" (partial) response. Circulating corticosterone levels were assessed over 2h after exposure with and without Δ9-THC. The behavioral effects of a CB1 antagonist (AM251) administered systemically 1h post exposure were evaluated. In the short term (1-6 h), 5 mg/kg of Δ9-THC effectively attenuated anxiety-like behaviors. In the longer-term (7 days), it showed no effect in attenuating PTSD-like behavioral stress responses, or freezing response to trauma cue. Δ9-THC significantly decreased corticosterone levels. In contrast, administration of AM251 (a CB1 antagonist/inverse agonist) 1 h post exposure attenuated long-term behavioral stress responses through activation of the HPA-axis. The demonstrated lack of preventive efficacy of early Δ9-THC treatment and reports of its anxiogenic effects in many individuals raises doubts not only regarding its potential clinical value, but also the advisability of clinical trials. The endocannabinoids exert complex effects on behavioral responses mediating glucocorticoid effects on memory of traumatic experiences.

  12. Determination of delta9-tetrahydrocannabinol in indoor air as an indicator of marijuana cigarette smoking using adsorbent sampling and in-injector thermal desorption gas chromatography-mass spectrometry.

    PubMed

    Chou, Su-Lien; Ling, Yong-Chien; Yang, Mo-Hsiung; Pai, Chung-Yen

    2007-08-13

    The marijuana leaves are usually mixed with tobaccos and smoked at amusement places in Taiwan. Recently, for investigation-legal purposes, the police asked if we can identify the marijuana smoke in a KTV stateroom (a private room at the entertainment spot for singing, smoking, alcohol drinking, etc.) without marijuana residues. A personal air-sampler pump fitted with the GC liner-tube packed with Tenax-TA adsorbent was used for air sampling. The GC-adsorbent tube was placed in the GC injector port and desorbed directly, followed by GC-MS analysis for the determination of delta9-tetrahydrocannabinol (delta9-THC) in indoor air. The average desorption efficiency and limit of detection for delta9-THC were 89% and 0.1 microg m(-3), respectively, approximately needing 1.09 mg of marijuana leaves smoked in an unventilated closed room (3.0 m x 2.4 m x 2.7 m) to reach this level. The mean delta9-THC contained in the 15 marijuana plants seized from diverse locations was measured to be 0.32%. The delta9-THC in room air can be successfully identified from mock marijuana cigarettes, mixtures of marijuana and tobacco, and an actual case. The characteristic delta9-THC peak in chromatogram can serve as the indicator of marijuana. Positive result suggests marijuana smoking at the specific scene in the recent past, facilitating the formulation of further investigation.

  13. Teratologic evaluation of delta9-tetrahydrocannabinol in mice, including a review of the literature.

    PubMed

    Fleischman, R W; Hayden, D W; Rosenkrantz, H; Braude, M C

    1975-08-01

    Pregnant CD1 mice received 5, 15, 50, 150 mg/kg/day of delta9-THC in sesame oil on days 6-15 of gestation orally by gavage and were killed about one day before expected delivery. Treatment had no effect on the maternal weight gain, prenatal mortality rate, fetal weight, and the frequency of gross external, internal, and skeletal abnormalities.

  14. Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to {delta}{sup 9}-tetrahydrocannabinol

    SciTech Connect

    Economidou, Daina; Mattioli, Laura; Ubaldi, Massimo; Lourdusamy, Anbarasu; Soverchia, Laura; Hardiman, Gary; Campolongo, Patrizia; Cuomo, Vincenzo; Ciccocioppo, Roberto

    2007-08-15

    The present study evaluated the consequences of perinatal {delta}{sup 9}-tetrahydrocannabinol ({delta}{sup 9}-THC) treatment (5 mg/kg/day by gavage), either alone or combined with ethanol (3% v/v as the only fluid available), on ethanol self-administration and alcohol-seeking behavior in rat adult offspring. Furthermore, the effect of the selective cannabinoid CB{sub 1} receptor antagonist, SR-141716A, on ethanol self-administration and on reinstatement of ethanol-seeking behavior induced either by stress or conditioned drug-paired cues was evaluated in adult offspring of rats exposed to the same perinatal treatment. Lastly, microarray experiments were conducted to evaluate if perinatal treatment with {delta}{sup 9}-tetrahydrocannabinol, ethanol or their combination causes long-term changes in brain gene expression profile in rats. The results of microarray data analysis showed that 139, 112 and 170 genes were differentially expressed in the EtOH, {delta}{sup 9}-THC, or EtOH + {delta}{sup 9}-THC group, respectively. No differences in alcohol self-administration and alcohol seeking were observed between rat groups. Intraperitoneal (IP) administration of SR-141716A (0.3-3.0 mg/kg) significantly reduced lever pressing for ethanol and blocked conditioned reinstatement of alcohol seeking. At the same doses SR-141716A failed to block foot-shock stress-induced reinstatement of alcohol seeking. The results reveal that perinatal exposure to {delta}{sup 9}-THC ethanol or their combination results in evident changes in gene expression patterns. However, these treatments do not significantly affect vulnerability to ethanol abuse in adult offspring. On the other hand, the results obtained with SR-141716A emphasize that endocannabinoid mechanisms play a major role in ethanol self-administration, as well as in the reinstatement of ethanol-seeking behavior induced by conditioned cues, supporting the idea that cannabinoid CB{sub 1} receptor antagonists may represent interesting

  15. Development of fluoroimmunoassay methods for delta-9-tetrahydrocannabinol

    SciTech Connect

    Mason, A.P.

    1986-01-01

    Heterogeneous, competitive, labelled-ligand solid-phase primary antibody fluoroimmunoassay methods for the detection of THC in blood and plasma were proposed, and the required assay components were produced and characterized. These components included polyclonal rabbit antisera and monoclonal antibodies reactive with tetrahydrocannabinols, solid-phase immunoglobin reagents, a fluoroligand, and protein conjugates of THC for immunization and immunoassay response amplification. The stereoselective rabbit anti-THC antiserum F-444-12 was found to have a high binding titer, a high affinity (K/sub D/ = 3.4 x 10/sup -/exclamation/sup 1/ M for 5'-iodo/sup -125/I-..delta../sup 2/-THC), and high specificity versus a large number of cannabinoid compounds. Immobilization of the immunoglobulin fraction of the antiserum on hydrophilic polyacrylamide microspheres resulted in only a four fold increase in K/sub D/, and a two fold increase in the concentration of binding sites required for the production of equivalent binding titers. Specificity for small ligands was not affected, but the binding of THC-protein conjugates was reduced in potency. Two monoclonal hybridoma cell lines were produced that secrete monoclonal antibodies which bind the radioligand. The fluoroligand was synthesized from 5'-carboxy-..delta../sup 2/-THC and FITC using a diamimoethane linkage structure. While the compound had the fluorescence properties of FTIC, it was bound to the antiserum F-144-12 with a cross-reactive potency 1.4x greater than the radioligand, and 10x greater than THC.

  16. A comparison of the apoptotic effect of Delta(9)-tetrahydrocannabinol in the neonatal and adult rat cerebral cortex.

    PubMed

    Downer, Eric J; Gowran, Aoife; Campbell, Veronica A

    2007-10-17

    The maternal use of cannabis during pregnancy results in a number of cognitive deficits in the offspring that persist into adulthood. The endocannabinoid system has a role to play in neurodevelopmental processes such as neurogenesis, migration and synaptogenesis. However, exposure to phytocannabinoids, such as Delta(9)-tetrahydrocannabinol, during gestation may interfere with these events to cause abnormal patterns of neuronal wiring and subsequent cognitive impairments. Aberrant cell death evoked by Delta(9)-tetrahydrocannabinol may also contribute to cognitive deficits and in cultured neurones Delta(9)-tetrahydrocannabinol induces apoptosis via the CB(1) cannabinoid receptor. In this study we report that Delta(9)-tetrahydrocannabinol (5-50 microM) activates the stress-activated protein kinase, c-jun N-terminal kinase, and the pro-apoptotic protease, caspase-3, in in vitro cerebral cortical slices obtained from the neonatal rat brain. The proclivity of Delta(9)-tetrahydrocannabinol to impact on these pro-apoptotic signalling molecules was not observed in in vitro cortical slices obtained from the adult rat brain. In vivo, subcutaneous administration of Delta(9)-tetrahydrocannabinol (1-30 mg/kg) activated c-jun N-terminal kinase, caspase-3 and cathepsin-D, and induced DNA fragmentation in the cerebral cortex of neonatal rats. In contrast, in vivo administration of Delta(9)-tetrahydrocannabinol to adult rats was not associated with the apoptotic pathway in the cerebral cortex. The data provide evidence which supports the hypothesis that the neonatal rat brain is more vulnerable to the neurotoxic influence of Delta(9)-tetrahydrocannabinol, suggesting that the cognitive deficits that are observed in humans exposed to marijuana during gestation may be due, in part, to abnormal engagement of the apoptotic cascade during brain development.

  17. Simplified analysis of 11-hydroxy-delta-9-tetrahydrocannabinol and 11-carboxy-delta-9-tetrahydrocannabinol in human meconium: method development and validation.

    PubMed

    Tynon, Marykathryn; Porto, Marcellino; Logan, Barry K

    2015-01-01

    We describe the development of a sensitive analytical method for the analysis of 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-delta-9-tetrahydrocannabinol (THCC) in meconium using a gas chromatography-mass spectrometry (GC/MS) platform. The method was validated according to protocols, which included assessment of accuracy, precision, robustness, stability in meconium and in-process stability, interference and sensitivity and specificity. The method consists of a solid phase extraction with alkaline hydrolysis and derivatization of the analytes with N, O-Bis(trimethylsilyl)trifluoroacteamide, followed by GC/MS analysis using selected ion monitoring. The method uses deuterated internal standards for both analytes. Calibration curves had r(2) values >0.998, and extraction efficiency was determined to be 84.7% for THCC and 78.6% for 11-OH-THC. The detection limit for both analytes was 5 ng/g. This confirmatory method was successfully applied to 183 meconium samples that had screened positive by enzyme-linked immunosorbent assay, and 67.2% were confirmed for THCC, and 2.2% were confirmed positive for 11-OH-THC. The mean (SD) and median (range) THCC (n = 123) concentrations detected were 55.0 ng/g (±59.0) and 33.75 ng/g (5-265 ng/g), while the mean and median (range) for 11-OH-THC (n = 4) concentrations were 8.25 ng/g (±4.71) and 6.5 ng/g (5-15 ng/g). PMID:25315472

  18. Simplified analysis of 11-hydroxy-delta-9-tetrahydrocannabinol and 11-carboxy-delta-9-tetrahydrocannabinol in human meconium: method development and validation.

    PubMed

    Tynon, Marykathryn; Porto, Marcellino; Logan, Barry K

    2015-01-01

    We describe the development of a sensitive analytical method for the analysis of 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-delta-9-tetrahydrocannabinol (THCC) in meconium using a gas chromatography-mass spectrometry (GC/MS) platform. The method was validated according to protocols, which included assessment of accuracy, precision, robustness, stability in meconium and in-process stability, interference and sensitivity and specificity. The method consists of a solid phase extraction with alkaline hydrolysis and derivatization of the analytes with N, O-Bis(trimethylsilyl)trifluoroacteamide, followed by GC/MS analysis using selected ion monitoring. The method uses deuterated internal standards for both analytes. Calibration curves had r(2) values >0.998, and extraction efficiency was determined to be 84.7% for THCC and 78.6% for 11-OH-THC. The detection limit for both analytes was 5 ng/g. This confirmatory method was successfully applied to 183 meconium samples that had screened positive by enzyme-linked immunosorbent assay, and 67.2% were confirmed for THCC, and 2.2% were confirmed positive for 11-OH-THC. The mean (SD) and median (range) THCC (n = 123) concentrations detected were 55.0 ng/g (±59.0) and 33.75 ng/g (5-265 ng/g), while the mean and median (range) for 11-OH-THC (n = 4) concentrations were 8.25 ng/g (±4.71) and 6.5 ng/g (5-15 ng/g).

  19. Validated method for the simultaneous determination of Delta9-THC and Delta9-THC-COOH in oral fluid, urine and whole blood using solid-phase extraction and liquid chromatography-mass spectrometry with electrospray ionization.

    PubMed

    Teixeira, Helena; Verstraete, Alain; Proença, Paula; Corte-Real, Francisco; Monsanto, Paula; Vieira, Duarte Nuno

    2007-08-01

    A fully validated, sensitive and specific method for the extraction and quantification of Delta(9)-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Delta(9)-THC (THC-COOH) and for the detection of 11-hydroxy-Delta(9)-THC (11-OH THC) in oral fluid, urine and whole blood is presented. Solid-phase extraction and liquid chromatography-mass spectrometry (LC-MS) technique were used, with electrospray ionization. Three ions were monitored for THC and THC-COOH and two for 11-OH THC. The compounds were quantified by selected ion recording of m/z 315.31, 329.18 and 343.16 for THC, 11-OH THC and THC-COOH, respectively, and m/z 318.27 and 346.26 for the deuterated internal standards, THC-d(3) and THC-COOH-d(3), respectively. The method proved to be precise for THC and THC-COOH both in terms of intra-day and inter-day analysis, with intra-day coefficients of variation (CV) less than 6.3, 6.6 and 6.5% for THC in saliva, urine and blood, respectively, and 6.8 and 7.7% for THC-COOH in urine and blood, respectively. Day-to-day CVs were less than 3.5, 4.9 and 11.3% for THC in saliva, urine and blood, respectively, and 6.2 and 6.4% for THC-COOH in urine and blood, respectively. Limits of detection (LOD) were 2 ng/mL for THC in oral fluid and 0.5 ng/mL for THC and THC-COOH and 20 ng/mL for 11-OH THC, in urine and blood. Calibration curves showed a linear relationship for THC and THC-COOH in all samples (r(2)>0.999) within the range investigated. The procedure presented here has high specificity, selectivity and sensitivity. It can be regarded as an alternative method to GC-MS for the confirmation of positive immunoassay test results, and can be used as a suitable analytical tool for the quantification of THC and THC-COOH in oral fluid, urine and/or blood samples.

  20. GC-MS analysis of the total delta9-THC content of both drug- and fiber-type cannabis seeds.

    PubMed

    Ross, S A; Mehmedic, Z; Murphy, T P; Elsohly, M A

    2000-01-01

    A GC-MS method was performed to determine the total delta9-THC content in both drug- and fiber-type cannabis seeds. Drug-type seeds were found to contain much higher levels of delta9-THC (35.6-124 microg/g) than fiber (hemp) seeds (0-12 microg/g). The majority of delta9-THC was found to be located on the surface of the seeds. Approximately 90% of the total delta9-THC was removed by a simple, quick wash with chloroform. Washed drug-type seeds contained less than 10 microg/g. Separation of the seeds into the kernel and testa showed that the bulk of delta9-THC is located in the testa, mainly on the outside. The kernels of drug- and fiber-type cannabis seeds contained less than 2 and 0.5 microg delta9-THC/g seeds, respectively. Fluctuations in the delta9-THC content of different replicates of the same type of seeds could be the result of the degree of contamination on the outside of the seeds.

  1. Effect of diamorphine, delta 9-tetrahydrocannabinol and ethanol on intravenous cocaine disposition.

    PubMed

    Vadlamani, N L; Pontani, R B; Misra, A L

    1984-08-01

    The disposition of cocaine (1 mg kg-1) was altered by diamorphine (0.1 mg kg-1) and that of morphine (1 mg kg-1) was altered after their concurrent administration as a bolus i.v. injection to rats by cocaine, without any changes in the metabolism of the drugs. delta 9-Tetrahydrocannabinol (10 mg kg-1 i.p.) did not affect the cocaine disposition. Chronic ethanol treatment (2.5 g kg-1 orally twice daily for 16 days) produced a significantly higher brain-to-plasma cocaine concentration ratio than did saline as control, without any changes in cocaine metabolism. PMID:6148403

  2. Effects of low doses of alcohol on delta-9-tetrahydrocannabinol's effects in pregnant rats

    SciTech Connect

    Abel, E.L.; Subramanian, M.G. )

    1990-01-01

    Pregnant rats were intubated with 50 mg/kg of delta-9-tetrahydrocannabinol (THC) or with THC plus alcohol to determine if a low dose of alcohol would significantly increase blood levels of THC. On the basis of this study, a second study was conducted in which pregnant rats were intubated with THC plus alcohol from gestation day six to parturition. THC reduced birth weights but did not significantly affect litter size or passive avoidance learning. Alcohol did not have a significant effect on offspring birth weight nor did it interact with THC to affect offspring.

  3. Behavioral effects of prolonged administration of delta 9-tetrahydrocannabinol in the rat.

    PubMed

    Stiglick, A; Kalant, H

    1983-01-01

    Rats treated chronically with delta 9-tetrahydrocannabinol (THC, daily oral dose 20 mg/kg) were examined for residual effects on a variety of behaviors following a 1-4-month drug-free period. Learning a 12-arm radial maze and a differential reinforcement of low-rate responding (DRL-20) task was significantly retarded in THC-treated animals, although performance reached control levels by the end of testing. Learning two-way shuttle box avoidance was slightly facilitated in the drug-treated subjects. In open field tests THC-treated rats displayed an initial hypoactivity, followed by hyperactivity, but these changes were not significant. Most of the effects of THC resemble, but are weaker than those of chronic treatment with cannabis extract in a dose containing the same amount of THC. The findings are discussed in terms of the role of other constituents of cannabis that may add to, or potentiate the effects of THC itself.

  4. Marijuana effects on immunity: suppression of human natural killer cell activity of delta-9-tetrahydrocannabinol.

    PubMed

    Specter, S C; Klein, T W; Newton, C; Mondragon, M; Widen, R; Friedman, H

    1986-01-01

    Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, was tested for its ability to modulate human natural killer (NK) cell function. THC was toxic for peripheral blood lymphocytes at 20 micrograms/ml but not at 10 micrograms/ml or less. This component of marijuana also was inhibitory for NK activity against K562, a human tumor cell line at concentrations down to 5 micrograms/ml when pre-incubated with the effector cells. Suppression of NK function was dependent upon the concentration of THC and the length of time of pre-incubation but was independent of the ratio of effector to target cells. Prostaglandins were not involved in suppression of NK activity.

  5. Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats

    SciTech Connect

    Evans, E.B.; Seifen, E.; Kennedy, R.H.; Kafiluddi, R.; Paule, M.G.; Scallet, A.C.; Ali, S.F.; Slikker, W. Jr.

    1987-10-01

    This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)(/sup 3/H)dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.

  6. An investigation of the involvement of GABA in certain pharmacological effects of delta-9-tetrahydrocannabinol.

    PubMed

    Pertwee, R G; Browne, S E; Ross, T M; Stretton, C D

    1991-11-01

    Experiments were performed with mice to determine whether doses of the benzodiazepine, flurazepam, or the GABA uptake inhibitor, NO-328, known to potentiate catalepsy induced by delta-9-tetrahydrocannabinol (THC), would also interact synergistically with THC in the production of certain other effects. No synergism was detected either in the production of antinociception (tail flick test) or in a test in which the ability of flurazepam to delay onset of clonic convulsions induced by intravenous infusion of pentylenetetrazole was compared in the presence and absence of THC or cannabidiol. The hypothermic effect of THC was unaffected by NO-328 but enhanced by flurazepam, albeit only at doses higher than those needed to potentiate THC-induced catalepsy. In vitro experiments with guinea pig ileum showed that the ability of THC to inhibit electrically evoked contractions was unaffected by delta-amino-n-valeric acid, a GABA(B) receptor antagonist, and that preparations rendered tolerant to GABA responded normally to THC. Contractions induced by GABA in unstimulated ileal longitudinal muscle were attenuated by THC. We conclude that there is little evidence from our data that any of the THC effects studied were GABA mediated.

  7. The effect of delta 9-tetrahydrocannabinol and LSD on the acquisition of an active avoidance response in the rat.

    PubMed

    Waser, P G; Martin, A; Heer-Carcano, L

    1976-04-15

    The course of active avoidance learning of rats in a symmetrical Y-maze under the influence of 1, 3, and 9 mg/kg of delta 9-THC i.p., and 5, 20, and mug/kg of LSD was investigated. Delta-THC in a dosage of 1 mg/kg had no effect on avoidance learning. Three to a lesser extent 9 mg/kg produced more rapid learning with a significantly better performance. Learning under delta 9-THC proved to be state-dependent. The withdrawal of delta 9-THC caused a decrease in the avoidance rate, which was dependent on the dosage. Upon renewal of the THC doses, the animals reattained their earlier preformance. In the course of the experiment there was rapid tolerance development, especially of the sedative properties of THC. LSD retarded the rate of acquisition of the active avoidance response. Whereas the control animals displayed over 80% successful active avoidance from the 14th session onwards, this was achieved by the LSD groups only after the 20th session. However, in contrast to the control group the LSD animals were able to increase their avoidance rate to over 90%, and this was maintained to the end of the experiment (a total of 24 sessions with LSD). The sudden withdrawal of LSD produced a fall in avoidance rate, which was dependent on the pervious training dosage; as with delta 9-THC state-dependent learning can also be assumed for LSD.

  8. High-performance liquid chromatographic determination of delta9-tetrahydrocannabinol and the corresponding acid in hemp containing foods with special regard to the fluorescence properties of delta9-tetrahydrocannabinol.

    PubMed

    Zoller, O; Rhyn, P; Zimmerli, B

    2000-03-01

    A solvent programmed reversed-phase HPLC method with UV detection for the determination of delta9-tetrahydrocannabinol (THC) and delta9-tetrahydrocannabinolic acid A (THCA-A) in foods containing parts of hemp such as edible oil, herb-teas (infusion), herbal hemp or hempseed is presented. The THC peak is also detected by fluorescence. The detection limits with UV detection are 0.01 ng for THC and 0.05 ng for THCA-A and with fluorescence detection 0.1 ng for THC. The relative standard deviation under repeatability conditions of the chromatographic procedure is about 0.5% and that of the over-all analytical procedure for THC in vegetable oils 2% (concentration range of 10-100 mg/kg).

  9. Passive inhalation of marijuana smoke: urinalysis and room air levels of delta-9-tetrahydrocannabinol

    SciTech Connect

    Cone, E.J.; Johnson, R.E.; Darwin, W.D.; Yousefnejad, D.; Mell, L.D.; Paul, B.D.; Mitchell, J.

    1987-05-01

    In two separate studies, 5 drug-free male volunteers with a history of marijuana use were passively exposed to the sidestream smoke of 4 and 16 marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol (THC)) for 1 h each day for 6 consecutive days. A third study was similarly performed with 2 marijuana-naive subjects passively exposed to the smoke of 16 marijuana cigarettes. Passive smoke exposure was conducted in a small, unventilated room. Room air levels of THC and CO were monitored frequently. All urine specimens were collected and analyzed by EMIT d.a.u. assay, Abuscreen radioimmunoassay and GC/MS. The studies show that significant amounts of THC were absorbed by all subjects at the higher level of passive smoke exposure (eg., smoke from 16 marijuana cigarettes), resulting in urinary excretion of significant amounts of cannabinoid metabolites. However, it seems improbable that subjects would unknowingly tolerate the noxious smoke conditions produced by this exposure. At the lower level of passive marijuana-smoke exposure, specimens tested positive only infrequently or were negative. Room air levels of THC during passive smoke exposure appeared to be the most critical factor in determining whether a subject produced cannabinoid-positive urine specimens.

  10. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis.

    PubMed

    Morgan, Celia J A; Freeman, Tom P; Schafer, Gráinne L; Curran, H Valerie

    2010-08-01

    Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.

  11. Delta9-tetrahydrocannabinol suppresses macrophage costimulation by decreasing heat-stable antigen expression.

    PubMed

    Clements, D J; Matveyeva, M; McCoy, K L

    1998-08-01

    Delta9-tetrahydrocannabinol (THC) suppresses several immunologic functions of macrophages. The costimulatory activity of a THC-exposed macrophage hybridoma was investigated by its ability to elicit interleukin-2 secretion by a helper T cell hybridoma activated with immobilized monoclonal anti-CD3 antibody. THC added at culture initiation inhibited the T cell response in a dose-dependent manner. When the macrophages were fixed with paraformaldehyde before culture, THC had no effect on T cell stimulation. However, macrophages, which were preincubated with THC and then fixed, were impaired in delivering costimulatory signals to T cells cultured without THC. The drug's inhibitory effect on macrophage costimulatory activity was reversible. THC exposure also decreased macrophage expression of heat-stable antigen (HSA). Antibody blocking experiments showed that HSA expressed on the macrophages provided an important costimulatory signal, whereas B7-1 and B7-2 molecules had a minor role. Treatment of the macrophages with phosphatidylinositol-specific phospholipase C cleaved HSA, but not the transmembrane B7 molecules, from the cell surface. Similar to THC, enzyme treatment significantly diminished macrophage costimulatory activity, which was also reversible. After drug or enzyme removal, HSA expression returned to the control level by 4 h. Therefore, THC suppresses macrophage costimulatory activity by diminishing cell surface expression of HSA.

  12. Effects of chronic administration of delta-9-tetrahydrocannabinol on early embryogenesis of the mouse.

    PubMed

    Shinohara, O; Henrich, R T; Morishima, A

    1983-10-01

    The effects of chronic administration of delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marihuana, on embryogenesis were investigated in the mouse treated with THC prior to sexual maturation. The study was designed to imitate the prolonged abuse of marihuana by sexually immature and adolescent girls. Female Swiss-Webster mice were injected, intraperitoneally, with THC 5 mg/kg per day or with the vehicle for 21 consecutive days, starting on the 30th day of life, which is prior to their sexual maturation. The dose of THC was approximately equivalent to that absorbed by a man smoking 1 to 2 marihuana cigarettes per day. Superovulation was then induced, and the mice were mated with untreated males. Ova were recovered from the oviducts just prior to the first cleavage division, and at about the time of the second cleavage division. The incidence of degenerative ova increased from 13.6% in the controls to 19.1% in the THC-treated group (P less than 0.001) at the time of the second cleavage division, but there was no difference in the incidence of morphologically abnormal ova between the two groups just prior to the first cleavage division. The rate of successful completion of the first cleavage division, but not the second cleavage division, was adversely affected by THC, resulting in accumulation of morphologically abnormal ova at the later stage. In view of the known disruptive effect of THC on the process of cell division, it was postulated that THC might have adversely affected meiosis, leading to the inability of the ova to undergo the first cleavage division.

  13. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol.

    PubMed

    Vann, Robert E; Gamage, Thomas F; Warner, Jonathan A; Marshall, Ericka M; Taylor, Nathan L; Martin, Billy R; Wiley, Jenny L

    2008-04-01

    Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Delta(9)-tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC's effects by these other cannabinoids (e.g., cannabidiol (CBD)) has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC's abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC's discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios. PMID:18206320

  14. Papain adulteration in 11-nor-Delta9-tetrahydrocannabinol- 9-carboxylic acid-positive urine samples.

    PubMed

    Larson, Scott J; Holler, Justin M; Magluilo, Joseph; Dunkley, Christopher S; Jacobs, Aaron

    2008-01-01

    The adulteration of urine samples is an ongoing problem in forensic drug-testing laboratories, even in the military where the practice of observed collections is performed. These adulterants are used to produce a false-negative result when samples are analyzed for drugs of abuse. It has been reported that papain, a cysteine protease, could be successfully used as a urine adulterant, altering the concentration of 11-nor-Delta9-tetrahydrocannabinol-9- carboxylic acid (THCCOOH) in urine samples. The current study analyzes the effects of latex papain (Sigma, 10 mg/mL) and Lawry's Adolph's Meat Tenderizer (papain is an active ingredient, 10 mg/mL) on immunoassays (FPIA, EMIT, KIMS) and gas chromatography-mass spectrometry (GC-MS) analysis for biological samples. The samples were analyzed initially between 2 and 4 h and then at 1-, 3-, 7-, and 10-day time intervals after the addition of papain. A decrease in response averaged over the course of the study was observed with FPIA (Abbott, 22%) and EMIT (Syva) Dade Behring, 26%, Microgenics, 10%) screening assays by the addition of latex papain to the samples. An increase in response was found using the KIMS (Roche) assay (156% increase). In addition, the GC-MS results (27% decrease) demonstrate that papain affects both the screening and confirmation assays. The addition of meat tenderizer caused decrease in the FPIA (Abbott, 11%) screening assay and GC-MS results (22%) similar to the latex papain while having varied results on the other screening assays. This study confirms papain could be a potential problem for urine drug-testing programs. PMID:18652751

  15. An acute dose of delta 9-tetrahydrocannabinol affects behavioral and neurochemical indices of mesolimbic dopaminergic activity.

    PubMed

    Navarro, M; Fernández-Ruiz, J J; de Miguel, R; Hernández, M L; Cebeira, M; Ramos, J A

    1993-10-21

    Cannabinoid consumption has been reported to affect several neurotransmitter systems and their related behaviors. The present study has been designed to examine cannabinoid effects on certain behaviors, which have been currently located in the limbic forebrain, in parallel to their effects on mesolimbic dopaminergic neurons. To this end, male rats treated with an oral dose of delta 9-tetrahydrocannabinol (THC) or vehicle were used 1 h after treatment for two different behavioral tests or neurochemical analyses of mesolimbic dopaminergic activity. Treatments, behavioral tests and sacrifice were performed in the dark phase of photoperiod because it corresponds to the maximum behavioral expression in the rat. Behavioral tests were a dark-light emergence test, which allows measurements of emotional reactivity, and a socio-sexual approach behavior test, which allows measurements of sexual motivation and also of spontaneous and stereotypic activities. Neurochemical analyses consisted of measurements of dopamine (DA) and L-3,4-dihydroxyphenylacetic acid (DOPAC) contents, tyrosine hydroxylase activity, in vitro DA release and number and affinity of D1 receptors in the limbic forebrain. Results were as follows. THC exposure markedly altered the pattern executed by the animals in both tests. Concretely, THC-exposed animals exhibited a low number of visits to an incentive female in addition to high time spent in the vicinity of an incentive male, both observed in the socio-sexual approach behavior test, and an increased emergence latency to go out of a dark compartment in the dark-light emergence test. However, the fact that THC also decreased spontaneous activity and the frequency of rearing and self-grooming behaviors, in addition to the observations of either low total number of visits to both incentive sexual areas or high escape latency to go out of a light compartment, when the animal is placed in this compartment, also suggest the possible existence of an accompanying

  16. Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of delta 9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH)

    PubMed

    Huestis, M A; Henningfield, J E; Cone, E J

    1992-01-01

    Two mathematical models are described for the prediction of time of marijuana use from the analysis of a single plasma sample for cannabinoids. The models were derived from cannabinoid data obtained from a controlled clinical study of acute marijuana smoking. Model I was based on plasma delta 9-tetrahydrocannabinol (THC) concentrations and Model II was based on the ratio of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH) to THC in plasma. The two models were validated with cannabinoid data from nine published and unpublished clinical studies. The data included plasma samples obtained from infrequent and frequent marijuana smokers and after oral marijuana administration. Cannabinoid plasma concentrations had been determined by a variety of analytical methods. The accuracy of model prediction was evaluated by comparison of the predicted time of prior drug use to the actual time of exposure. Predictions of time of exposure were generally accurate but tended to overestimate time immediately after smoking and tended to underestimate later times. A second assessment of the validity of the models was made by determining if actual time of use was within the 95% confidence interval. Model I correctly predicted the time of exposure within the 95% confidence interval for 235 of 261 samples (90.0%), and Model II was correct in 232 of 260 samples (89.2%). These prediction models may be beneficial to forensic scientists in the interpretation of cannabinoid plasma levels.

  17. Stereodivergent total synthesis of Δ9-tetrahydrocannabinols.

    PubMed

    Schafroth, Michael A; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M

    2014-12-01

    All four stereoisomers of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same set of starting materials, selective access to the four stereoisomers of THC was achieved in five steps. PMID:25303495

  18. Stereodivergent total synthesis of Δ9-tetrahydrocannabinols.

    PubMed

    Schafroth, Michael A; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M

    2014-12-01

    All four stereoisomers of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same set of starting materials, selective access to the four stereoisomers of THC was achieved in five steps.

  19. In vivo metabolism of the methyl homologues of delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol and abn-delta-8-tetrahydrocannabinol in the mouse.

    PubMed

    Brown, N K; Harvey, D J

    1988-04-01

    Methyl-delta-8-tetrahydrocannabinol (methyl-delta-8-THC), methyl-delta-9-THC and abn-methyl-delta-8-THC were synthesized by condensation of orcinol and (1S)-cis-verbenol and were administered to male Charles River CD-1 mice. Extracted hepatic metabolites were isolated by chromatography on Sephadex LH-20 and examined by gas chromatography/mass spectrometry as trimethylsilyl (TMS), (2H9)TMS and methyl ester/TMS derivatives. In addition, metabolic fractions were reduced with lithium aluminium deuteride to convert carboxylic acids to alcohols for structural correlation. Metabolites from methyl-delta-8-THC were similar with respect to the positions substituted to those produced by higher homologues; the major metabolite was methyl-delta-8-THC-11-oic acid. abn-Methyl-delta-8-THC was metabolized in a different manner. The location of the aromatic methyl group at the position adjacent to ring fusion appeared to inhibit metabolism at C(11) to a considerable extent and also to reduce the amount of the resulting alcohol from being oxidized to a carboxylic acid. This caused other metabolic pathways to become dominant, with the result that a compound containing a hydroxy group at the gem-methyl position was the major metabolite. Hydroxylation at this position has not been confirmed with any other cannabinoid, although it is thought to result in trace concentrations of hydroxy metabolites from some compounds. Metabolism of methyl-delta-9-THC was also similar to that of the higher homologues, with the exception that less metabolism occurred at C(8) and a higher percentage of the total metabolic fraction was accounted for by the 11-oic acid metabolite. Minor metabolites were mainly dihydroxy compounds and hydroxylated derivatives of delta-9-THC-11-oic acid.

  20. Passive consumption of marijuana through milk: a low level chronic exposure to delta-9-tetrahydrocannabinol(THC).

    PubMed

    Ahmad, G R; Ahmad, N

    1990-01-01

    Cannabis sativa grows abundantly among other natural vegetation in the northern part of Pakistan. Buffalo, the common dairy animals of the region, are allowed to graze upon this vegetation. These animals ingest significant amounts of marijuana, which after absorption is metabolized into a number of psychoactive agents which are ultimately excreted through the urine and milk. This potentially contaminated milk is used by the people of the region. Depending upon the amount of milk ingested and the degree of contamination, the milk could result in a low to moderate level of chronic exposure to Delta-9-Tetrahydrocannabinol (THC) and other metabolites especially among the children raised on this milk. This research was conducted to investigate the extent of passive consumption of marijuana by the consumers of potentially contaminated milk. Urine and milk specimens were obtained from buffalo and were analyzed for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) which is a major metabolite for THC. The analysis was done by using gas chromatography/mass spectrometry. It was observed that during the months of June and July, 60 percent of the buffalo contained detectable levels of THC-COOH in their urine and 50 percent of these animals produced milk which was contaminated with THC or other metabolites. Analysis of the urine obtained from children with ages ranging from six months to 3 years, who were being raised on the milk from these animals, indicated that 29 percent of them had low levels of THC-COOH in their urine.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Sex-dimorphic psychomotor activation after perinatal exposure to (-)-delta 9-tetrahydrocannabinol. An ontogenic study in Wistar rats.

    PubMed

    Navarro, M; Rubio, P; Rodríguez de Fonseca, F

    1994-12-01

    The ontogeny and the adult expression of motor behaviors were studied in male and female rats born from mothers exposed to delta 9-tetrahydrocannabinol (THC, 5 mg/kg) during gestation and lactation. Perinatal exposure to THC increased both rearing and locomotor activities in males and females at immature preweanling ages (P-15 and P-20). These effects disappeared after ceasing THC exposure (postweaning ages), but they were observed again in adult (P-70) females. The effects appeared as persistently high motor activity in familiar environments, disappearing the characteristic habituation profile in locomotor and exploratory behaviors. In novel environment condition tests, adult (P-70) THC-exposed females, but not males, exhibited lower locomotor activity in the socio-sexual approach test, and an increase in the emergence latency in the dark-light emergence test. Additionally, animals of both sexes exposed to THC showed a increase in the time spent grooming measured in novelty conditions. These findings suggest that perinatal exposure to THC affects both the development and the adult expression of motor behaviors and it resulted in a sex-dimorphic psychomotor activation very similar to that observed after perinatal exposure to other drugs of abuse. A possible role of THC-induced pituitary-adrenal (PA) axis activation was also evaluated by measuring plasma corticosterone levels in adult animals perinatally exposed: THC-exposed females exhibit a clear increase of this adrenal hormone, whereas THC-exposed males displayed lower levels of this hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Sex-dimorphic psychomotor activation after perinatal exposure to (-)-delta 9-tetrahydrocannabinol. An ontogenic study in Wistar rats.

    PubMed

    Navarro, M; Rubio, P; Rodríguez de Fonseca, F

    1994-12-01

    The ontogeny and the adult expression of motor behaviors were studied in male and female rats born from mothers exposed to delta 9-tetrahydrocannabinol (THC, 5 mg/kg) during gestation and lactation. Perinatal exposure to THC increased both rearing and locomotor activities in males and females at immature preweanling ages (P-15 and P-20). These effects disappeared after ceasing THC exposure (postweaning ages), but they were observed again in adult (P-70) females. The effects appeared as persistently high motor activity in familiar environments, disappearing the characteristic habituation profile in locomotor and exploratory behaviors. In novel environment condition tests, adult (P-70) THC-exposed females, but not males, exhibited lower locomotor activity in the socio-sexual approach test, and an increase in the emergence latency in the dark-light emergence test. Additionally, animals of both sexes exposed to THC showed a increase in the time spent grooming measured in novelty conditions. These findings suggest that perinatal exposure to THC affects both the development and the adult expression of motor behaviors and it resulted in a sex-dimorphic psychomotor activation very similar to that observed after perinatal exposure to other drugs of abuse. A possible role of THC-induced pituitary-adrenal (PA) axis activation was also evaluated by measuring plasma corticosterone levels in adult animals perinatally exposed: THC-exposed females exhibit a clear increase of this adrenal hormone, whereas THC-exposed males displayed lower levels of this hormone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7701042

  3. Determination of delta 9-tetrahydrocannabinol from human saliva by tandem immunoaffinity chromatography--high-performance liquid chromatography.

    PubMed

    Kircher, V; Parlar, H

    1996-03-01

    Smoking or ingestion of cannabis causes cognitive, perceptual and behavioural changes, which are responsive for impaired performance in driving motor vehicles. In this paper a novel liquid chromatographic assay for the selective quantification of delta 9-tetrahydrocannabinol, the major indicator of a present cannabis intoxication in saliva, is described. The method involves a column-switching procedure and requires an extremely simple pre-treatment of the sample. Deproteinized saliva was directly injected into the chromatographic system. The clean-up and enrichment procedure was performed in an immunoaffinity column, followed by the transfer of the antigens to an octysilica analytical column. The immunoaffinity sorbent was obtained by covalent immobilization of specific antibodies on epoxy-activated silica. The mobile phase consisted of methanol-aqueous 0.15 mol/1 NaCl solution (elution programmed) and the analyte was detected by measuring the UV absorption at 220 nm. Using an injection volume of 4.5 ml (dilution 3:2, v/v) the limit of quantification was 20 ng/ml, at a signal-to-noise ratio of 5. Recoveries were estimated to be in the range of 70%. Both intra- and inter- day coefficients of variation were below 5%.

  4. Chronic Δ9-Tetrahydrocannabinol Administration May Not Attenuate Simian Immunodeficiency Virus Disease Progression in Female Rhesus Macaques

    PubMed Central

    Amedee, Angela M.; Nichols, Whitney A.; LeCapitaine, Nicole J.; Stouwe, Curtis Vande; Birke, Leslie L.; Lacour, Nedra; Winsauer, Peter J.

    2014-01-01

    Abstract Persons living with HIV/AIDS (PLWHA) frequently use cannabinoids, either recreationally by smoking marijuana or therapeutically (delta-9-tetrahydrocannabinol; Δ9-THC dronabinol). Previously, we demonstrated that chronic Δ9-THC administration decreases early mortality in male simian immunodeficiency virus (SIV)-infected macaques. In this study, we sought to examine whether similar protective effects resulted from chronic cannabinoid administration in SIV-infected female rhesus macaques. Clinical and viral parameters were evaluated in eight female rhesus macaques that received either Δ9-THC (0.18–0.32 mg/kg, intramuscularly, twice daily) or vehicle (VEH) starting 28 days prior to intravenous inoculation with SIVmac251. SIV disease progression was assessed by changes in body weight, mortality, viral levels in plasma and mucosal sites, and lymphocyte subsets. In contrast to our results in male animals, chronic Δ9-THC did not protect SIV-infected female rhesus macaques from early mortality. Markers of SIV disease, including viral load and CD4+/CD8+ ratio, were not altered by Δ9-THC compared to control females; however, females that received chronic Δ9-THC did not gain as much weight as control animals. In addition, Δ9-THC administration increased total CXCR4 expression in both peripheral and duodenal CD4+ and CD8+ T lymphocytes prior to SIV inoculation. Although protection from early mortality was not evident, chronic Δ9-THC did not affect clinical markers of SIV disease progression. The contrasting effects of chronic Δ9-THC in males versus females remain to be explained, but highlight the need for further studies to explore the sex-dependent effects of Δ9-THC and other cannabinoids on the HIV disease course and their implications for virus transmission. PMID:25113915

  5. Metabolomics of Δ9-tetrahydrocannabinol: implications in toxicity.

    PubMed

    Dinis-Oliveira, Ricardo Jorge

    2016-01-01

    Cannabis sativa is the most commonly used recreational drug, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) being the main addictive compound. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic effects. The pharmacokinetics of Δ(9)-THC is dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. This review aims to discuss metabolomics of Δ(9)-THC, namely by presenting all known metabolites of Δ(9)-THC described both in vitro and in vivo, and their roles in the Δ(9)-THC-mediated toxic effects. Since medicinal use is increasing, metabolomics of Δ(9)-THC will also be discussed in order to uncover potential active metabolites that can be made available for this purpose. PMID:26828228

  6. Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults.

    PubMed

    Nicholson, Anthony N; Turner, Claire; Stone, Barbara M; Robson, Philip J

    2004-06-01

    The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Delta-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC. PMID:15118485

  7. Gonadal hormones do not alter the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol in adult rats

    PubMed Central

    Wakley, Alexa A; Wiley, Jenny L; Craft, Rebecca M

    2015-01-01

    The purpose of this study was to determine whether sex differences in the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) are due to activational effects of gonadal hormones. Rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX). GDX females received no hormone replacement (GDX+0), estradiol (GDX+E2), progesterone (GDX+P4), or both (GDX+E2/P4). GDX male rats received no hormone (GDX+0) or testosterone (GDX+T). Two weeks later, antinociceptive potency of THC was determined (pre-chronic test) on the warm water tail withdrawal and paw pressure assays. Vehicle or a sex-specific THC dose (females, 5.7 mg/kg, males, 9.9 mg/kg) was administered twice-daily for 9 days, then the THC dose-effect curves were re-determined (post-chronic test). On the pre-chronic test (both assays), THC was more potent in sham-GDX females than males, and gonadectomy did not alter this sex difference. In GDX females, P4 significantly decreased THC’s antinociceptive potency, whereas E2 had no effect. In GDX males, T did not alter THC’s antinociceptive potency. After chronic THC treatment, THC’s antinociceptive potency was decreased more in sham-GDX females than males, on the tail withdrawal test; this sex difference in tolerance was not altered in GDX or hormone-treated groups. These results suggest that greater antinociceptive tolerance in females, which occurred despite females receiving 40% less THC than males, is not due to activational effects of gonadal hormones. PMID:25863271

  8. Acute delta 9-tetrahydrocannabinol exposure alters Ca2+ ATPase activity in neuroendocrine and gonadal tissues in mice.

    PubMed

    Dalterio, S L; Bernard, S A; Esquivel, C R

    1987-05-01

    Acute administration of delta 9-tetrahydrocannabinol (THC) (50 mg/kg) at puberty (35-40 days) significantly (P less than 0.05) reduced Ca2+ ATPase activity in hypothalamic plasma membranes but increased, although not significantly, enzyme activity in hypothalamic tissue obtained from adult mice. In contrast, testicular Ca2+ ATPase activity was increased in pubertal THC-treated males, and significantly reduced in adults. Pituitary Ca2+ ATPase activity exhibited a dose-related decrease after acute THC administration at 0.5, 5 or 50 mg/kg, but there were no differential effects of age. Pituitary plasma membranes obtained from THC-treated males did not respond to in vitro exposure to luteinizing hormone releasing hormone (LHRH, 10(-7) M) with the marked reduction (approximately 40%) in Ca2+ ATPase activity observed in pituitaries from oil-treated controls. In addition, effects of THC appear specific for Ca2+ ATPase activity, since Mg2+ ATPase and Na+/K+ ATPase activities were not affected. These findings indicate that acute in vivo administration of THC influences Ca2+ membrane transport, in particular Ca2+ ATPase activity. These effects occur at each level of the hypothalamic-pituitary-gonadal (HPG) axis, are related to dose and developmental age at exposure, and also appear specific for Ca2+-dependent ATPase activity. Furthermore, THC exposure modulates pituitary sensitivity to LHRH receptor-mediated effects on Ca2+ ATPase activity. Therefore, effects on Ca2+ membrane transport may be involved in acute THC actions on hormonal activity at these HPG sites.

  9. Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats.

    PubMed

    Zamberletti, Erica; Gabaglio, Marina; Prini, Pamela; Rubino, Tiziana; Parolaro, Daniela

    2015-12-01

    Over 180 million people consume cannabis globally. Cannabis use peaks during adolescence with a trend for continued consumption by adults. Notably, several studies have shown that long-term and heavy cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders, although the neurobiological mechanisms underlying this association remain largely unknown. In this study, we evaluated whether, in female rats, chronic administration of increasing doses of the psychotropic plant-derived cannabis constituent, delta-9-tetrahydrocannabinol (THC), during adolescence (PND 35-45) could affect microglia function in the long-term. Furthermore, we explored a possible contribution of microglia to the development of THC-induced alterations in mood and cognition in adult female rats. Present data indicate that adolescent THC administration induces a persistent neuroinflammatory state specifically localized within the adult prefrontal cortex (PFC), characterized by increased expression of the pro-inflammatory markers, TNF-α, iNOS and COX-2, and reduction of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with down-regulation of CB1 receptor on neuronal cells and up-regulation of CB2 on microglia cells, conversely. Interestingly, blocking microglia activation with ibudilast during THC treatment significantly attenuates short-term memory impairments in adulthood, simultaneously preventing the increases in TNF-α, iNOS, COX-2 levels as well as the up-regulation of CB2 receptors on microglia cells. In contrast, THC-induced depressive-like behaviors were unaffected by ibudilast treatment. Our findings demonstrate that adolescent THC administration is associated with persistent neuroinflammation within the PFC and provide evidence for a causal association between microglial activation and the development long-term cognitive deficits induced by adolescent THC treatment.

  10. Maternal exposure to low doses of delta9-tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring.

    PubMed

    Rubio, P; Rodríguez de Fonseca, F; Martín-Calderón, J L; Del Arco, I; Bartolomé, S; Villanúa, M A; Navarro, M

    1998-11-01

    The possible existence of an increased susceptibility to the reinforcing properties of morphine was analyzed in male and female rats born from mothers exposed to delta9-tetrahydrocannabinol (THC, 1, 5, or 20 mg/kg) during gestation and lactation. Maternal exposure to low doses of THC (1 and 5 mg/kg), relevant for human consumption, resulted in an increased response to the reinforcing effects of a moderate dose of morphine (350 microg/kg), as measured in the place-preference conditioning paradigm (CPP) in the adult male offspring. These animals also displayed an enhanced exploratory behavior in the defensive withdrawal test. However, only females born from mothers exposed to THC 1 mg/kg exhibited a small increment in the place conditioning induced by morphine. The possible implication of the hypothalamo-pituitary-adrenal axis (HPA) was analyzed by monitoring plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in basal and moderate-stress conditions (after the end of the CPP test). Female offspring perinatally exposed to THC (1 or 5 mg/kg) displayed high basal levels of corticosterone and a blunted adrenal response to the HPA-activating effects of the CPP test. However, male offspring born from mothers exposed to THC (1 or 5 mg/kg) displayed the opposite pattern: normal to low basal levels of corticosterone, and a sharp adrenal response to the CPP challenge. The present study reveals that maternal exposure to low doses of THC results in an increased sensitivity to the reinforcing effects of morphine in the adult male offspring, and in sexually dimorphic behavioral and endocrine alterations in the adaptative responses to stressors such as novelty or place-preference testing. These results support the growing evidence of the importance of monitoring the long-term consequences of maternal consumption of cannabis derivatives.

  11. Despite strong behavioral disruption, Delta9-tetrahydrocannabinol does not affect cell proliferation in the adult mouse dentate gyrus.

    PubMed

    Kochman, Linda J; dos Santos, Angela Amancio; Fornal, Casimir A; Jacobs, Barry L

    2006-10-01

    Marijuana is a widely abused illicit drug known to cause significant cognitive impairments. Marijuana has been hypothesized to target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana's more subtle effects on neural mechanisms subserving cognitive functions. We examined the effects of different doses and treatment regimens of Delta(9)-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the dentate gyrus of adult male mice. Following drug treatment, the thymidine analog 5-bromo-2'-deoxyuridine (BrdU; 200 mg/kg, i.p.) was administered two hours prior to sacrifice to assess cell proliferation, the first step in neurogenesis. Administration of THC produced dose-dependent catalepsy and suppression of motor activity. The number of BrdU-labeled cells was not significantly changed from vehicle control levels following either acute (1, 3, 10, 30 mg/kg, i.p.), sequential (two injections of 10 or 30 mg/kg, i.p., separated by 5 h), or chronic escalating (20 to 80 mg/kg, p.o.; for 3 weeks) drug administration. Furthermore, acute administration of the potent synthetic cannabinoid receptor agonist R-(+)-WIN 55,212-2 (WIN; 5 mg/kg, i.p.) also had no significant effect on cell proliferation. These findings provide no evidence for an effect of THC on hippocampal cell proliferation, even at doses producing gross behavioral intoxication. Whether marijuana or THC affects neurogenesis remains to be explored.

  12. Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

    SciTech Connect

    O'Sullivan, Saoirse E. . E-mail: Saoirse.o'sullivan@nottingham.ac.uk; Tarling, Elizabeth J.; Bennett, Andrew J.; Kendall, David A.; Randall, Michael D.

    2005-11-25

    Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.

  13. Maternal exposure to low doses of delta9-tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring.

    PubMed

    Rubio, P; Rodríguez de Fonseca, F; Martín-Calderón, J L; Del Arco, I; Bartolomé, S; Villanúa, M A; Navarro, M

    1998-11-01

    The possible existence of an increased susceptibility to the reinforcing properties of morphine was analyzed in male and female rats born from mothers exposed to delta9-tetrahydrocannabinol (THC, 1, 5, or 20 mg/kg) during gestation and lactation. Maternal exposure to low doses of THC (1 and 5 mg/kg), relevant for human consumption, resulted in an increased response to the reinforcing effects of a moderate dose of morphine (350 microg/kg), as measured in the place-preference conditioning paradigm (CPP) in the adult male offspring. These animals also displayed an enhanced exploratory behavior in the defensive withdrawal test. However, only females born from mothers exposed to THC 1 mg/kg exhibited a small increment in the place conditioning induced by morphine. The possible implication of the hypothalamo-pituitary-adrenal axis (HPA) was analyzed by monitoring plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in basal and moderate-stress conditions (after the end of the CPP test). Female offspring perinatally exposed to THC (1 or 5 mg/kg) displayed high basal levels of corticosterone and a blunted adrenal response to the HPA-activating effects of the CPP test. However, male offspring born from mothers exposed to THC (1 or 5 mg/kg) displayed the opposite pattern: normal to low basal levels of corticosterone, and a sharp adrenal response to the CPP challenge. The present study reveals that maternal exposure to low doses of THC results in an increased sensitivity to the reinforcing effects of morphine in the adult male offspring, and in sexually dimorphic behavioral and endocrine alterations in the adaptative responses to stressors such as novelty or place-preference testing. These results support the growing evidence of the importance of monitoring the long-term consequences of maternal consumption of cannabis derivatives. PMID:9768557

  14. Oxidative cleavage of the pentyl side-chain of cannabinoids. Identification of new biotransformation pathways in the metabolism of 4'-hydroxy-delta-9-tetrahydrocannabinol in the mouse.

    PubMed

    Harvey, D J

    1990-01-01

    During an investigation of the mechanisms leading to the formation of metabolites of cannabinoids in which the pentyl side chain is reduced to 2, 3 or 4 carbon atoms, the further metabolism of 4'-hydroxy-delta 9-tetrahydrocannabinol was investigated in vivo in mice. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and identified by GC/MS. Ten metabolites were identified and a further two had tentative structural assignments made. The major metabolic route, in common with that seen with most cannabinoids, was hydroxylation at the allylic 11-position, followed by oxidation to a carboxylic acid. Additional hydroxylation occurred at C-8. Abundant metabolites were also formed by oxidative cleavage of the pentyl side chain. The major metabolites of this type had lost the terminal two carbon atoms to give compounds containing a carboxyethyl side chain. This is the major product normally produced by beta-oxidation of the acid formed from 5'-hydroxy-delta 9-tetrahydrocannabinol. Trace concentrations of two other acids that appeared to have a carboxypropyl side chain were also found. The results show that, in addition to beta-oxidation, initiated by hydroxylation at the 5'-carbon atom (omega-hydroxylation), at least one other oxidative route, initiated by omega-1-hydroxylation, is involved in the production of metabolites with two carbon atoms missing from the pentyl side chain. This pathway does not seem to have been characterized as a biotransformation mechanism in drug metabolism and a possible mechanism is suggested. PMID:1974198

  15. Potassium nitrite reaction with 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid in urine in relation to the drug screening analysis.

    PubMed

    Lewis, S A; Lewis, L A; Tuinman, A

    1999-09-01

    Recently potassium nitrite has been used as an adulterant to interfere with the analysis of 11-nor-delta 9-tetrahydro-cannabinol-9-carboxylic acid (THC-COOH) in urine. A comprehensive study of the THC-COOH and nitrite reaction chemistry and stability under various conditions is presented. Reverse phase high performance liquid chromatography (HPLC) and negative electrospray mass spectrometry (ESMS) results are given to substantiate the derived reaction mechanism and properties leading to reaction termination. The addition of potassium carbonate as a buffering agent prior to or following sample void as a means of preventing the formation of a nitroso-complexed form of the 11-nor-delta 9+-tetrahydrocannabinol-9-carboxylic acid is evaluated.

  16. Simultaneous quantification of delta-9-THC, THC-acid A, CBN and CBD in seized drugs using HPLC-DAD.

    PubMed

    Ambach, Lars; Penitschka, Franziska; Broillet, Alain; König, Stefan; Weinmann, Wolfgang; Bernhard, Werner

    2014-10-01

    An HPLC-DAD method for the quantitative analysis of Δ(9)-tetrahydrocannabinol (THC), Δ(9)-tetrahydrocannabinolic acid-A (THCA-A), cannabidiol (CBD), and cannabinol (CBN) in confiscated cannabis products has been developed, fully validated and applied to analyse seized cannabis products. For determination of the THC content of plant material, this method combines quantitation of THCA-A, which is the inactive precursor of THC, and free THC. Plant material was dried, homogenized and extracted with methanol by ultrasonication. Chromatographic separation was achieved with a Waters Alliance 2695 HPLC equipped with a Merck LiChrospher 60 RP-Select B (5μm) precolumn and a Merck LiChroCart 125-4 LiChrospher 60 RP-Select B (5μm) analytical column. Analytes were detected and quantified using a Waters 2996 photo diode array detector. This method has been accepted by the public authorities of Switzerland (Bundesamt für Gesundheit, Federal Office of Public Health), and has been used to analyse 9092 samples since 2000. Since no thermal decarboxylation of THCA-A occurs, the method is highly reproducible for different cannabis materials. Two calibration ranges are used, a lower one for THC, CBN and CBD, and a higher one for THCA-A, due to its dominant presence in fresh plant material. As provider of the Swiss proficiency test, the robustness of this method has been tested over several years, and homogeneity tests even in the low calibration range (1%) show high precision (RSD≤4.3%, except CBD) and accuracy (bias≤4.1%, except CBN).

  17. Identification of 11-Nor-delta9-tetrahydrocannabinol-9-carboxylic acid in urine by ion trap GC-MS-MS in the context of doping analysis.

    PubMed

    Caballero, Gerardo M; D'Angelo, Carlos; Fraguío, Mariá Sol; Centurión, Osvaldo Teme

    2004-01-01

    The purpose of this study is to develop a sensitive and specific alternative to current gas chromatography (GC)-mass spectrometry (MS) selected ion monitoring confirmation methods of 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid (cTHC) in human urine samples, in the context of doping analysis. An identification procedure based on the comparison, among suspicious and control samples, of the relative abundances of cTHC selected product ions obtained by GC-tandem MS in an ion trap is presented. The method complies with the identification criteria for qualitative assays established by sports authorities; the comparison procedure is precise, reproducible, specific, and sensitive, thus indicating that it is fit for the purpose of identification accordingly to World Antidoping Agency requirements. PMID:15768841

  18. Identification of 11-Nor-delta9-tetrahydrocannabinol-9-carboxylic acid in urine by ion trap GC-MS-MS in the context of doping analysis.

    PubMed

    Caballero, Gerardo M; D'Angelo, Carlos; Fraguío, Mariá Sol; Centurión, Osvaldo Teme

    2004-01-01

    The purpose of this study is to develop a sensitive and specific alternative to current gas chromatography (GC)-mass spectrometry (MS) selected ion monitoring confirmation methods of 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid (cTHC) in human urine samples, in the context of doping analysis. An identification procedure based on the comparison, among suspicious and control samples, of the relative abundances of cTHC selected product ions obtained by GC-tandem MS in an ion trap is presented. The method complies with the identification criteria for qualitative assays established by sports authorities; the comparison procedure is precise, reproducible, specific, and sensitive, thus indicating that it is fit for the purpose of identification accordingly to World Antidoping Agency requirements.

  19. Development and validation of a method for the quantitation of Delta9 tetrahydrocannabinol in human plasma by high performance liquid chromatography after solid-phase extraction.

    PubMed

    Abbara, Chadi; Galy, Romain; Benyamina, Amine; Reynaud, Michel; Bonhomme-Faivre, Laurence

    2006-06-01

    A high performance liquid chromatography (HPLC) procedure for the determination of Delta9 tetrahydrocannabinol (THC) in human plasma is described. A two-step solid-phase extraction on CN cartridges was coupled with a reversed phase HPLC system. THC was eluted using a mobile phase composed of methanol, acetonitrile and tetrabutylammonium perchlorate solution (0.005 M, pH 3.2), through a C18 Nucleosil column and detected at a wavelength of 215 nm. Calibration curve was linear over the range 5-100 ng/ml with a lower limit of quantification validated at 5 ng/ml. Extraction recovery using the developed extraction procedure was higher than 85%. This method is presently used for the quantification of THC in plasma samples from regular cannabis smokers.

  20. Combined effects of acute, very-low-dose ethanol and delta(9)-tetrahydrocannabinol in healthy human volunteers

    PubMed Central

    Ballard, Michael E.; de Wit, Harriet

    2011-01-01

    Rationale Previous studies examining the combined effects of ethanol and cannabis, or its primary psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), have provided mixed results. Data from an in vitro study suggests that combined, sub-threshold doses of these drugs may interact to produce synergistic effects. Very low doses of the two drugs in combination have not been tested in humans. Materials and Methods This study assessed whether combinations of acute, very-low doses of ethanol and THC produce synergistic effects on subjective, cognitive, and physiological measures. Healthy volunteers (n=11) received capsules containing placebo or THC (2.5mg), and beverages containing placebo or ethanol (0.1 and 0.2g/kg) alone, and in combination, across separate sessions, in a within-subjects, randomized, double-blind design. During each session, participants completed measures of working memory, psychomotor ability, and simple reaction time, and provided subjective mood and drug effect ratings. Cardiovascular measures were obtained at regular intervals. Results As intended, when administered alone, these very-low doses of ethanol and THC had only moderate effects on isolated measures. The combined effects of these drugs were not synergistic, and in some cases appeared to be less-than-additive. Conclusions Our data provide no evidence for synergistic effects of acute combinations of very-low-dose ethanol and THC on subjective or physiologic response, or on cognitive performance. PMID:21110996

  1. Delta-9-tetrahydrocannabinol disrupts hippocampal neuroplasticity and neurogenesis in trained, but not untrained adolescent Sprague-Dawley rats.

    PubMed

    Steel, Ryan W J; Miller, John H; Sim, Dalice A; Day, Darren J

    2014-02-22

    Cannabis is the most widely used illicit drug, and disruption of learning and memory are commonly reported consequences of cannabis use. We have previously demonstrated a spatial learning impairment by ∆(9)-tetrahydrocannabinol (THC) in adolescent Sprague-Dawley rats (Steel et al., 2011). The molecular mechanisms underlying behavioural impairment by cannabis remain poorly understood, although the importance of adaptive changes in neuroplasticity (synaptic number and strength) and neurogenesis during learning are accepted. Here we aimed to identify any effects of THC on the early induction of these adaptive processes supporting learning, so we conducted our analyses at the mid-training point of our previous study. Both untrained and trained (15 days of training) adolescent (P28-P42) Sprague-Dawley rats were treated daily with THC (6 mg/kg i.p.) or its vehicle, and changes in the levels of markers of hippocampal neuroplasticity (CB1R, PSD95, synapsin-I, synapsin-III) and neurogenesis (Ki67, DCX, PSA-NCAM, BrdU labelling) by training were measured. Training of control animals, but not THC-treated animals increased neuroplasticity marker levels. However training of THC-treated animals, but not control animals reduced immature neuronal marker levels. Levels of hippocampal proliferation, and survival of the BrdU-labelled progeny of these divisions were unaffected by THC in trained and untrained animals. These data show a smaller neuroplastic response, and a reduction of new-born neuronal levels not attributable to effects on proliferation or survival by THC-treatment during training. Importantly no effects of THC were seen in the absence of training, indicating that these effects represent specific impairments by THC on training-induced responses.

  2. Sex-Specific Alterations in Hippocampal Cannabinoid 1 Receptor Expression Following Adolescent Delta-9-Tetrahydrocannabinol Treatment in the Rat

    PubMed Central

    Silva, Lindsay; Harte-Hargrove, Lauren; Izenwasser, Sari; Frank, Ashley; Wade, Dean; Dow-Edwards, Diana

    2015-01-01

    Marijuana use by adolescents has been on the rise since the early 1990’s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we used [3H]CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24 hours and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24 hours post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents. PMID:26118897

  3. Chronic Δ(9)-Tetrahydrocannabinol Administration Reduces IgE(+)B Cells but Unlikely Enhances Pathogenic SIVmac251 Infection in Male Rhesus Macaques of Chinese Origin.

    PubMed

    Wei, Qiang; Liu, Li; Cong, Zhe; Wu, Xiaoxian; Wang, Hui; Qin, Chuan; Molina, Patricia; Chen, Zhiwei

    2016-09-01

    Delta9-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive component of the cannabis plant. Δ(9)-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ(9)-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ(9)-THC administration using 0.32 mg/kg or placebo (PBO), i.m., twice daily for 428 days on SIVmac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ(9)-THC(+)SIV(+), Δ(9)-THC(+)SIV(-), PBO/SIV(+) and PBO/SIV(-) (n = 4/group). One-month after daily Δ(9)-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIVmac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ(9)-THC(+)SIV(+) and PBO/SIV(+) macaques. Regardless of Δ(9)-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4(+) T cells and higher persistent levels of Ki67(+)CD8(+) T cells compared with uninfected animals. Moreover, long-term Δ(9)-THC treatment reduced significantly the frequency of circulating IgE(+)B cells. Only one Δ(9)-THC(+)SIV(+) macaque died of simian AIDS with paralyzed limbs compared with two deaths in the PBO/SIV(+) group during the study period. These findings indicate that chronic Δ(9)-THC administration resulted in reduction of IgE(+)B cells, yet it unlikely enhanced pathogenic SIVmac251/CNS infection in male Rhesus macaques of Chinese origin. PMID:27109234

  4. Chronic Δ(9)-Tetrahydrocannabinol Administration Reduces IgE(+)B Cells but Unlikely Enhances Pathogenic SIVmac251 Infection in Male Rhesus Macaques of Chinese Origin.

    PubMed

    Wei, Qiang; Liu, Li; Cong, Zhe; Wu, Xiaoxian; Wang, Hui; Qin, Chuan; Molina, Patricia; Chen, Zhiwei

    2016-09-01

    Delta9-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive component of the cannabis plant. Δ(9)-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ(9)-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ(9)-THC administration using 0.32 mg/kg or placebo (PBO), i.m., twice daily for 428 days on SIVmac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ(9)-THC(+)SIV(+), Δ(9)-THC(+)SIV(-), PBO/SIV(+) and PBO/SIV(-) (n = 4/group). One-month after daily Δ(9)-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIVmac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ(9)-THC(+)SIV(+) and PBO/SIV(+) macaques. Regardless of Δ(9)-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4(+) T cells and higher persistent levels of Ki67(+)CD8(+) T cells compared with uninfected animals. Moreover, long-term Δ(9)-THC treatment reduced significantly the frequency of circulating IgE(+)B cells. Only one Δ(9)-THC(+)SIV(+) macaque died of simian AIDS with paralyzed limbs compared with two deaths in the PBO/SIV(+) group during the study period. These findings indicate that chronic Δ(9)-THC administration resulted in reduction of IgE(+)B cells, yet it unlikely enhanced pathogenic SIVmac251/CNS infection in male Rhesus macaques of Chinese origin.

  5. Hair analysis for Delta9-tetrahydrocannabinolic acid A--new insights into the mechanism of drug incorporation of cannabinoids into hair.

    PubMed

    Auwärter, Volker; Wohlfarth, Ariane; Traber, Jessica; Thieme, Detlef; Weinmann, Wolfgang

    2010-03-20

    Differentiation between external contamination and incorporation of drugs or their metabolites from inside the body via blood, sweat or sebum is a general issue in hair analysis and of high concern when interpreting analytical results. In hair analysis for cannabinoids the most common target is Delta9-tetrahydrocannabinol (THC), sometimes cannabidiol (CBD) and cannabinol (CBN) are determined additionally. After repeated external contamination by cannabis smoke these analytes are known to be found in hair even after performing multiple washing steps. A widely accepted strategy to unequivocally prove active cannabis consumption is the analysis of hair extracts for the oxidative metabolite 11-nor-9-carboxy-THC (THC-COOH). Although the acidic nature of this metabolite suggests a lower rate of incorporation into the hair matrix compared to THC, it is not fully understood up to now why hair concentrations of THC-COOH are generally found to be much lower (mostly <10 pg/mg) than the corresponding THC concentrations. Delta9-Tetrahydrocannabinolic acid A (THCA A) is the preliminary end product of the THC biosynthesis in the cannabis plant. Unlike THC it is non-psychoactive and can be regarded as a 'precursor' of THC being largely decarboxylated when heated or smoked. The presented work shows for the first time that THCA A is not only detectable in blood and urine of cannabis consumers but also in THC positive hair samples. A pilot experiment performed within this study showed that after oral intake of THCA A on a regular basis no relevant incorporation into hair occurred. It can be concluded that THCA A in hair almost exclusively derives from external contamination e.g. by side stream smoke. Elevated temperatures during the analytical procedure, particularly under alkaline conditions, can lead to decarboxylation of THCA A and accordingly increase THC concentrations in hair. Additionally, it has to be kept in mind that in hair samples tested positive for THCA A at least a

  6. The reinforcing, self-reported performance and physiological effects of Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in cannabis users.

    PubMed

    Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

    2010-02-01

    The use of illicit prescription drugs is common in cannabis users; however, the effects of few psychoactive drugs have been characterized in this population. In this study, Delta-tetrahydrocannabinol (i.e. Delta-THC), triazolam, hydromorphone, and methylphenidate were administered to cannabis users (n=8). Subjects completed the multiple-choice procedure to assess drug reinforcement, as well as self-report questionnaires and performance tasks; physiological assessments were also conducted. Only Delta-THC increased the crossover point on the multiple-choice procedure, but all of the drugs increased ratings on one or more 'positive' drug-effect questionnaire items, as well as items specific for each drug. Triazolam produced the most robust performance impairment, except on a time reproduction task, which was impacted to a greater degree by Delta-THC. Delta-THC elevated heart rate and decreased temperature, triazolam increased heart rate, methylphenidate elevated all cardiovascular indices, and hydromorphone reduced respiration. The effects of the drugs tested in this study were generally consistent with their known pharmacology, although minimal responses to hydromorphone were observed. Future research to directly compare the effects of different psychoactive drugs in cannabis users and nonusers would be useful for identifying potential differences in drug effects as a function of use history. PMID:19949319

  7. 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.

  8. Quantification of 11-Carboxy-Delta-9-Tetrahydrocannabinol (THC-COOH) in Meconium Using Gas Chromatography/Mass Spectrometry (GC/MS).

    PubMed

    Peat, Judy; Davis, Brehon; Frazee, Clint; Garg, Uttam

    2016-01-01

    Maternal substance abuse is an ongoing concern and detecting drug use during pregnancy is an important component of neonatal care when drug abuse is suspected. Meconium is the preferred specimen for drug testing because it is easier to collect than neonatal urine and it provides a much broader time frame of drug exposure. We describe a method for quantifying 11-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in meconium. After adding a labeled internal standard (THC-COOH D9) and acetonitrile, samples are sonicated to release both free and conjugated THC-COOH. The acetonitrile/aqueous layer is removed and mixed with a strong base to hydrolyze the conjugated THC-COOH. The samples are then extracted with an organic solvent mixture as part of a sample "cleanup." The organic solvent layer is discarded and the remaining aqueous sample is acidified. Following extraction with a second organic mixture, the organic layer is removed and concentrated to dryness. The resulting residue is converted to a trimethylsilyl (TMS) derivative and analyzed using gas chromatography/mass spectrometry (GC/MS) in selective ion monitoring (SIM) mode.

  9. Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ9-THC in humans discriminating Δ9-THC

    PubMed Central

    Lile, Joshua A.; Kelly, Thomas H.; Hays, Lon R.

    2014-01-01

    Background Our previous research suggested the involvement γ-aminobutyric acid (GABA), in particular the GABAB receptor subtype, in the interoceptive effects of Δ9-tetrahydrocannabinol9-THC). The aim of the present study was to determine the potential involvement of the GABAA receptor subtype by assessing the separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ9-THC using pharmacologically selective drug-discrimination procedures. Methods Ten cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received diazepam (5 and 10 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Results Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug) and elevated heart rate. Diazepam alone impaired performance on psychomotor performance tasks and increased ratings on a limited number of self-report questionnaire items (e.g., Any Effect, Sedated), but did not substitute for the Δ9-THC discriminative stimulus or alter the Δ9-THC discrimination dose-response function. Similarly, diazepam had limited impact on the other behavioral effects of Δ9-THC. Conclusions These results suggest that the GABAA receptor subtype has minimal involvement in the interoceptive effects of Δ9-THC, and by extension cannabis, in humans. PMID:25124305

  10. A Preliminary Investigation of Individual Differences in Subjective Responses to D-Amphetamine, Alcohol, and Delta-9-Tetrahydrocannabinol Using a Within-Subjects Randomized Trial

    PubMed Central

    Wardle, Margaret C.; Marcus, Benjamin A.; de Wit, Harriet

    2015-01-01

    Polydrug use is common, and might occur because certain individuals experience positive effects from several different drugs during early stages of use. This study examined individual differences in subjective responses to single oral doses of d-amphetamine, alcohol, and delta-9-tetrahydrocannabinol (THC) in healthy social drinkers. Each of these drugs produces feelings of well-being in at least some individuals, and we hypothesized that subjective responses to these drugs would be positively correlated. We also examined participants’ drug responses in relation to personality traits associated with drug use. In this initial, exploratory study, 24 healthy, light drug users (12 male, 12 female), aged 21–31 years, participated in a fully within-subject, randomized, counterbalanced design with six 5.5-hour sessions in which they received d-amphetamine (20mg), alcohol (0.8 g/kg), or THC (7.5 mg), each paired with a placebo session. Participants rated the drugs’ effects on both global measures (e.g. feeling a drug effect at all) and drug-specific measures. In general, participants’ responses to the three drugs were unrelated. Unexpectedly, “wanting more” alcohol was inversely correlated with “wanting more” THC. Additionally, in women, but not in men, “disliking” alcohol was negatively correlated with “disliking” THC. Positive alcohol and amphetamine responses were related, but only in individuals who experienced a stimulant effect of alcohol. Finally, high trait constraint (or lack of impulsivity) was associated with lower reports of liking alcohol. No personality traits predicted responses across multiple drug types. Generally, these findings do not support the idea that certain individuals experience greater positive effects across multiple drug classes, but instead provide some evidence for a “drug of choice” model, in which individuals respond positively to certain classes of drugs that share similar subjective effects, and dislike other

  11. Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis.

    PubMed

    Syed, Yahiya Y; McKeage, Kate; Scott, Lesley J

    2014-04-01

    Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and thus, may modulate the effects of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks' double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks' single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale. A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥ 30% reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment. Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication. PMID:24671907

  12. 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid ethyl ester (THC-COOEt): unsuccessful search for a marker of combined cannabis and alcohol consumption.

    PubMed

    Nadulski, Thomas; Bleeck, Simona; Schräder, Johannes; Bork, Wolf-Rainer; Pragst, Fritz

    2010-03-20

    11-Nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid ethyl ester (THC-COOEt) can be presumed to be a mixed metabolite formed during combined consumption of cannabinoids and alcohol. In order to examine this hypothesis, THC-COOEt and its deuterated analogue D(3)-THC-COOEt were synthesized as reference substance and internal standard from the corresponding carboxylic acids and diazoethane and methods were developed for the sensitive detection of THC-COOEt in plasma and hair based on gas chromatography-electron impact mass spectrometry after silylation with N-methyl-N-tert-butyldimethylsilyl-trifluoroacetamide and gas chromatography-negative chemical ionization mass spectrometry (GC-NCI-MS) as well as tandem mass spectrometry (GC-NCI-MS-MS) after derivatization with pentafluoropropionyl anhydride. The methods were applied for THC-COOEt determination to plasma samples from 22 drunk driving cases which contained both ethanol (0.30-2.16 mg/g) and THC-COOH (15-252 ng/mL) as well as to 12 hair samples from drug fatalities which were both positive for THC (0.09-2.04 ng/mg) and fatty acid ethyl esters as markers of chronic alcohol abuse (0.70-6.3 ng/mg). In none of these samples THC-COOEt could be found with limits of detection of 0.3 ng/mL in plasma and 2 pg/mg in hair in 11 samples using GC-NCI-MS and 0.2 pg/mg in one sample using GC-NCI-MS. Therefore, the use of this compound as a marker for combined cannabis and alcohol consumption could not be achieved. PMID:20074877

  13. A Preliminary Investigation of Individual Differences in Subjective Responses to D-Amphetamine, Alcohol, and Delta-9-Tetrahydrocannabinol Using a Within-Subjects Randomized Trial.

    PubMed

    Wardle, Margaret C; Marcus, Benjamin A; de Wit, Harriet

    2015-01-01

    Polydrug use is common, and might occur because certain individuals experience positive effects from several different drugs during early stages of use. This study examined individual differences in subjective responses to single oral doses of d-amphetamine, alcohol, and delta-9-tetrahydrocannabinol (THC) in healthy social drinkers. Each of these drugs produces feelings of well-being in at least some individuals, and we hypothesized that subjective responses to these drugs would be positively correlated. We also examined participants' drug responses in relation to personality traits associated with drug use. In this initial, exploratory study, 24 healthy, light drug users (12 male, 12 female), aged 21-31 years, participated in a fully within-subject, randomized, counterbalanced design with six 5.5-hour sessions in which they received d-amphetamine (20mg), alcohol (0.8 g/kg), or THC (7.5 mg), each paired with a placebo session. Participants rated the drugs' effects on both global measures (e.g. feeling a drug effect at all) and drug-specific measures. In general, participants' responses to the three drugs were unrelated. Unexpectedly, "wanting more" alcohol was inversely correlated with "wanting more" THC. Additionally, in women, but not in men, "disliking" alcohol was negatively correlated with "disliking" THC. Positive alcohol and amphetamine responses were related, but only in individuals who experienced a stimulant effect of alcohol. Finally, high trait constraint (or lack of impulsivity) was associated with lower reports of liking alcohol. No personality traits predicted responses across multiple drug types. Generally, these findings do not support the idea that certain individuals experience greater positive effects across multiple drug classes, but instead provide some evidence for a "drug of choice" model, in which individuals respond positively to certain classes of drugs that share similar subjective effects, and dislike other types of drugs.

  14. Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates.

    PubMed

    Rubino, Tiziana; Vigano', Daniela; Realini, Natalia; Guidali, Cinzia; Braida, Daniela; Capurro, Valeria; Castiglioni, Chiara; Cherubino, Francesca; Romualdi, Patrizia; Candeletti, Sanzio; Sala, Mariaelvina; Parolaro, Daniela

    2008-10-01

    Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Delta(9)-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35-45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.

  15. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors

    PubMed Central

    Lanfumey, Laurence; Cordomí, Arnau; Pastor, Antoni; de La Torre, Rafael; Gasperini, Paola; Navarro, Gemma; Howell, Lesley A.; Pardo, Leonardo; Lluís, Carmen; Canela, Enric I.; McCormick, Peter J.; Maldonado, Rafael; Robledo, Patricia

    2015-01-01

    Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties. PMID:26158621

  16. Delta(9)-tetrahydrocannabinol prolongs the immobility time in the mouse forced swim test: involvement of cannabinoid CB(1) receptor and serotonergic system.

    PubMed

    Egashira, Nobuaki; Matsuda, Tomomi; Koushi, Emi; Higashihara, Fuminori; Mishima, Kenichi; Chidori, Shozo; Hasebe, Nobuyoshi; Iwasaki, Katsunori; Nishimura, Ryoji; Oishi, Ryozo; Fujiwara, Michihiro

    2008-07-28

    In the present study, we investigated the effect of Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, on immobility time during the forced swim test. THC (2 and 6 mg/kg, i.p.) significantly prolonged the immobility time. In addition, THC at the same doses did not significantly affect locomotor activity in the open-field test. The selective cannabinoid CB(1) receptor antagonist rimonabant (3 mg/kg, i.p.) significantly reduced the enhancement of immobility by THC (6 mg/kg). Similarly, the selective serotonin (5-HT) reuptake inhibitor (SSRI) citalopram (10 mg/kg, i.p.) and 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.3 mg/kg, i.p.) significantly reduced this THC-induced effect. Moreover, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide dihydrochloride (WAY100635, 1 mg/kg, i.p.) and the postsynaptic 5-HT(1A) receptor antagonist MM-77 (0.1 mg/kg, i.p.) reversed this reduction effect of 8-OH-DPAT (0.3 mg/kg). In contrast, the selective 5-HT(7) receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this reduction effect of 8-OH-DPAT. WAY100635 (1 mg/kg) also reversed the reduction effect of citalopram (10 mg/kg). These findings suggest that the 5-HT(1A) receptors are involved in THC-induced enhancement of immobility.

  17. Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

    PubMed

    Castelli, M Paola; Madeddu, Camilla; Casti, Alberto; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M Grazia

    2014-01-01

    Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

  18. Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

    PubMed Central

    Bhattacharyya, Sagnik; Morrison, Paul D; Fusar-Poli, Paolo; Martin-Santos, Rocio; Borgwardt, Stefan; Winton-Brown, Toby; Nosarti, Chiara; O' Carroll, Colin M; Seal, Marc; Allen, Paul; Mehta, Mitul A; Stone, James M; Tunstall, Nigel; Giampietro, Vincent; Kapur, Shitij; Murray, Robin M; Zuardi, Antonio W; Crippa, José A; Atakan, Zerrin; McGuire, Philip K

    2010-01-01

    Δ-9-tetrahydrocannabinol (Δ-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Δ-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Δ-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Δ-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Δ-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Δ-9-THC. Δ-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Δ-9-THC. PMID:19924114

  19. Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity.

    PubMed

    Katsidoni, Vicky; Kastellakis, Andreas; Panagis, George

    2013-11-01

    Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main psychoactive ingredient of marijuana, has led to equivocal results when tested with the intracranial self-stimulation (ICSS) procedure or the open-field test for motor activity, two behavioural models for evaluating the reward-facilitating and locomotor stimulating effects of drugs of abuse, respectively. Therefore, in the present study, the effects of high and low doses of Δ(9)-THC were compared in the ICSS procedure and the open-field test. Moreover, the involvement of CB(1) receptors in tentative Δ(9)-THC-induced effects was investigated by pre-treating the animals with the CB(1) receptor antagonist SR141716A (rimonabant). The results obtained show that low doses of Δ(9)-THC induce opposite effects from high doses of Δ(9)-THC. Specifically, 0.1 mg/kg Δ(9)-THC decreased ICSS thresholds and produced hyperactivity, whereas 1 mg/kg increased ICSS thresholds and produced hypoactivity. Both effects were reversed by pre-treatment with SR141716A, indicating the involvement of CB(1) receptors on these actions. Altogether, our results indicate that Δ(9)-THC can produce acute activating effects in locomotion that coincide with its reward-facilitating effects in the ICSS paradigm. The present findings provide further support that Δ(9)-THC induces behaviours typical of abuse and substantiate the notion that marijuana resembles other drugs of abuse.

  20. 9 -Tetrahydrocannabinol: effects on mammalian nonmyelinated nerve fibers.

    PubMed

    Byck, R; Ritchie, J M

    1973-04-01

    Delta(9)-Tetrahydrocannabinol can be applied to tissue in vitro by dissolving it in Pluronic F68 and ethanol. It causes a decrease in size of the compound action potential of the nonmnyelinated fibers of the vagus nerve of the rabbit. This effect appears to be dose-related and chloride-dependent. Effects on other measurable parameters of nerve function seem to be minimal. Although the amounts required seem to be higher than those required to produce hallucinogenic effects in man, this effect is consistent with other work on Delta(9)-tetrahydrocannabinol and may ultimately account for a significant portion of the pharmacological activity of this drug.

  1. Rapid reversed-phase high-performance liquid chromatographic method for the assay of urinary 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid and confirmation of use of cannabis derivatives.

    PubMed

    Bianchi, V; Donzelli, G

    1996-01-12

    The main active cannabis (marijuana and hashish) derivative delta 9-tetrahydrocannabinol is, in vivo, transformed and excreted mainly as 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and its glucuronide. The method presented here allows the confirmation of the presence of THC-COOH by means of a basic hydrolysis, solid-phase extraction clean-up on reversed-phase (RP) disposable cartridges followed by analysis on a C8 RP column and UV detection; the mobile phase used was a 55% acetonitrile solution in acid phosphate buffer. Over 600 samples both from drug addicts in therapeutic communities and subjects who were not on any drugs therapy were analysed. This method was precise with a linearity range from 10 to more than 500 ng/ml [the lower limit proposed by the National Institute on Drug Abuse (NIDA) for cannabinoid confirmation method is 15 ng/ml]. The sample preparation is simple and fast, allowing the analysis of large numbers of samples. Perfect correlation was observed between data from the HPLC method and a fluorescence polarization immunoassay screening method. The THC-COOH metabolite was found to constitute 30% of all the cannabinoids excreted in urine of abusers.

  2. Opposing Actions of Chronic[Deta][superscript 9] Tetrahydrocannabinol and Cannabinoid Antagonists on Hippocampal Long-Term Potentiation

    ERIC Educational Resources Information Center

    Hoffman, Alexander F.; Oz, Murat; Yang, Ruiqin; Lichtman, Aron H.; Lupica, Carl R.

    2007-01-01

    Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, [Deta][superscript 9]-tetrahydrocannabinol ([Deta][superscript 9]-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for…

  3. Cross-Substitution of Δ9-Tetrahydrocannabinol and JWH-018 in Drug Discrimination in Rats

    PubMed Central

    Wiley, Jenny L.; Lefever, Timothy W.; Cortes, Ricardo A.; Marusich, Julie A.

    2014-01-01

    Synthetic indole-derived cannabinoids, originally developed to probe cannabinoid CB1 and CB2 receptors, have become widely abused for their marijuana-like intoxicating properties. The present study examined the effects of indole-derived cannabinoids in rats trained to discriminate Δ9-tetrahydrocannabinol9-THC) from vehicle. In addition, the effects of Δ9-THC in rats trained to discriminate JWH-018 from vehicle were assessed. Adult male Sprague-Dawley rats were trained to discriminate 3 mg/kg Δ9-THC or 0.3 mg/kg JWH-018 from vehicle. JWH-018, JWH-073, and JWH-210 fully substituted in Δ9-THC-trained rats and Δ9-THC substituted in JWH-018-trained rats. In contrast, JWH-320, an indole-derived cannabinoid without affinity for CB1 receptors, failed to substitute for Δ9-THC. Pre-treatment with 1 mg/kg rimonabant significantly reduced responding on the JWH-018-associated lever in JWH-018-trained rats. These results support the conclusion that the interoceptive effects of Δ9-THC and synthetic indole-derived cannabinoids show a large degree of overlap, which is predictive of their use for their marijuana-like intoxicating properties. Characterization of the extent of pharmacological differences among structural classes of cannabinoids, and determination of their mechanisms remain important goals. PMID:24887450

  4. Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats.

    PubMed

    Wiley, Jenny L; Lefever, Timothy W; Cortes, Ricardo A; Marusich, Julie A

    2014-09-01

    Synthetic indole-derived cannabinoids, originally developed to probe cannabinoid CB1 and CB2 receptors, have become widely abused for their marijuana-like intoxicating properties. The present study examined the effects of indole-derived cannabinoids in rats trained to discriminate Δ(9)-tetrahydrocannabinol (Δ(9)-THC) from vehicle. In addition, the effects of Δ(9)-THC in rats trained to discriminate JWH-018 from vehicle were assessed. Adult male Sprague-Dawley rats were trained to discriminate 3mg/kg Δ(9)-THC or 0.3mg/kg JWH-018 from vehicle. JWH-018, JWH-073, and JWH-210 fully substituted in Δ(9)-THC-trained rats and Δ(9)-THC substituted in JWH-018-trained rats. In contrast, JWH-320, an indole-derived cannabinoid without affinity for CB1 receptors, failed to substitute for Δ(9)-THC. Pre-treatment with 1mg/kg rimonabant significantly reduced responding on the JWH-018-associated lever in JWH-018-trained rats. These results support the conclusion that the interoceptive effects of Δ(9)-THC and synthetic indole-derived cannabinoids show a large degree of overlap, which is predictive of their use for their marijuana-like intoxicating properties. Characterization of the extent of pharmacological differences among structural classes of cannabinoids, and determination of their mechanisms remain important goals.

  5. Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ(9) -THC in cannabis users.

    PubMed

    Lile, Joshua A; Kelly, Thomas H; Charnigo, Richard J; Stinchcomb, Audra L; Hays, Lon R

    2013-07-01

    Oral Δ(9) -tetrahydrocannabinol (Δ(9) -THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioural effects of oral Δ(9) -THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ(9) -THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Δ(9) -THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug-sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral Δ(9) -THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ(9) -THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response.

  6. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users.

    PubMed

    Hindocha, Chandni; Freeman, Tom P; Schafer, Grainne; Gardener, Chelsea; Das, Ravi K; Morgan, Celia J A; Curran, H Valerie

    2015-03-01

    Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8mg), CBD (16mg), THC+CBD (8mg+16mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling 'stoned' was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being 'stoned'. CBD did not influence feelings of 'stoned'. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces.

  7. Δ9tetrahydrocannabinol impairs reversal learning but not extra-dimensional shifts in rhesus macaques

    PubMed Central

    Wright, M. Jerry; Vandewater, Sophia A.; Parsons, Loren H.; Taffe, Michael A.

    2013-01-01

    Expansion of medical marijuana use in the US and the recently successful decriminalization of recreational marijuana in two States elevates interest in the specific cognitive effects of Δ9tetrahydrocannabinol9THC), the major psychoactive constituent of marijuana. Controlled laboratory studies in nonhuman primates provide mixed evidence for specific effects of Δ9THC in learning and memory tasks, with a suggestion that frontal-mediated tasks may be most sensitive. In this study, adult male rhesus monkeys were trained on tasks which assess reversal learning, extradimensional attentional shift learning and spatial delayed-response. Subjects were challenged with 0.1–0.5 mg/kg Δ9THC, i.m., in randomized order and evaluated on the behavioral measures. Peak plasma levels of Δ9THC were observed 30 min after 0.2 mg/kg (69 ±29 ng/ml) and 60 min after 0.5 mg/kg (121 ±23 ng/ml) was administered and behavioral effects on a bimanual motor task persisted for up to 2 hrs after injection. An increase in errors-to-criterion (ETC) associated with reversal learning was further increased by Δ9THC in a dose-dependent manner. The increase in ETC associated with extradimensional shifts was not affected by Δ9-THC. Spatial delayed-response performance was impaired by Δ9THC in a retention-interval dependent manner. Overall the pattern of results suggest a more profound effect of Δ9THC on tasks mediated by orbitofrontal (reversal learning) versus dorsolateral (extradimensional shifts) prefrontal mechanisms. PMID:23333671

  8. JWH-018 and JWH-073: Δ9-Tetrahydrocannabinol-Like Discriminative Stimulus Effects in Monkeys

    PubMed Central

    Ginsburg, Brett C.; Schulze, David R.; Hruba, Lenka

    2012-01-01

    Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n = 4) discriminating Δ9-tetrahydrocannabinol9-THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n = 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic Δ9-THC (1 mg/kg s.c. 12 h) treatment. Δ9-THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating Δ9-THC; the ED50 values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32–3.2 mg/kg) produced surmountable antagonism of Δ9-THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA2/pKB values of 6.65, 6.68, and 6.79 in the presence of Δ9-THC, JWH-018, and JWH-073, respectively. In Δ9-THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED50 value of rimonabant was 0.20 mg/kg. Δ9-THC (1–10 mg/kg), JWH-018 (0.32–3.2 mg/kg), and JWH-073 (3.2–32 mg/kg) dose-dependently attenuated the rimonabant-discriminative stimulus (i.e., withdrawal). These results suggest that Δ9-THC, JWH-018, and JWH-073 act through the same receptors to produce Δ9-THC-like subjective effects and attenuate Δ9-THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulus-outcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than Δ9-THC. PMID:21965552

  9. Supported liquid extraction (SLE) for the analysis of methylamphetamine, methylenedioxymethylamphetamine and delta-9-tetrahydrocannabinol in oral fluid and blood of drivers.

    PubMed

    Rositano, Joanna; Harpas, Peter; Kostakis, Chris; Scott, Timothy

    2016-08-01

    Since 2006, the South Australian Government has been conducting roadside oral fluid testing of drivers for the illicit drugs methylamphetamine (MA), methylenedioxymethylamphetamine (MDMA) and Δ(9)-tetrahydrocannabinol (THC) using the Securetec Drugwipe II Twin and Alere DDS 805 AP saliva collection kit. Forensic Science South Australia carries out the confirmatory analysis by LC/MS for the positive test results of oral fluid roadside testing along with the pre-screened ELISA positive road traffic accident blood samples. The number of blood and oral fluid samples received in the laboratory has been steadily increasing during this time, and over 10,000 samples were received in 2014. The proportion of positive results from these samples has also been increasing over the decade of driver drug testing, and this data is presented. A simple and efficient method has been developed for the analysis of the three drugs using Biotage Isolute(®) SLE+ 96-well plates. Sample preparation included 1:1 dilution with a dilute ammonia solution for buffered oral fluids (1:3 dilution for blood samples), and addition of deuterated internal standards. Samples were loaded onto the phase, left to absorb for 5min then eluted with methyl t-butyl ether (MTBE). The samples were evaporated and reconstituted in methanol. LC/MS analysis was performed on an AB Sciex 5500 Q-Trap in positive ion mode, monitoring 3 transitions for each analyte. Separation was achieved on a Restek Ultrabiphenyl 50×2.1mm column with a gradient system of acetonitrile/0.1% formic acid over 5min. Method validation and recoveries were carried out on drug free ante mortem blood and DDS buffer solution provided by Alere, Australia. Recoveries above 80% were achieved for MA and MDMA at a concentration of 25ng/mL, whilst recoveries of greater than 65% were achieved for THC at 4.5ng/mL. Accuracy and precision were acceptable down to the LLOQ for all three analytes (5, 5 and 1ng/mL for MA, MDMA and THC, respectively). Mean

  10. Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Δ(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva).

    PubMed

    Darmani, Nissar A; Chebolu, Seetha; Zhong, Weixia; Trinh, Chung; McClanahan, Bryan; Brar, Rajivinder S

    2014-01-01

    Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ(9)-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Δ(9)-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18 μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ(9)-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3-1.8 mg/kg. Combinations of 1 or 5 μg/kg RTX with varying doses of Δ(9)-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5-50 times lower than Δ(9)-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30 min but not at 2 h. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5mg/kg; however, another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually.

  11. Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling

    PubMed Central

    Yang, Hongwei; Tang, Ya-ping; Sun, Hao; Song, Yunping; Chen, Chu

    2013-01-01

    SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. PMID:24267894

  12. Estimation of measurement uncertainty for the quantification of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid and its glucuronide in urine using liquid chromatography-tandem mass spectrometry.

    PubMed

    Kim, Jin Young; Kwon, Woonyong; Kim, Hee Seung; Suh, Sungill; In, Moon Kyo

    2014-04-01

    Recently, the estimation of the measurement uncertainty has become a significant issue in the quality control of forensic drug testing. In the present study, the uncertainty of the measurement was calculated for the quantification of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and its glucuronide conjugate (THC-COOH-glu) in urine using liquid chromatography-tandem mass spectrometry. The procedure was based on liquid-liquid extraction of a volume of urine (800 µL) with ethyl acetate. The sources of uncertainty were identified and classified into four major categories as follows: standard preparation, calibration curve, method precision and bias. The overall contribution of combined standard uncertainty on THC-COOH increased in the order of standard preparation (0.9%), method precision (10.4%), calibration curve (30.3%) and bias (58.4%) and, while calibration curve (53.0%) and bias (40.4%) gave the bigger contributions to the combined standard uncertainty for THC-COOH-glu than method precision and standard preparation, which accounted for 6.3 and 0.3%, respectively. The reliability of a measurement was expressed by stating the expanded uncertainty of the measurement result at 95% confidence level. The concentrations of THC-COOH and THC-COOH-glu in the urine sample with their expanded uncertainties were 10.20 ± 1.14 ng/mL and 25.42 ± 5.01 ng/mL, respectively.

  13. Δ9-Tetrahydrocannabinol-Like Discriminative Stimulus Effects of Compounds Commonly Found in K2/Spice

    PubMed Central

    Gatch, Michael B.; Forster, Michael J.

    2014-01-01

    A number of cannabinoid compounds are being sold in the form of incense as “legal” alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Δ9-tetrahydrocannabinol, the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH-200, JWH-203, JWH-250, AM-2201 and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Δ9-tetrahydrocannabinol (3 mg/kg, i.p.). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for one to two hours. Each of the compounds fully substituted for the discriminative stimulus effects of Δ9-tetrahydrocannabinol, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8-homolog suppressed response rates at doses that fully substituted for Δ9-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Δ9-THC, and three lasted substantially longer (JWH-073, JWH-250 and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable to those of Δ9-tetrahydrocannabinol, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards in humans. PMID:25325289

  14. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults

    PubMed Central

    Kollins, Scott H.; Schoenfelder, Erin N.; English, Joseph S.; Holdaway, Alex; Van Voorhees, Elizabeth; O’Brien, Benjamin R.; Dew, Rachel; Chrisman, Allan K.

    2014-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10 mg THC + 0 mg, 10 mg, and 40 mg MPH = 89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of “Feel Drug,” “Good Effects,” and “Take Drug Again.” THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. PMID:25175495

  15. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

    PubMed

    Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

    2015-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures.

  16. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

    PubMed

    Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

    2015-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. PMID:25175495

  17. Cannabinoids in Disguise: Δ9-Tetrahydrocannabinol-Like Effects of Tetramethylcyclopropyl Ketone Indoles

    PubMed Central

    Wiley, Jenny L.; Marusich, Julie A.; Lefever, Timothy W.; Grabenauer, Megan; Moore, Katherine N.; Thomas, Brian F.

    2013-01-01

    Synthetic indole-derived cannabinoids have become commonly used recreational drugs and continue to be abused despite their adverse consequences. As compounds that were identified early in the epidemic (e.g., naphthoylindoles) have become legally banned, new compounds have appeared on the drug market. Two tetramethylcyclopropyl ketone indoles, UR-144 [(1-pentyl-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone] and XLR-11 [(1-(5-fluoropentyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone], recently have been identified in confiscated products. These compounds are structurally related to a series of CB2-selective compounds explored by Abbott Labs. The purpose of the present study was to evaluate the extent to which UR-144 and XLR-11 shared cannabinoid effects with Δ9-tetrahydrocannabinol9-THC). Indices of in vitro and in vivo activity at cannabinoid receptors were assessed. Similar to other psychoactive cannabinoid agonists, XLR-11 and UR-144 showed low nanomolar (< 30) affinity for CB1 and CB2 receptors, activated these receptors as full agonists, and produced dose-dependent effects that were blocked by rimonabant in mice, including antinociception, hypothermia, catalepsy and suppression of locomotor activity. The potency of both compounds was several-fold greater than Δ9-THC. XLR-11 and UR-144 also substituted for Δ9-THC in a Δ9-THC discrimination procedure in mice, effects that were attenuated by rimonabant. Analysis of urine from mice treated with the compounds revealed that both were extensively metabolized, with predominant urinary excretion as glucuronide conjugates. Together, these results demonstrate that UR-144 and XLR-11 share a pharmacological profile of in vitro and in vivo effects with Δ9-THC and other abused indole-derived cannabinoids and would be predicted to produce Δ9-THC-like subjective effects in humans. PMID:23916483

  18. In vitro effect of. Delta. sup 9 -tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E sub 2

    SciTech Connect

    Rettori, V.; Aguila, M.C.; McCann, S.M. ); Gimeno, M.F.; Franchi, A.M. )

    1990-12-01

    Previous in vivo studies have shown that {Delta}{sup 9}-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E{sub 2} (PGE{sub 2}) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE{sub 2} suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE{sub 2} synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.

  19. Δ9-THC Disrupts Gamma (γ)-Band Neural Oscillations in Humans.

    PubMed

    Cortes-Briones, Jose; Skosnik, Patrick D; Mathalon, Daniel; Cahill, John; Pittman, Brian; Williams, Ashley; Sewell, R Andrew; Ranganathan, Mohini; Roach, Brian; Ford, Judith; D'Souza, Deepak Cyril

    2015-08-01

    Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ(9)-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ(9)-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ(9)-THC. Δ(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders. PMID:25709097

  20. Δ9-THC Disrupts Gamma (γ)-Band Neural Oscillations in Humans.

    PubMed

    Cortes-Briones, Jose; Skosnik, Patrick D; Mathalon, Daniel; Cahill, John; Pittman, Brian; Williams, Ashley; Sewell, R Andrew; Ranganathan, Mohini; Roach, Brian; Ford, Judith; D'Souza, Deepak Cyril

    2015-08-01

    Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ(9)-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ(9)-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ(9)-THC. Δ(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders.

  1. A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

    PubMed

    Weinstein, A; Brickner, O; Lerman, H; Greemland, M; Bloch, M; Lester, H; Chisin, R; Sarne, Y; Mechoulam, R; Bar-Hamburger, R; Freedman, N; Even-Sapir, E

    2008-06-01

    Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana. PMID:18635724

  2. Δ9-Tetrahydrocannabinol-Like Effects of Novel Synthetic Cannabinoids Found on the Gray Market

    PubMed Central

    Gatch, Michael B.; Forster, Michael J.

    2015-01-01

    When synthetic cannabinoid compounds became controlled by state and federal governments, different, non-controlled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Δ9-tetrahydrocannabinol9-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F-PB-22 and AB-FUBINACA were tested for locomotor depressant effects in male Swiss-Webster mice and subsequently for their ability to substitute for Δ9-THC (3 mg/kg, i.p.) in drug discrimination experiments with male Sprague-Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Δ9-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability. PMID:26061356

  3. Voltammetric determination of Δ9-THC in glassy carbon electrode: An important contribution to forensic electroanalysis.

    PubMed

    Balbino, Marco Antonio; de Menezes, Matheus Manoel Teles; Eleotério, Izabel Cristina; Saczk, Adelir Aparecida; Okumura, Leonardo Luiz; Tristão, Heloísa Maria; de Oliveira, Marcelo Firmino

    2012-09-10

    A new voltammetric method for the determination of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is described. The voltammetric experiments were accomplished in N-N dimethylformamide/water (9:1, v/v), using tetrabutylammonium tetrafluoroborate (TBATFB) 0.1mol/L as supporting electrolyte and a glassy carbon disk electrode as the working electrode. The anodic peak current was observed at 0.0V (vs. Ag/AgCl) after a 30s pre-concentration step under an applied potential of -1.2V (vs. Ag/AgCl). A linear dependence of Δ(9)-THC detection was obtained in the concentration range 2.4-11.3ng/mL, with a linear correlation coefficient of 0.999 and a detection limit of 0.34ng/mL. The voltammetric method was used to measure the content of Δ(9)-THC in samples (hemp and hashish) confiscated by the police. The elimination of chemical interferences from the samples was promptly achieved through prior purification using the TLC technique, by employing methanol/water (4:1, v/v) as the mobile phase. The results showed excellent correlation with results attained by HPLC.

  4. Apparent Inverse Relationship between Cannabinoid Agonist Efficacy and Tolerance/Cross-Tolerance Produced by Δ9-Tetrahydrocannabinol Treatment in Rhesus Monkeys

    PubMed Central

    Hruba, Lenka; Ginsburg, Brett C.

    2012-01-01

    Synthetic cannabinoids (CBs) [naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073)] are marketed, sold, and used as alternatives to cannabis. Synthetic CBs appear to have effects similar to those of Δ9-tetrahydrocannabinol9-THC), the drug primarily responsible for the behavioral effects of cannabis. However, synthetic CB products produce atypical effects (e.g., hypertension, seizures, and panic attacks). One potential explanation for atypical effects is CB1 receptor agonist efficacy, which is reportedly higher for JWH-018 and JWH-073 compared with Δ9-THC. The goal of this study was to test a prediction from receptor theory that tolerance/cross-tolerance (i.e., resulting from daily Δ9-THC treatment) is greater for a low-efficacy agonist compared with a high-efficacy agonist. Rhesus monkeys discriminated 0.1 mg/kg Δ9-THC i.v. from vehicle, and sensitivity to CB1 agonists was determined before and after 3 and 14 days of Δ9-THC treatment (1 mg/kg per day s.c.). (1R,3R,4R)-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP-55,940), a prototype high-efficacy CB1 receptor agonist, JWH-018, and JWH-073 substituted for the discriminative stimulus effects of Δ9-THC. Three days of Δ9-THC treatment produced less tolerance/cross-tolerance than 14 days of Δ9-THC treatment. Three days of Δ9-THC did not result in cross-tolerance to CP-55,940, JWH-073, and JWH-018; in contrast, as reported previously, 3 days of Δ9-THC treatment decreased sensitivity to Δ9-THC 3-fold. Fourteen days of Δ9-THC decreased sensitivity to Δ9-THC, CP-55,940, JWH-018, and JWH-073 9.2-fold, 3.6-fold, 4.3-fold, and 5.6-fold, respectively. The greater loss of sensitivity to Δ9-THC relative to CP-55,940 and JWH-018 suggests that differences in CB1 receptor agonist efficacy are important in vivo and might underlie differences in the dependence liability and adverse effects of synthetic CBs versus

  5. Acute Δ9-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice

    PubMed Central

    Kinsey, Steven G.; Cole, Erica C.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening. Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ9-THC (.01–50 mg/kg; oral or intraperitoneal), and then treated with the NSAID diclofenac sodium (100 mg/kg, p.o.) to induce gastric lesions. In separate groups of mice, the cannabimimetic behavioral effects of Δ9-THC given via each route of administration were compared using a battery of tests, consisting of assessment of locomotor activity, nociception in the tail withdrawal test, catalepsy in the bar test, and hypothermia. Δ9-THC dose-dependently attenuated diclofenac-induced gastric hemorrhagic streaks through both p.o. and i.p. routes of administration (ED50 (95% confidence interval) = 0.64 (0.26 – 1.55) mg/kg and 0.06 (0.01 – 0.34) mg/kg, respectively). Δ9-THC given i.p. was 2–3 orders of magnitude more potent in reducing diclofenac-induced gastric ulcers than in producing locomotor immobility, antinociception, hypothermia, and catalepsy, while the potency of ratio of p.o. Δ9-THC between each behavior measure was 7–18. These data indicate that the phytocannabinoid Δ9-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects. PMID:23769745

  6. Acute Δ(9)-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice.

    PubMed

    Kinsey, Steven G; Cole, Erica C

    2013-09-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening. Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ(9)-THC (.01-50mg/kg; oral or intraperitoneal), and then treated with the NSAID diclofenac sodium (100mg/kg, p.o.) to induce gastric lesions. In separate groups of mice, the cannabimimetic behavioral effects of Δ(9)-THC given via each route of administration were compared using a battery of tests, consisting of assessment of locomotor activity, nociception in the tail withdrawal test, catalepsy in the bar test, and hypothermia. Δ(9)-THC dose-dependently attenuated diclofenac-induced gastric hemorrhagic streaks through both p.o. and i.p. routes of administration (ED50 (95% confidence interval)=0.64 (0.26-1.55)mg/kg and 0.06 (0.01-0.34) mg/kg, respectively). Δ(9)-THC given i.p. was 2-3 orders of magnitude more potent in reducing diclofenac-induced gastric ulcers than in producing locomotor immobility, antinociception, hypothermia, and catalepsy, while the potency of ratio of p.o. Δ(9)-THC between each behavior measure was 7-18. These data indicate that the phytocannabinoid Δ(9)-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects.

  7. Functional interaction and cross-tolerance between ethanol and Δ9-THC: possible modulation by mouse cerebellar adenosinergic A1/GABAergic-A receptors.

    PubMed

    Dar, M Saeed

    2014-08-15

    We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population.

  8. Determination of the relative percentage distribution of THCA and Δ(9)-THC in herbal cannabis seized in Austria - Impact of different storage temperatures on stability.

    PubMed

    Taschwer, Magdalena; Schmid, Martin G

    2015-09-01

    Cannabis is globally by far the most widespread illicit drug of abuse. Especially since its legalization in some of the US, controversies about the legal status of cannabis for recreational and medical use have come up. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), which is the major active ingredient in cannabis products, is mainly responsible for the psychoactive effects. Its inactive biosynthetic precursor tetrahydrocannabinolic acid (THCA) is present in different quantities in fresh and undried cannabis plants. Under influence of drying, temperature and UV exposure it decomposes to Δ(9)-THC. In this study, a quantification of Δ(9)-THC and THCA was carried out to check the stability of cannabis samples. The determination of the degradation of THCA to Δ(9)-THC in 29 cannabis products seized in Austria was monitored by HPLC-UV. Mobile phase consisted of a 25mM triethylammoniumphosphate buffer (pH 3.0) and acetonitrile (36:64). A common LiChrospher(®) 100 RP-18 column was utilized as stationary phase. To check the influence of low as well as high temperature on the degradation process of the cannabinoid THCA to Δ(9)-THC, samples were stored in a freezer or in a drying cabinet for a specified time period. It was shown successfully that high storage temperatures led to a more rapid and complete decomposition of THCA to Δ(9)-THC while at low temperatures only slight or no changes of the percentage distribution were determined.

  9. Δ9-Tetrahydrocannabinolic acid synthase: The application of a plant secondary metabolite enzyme in biocatalytic chemical synthesis.

    PubMed

    Lange, Kerstin; Schmid, Andreas; Julsing, Mattijs K

    2016-09-10

    Δ(9)-Tetrahydrocannabinolic acid synthase (THCAS) from the secondary metabolism of Cannabis sativa L. catalyzes the oxidative formation of an intramolecular CC bond in cannabigerolic acid (CBGA) to synthesize Δ(9)-tetrahydrocannabinolic acid (THCA), which is the direct precursor of Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Aiming on a biotechnological production of cannabinoids, we investigated the potential of the heterologously produced plant oxidase in a cell-free system on preparative scale. THCAS was characterized in an aqueous/organic two-liquid phase setup in order to solubilize the hydrophobic substrate and to allow in situ product removal. Compared to the single phase aqueous setup the specific activity decreased by a factor of approximately 2 pointing to a substrate limitation of CBGA in the two-liquid phase system. However, the specific activity remained stable for at least 3h illustrating the benefit of the two-liquid phase setup. In a repeated-batch setup, THCAS showed only a minor loss of specific activity in the third batch pointing to a high intrinsic stability and high solvent tolerance of the enzyme. Maximal space-time-yields of 0.121gL(-1)h(-1) were reached proving the two-liquid phase concept suitable for biotechnological production of cannabinoids. PMID:27369551

  10. Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.

    PubMed

    Kangas, Brian D; Leonard, Michael Z; Shukla, Vidyanand G; Alapafuja, Shakiru O; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack

    2016-04-01

    The primary psychoactive ingredient of marijuana, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist Δ(9)-THC, fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597), and endocannabinoid anandamide and its stable synthetic analog methanandamide [(R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide]. The effects of Δ(9)-THC and anandamide after treatment with the cannabinoid receptor type 1 inverse agonist/antagonist rimonabant [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1Hpyrazole-3-carboxamide] and the FAAH inhibitor URB597, respectively, also were examined. The results showed the following: 1) Δ(9)-THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability < learning < flexibility < short-term memory); 2) anandamide alone and URB597 alone were without effect on all endpoints; 3) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but following large doses affected delayed matching-to-sample performance in some subjects; 4) all drugs, except anandamide and URB597, disrupted attention; and 5) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate

  11. Impaired NFAT and NFκB activation are involved in suppression of CD40 ligand expression by Δ{sup 9}-tetrahydrocannabinol in human CD4{sup +} T cells

    SciTech Connect

    Ngaotepprutaram, Thitirat; Kaplan, Barbara L.F.; Kaminski, Norbert E.

    2013-11-15

    We have previously reported that Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), the main psychoactive cannabinoid in marijuana, suppresses CD40 ligand (CD40L) expression by activated mouse CD4{sup +} T cells. CD40L is involved in pathogenesis of many autoimmune and inflammatory diseases. In the present study, we investigated the molecular mechanism of Δ{sup 9}-THC-mediated suppression of CD40L expression using peripheral blood human T cells. Pretreatment with Δ{sup 9}-THC attenuated CD40L expression in human CD4{sup +} T cells activated by anti-CD3/CD28 at both the protein and mRNA level, as determined by flow cytometry and quantitative real-time PCR, respectively. Electrophoretic mobility shift assays revealed that Δ{sup 9}-THC suppressed the DNA-binding activity of both NFAT and NFκB to their respective response elements within the CD40L promoter. An assessment of the effect of Δ{sup 9}-THC on proximal T cell-receptor (TCR) signaling induced by anti-CD3/CD28 showed significant impairment in the rise of intracellular calcium, but no significant effect on the phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β. Collectively, these findings identify perturbation of the calcium-NFAT and NFκB signaling cascade as a key mechanistic event by which Δ{sup 9}-THC suppresses human T cell function. - Highlights: • Δ{sup 9}-THC attenuated CD40L expression in activated human CD4+ T cells. • Δ{sup 9}-THC suppressed DNA-binding activity of NFAT and NFκB. • Δ{sup 9}-THC impaired elevation of intracellular Ca2+. • Δ{sup 9}-THC did not affect phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β.

  12. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

    PubMed

    Fantegrossi, William E; Moran, Jeffery H; Radominska-Pandya, Anna; Prather, Paul L

    2014-02-27

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances.

  13. Δ9-THC exposure attenuates aversive effects and reveals appetitive effects of K2/'Spice' constituent JWH-018 in mice.

    PubMed

    Hyatt, William S; Fantegrossi, William E

    2014-06-01

    The emergence of high-efficacy synthetic cannabinoids as drugs of abuse in readily available K2/'Spice' smoking blends has exposed users to much more potent and effective substances than the phytocannabinoids present in cannabis. Increasing reports of adverse reactions, including dependence and withdrawal, are appearing in the clinical literature. Here we investigated whether the effects of one such synthetic cannabinoid, 1-pentyl-3-(1-naphthoyl)indole (JWH-018), would be altered by a prior history of Δ9-tetrahydrocannabinol9-THC) exposure, in assays of conditioned taste aversion and conditioned place preference. In the conditioned taste aversion procedure, JWH-018 induced marked and persistent aversive effects in mice with no previous cannabinoid history, but the magnitude and duration of these aversive effects were significantly blunted in mice previously treated with an ascending dose regimen of Δ9-THC. Similarly, in the conditioned place preference procedure, JWH-018 induced dose-dependent aversive effects in mice with no previous drug history, but mice exposed to Δ9-THC before place conditioning showed reduced aversions at a high JWH-018 dose and apparent rewarding effects at a low dose of JWH-018. These findings suggest that a history of Δ9-THC exposure 'protects' against aversive effects and 'unmasks' appetitive effects of the high-efficacy synthetic cannabinoid JWH-018 in mice. This pattern of results implies that cannabinoid-naive individuals administering K2/'Spice' products for the first-time may be at an increased risk for adverse reactions, whereas those with a history of marijuana use may be particularly sensitive to the reinforcing effects of high-efficacy cannabinoids present in these commercial smoking blends.

  14. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity?

    PubMed Central

    Fantegrossi, William E.; Moran, Jeffery H.; Radominska-Pandya, Anna; Prather, Paul L.

    2013-01-01

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a “safe” and “legal” alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol9-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed “advantages” have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. PMID:24084047

  15. In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: inhalation versus intraperitoneal injection.

    PubMed

    Marshell, R; Kearney-Ramos, T; Brents, L K; Hyatt, W S; Tai, S; Prather, P L; Fantegrossi, W E

    2014-09-01

    Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Mice inhaled various doses of Δ(9)-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ(9)-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ(9)-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ(9)-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ(9)-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds.

  16. In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: Inhalation versus intraperitoneal injection

    PubMed Central

    Marshell, R.; Kearney-Ramos, T.; Brents, L.K.; Hyatt, W.S.; Tai, S.; Prather, P.L.; Fantegrossi, W.E.

    2015-01-01

    Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ9-tetrahydrocannabinol9-THC). Mice inhaled various doses of Δ9-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ9-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ9-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ9-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ9-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds. PMID:24857780

  17. Decarboxylation of Δ 9-tetrahydrocannabinol: Kinetics and molecular modeling

    NASA Astrophysics Data System (ADS)

    Perrotin-Brunel, Helene; Buijs, Wim; van Spronsen, Jaap; van Roosmalen, Maaike J. E.; Peters, Cor J.; Verpoorte, Rob; Witkamp, Geert-Jan

    2011-02-01

    Efficient tetrahydrocannabinol (Δ 9-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ 9-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ 9-THC-acid naturally present in the plant into the psychoactive Δ 9-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol -1 and a pre-exponential factor of 3.7 × 10 8 s -1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ 9-THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ 9-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ 9-THC from the plant.

  18. Acute and chronic effects of beta9-tetrahydrocannabinol on seizures in the gerbil.

    PubMed

    Ten Ham, M; Loskota, W J; Lomax, P

    1975-03-01

    Beta9-THC was injected daily for 6 days into gerbils from our breeding colony that exhibit spontaneous epileptiform seizures. At a dose of 20 mg/kg no effect was seen on the latency, duration or severity of the seizures induced after 1 and 6 days of treatment. Delta9-THC (50 mg/kg) completely abolished the seizures after a single injection but tolerance developed to this effect so that no protection was afforded after 6 daily doses. Severe toxic signs were evident at the higher dose level with marked depression of spontaneous motor activity. The toxic effect increased progressively with chronic treatment and half the animals failed to survive. PMID:1126373

  19. The effects of Δ9-Tetrahydrocannabinole treatment on gonadal micro-vascularization and affected fertility examined by SEM and 3D-morphometry

    NASA Astrophysics Data System (ADS)

    Erlbacher, K. M. T.; Minnich, B.

    2015-10-01

    The present study focuses on the effects of Δ9-tetrahydrocannabinol (THC) on the reproductive system in nude rats with special emphasis on how Δ9-THC impacts the vascularization of testes which in turn indirectly influences fertility. Basically, Δ9-tetrahydrocannabinol (THC) causes not only negative (psychoactive) effects in the human body as cannabinole administration in medical use (dose-dependent) offers multiple new treatment opportunities such as pain relief or containment of various cancers. Concerning the reproductive system it strongly influences CB-receptors along the hypothalamic-pituitary-gonadal axis resulting in reduced plasma testosterone levels. There is also altered sperm quality parameters reported such as sperm motility or sperm count. On the other hand Δ9-THC effects endothelial growth factors (VEGF, Ang-1 etc.) respectively acts on their specific receptors which in turn modify angiogenesis and vascularization of tissues and organs (e.g. tumorous tissues). This leads to new therapeutical strategies in the suppression of various cancers by inhibiting (neo-)vascularization and in turn famishment of tumorous tissues (lack of nutrition supply). Here we studied the micro-vascularization of gonads in a long-term THC-treated nude rat model by vascular corrosion casting, SEM and 3D-morphometry.

  20. Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.

    PubMed

    Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong; Harada, Mari; Okazaki, Hiroyuki; Yoshioka, Yasushi; Nishimura, Hajime; Ishii, Hiroyuki; Kakizoe, Kazuhiro; Taniguchi, Aya; Tokuyasu, Miki; Himeno, Taichi; Watanabe, Kazuhito; Omiecinski, Curtis J; Aramaki, Hironori

    2014-12-01

    We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells.

  1. Effects of Δ9-THC on Working Memory: Implications for Schizophrenia?

    PubMed Central

    Vadhan, Nehal P.; Serper, Mark R.; Haney, Margaret

    2009-01-01

    This article reviews the literature on the acute effects of Delta 9-tetrahydrocannabinol, the primary psychoactive component of marijuana, on working memory, and the implications for schizophrenia. Working memory deficits are a hallmark feature of schizophrenia, and have been implicated as an etiologic mechanism contributing to the onset of the disorder. Regular marijuana smokers may also exhibit subtle working memory impairment relative to healthy controls, and an association between marijuana abuse and subsequent development of schizophrenia, though controversial, has been reported in the literature. The causal role that marijuana plays in working memory impairment related to schizophrenia, however, remains unclear. Thus, this article specifically considers the acute effects of marijuana on working memory performance. The ecologic relevance and clinical significance of these findings will be examined, and directions for future research will be recommended. PMID:20351792

  2. Cloud point extraction of Δ9-tetrahydrocannabinol from cannabis resin.

    PubMed

    Ameur, S; Haddou, B; Derriche, Z; Canselier, J P; Gourdon, C

    2013-04-01

    A cloud point extraction coupled with high performance liquid chromatography (HPLC/UV) method was developed for the determination of Δ(9)-tetrahydrocannabinol (THC) in micellar phase. The nonionic surfactant "Dowfax 20B102" was used to extract and pre-concentrate THC from cannabis resin, prior to its determination with a HPLC-UV system (diode array detector) with isocratic elution. The parameters and variables affecting the extraction were investigated. Under optimum conditions (1 wt.% Dowfax 20B102, 1 wt.% Na2SO4, T = 318 K, t = 30 min), this method yielded a quite satisfactory recovery rate (~81 %). The limit of detection was 0.04 μg mL(-1), and the relative standard deviation was less than 2 %. Compared with conventional solid-liquid extraction, this new method avoids the use of volatile organic solvents, therefore is environmentally safer.

  3. Chronic Administration of Δ9-Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

    PubMed Central

    Chandra, Lawrance C.; Kumar, Vinay; Torben, Workineh; Stouwe, Curtis Vande; Winsauer, Peter; Amedee, Angela; Molina, Patricia E.

    2014-01-01

    ABSTRACT Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including Δ9-THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of Δ9-THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving Δ9-THC (n = 3) and SIV-infected macaques administered either vehicle (VEH/SIV; n = 4) or THC (THC/SIV; n = 4). Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ∼28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal

  4. Cannabis and Δ9-tetrahydrocannabinol (THC) for weight loss?

    PubMed

    Le Foll, Bernard; Trigo, Jose M; Sharkey, Keith A; Le Strat, Yann

    2013-05-01

    Obesity is one of the highest preventable causes of morbidity and mortality in the developed world [1]. It has been well known for a long time that exposure to cannabis produces an increase of appetite (a phenomenon referred to as the 'munchies'). This phenomenon led to an exploration of the role of the endocannabinoid system in the regulation of obesity and associated metabolic syndrome. This effort subsequently led to the development of a successful therapeutic approach for obesity that consisted of blocking the cannabinoid CB1 receptors using ligands such as Rimonabant in order to produce weight loss and improve metabolic profile [2]. Despite being efficacious, Rimonabant was associated with increased rates of depression and anxiety and therefore removed from the market. We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age. Here, we propose that this effect is directly related to exposure to the Δ(9)-tetrahydrocannabinol (THC) present in cannabis smoke. We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications. PMID:23410498

  5. AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol-Like Effects in Mice.

    PubMed

    Wiley, Jenny L; Marusich, Julie A; Lefever, Timothy W; Antonazzo, Kateland R; Wallgren, Michael T; Cortes, Ricardo A; Patel, Purvi R; Grabenauer, Megan; Moore, Katherine N; Thomas, Brian F

    2015-09-01

    Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids, AB-CHMINACA (N-[1-amino-3-methyl-oxobutan-2-yl]-1-[cyclohexylmethyl]-1H-indazole-3-carboxamide), AB-PINACA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide], and FUBIMINA [(1-(5-fluoropentyl)-1H-benzo[d]imadazol-2-yl)(naphthalen-1-yl)methanone], with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB1 receptors, and in vivo for pharmacological effects in mice and in Δ(9)-tetrahydrocannabinol (Δ(9)-THC) discrimination. AB-CHMINACA, AB-PINACA, and FUBIMINA bound to and activated CB1 and CB2 receptors, and produced locomotor suppression, antinociception, hypothermia, and catalepsy. Furthermore, these compounds, along with JWH-018 [1-pentyl-3-(1-naphthoyl)indole], CP47,497 [rel-5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol], and WIN55,212-2 ([(3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone, monomethanesulfonate), substituted for Δ(9)-THC in Δ(9)-THC discrimination. Rank order of potency correlated with CB1 receptor-binding affinity, and all three compounds were full agonists in [(35)S]GTPγS binding, as compared with the partial agonist Δ(9)-THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB1 receptor efficacies. Further studies on these chemicals are likely to include research on understanding cannabinoid

  6. Development and validation of a LC/MS method for the determination of Δ(9)-tetrahydrocannabinol and 11-carboxy-Δ(9)-tetrahydrocannabinol in the larvae of the blowfly Lucilia sericata: Forensic applications.

    PubMed

    Karampela, Sevasti; Pistos, Constantinos; Moraitis, Konstantinos; Stoukas, Vasilios; Papoutsis, Ioannis; Zorba, Eleni; Koupparis, Michalis; Spiliopoulou, Chara; Athanaselis, Sotiris

    2015-12-01

    In a number of forensic toxicological cases, Δ(9)-tetrahydrocannabinol (THC) and its metabolite 11-carboxy-delta-9-tetrahydrocannabinol (THCA) are frequently considered as contributor factors to the event. To that, a liquid chromatographic mass spectrometric method is described for the identification and quantitation of THC and its metabolite THCA in the forensically important larvae of L. sericata. Larvae of Lucilia sericata were fortified with varying concentrations of THC and THCA covering the calibration range between 10 and 500pg/mg. For the isolation of the analytes from larvae, several extraction techniques were evaluated and finally liquid-liquid extraction under acidic pH was selected using hexane-ethyl acetate (50:50, v/v) as extraction solvent. For the chromatographic separation, a Waters Symmetry® C18 analytical column was used while the mobile phase was acetonitrile-ammonium acetate (2mM) (30:70, v/v). The detection was performed using electrospray ionization source in negative mode (ESI-) and the selected ions monitored were m/z 313 for THC and m/z 343 for THCA. The proposed method which is simple and sufficiently sensitive for the detection of THC and THCA even in a single larva sampling, assisted the investigation of a forensic case. PMID:26654083

  7. Development and validation of a LC/MS method for the determination of Δ(9)-tetrahydrocannabinol and 11-carboxy-Δ(9)-tetrahydrocannabinol in the larvae of the blowfly Lucilia sericata: Forensic applications.

    PubMed

    Karampela, Sevasti; Pistos, Constantinos; Moraitis, Konstantinos; Stoukas, Vasilios; Papoutsis, Ioannis; Zorba, Eleni; Koupparis, Michalis; Spiliopoulou, Chara; Athanaselis, Sotiris

    2015-12-01

    In a number of forensic toxicological cases, Δ(9)-tetrahydrocannabinol (THC) and its metabolite 11-carboxy-delta-9-tetrahydrocannabinol (THCA) are frequently considered as contributor factors to the event. To that, a liquid chromatographic mass spectrometric method is described for the identification and quantitation of THC and its metabolite THCA in the forensically important larvae of L. sericata. Larvae of Lucilia sericata were fortified with varying concentrations of THC and THCA covering the calibration range between 10 and 500pg/mg. For the isolation of the analytes from larvae, several extraction techniques were evaluated and finally liquid-liquid extraction under acidic pH was selected using hexane-ethyl acetate (50:50, v/v) as extraction solvent. For the chromatographic separation, a Waters Symmetry® C18 analytical column was used while the mobile phase was acetonitrile-ammonium acetate (2mM) (30:70, v/v). The detection was performed using electrospray ionization source in negative mode (ESI-) and the selected ions monitored were m/z 313 for THC and m/z 343 for THCA. The proposed method which is simple and sufficiently sensitive for the detection of THC and THCA even in a single larva sampling, assisted the investigation of a forensic case.

  8. The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors.

    PubMed

    Moreno-Martet, Miguel; Feliú, Ana; Espejo-Porras, Francisco; Mecha, Miriam; Carrillo-Salinas, Francisco J; Fernández-Ruiz, Javier; Guaza, Carmen; de Lago, Eva

    2015-11-01

    Sativex(®), an equimolecular combination of Δ(9)-tetrahydrocannabinol-botanical drug substance (Δ(9)-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain. However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components. In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice. We compared the effect of a Sativex-like combination of Δ(9)-THC-BDS (10 mg/kg) and CBD-BDS (10 mg/kg) with Δ(9)-THC-BDS (20 mg/kg) or CBD-BDS (20 mg/kg) administered separately by intraperitoneal administration to EAE mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease. The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS. These effects were completely reproduced by the treatment with Δ(9)-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord. Next, we investigated the potential targets involved in the effects of Δ(9)-THC-BDS by selectively blocking CB(1) or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB(1) receptor antagonist. Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ(9)-THC-BDS acting through CB(1

  9. The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors.

    PubMed

    Moreno-Martet, Miguel; Feliú, Ana; Espejo-Porras, Francisco; Mecha, Miriam; Carrillo-Salinas, Francisco J; Fernández-Ruiz, Javier; Guaza, Carmen; de Lago, Eva

    2015-11-01

    Sativex(®), an equimolecular combination of Δ(9)-tetrahydrocannabinol-botanical drug substance (Δ(9)-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain. However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components. In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice. We compared the effect of a Sativex-like combination of Δ(9)-THC-BDS (10 mg/kg) and CBD-BDS (10 mg/kg) with Δ(9)-THC-BDS (20 mg/kg) or CBD-BDS (20 mg/kg) administered separately by intraperitoneal administration to EAE mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease. The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS. These effects were completely reproduced by the treatment with Δ(9)-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord. Next, we investigated the potential targets involved in the effects of Δ(9)-THC-BDS by selectively blocking CB(1) or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB(1) receptor antagonist. Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ(9)-THC-BDS acting through CB(1

  10. Regioselective synthesis of isotopically labeled Δ9-tetrahydrocannabinolic acid A (THCA-A-D3) by reaction of Δ9-tetrahydrocannabinol-D3 with magnesium methyl carbonate.

    PubMed

    Roth, Nadine; Wohlfarth, Ariane; Müller, Michael; Auwärter, Volker

    2012-10-10

    For the reliable quantification of Δ9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of Δ9-tetrahydrocannabinol (THC), in biological matrices by LC-MS/MS and GC-MS(/MS), an isotopically labeled internal standard was synthesized starting from Δ9-tetrahydrocannabinol-D(3) (THC-D(3)). Synthesis strategy was based on a method reported by Mechoulam et al. in 1969 using magnesium methyl carbonate (MMC) as carboxylation reagent for the synthesis of cannabinoid acids. Preliminary experiments with THC to optimize yield of the product (THCA-A) resulted in the synthesis of the positional isomer tetrahydrocannabinolic acid B (THCA-B) as a byproduct. Using the optimized conditions for the desired isomer, THCA-A-D(3) was prepared and isolated with a yield of approx. 10% after two synthesis cycles. Isotope purity was estimated to be >99% by relative abundance of the molecular ions. The synthesized compound proved to be suitable as an internal standard for quantification of THCA-A in serum and hair samples of cannabis consumers.

  11. Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L

    PubMed Central

    El-Alfy, Abir T.; Ivey, Kelly; Robinson, Keisha; Ahmed, Safwat; Radwan, Mohamed; Slade, Desmond; Khan, Ikhlas; ElSohly, Mahmoud; Ross, Samir

    2010-01-01

    The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Δ9-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Δ9-THC and Δ8-THC showed a U-shaped dose response with only Δ9-THC showing significant antidepressant-like effects at 2.5 mg/kg (p < 0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200 mg/kg, respectively (p < 0.01). The antidepressant-like action of Δ9-THC and CBC was further confirmed in the TST. Δ9 -THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p < 0.05) while CBC resulted in a significant dose dependent decrease in immobility at 40 and 80 mg/kg doses (p < 0.01). Results of this study show that Δ9-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis. PMID:20332000

  12. Distribution of ∆(9)-Tetrahydrocannabinol and 11-Nor-9-Carboxy-∆(9)-Tetrahydrocannabinol Acid in Postmortem Biological Fluids and Tissues From Pilots Fatally Injured in Aviation Accidents.

    PubMed

    Kemp, Philip M; Cardona, Patrick S; Chaturvedi, Arvind K; Soper, John W

    2015-07-01

    Little is known of the postmortem distribution of ∆(9)-tetrahydrocannabinol (THC) and its major metabolite, 11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THCCOOH). Data from 55 pilots involved in fatal aviation accidents are presented in this study. Gas chromatography/mass spectrometry analysis obtained mean THC concentrations in blood from multiple sites, liver, lung, and kidney of 15.6 ng/mL, 92.4 ng/g, 766.0 ng/g, 44.1 ng/g and mean THCCOOH concentrations of 35.9 ng/mL, 322.4 ng/g, 42.6 ng/g, 138.5 ng/g, respectively. Heart THC concentrations (two cases) were 184.4 and 759.3 ng/g, and corresponding THCCOOH measured 11.0 and 95.9 ng/g, respectively. Muscle concentrations for THC (two cases) were 16.6 and 2.5 ng/g; corresponding THCCOOH, "confirmed positive" and 1.4 ng/g. The only brain tested in this study showed no THC detected and 2.9 ng/g THCCOOH, low concentrations that correlated with low values in other specimens from this case. This research emphasizes the need for postmortem cannabinoid testing and demonstrates the usefulness of a number of tissues, most notably lung, for these analyses.

  13. Distribution of ∆(9)-Tetrahydrocannabinol and 11-Nor-9-Carboxy-∆(9)-Tetrahydrocannabinol Acid in Postmortem Biological Fluids and Tissues From Pilots Fatally Injured in Aviation Accidents.

    PubMed

    Kemp, Philip M; Cardona, Patrick S; Chaturvedi, Arvind K; Soper, John W

    2015-07-01

    Little is known of the postmortem distribution of ∆(9)-tetrahydrocannabinol (THC) and its major metabolite, 11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THCCOOH). Data from 55 pilots involved in fatal aviation accidents are presented in this study. Gas chromatography/mass spectrometry analysis obtained mean THC concentrations in blood from multiple sites, liver, lung, and kidney of 15.6 ng/mL, 92.4 ng/g, 766.0 ng/g, 44.1 ng/g and mean THCCOOH concentrations of 35.9 ng/mL, 322.4 ng/g, 42.6 ng/g, 138.5 ng/g, respectively. Heart THC concentrations (two cases) were 184.4 and 759.3 ng/g, and corresponding THCCOOH measured 11.0 and 95.9 ng/g, respectively. Muscle concentrations for THC (two cases) were 16.6 and 2.5 ng/g; corresponding THCCOOH, "confirmed positive" and 1.4 ng/g. The only brain tested in this study showed no THC detected and 2.9 ng/g THCCOOH, low concentrations that correlated with low values in other specimens from this case. This research emphasizes the need for postmortem cannabinoid testing and demonstrates the usefulness of a number of tissues, most notably lung, for these analyses. PMID:25800046

  14. Hair analysis for Δ(9) -tetrahydrocannabinolic acid A (THCA-A) and Δ(9) -tetrahydrocannabinol (THC) after handling cannabis plant material.

    PubMed

    Moosmann, Bjoern; Roth, Nadine; Auwärter, Volker

    2016-01-01

    A previous study has shown that Δ(9) -tetrahydrocannabinolic acid A (THCA-A), the non-psychoactive precursor of Δ(9) -tetrahydrocannabinol (THC) in the cannabis plant does not get incorporated in relevant amounts into the hair through the bloodstream after repeated oral intake. However, THCA-A can be measured in forensic hair samples in concentrations often exceeding the detected THC concentrations. To investigate whether the handling of cannabis plant material prior to consumption is a contributing factor for THC-positive hair results and also the source for THCA-A findings in hair, a study comprising ten participants was conducted. In this study, the participants rolled a marijuana joint on five consecutive days and hair samples of each participant were obtained. Urine samples were taken to exclude cannabis consumption prior to and during the study. THCA-A and THC could be detected in the hair samples from all participants taken at the end of the exposure period (concentration range: 15-1800 pg/mg for THCA-A and < 10-93 pg/mg for THC). Four weeks after the first exposure, THCA-A could still be detected in the hair samples of nine participants (concentration range: 4-57 pg/mg). Furthermore, THC could be detected in the hair samples of five participants (concentration range: < 10-17 pg/mg). Based on these results, it can be concluded that at least parts of the THC as well as the major part of THCA-A found in routine hair analysis derives from external contamination caused by direct transfer through contaminated fingers. This finding is of particular interest in interpreting THC-positive hair results of children or partners of cannabis users, where such a transfer can occur due to close body contact. Analytical findings may be wrongly interpreted as a proof of consumption or at least passive exposure to cannabis smoke. Such misinterpretation could lead to severe consequences for the people concerned.

  15. Synthesis of [13C4]-labeled ∆9-tetrahydrocannabinol and 11-nor-9-carboxy-∆9-tetrahydrocannabinol as internal standards for reducing ion suppressing/alteration effects in LC/MS-MS quantification.

    PubMed

    Karlsen, Morten; Liu, Huiling; Johansen, Jon Eigill; Hoff, Bård Helge

    2014-09-01

    (-)-∆9-Tetrahydrocannabinol is the principal psychoactive component of the cannabis plant and also the active ingredient in some prescribed drugs. To detect and control misuse and monitor administration in clinical settings, reference samples of the native drugs and their metabolites are needed. The accuracy of liquid chromatography/mass spectrometric quantification of drugs in biological samples depends among others on ion suppressing/alteration effects. Especially, 13C-labeled drug analogues are useful for minimzing such interferences. Thus, to provide internal standards for more accurate quantification and for identification purpose, synthesis of [13C4]-∆9-tetrahydro-cannabinol and [13C4]-11-nor-9-carboxy-∆9-tetrahydrocannabinol was developed via [13C4]-olivetol. Starting from [13C4]-olivetol the synthesis of [13C4]-11-nor-9-carboxy-∆9-tetrahydrocannabinol was shortened from three to two steps by employing nitromethane as a co-solvent in condensation with (+)-apoverbenone.

  16. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

    PubMed

    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy. PMID:27214593

  17. Mother-Infant Interaction in Rhesus Monkeys Treated Chronically with Delta-9-Tetrahydrocannabinol.

    ERIC Educational Resources Information Center

    Golub, Mari S.; And Others

    1981-01-01

    Drug-exposed mother-infant rhesus monkey pairs were similar to nontreated controls in the amount and types of activity displayed at the infant's tenth and ninetieth day of age. At about 3 months of age drug-exposed pairs increased in interaction, signaling mother-infant independence. This finding suggests that mother-infant attachment may be…

  18. Disposition of smoked cannabis with high {Delta}{sup 9}-tetrahydrocannabinol content: A kinetic model

    SciTech Connect

    Hunault, Claudine C.; Eijkeren, Jan C.H. van; Mensinga, Tjeert T.; Vries, Irma de; Leenders, Marianne E.C.; Meulenbelt, Jan

    2010-08-01

    Introduction: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3 mg, 49.1 mg, and 69.4 mg THC. Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were C{sub max} = 175 ng/mL, T{sub max} = 14 min, and AUC{sub 0-8h} = 8150 ng x min/mL for the 69.4 mg THC dose. Median model results show an almost linear dose response relation for C{sub max}/Dose = 2.8 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 136 x 10{sup -6} min/mL. However, for increasing dose level, there was a clear decreasing trend: C{sub max}/Dose = 3.4, 2.6 and 2.5 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 157, 133 and 117 x 10{sup -6} min/mL for the 29.3, 49.1 and 69.4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).

  19. Synaptic Targets of Δ9-Tetrahydrocannabinol in the Central Nervous System

    PubMed Central

    Hoffman, Alexander F.; Lupica, Carl R.

    2013-01-01

    The availability of potent synthetic agonists for cannabinoid receptors has facilitated our understanding of cannabinoid actions on synaptic transmission in the central nervous system. Moreover, the ability of these compounds to inhibit neurotransmitter release at many central synapses is thought to underlie most of the behavioral effects of cannabinoid agonists. However, despite the widespread use and misuse of marijuana, and recognition of its potential adverse psychological effects in humans, comparatively few studies have examined the actions of its primary psychoactive constituent, Δ9-tetrahydrocannabinol (THC), at well-defined synaptic pathways. Here we examine the recent literature describing the effects of acute and repeated THC exposure on synaptic function in several brain regions and explore the importance of these neurobiological actions of THC in drug addiction. PMID:23209160

  20. Investigation of a recently detected 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol isomer: Studies on the degradation of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol glucuronide.

    PubMed

    Hanisch, Stephanie; Paulke, Alexander; Toennes, Stefan W

    2016-09-10

    An isomer of the tetrahydrocannabinol (THC) metabolite 11-nor-9-carboxy-Δ(9)-THC (THCCOOH) had been detected in blood of cannabis users. The present study was initiated to elucidate whether the labile metabolite THCCOOH-glucuronide could be the precursor. THCCOOH-glucuronide was incubated in human serum and albumin (HSA) solution at various temperatures (-18, 4.5, 22 and 37°C) and pH values (pH 7.4 and 8.3) for seven days in the presence or absence of the esterase inhibitor sodium fluoride. Analysis of incubation samples was performed using LC-MS/MS. Marked degradation of THCCOOH-glucuronide was observed at 37°C. It was found that not only THCCOOH, but also the isomer is a degradation product of THCCOOH-glucuronide and its in-vivo production is assumed. Degradation to THCCOOH and the isomer occurred at alkaline pH, in the presence of fluoride-sensitive esterases and of HSA alone. To inhibit isomer formation during sample storage, refrigeration and controlling of the pH are recommended. However, THCCOOH and the isomer exhibit similar properties during incubations in serum, but differ in their interaction with HSA. The present study confirmed the nature of the isomer as degradation product of the abundant THC metabolite THCCOOH-glucuronide. Serum albumin and esterases are obviously involved. The isomer is formed not only during storage, but also under physiological conditions, suggesting that it can be considered an in-vivo metabolite. However, the chemical structure of the isomer remains unknown and further research is necessary.

  1. Investigation of a recently detected 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol isomer: Studies on the degradation of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol glucuronide.

    PubMed

    Hanisch, Stephanie; Paulke, Alexander; Toennes, Stefan W

    2016-09-10

    An isomer of the tetrahydrocannabinol (THC) metabolite 11-nor-9-carboxy-Δ(9)-THC (THCCOOH) had been detected in blood of cannabis users. The present study was initiated to elucidate whether the labile metabolite THCCOOH-glucuronide could be the precursor. THCCOOH-glucuronide was incubated in human serum and albumin (HSA) solution at various temperatures (-18, 4.5, 22 and 37°C) and pH values (pH 7.4 and 8.3) for seven days in the presence or absence of the esterase inhibitor sodium fluoride. Analysis of incubation samples was performed using LC-MS/MS. Marked degradation of THCCOOH-glucuronide was observed at 37°C. It was found that not only THCCOOH, but also the isomer is a degradation product of THCCOOH-glucuronide and its in-vivo production is assumed. Degradation to THCCOOH and the isomer occurred at alkaline pH, in the presence of fluoride-sensitive esterases and of HSA alone. To inhibit isomer formation during sample storage, refrigeration and controlling of the pH are recommended. However, THCCOOH and the isomer exhibit similar properties during incubations in serum, but differ in their interaction with HSA. The present study confirmed the nature of the isomer as degradation product of the abundant THC metabolite THCCOOH-glucuronide. Serum albumin and esterases are obviously involved. The isomer is formed not only during storage, but also under physiological conditions, suggesting that it can be considered an in-vivo metabolite. However, the chemical structure of the isomer remains unknown and further research is necessary. PMID:27448313

  2. Evaluation of Δ9-tetrahydrocannabinol metabolites and oxidative stress in type 2 diabetic rats

    PubMed Central

    Coskun, Zeynep Mine; Bolkent, Sema

    2016-01-01

    Objective(s): The object of the study is to examine the effects of Δ9-tetrahydrocannabinol (THC) against oxidative stress in the blood and excretion of THC metabolites in urine of type 2 diabetic rats. Materials and Methods: The control (n=8), THC control (n=6), diabetes (n=8) and diabetes + THC (n=7) groups were created. Type 2 diabetes was induced by nicotinamide (NA, 85 mg/kg) + streptozotocin (STZ, 65 mg/kg). THC was administered intraperitoneally for seven days. The glutathione (GSH) level in erythrocytes and malondialdehyde (MDA) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities in plasma were measured. THC metabolites were analyzed in urine. Results: The results showed that the erythrocyte GSH levels were significantly increased (P<0.05), but plasma MDA levels were non-significantly decreased in diabetes group treated with THC when compared with the diabetes group. The CAT activity was non-significantly reduced and SOD was significantly increased (P<0.01) in the plasma of diabetes induced by THC in comparison with the diabetic group. The excretion of THC metabolites was higher in the urine of diabetes + THC rats as compared to the THC control rats. Conclusion: These findings highlight that THC treatment may attenuate slightly the oxidative stress in diabetic rats. The excretion rate of THC may vary in the type 2 diabetes mellitus status. PMID:27081459

  3. Automated GC-MS Determination of Δ9-Tetrahydrocannabinol, Cannabinol and Cannabidiol in Hair.

    PubMed

    Heinl, Sonja; Lerch, Oliver; Erdmann, Freidoon

    2016-09-01

    The determination of Δ(9)-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) in hair is a major routine task in forensic laboratories worldwide. A comprehensively automated liquid-liquid extraction (LLE) method has been developed. The automation was carried out by an x-y-z sample robot equipped with modules capable of shaking, centrifugation and solvent evaporation. It comprises digestion of hair in sodium hydroxide solution, LLE, extract evaporation, reconstitution in silylation reagent, inlet derivatization and GC-MS analysis. Method validation guidelines of the Society for Toxicological and Forensic Chemistry were fulfilled. The limit of quantification (LOQ) was 0.01 ng/mg for THC, 0.06 ng/mg for CBN and 0.03 ng/mg for CBD. This is below the required LOQ for THC (0.02 ng/mg) in medical psychological assessments in Germany. Also it is far below the required LOQ of the Society of Hair Testing of 0.1 ng/mg for THC. Four-round robin tests were passed successfully and several post- and ante-mortem samples were analyzed. To date the method is routinely employed at the Institute of Legal Medicine in Giessen, Germany. To the best of our knowledge, this is the first publication on a comprehensively automated classical LLE workflow in the field of hair analysis. PMID:27344041

  4. Genetic Dissection of Behavioural and Autonomic Effects of Δ9-Tetrahydrocannabinol in Mice

    PubMed Central

    Monory, Krisztina; Blaudzun, Heike; Massa, Federico; Kaiser, Nadine; Lemberger, Thomas; Schütz, Günther; Wotjak, Carsten T; Lutz, Beat; Marsicano, Giovanni

    2007-01-01

    Marijuana and its main psychotropic ingredient Δ9-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release γ aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions. PMID:17927447

  5. Temperature Stability and Bioadhesive Properties of Δ9-Tetrahydrocannabinol Incorporated Hydroxypropylcellulose Polymer Matrix Systems

    PubMed Central

    Repka, Michael A.; Munjal, Manish; ElSohly, Mahmoud A.; Ross, Samir A.

    2010-01-01

    The purpose of this study was to determine and compare the bioadhesive profiles of hydroxypropylcellulose (HPC) polymer matrices as a function of Δ9-tetrahydrocannabinol (THC) content. In addition, the effect of processing temperature on the stability of THC and its extent of degradation to cannabinol (CBN) was investigated. A hot-melt cast molding method was used to prepare HPC polymer matrix systems incorporated with THC at 0, 4, 8, and 16 percent. Bioadhesive measurements including peak adhesive force, area under the curve, and elongation at adhesive failure were recorded utilizing the TA.XT2i Texture Analyzer™. Data obtained from these tests at various contact time intervals suggested that the incorporation of THC led to an increase in the bioadhesive strength of the HPC polymer matrices. To determine the stability of THC and the resulting CBN content in the matrices, three different processing temperatures were utilized (120, 160, and 200°C). Post-production High Performance Liquid Chromotography (HPLC) analysis revealed that the processed systems contained at least 94% of THC and the relative percent formation of CBN was 0.5% at 120°C and 0.4% at 160°C compared to 1.6% at 200°C. These findings indicate that the cannabinoid may be a plausible candidate for incorporation into systems utilizing hot-melt extrusion techniques for the development of an effective mucoadhesive transmucosal matrix system for delivery of THC. PMID:16455601

  6. Automated GC-MS Determination of Δ9-Tetrahydrocannabinol, Cannabinol and Cannabidiol in Hair.

    PubMed

    Heinl, Sonja; Lerch, Oliver; Erdmann, Freidoon

    2016-09-01

    The determination of Δ(9)-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) in hair is a major routine task in forensic laboratories worldwide. A comprehensively automated liquid-liquid extraction (LLE) method has been developed. The automation was carried out by an x-y-z sample robot equipped with modules capable of shaking, centrifugation and solvent evaporation. It comprises digestion of hair in sodium hydroxide solution, LLE, extract evaporation, reconstitution in silylation reagent, inlet derivatization and GC-MS analysis. Method validation guidelines of the Society for Toxicological and Forensic Chemistry were fulfilled. The limit of quantification (LOQ) was 0.01 ng/mg for THC, 0.06 ng/mg for CBN and 0.03 ng/mg for CBD. This is below the required LOQ for THC (0.02 ng/mg) in medical psychological assessments in Germany. Also it is far below the required LOQ of the Society of Hair Testing of 0.1 ng/mg for THC. Four-round robin tests were passed successfully and several post- and ante-mortem samples were analyzed. To date the method is routinely employed at the Institute of Legal Medicine in Giessen, Germany. To the best of our knowledge, this is the first publication on a comprehensively automated classical LLE workflow in the field of hair analysis.

  7. CB1 cannabinoid receptors mediate endochondral skeletal growth attenuation by Δ9-tetrahydrocannabinol.

    PubMed

    Wasserman, Elad; Tam, Joseph; Mechoulam, Raphael; Zimmer, Andreas; Maor, Gila; Bab, Itai

    2015-01-01

    The endocannabinoid (EC) system regulates bone mass. Because cannabis use during pregnancy results in stature shorter than normal, we examined the role of the EC system in skeletal elongation. We show that CB1 and CB2 cannabinoid receptors are expressed specifically in hypertrophic chondrocytes of the epiphyseal growth cartilage (EGC), which drives vertebrate growth. These cells also express diacylglycerol lipases, critical biosynthetic enzymes of the main EC, and 2-arachidonoylglycerol (2-AG), which is present at significant levels in the EGC. Femora of CB1- and/or CB2-deficient mice at the end of the rapid growth phase are longer compared to wild-type (WT) animals. We find that Δ(9) -tetrahydrocannabinol (THC) slows skeletal elongation of female WT and CB2-, but not CB1-, deficient mice, which is reflected in femoral and lumbar vertebral body length. This in turn results in lower body weight, but unaltered fat content. THC inhibits EGC chondrocyte hypertrophy in ex vivo cultures and reduces the hypertrophic cell zone thickness of CB1-, but not CB2-, deficient mice. These results demonstrate a local growth-restraining EC system in the EGC. The relevance of the present findings to humans remains to be studied.

  8. The safety of modafinil in combination with oral ∆9-tetrahydrocannabinol in humans.

    PubMed

    Sugarman, Dawn E; Poling, James; Sofuoglu, Mehmet

    2011-03-01

    Marijuana (cannabis) is the most widely used illicit substance globally, and cannabis use is associated with a range of adverse consequences. Currently, no medications have been proven to be effective for the treatment of cannabis addiction. The goals of this study were to examine the safety and efficacy of a potential treatment medication, modafinil, in combination with oral ∆9-tetrahydrocannabinol (THC). Twelve male and female occasional cannabis users participated in an outpatient double-blind, placebo-controlled, crossover study. Across four sessions, participants were randomly assigned to a sequence of four oral treatments: (1) 400 mg modafinil+placebo, (2) 15 mg THC+placebo, (3) 400 mg modafinil+15 mg THC, or (4) placebo+placebo. Outcome measures included heart rate, blood pressure, performance on the Rapid Visual Information Processing (RVIP), and the Hopkins Verbal Learning Test (HVLT), and subjective measures. Oral THC increased heart rate, and produced increased subjective ratings of feeling "high" and "sedated," as well as increased ratings of euphoria. Modafinil alone increased the Profiles of Mood States (POMS) subscales of vigor and tension. These findings support the safety of modafinil in combination with THC. The effects of modafinil in combination with a range of doses of THC need to be determined in future studies. PMID:21176784

  9. Ocular Disposition of the Hemiglutarate Ester Prodrug of ∆9-Tetrahydrocannabinol from Various Ophthalmic Formulations

    PubMed Central

    Hingorani, Tushar; Adelli, Goutham R.; Punyamurthula, Nagendra; Gul, Waseem; ElSohly, Mahmoud A.; Repka, Michael A.; Majumdar, Soumyajit

    2013-01-01

    Purpose The overall goal of this project is to enhance ocular delivery of ∆9-Tetrahydrocannabinol (THC) through the topical route. Methods Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo. Results Aqueous solubility and stability and in vitro transcorneal permeability of THCHG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber. Conclusion In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye. PMID:23737345

  10. Interactions between Δ(9)-tetrahydrocannabinol and heroin: self-administration in rhesus monkeys.

    PubMed

    Li, Jun-Xu; Koek, Wouter; France, Charles P

    2012-12-01

    The cannabinoid receptor agonist Δ(9)-tetrahydrocannabinol (THC) enhances the antinociceptive effects of µ-opioid receptor agonists, raising the possibility of using a combination of THC and opioids for treating pain. This study examined the effects of noncontingent and contingent administration of THC on intravenous heroin self-administration in rhesus monkeys. Self-administration of different unit doses of heroin (0.0001-0.1 mg/kg/infusion) generated a typical inverted U-shaped dose-response curve. In one experiment (n=4), noncontingent THC (0.1-1.0 mg/kg) dose dependently shifted the heroin dose-response curve downward in three monkeys and slightly leftward in one monkey. In a second experiment (n=4), monkeys could self-administer THC alone (0.0032-0.032 mg/kg/infusion), heroin alone, or a mixture of THC and heroin. THC alone did not maintain responding above that obtained with saline; however, increasing the THC dose with heroin dose dependently decreased the number of infusions received and the rate of responding, as compared with data that were obtained with heroin alone. These results indicate that THC does not significantly enhance the positive reinforcing effects of heroin, further supporting the view that combining cannabinoid and opioid receptor agonists (e.g. for treating pain) does not increase, and might decrease, the abuse liability of individual drugs. PMID:23044830

  11. Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology.

    PubMed

    Nguyen, Jacques D; Aarde, Shawn M; Vandewater, Sophia A; Grant, Yanabel; Stouffer, David G; Parsons, Loren H; Cole, Maury; Taffe, Michael A

    2016-10-01

    Most human Δ(9)-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano(®), e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt "vaping" for the administration of cannabis. PMID:27256501

  12. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

    PubMed

    Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

    2015-02-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

  13. Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa

    PubMed Central

    Marks, M. David; Tian, Li; Wenger, Jonathan P.; Omburo, Stephanie N.; Soto-Fuentes, Wilfredo; He, Ji; Gang, David R.; Weiblen, George D.; Dixon, Richard A.

    2009-01-01

    RNA isolated from the glands of a Δ9-tetrahydrocannabinolic acid (THCA)-producing strain of Cannabis sativa was used to generate a cDNA library containing over 100 000 expressed sequence tags (ESTs). Sequencing of over 2000 clones from the library resulted in the identification of over 1000 unigenes. Candidate genes for almost every step in the biochemical pathways leading from primary metabolites to THCA were identified. Quantitative PCR analysis suggested that many of the pathway genes are preferentially expressed in the glands. Hexanoyl-CoA, one of the metabolites required for THCA synthesis, could be made via either de novo fatty acids synthesis or via the breakdown of existing lipids. qPCR analysis supported the de novo pathway. Many of the ESTs encode transcription factors and two putative MYB genes were identified that were preferentially expressed in glands. Given the similarity of the Cannabis MYB genes to those in other species with known functions, these Cannabis MYBs may play roles in regulating gland development and THCA synthesis. Three candidates for the polyketide synthase (PKS) gene responsible for the first committed step in the pathway to THCA were characterized in more detail. One of these was identical to a previously reported chalcone synthase (CHS) and was found to have CHS activity. All three could use malonyl-CoA and hexanoyl-CoA as substrates, including the CHS, but reaction conditions were not identified that allowed for the production of olivetolic acid (the proposed product of the PKS activity needed for THCA synthesis). One of the PKS candidates was highly and specifically expressed in glands (relative to whole leaves) and, on the basis of these expression data, it is proposed to be the most likely PKS responsible for olivetolic acid synthesis in Cannabis glands. PMID:19581347

  14. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

    PubMed

    Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

    2015-02-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

  15. The psychoactive compound of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC) inhibits the human trophoblast cell turnover.

    PubMed

    Costa, M A; Fonseca, B M; Marques, F; Teixeira, N A; Correia-da-Silva, G

    2015-08-01

    The noxious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. Its consumption during gestation is associated with alterations in foetal growth, low birth weight and preterm labor. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) impairs the production of reproductive hormones and is also able to cross the placenta barrier. However, its effect on the main placental cells, the trophoblasts, are unknown. Actually, the role of THC in cell survival/death of primary human cytotrophoblasts (CTs) and syncytiotrophoblasts (STs) and in the syncytialization process remains to be explored. Here, we show that THC has a dual effect, enhancing MTT metabolism at low concentrations, whereas higher doses decreased cell viability, on both trophoblast phenotypes, though the effects on STs were more evident. THC also diminished the generation of oxidative and nitrative stress and the oxidized form of glutathione, whereas the reduced form of this tripeptide was increased, suggesting that THC prevents ST cell death due to an antioxidant effect. Moreover, this compound enhanced the mitochondrial function of STs, as observed by the increased MTT metabolism and intracellular ATP levels. These effects were independent of cannabinoid receptors activation. Besides, THC impaired CT differentiation into STs, since it decreased the expression of biochemical and morphological biomarkers of syncytialization, through a cannabinoid receptor-dependent mechanism. Together, these results suggest that THC interferes with trophoblast turnover, preventing trophoblast cell death and differentiation, and contribute to disclose the cellular mechanisms that lead to pregnancy complications in women that consume cannabis-derived drugs during gestation. PMID:26070387

  16. The psychoactive compound of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC) inhibits the human trophoblast cell turnover.

    PubMed

    Costa, M A; Fonseca, B M; Marques, F; Teixeira, N A; Correia-da-Silva, G

    2015-08-01

    The noxious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. Its consumption during gestation is associated with alterations in foetal growth, low birth weight and preterm labor. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) impairs the production of reproductive hormones and is also able to cross the placenta barrier. However, its effect on the main placental cells, the trophoblasts, are unknown. Actually, the role of THC in cell survival/death of primary human cytotrophoblasts (CTs) and syncytiotrophoblasts (STs) and in the syncytialization process remains to be explored. Here, we show that THC has a dual effect, enhancing MTT metabolism at low concentrations, whereas higher doses decreased cell viability, on both trophoblast phenotypes, though the effects on STs were more evident. THC also diminished the generation of oxidative and nitrative stress and the oxidized form of glutathione, whereas the reduced form of this tripeptide was increased, suggesting that THC prevents ST cell death due to an antioxidant effect. Moreover, this compound enhanced the mitochondrial function of STs, as observed by the increased MTT metabolism and intracellular ATP levels. These effects were independent of cannabinoid receptors activation. Besides, THC impaired CT differentiation into STs, since it decreased the expression of biochemical and morphological biomarkers of syncytialization, through a cannabinoid receptor-dependent mechanism. Together, these results suggest that THC interferes with trophoblast turnover, preventing trophoblast cell death and differentiation, and contribute to disclose the cellular mechanisms that lead to pregnancy complications in women that consume cannabis-derived drugs during gestation.

  17. Recovery of spiked Δ9-tetrahydrocannabinol in oral fluid from polypropylene containers.

    PubMed

    Molnar, Anna; Lewis, John; Fu, Shanlin

    2013-04-10

    Oral fluid is currently used by Australian and international law enforcement agencies and employers to detect recent use of cannabis and other drugs of abuse. The main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol (THC), is highly lipophilic and losses occur when in contact with plastic, possibly due to its adsorption onto the plastic surface. This study aims to investigate factors governing the interaction of THC with plastic and search for ways of overcoming such interaction so to improve THC recovery. As polypropylene is one of the most common types of plastic used in collection devices, it was the focus of this study. All experiments were done by preparing neat oral fluid samples spiked with THC in 2-mL polypropylene centrifuge tubes. Samples were transferred with or without prior addition of Triton(®) X-100 (0.25%) to glass tubes containing d3-THC as internal standard and 0.1M phosphate buffer was then added. Samples were extracted by liquid-liquid extraction using hexane/ethyl acetate (9:1, v/v), dried and analysed by gas chromatography-mass spectrometry (GC-MS) after derivatisation. No significant difference was found in terms of THC loss to plastic when the concentration ranged from 25 to 1000 ng/mL in the same volume of oral fluid. Varying the oral fluid volume (0.5-1.5 mL) while keeping THC at a constant concentration showed an upward trend with more loss associated with lower volumes. The use of Triton(®) X-100 significantly decreased the adherence of THC to the plastic tubes and increased the THC transfer (>96%) at all volumes tested. Degradation of THC during storage was also studied over a 4-week period and it was found that azide did not seem to play a significant role in preserving THC in oral fluid. PMID:23219099

  18. Evidence based decontamination protocols for the removal of external Δ9-tetrahydrocannabinol (THC) from contaminated hair.

    PubMed

    Duvivier, Wilco F; Peeters, Ruth J P; van Beek, Teris A; Nielen, Michel W F

    2016-02-01

    External contamination can cause false positive results in forensic hair testing for drugs of abuse and is therefore a major concern when hair evidence is used in court. Current literature about decontamination strategies is mainly focused on external cocaine contamination and no consensus on the best decontamination procedure for hair samples containing cannabinoids has been reached so far. In this study, different protocols with solvents, both organic as well as aqueous, were tested on blank and drug user hair for their performance on removing external cannabis contamination originating from either smoke or indirect contact with cannabis plant material. Smoke contamination was mimicked by exposing hair samples to smoke from a cannabis cigarette and indirect contact contamination by handling hair with cannabis contaminated gloves or hands. Δ9-tetrahydrocannabinol (THC) levels in the hair samples and wash solvents were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Aqueous surfactant solutions removed more THC contamination compared to water, but much less than organic solvents. Methanol, dichloromethane and chloroform were most efficient in removing THC contamination. Due to its lower environmental impact, methanol was chosen as the preferred decontamination solvent. After testing of different sequential wash steps on externally contaminated blank hair, three protocols performed equally well, removing all normal level and more than 99% of unrealistically high levels of external cannabis contamination. Thorough testing on cannabis users' hair, both as such and after deliberate contamination, showed that using these protocols all contamination could be washed from the hair while no incorporated THC was removed from truly positive samples. The present study provides detailed scientific evidence in support of the recommendations of the Society of Hair Testing: a protocol using a single methanol wash followed by a single aqueous

  19. Plasma Cannabinoid Pharmacokinetics following Controlled Oral Δ9-Tetrahydrocannabinol and Oromucosal Cannabis Extract Administration

    PubMed Central

    Karschner, Erin L.; Darwin, W. David; Goodwin, Robert S.; Wright, Stephen; Huestis, Marilyn A.

    2013-01-01

    BACKGROUND Sativex®, a cannabis extract oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC’s effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. METHODS Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board–approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (Cmax) and areas under the curve from 0–10.5 h postdose (AUC0→10.5) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in Cmax, time to maximum concentration or in the AUC0→10.5 between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. CONCLUSION These data suggest that CBD modulation of THC’s effects is not due to a pharmacokinetic interaction at these therapeutic doses. PMID:21078841

  20. Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.

    PubMed

    Stern, Cristina A J; Gazarini, Lucas; Vanvossen, Ana C; Zuardi, Antonio W; Galve-Roperh, Ismael; Guimaraes, Francisco S; Takahashi, Reinaldo N; Bertoglio, Leandro J

    2015-06-01

    Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.

  1. Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

    PubMed

    Gerak, L R; France, C P

    2016-05-01

    Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not

  2. Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

    PubMed

    Gerak, L R; France, C P

    2016-05-01

    Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not

  3. Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

    PubMed

    Justinová, Zuzana; Redhi, Godfrey H; Goldberg, Steven R; Ferré, Sergi

    2014-05-01

    Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

  4. 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol quantification in human oral fluid by liquid chromatography–tandem mass spectrometry

    PubMed Central

    Scheidweiler, Karl B.; Himes, Sarah K.; Chen, Xiaohong; Liu, Hua-Fen

    2013-01-01

    Currently, Δ9-tetrahydrocannabinol (THC) is the analyte quantified for oral fluid cannabinoid monitoring. The potential for false-positive oral fluid cannabinoid results from passive exposure to THC-laden cannabis smoke raises concerns for this promising new monitoring technology. Oral fluid 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) is proposed as a marker of cannabis intake since it is not present in cannabis smoke and was not measureable in oral fluid collected from subjects passively exposed to cannabis. THCCOOH concentrations are in the picogram per milliliter range in oral fluid and pose considerable analytical challenges. A liquid chromatography–tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying THCCOOH in 1 mL Quantisal-collected oral fluid. After solid phase extraction, chromatography was performed on a Kinetex C18 column with a gradient of 0.01 % acetic acid in water and 0.01 % acetic acid in methanol with a 0.5-mL/min flow rate. THCCOOH was monitored in negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. The THCCOOH linear range was 12–1,020 pg/mL (R2>0.995). Mean extraction efficiencies and matrix effects evaluated at low and high quality control (QC) concentrations were 40.8–65.1 and −2.4–11.5 %, respectively (n=10). Analytical recoveries (bias) and total imprecision at low, mid, and high QCs were 85.0–113.3 and 6.6–8.4 % coefficient of variation, respectively (n=20). This is the first oral fluid THCCOOH LCMSMS triple quadrupole method not requiring derivatization to achieve a <15 pg/mL limit of quantification. The assay is applicable for the workplace, driving under the influence of drugs, drug treatment, and pain management testing. PMID:23681203

  5. Rapid isolation procedure for Δ9-tetrahydrocannabinolic acid A (THCA) from Cannabis sativa using two flash chromatography systems.

    PubMed

    Wohlfarth, Ariane; Mahler, Hellmut; Auwärter, Volker

    2011-10-15

    Two isolation procedures for Δ9-tetrahydrocannabinolic acid A (THCA), the biogenetic precursor in the biosynthesis of the psychoactive Δ9-tetrahydrocannabinol (THC) in the cannabis plant, are presented. Two flash chromatography systems that can be used independently from each other were developed to separate THCA from other compounds of a crude cannabis extract. In both systems UV absorption at 209 and 270 nm was monitored. Purity was finally determined by HPLC-DAD, NMR and GC-MS analysis with a focus on the impurity THC. System 1 consisted of a normal phase silica column (120 g) as well as cyclohexane and acetone--both spiked with the modifier pyridine--as mobile phases. Gradient elution was performed over 15 min. After the chromatographic run the fractions containing THCA fractions were pooled, extracted with hydrochloric acid to eliminate pyridine and evaporated to dryness. Loading 1800 mg cannabis extract yielded 623 mg THCA with a purity of 99.8% and a THC concentration of 0.09%. System 2 was based on a reversed-phase C18 column (150 g) combined with 0.55% formic acid and methanol as mobile phases. A very flat gradient was set over 20 minutes. After pooling the THCA-containing fractions methanol was removed in a rotary evaporator. THCA was re-extracted from the remaining aqueous phase with methyl tert-butyl ether. The organic phase was finally evaporated under high vacuum conditions. Loading 300 mg cannabis extract yielded 51 mg THCA with a purity of 98.8% and a THC concentration of 0.67%.

  6. Effects of 20 mg oral Δ9-tetrahydrocannabinol on the olfactory function of healthy volunteers*

    PubMed Central

    Walter, Carmen; Oertel, Bruno G; Ludyga, Dagmar; Ultsch, Alfred; Hummel, Thomas; Lötsch, Jörn

    2014-01-01

    Aims Olfactory loss impairs the patient's quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Δ9-tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment. Methods The effects of 20 mg oral THC on olfaction were assessed in a placebo-controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration. Results Δ9-Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 ± 4.2 to 32.2 ± 5.6, 95% confidence interval for differences THC vs. placebo, −7.8 to −2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function. Conclusions Considering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies. PMID:24802974

  7. Suppression of polymorphonuclear (PMN) and monocyte-mediated inhibition of Candida albicans growth by delta-9-tetrahydrocannabinol

    SciTech Connect

    Djeu, J.Y.; Parapanios, A.; Halkias, D.; Friedman, H.

    1986-03-05

    This study was an in vitro attempt to identify the effector cells responsible for growth inhibition of the opportunistic fungus, candida albicans, and to determine if THC or another marijuana derivatives, 11-hydroxyTHC, would adversely affect their function. Using a 24h radiolabel assay, the authors found that growth inhibition of C. albicans was primarily mediated by PMN and monocytes that could be isolated normal human peripheral blood. Both effector cell types caused almost complete inhibition of Candida growth at effector/target ratio of 300/1 and inhibition was often still seen at 30/1-. Incubation of PMN, PBL, or monocytes for 1 hr at 37C with THC or 11-hydroxyTHC caused a marked suppression of function in all 3 cell populations. Maximal suppression was obtained with 7.5-10..mu..g/ml of the drugs in medium containing 10% fetal bovine serum (FBS) or with 2-4..mu..g/ml in 1% FBS. These drug concentrations did not affect lymphoid cell viability or candida growth in the absence of lymphoid effector cells. Marijuana derivatives, therefore, are doubly dangerous in that opportunistic fungi such as C. albicans can grow in their presence while the effector cells that control fungal growth are readily inactivated.

  8. Effects of prenatal exposure to delta-9-tetrahydrocannabinol on reproductive, endocrine and immune parameters of male and female rat offspring.

    PubMed

    Murphy, L L; Gher, J; Szary, A

    1995-12-01

    The effects of prenatal THC administration, given during the third week of gestation in rats, on the reproductive, endocrine and immune systems of the adult offspring were examined. THC treatment blocked the surge of testosterone which occurs in the male rat fetus on gestation day 18. Moreover, when copulatory parameters were measured in adult male offspring, males that had been exposed to THCin utero exhibited an increased latency to mount (THC: 245±49vs vehicle: 99±12 sec) and none of the males ejaculated. Female rats exposed to THCin utero, exhibited an increased incidence of irregular estrous cycles and the number of females exhibiting lordosis behavior was reduced when compared to vehicle controls. Hormone analyses revealed that prolactin levels were significantly lower in the THC-vs vehicle-exposed male (THC: 5.2±0.4vs vehicle: 8.4±0.6 ng/ml) and female offspring (THC: 5.7±0.3vs vehicle: 12.2±1.8 ng/ml). However, there were no significant differences in basal plasma LH levels or in testicular weights of the male offspring. Thymus weight and total number of thymocytes were significantly higher in THC-exposed male and female rats when compared to vehicle controls. Together, these results indicate that maternal THC exposure has long-lasting effects on reproductive, endocrine and immune parameters of both male and female rat offspring. PMID:21153215

  9. Comparative effects of phencyclidine (PCP) and. delta. /sup 9/-tetrahydrocannabinol (THC) on glucose oxidation in the rat testis

    SciTech Connect

    Husain, S.; Bauer, V.

    1986-03-05

    Glucose and fructose are important fuels of cellular energetics in organs like testis and brain. The previous in-vitro studies indicated that THC may disrupt many gonadal functions by inhibiting energy metabolism in the testis. PCP is sold on the street as any one of a variety of psychoactive drugs. Most commonly it is misrepresented as THC. Therefore, to compare the effects of PCP and THC on glucose utilization, in-vitro radiorespirometric experiments were conducted in rat testicular tissues. The /sup 14/CO/sub 2/ production from 5.5 mM radiolabelled glucose was followed in the presence and absence of 0.2, 0.1, 0.05, 0.01, 0.005, 0.0025 mM PCP. PCP produced a dose-dependent biphasic effect, stimulating /sup 14/CO/sub 2/ production by 6.2, 17 and 5.8% and then inhibiting it by 13.2, 15.4 and 8.9% with respective concentrations of PCP. This is in contrast to THC which produced a dose-related inhibition of 15.2, 18.1, 20.1 and 25.3% in /sup 14/CO/sub 2/ production with 0.1, 0.2, 0.3 and 0.4 mM THC. These observations are significant due to the possible abuse of PCP together with THC either deliberately or by misrepresentation.

  10. Delta-9-tetrahydrocannabinol accumulation, metabolism and cell-type-specific adverse effects in aggregating brain cell cultures

    SciTech Connect

    Monnet-Tschudi, Florianne Hazekamp, Arno; Perret, Nicolas; Zurich, Marie-Gabrielle; Mangin, Patrice; Giroud, Christian; Honegger, Paul

    2008-04-01

    Despite the widespread use of Cannabis as recreational drug or as medicine, little is known about its toxicity. The accumulation, metabolism and toxicity of THC were analyzed 10 days after a single treatment, and after repeated exposures during 10 days. Mixed-cell aggregate cultures of fetal rat telencephalon were used as in vitro model, as well as aggregates enriched either in neurons or in glial cells. It was found that THC accumulated preferentially in neurons, and that glia-neuron interactions decreased THC accumulation. The quantification of 11-OH-THC and of THC-COOH showed that brain aggregates were capable of THC metabolism. No cell-type difference was found for the metabolite 11-OH-THC, whereas the THC-COOH content was higher in mixed-cell cultures. No cell death was found at THC concentrations of 2 {mu}M in single treatment and of 1 {mu}M and 2 {mu}M in repeated treatments. Neurons, and particularly GABAergic neurons, were most sensitive to THC. Only the GABAergic marker was affected after the single treatment, whereas the GABAergic, cholinergic and astrocytic markers were decreased after the repeated treatments. JWH 015, a CB2 receptor agonist, showed effects similar to THC, whereas ACEA, a CB1 receptor agonist, had no effect. The expression of the cytokine IL-6 was upregulated 48 h after the single treatment with 5 {mu}M of THC or JWH 015, whereas the expression of TNF-{alpha} remained unchanged. These results suggest that the adverse effects of THC were related either to THC accumulation or to cannabinoid receptor activation and associated with IL-6 upregulation.

  11. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain.

    PubMed

    Ali, S F; Newport, G D; Scallet, A C; Gee, K W; Paule, M G; Brown, R M; Slikker, W

    1989-01-01

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects. Results from these experiments suggest that chronic exposure to THC does not produce significant alterations in catecholamine or indoleamine neurotransmitter systems or in opiate or GABA receptor systems in the rat brain.

  12. An on-line stacking capillary electrophoresis method for the analysis of Δ(9)-tetrahydrocannabinol and its metabolites.

    PubMed

    Cheng, Hui-Ling; Tsai, Yi-Hsuan; Hsu, Wan-Ling; Lin, Yi-Hui

    2015-12-24

    The objective of this study was to establish a practical and reliable analytical method for monitoring trace amounts of Δ(9)-tetrahydrocannabinol (THC) and its metabolites in biological samples. A novel on-line preconcentration capillary electrophoresis method combining large volume sample injection, anion selective exhaustive injection and sweeping was developed to enhance analytical sensitivity. A background buffer composed with 30mM phosphate buffer (pH 2.5) containing 40% methanol and 100mM SDS was used to suppress the electroosmotic flow of the uncoated fused silica capillary (40cm×50μm i.d.). High conductivity buffer (200mM phosphate, pH 2.5) was injected for analyte accumulation. The samples, prepared in phosphate buffer or Tris buffer, were introduced by hydrodynamic injection and electrokinetic injection. After sweeping, the separation was performed in micellar electrokinetic chromatography (MEKC) mode at -15kV. During the method validation, the coefficient of determination of the regression curve was measured at greater than 0.993, and the relative standard deviation and relative error were lower than 11.06% and 9.24%, respectively. Under optimized conditions, an improvement of up to 2000-fold higher sensitivity was achieved. This method was applied to the analysis of urine samples, indicating that it could be satisfactorily utilized in the toxicological and clinical monitoring of cannabis. PMID:26643722

  13. Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway

    PubMed Central

    Tortoriello, Giuseppe; Morris, Claudia V; Alpar, Alan; Fuzik, Janos; Shirran, Sally L; Calvigioni, Daniela; Keimpema, Erik; Botting, Catherine H; Reinecke, Kirstin; Herdegen, Thomas; Courtney, Michael; Hurd, Yasmin L; Harkany, Tibor

    2014-01-01

    Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring. PMID:24469251

  14. Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers.

    PubMed

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2013-01-01

    Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic Δ9-tetrahydrocannabinol (THC) (20 mg every 3.5-6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2-4; 120 mg on Days 5-6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects. PMID:23074216

  15. Establishment of the measurement uncertainty of 11-nor-D9-tetrahydrocannabinol-9-carboxylic acid in hair.

    PubMed

    Han, Eunyoung; Yang, Wonkyung; Lee, Sooyeun; Kim, Eunmi; In, Sangwhan; Choi, Hwakyung; Lee, Sangki; Chung, Heesun; Song, Joon Myong

    2011-03-20

    The quantitative analysis of 11-nor-D(9)-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in hair requires a sensitive method to detect a low-pg level. Before applying the method to real hair samples, the method was validated; in this study, we examined the uncertainty obtained from around the cut-off level of THCCOOH in hair. We calculated the measurement uncertainty (MU) of THCCOOH in hair as follows: specification of the measurand, identification of parameters using "cause and effect" diagrams, quantification of the uncertainty contributions using three factors, the uncertainty of weighing the hair sample, the uncertainty from calibrators and the calibration curve, and the uncertainty of the method precision. Finally, we calculated the degrees of freedom and the expanded uncertainty (EU). The concentration of THCCOOH in the hair sample with its EU was (0.60 ± 0.1) × 10(-4)ng/mg. The relative uncertainty percent for the measurand 0.60 × 10(-4)ng was 9.13%. In this study, we also selected different concentrations of THCCOOH in real hair samples and then calculated the EU, the relative standard uncertainty (RSU) of the concentration of THCCOOH in the test sample [u(r)(c0)], the relative uncertainty percent, and the effective degree of freedom (v(eff)). When the concentrations of THCCOOH approached the cut-off level, u(r)(c0) and the relative uncertainty percent increased but absolute EU and v(eff) decreased.

  16. Analysis of Δ9-tetrahydrocannabinol driving under the influence of drugs cases in Colorado from January 2011 to February 2014.

    PubMed

    Urfer, Sarah; Morton, Jaime; Beall, Vanessa; Feldmann, Jeanna; Gunesch, Justin

    2014-10-01

    Driving under the influence (DUI) and DUI drugs (DUID) law enforcement (LE) cases (n = 12,082) where whole blood samples were submitted to ChemaTox Laboratory, Inc. in Boulder, CO, for testing were examined. Of these 12,082 cases, there were 4,235 cannabinoid screens (CS) requested. Samples that yielded a positive CS (n = 2,621) were further analyzed. A total of 1,848 samples were confirmed for Δ9-tetrahydrocannabinol (THC) after a positive CS. Due to a decrease in the confirmation limit of detection (LOD) for THC from 2 to 1 ng/mL, samples that were confirmed for THC and quantitated below 2 ng/mL (n = 250) were considered negative. After this normalization, there were 1,598 samples that were confirmed positive for THC and included in the analysis. The percentage of LE cases with requests for CS for all years was 35%, increasing from 28% in 2011 to 37% in 2013. The positivity rate of CS overall was 62% (range: 59-68% by year) with no significant change over the time frame examined. The percentage of positive CS in which THC was confirmed positive at or above 2 ng/mL (n = 1,598) increased significantly from 28% in 2011 to 65% in 2013. The mean and median THC concentrations were 8.1 and 6.3 ng/mL, respectively (range: 2-192 ng/mL, n = 1,367). The data presented illustrate a statistically significant increase in CS that result in positive THC confirmations. Although the specific cause of this increase is not known at this time, possible ties to ongoing developments in Colorado's marijuana legislation merit further analysis. PMID:25217549

  17. Histone Modifications Are Associated with Δ9-Tetrahydrocannabinol-mediated Alterations in Antigen-specific T Cell Responses*

    PubMed Central

    Yang, Xiaoming; Hegde, Venkatesh L.; Rao, Roshni; Zhang, Jiajia; Nagarkatti, Prakash S.; Nagarkatti, Mitzi

    2014-01-01

    Marijuana is one of the most abused drugs due to its psychotropic effects. Interestingly, it is also used for medicinal purposes. The main psychotropic component in marijuana, Δ9-tetrahydrocannabinol (THC), has also been shown to mediate potent anti-inflammatory properties. Whether the immunomodulatory activity of THC is mediated by epigenetic regulation has not been investigated previously. In this study, we employed ChIP-Seq technology to examine the in vivo effect of THC on global histone methylation in lymph node cells of mice immunized with a superantigen, staphylococcal enterotoxin B. We compared genome-wide histone H3 Lys-4, Lys-27, Lys-9, and Lys-36 trimethylation and histone H3 Lys-9 acetylation patterns in such cells exposed to THC or vehicle. Our results showed that THC treatment leads to the association of active histone modification signals to Th2 cytokine genes and suppressive modification signals to Th1 cytokine genes, indicating that such a mechanism may play a critical role in the THC-mediated switch from Th1 to Th2. At the global level, a significant portion of histone methylation and acetylation regions were altered by THC. However, the overall distribution of these histone methylation signals among the genomic features was not altered significantly by THC, suggesting that THC activates the expression of a subset of genes while suppressing the expression of another subset of genes through histone modification. Functional classification of these histone marker-associated genes showed that these differentially associated genes were involved in various cellular functions, from cell cycle regulation to metabolism, suggesting that THC had a pleiotropic effect on gene expression in immune cells. Altogether, the current study demonstrates for the first time that THC may modulate immune response through epigenetic regulation involving histone modifications. PMID:24841204

  18. Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Ù9-tetrahydrocannabinol in Sprague-Dawley rats

    PubMed Central

    Taffe, Michael A; Creehan, Kevin M; Vandewater, Sophia A

    2015-01-01

    Background and Purpose Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ9-tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats. Experimental Approaches Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10–30 mg·kg−1, i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant). Key Results CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model. Conclusions and Implications There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats. PMID:25425111

  19. Subjective Effects of Ethanol, Morphine, Δ(9)-Tetrahydrocannabinol, and Ketamine Following a Pharmacological Challenge Are Related to Functional Brain Connectivity.

    PubMed

    Kleinloog, Daniël; Rombouts, Serge; Zoethout, Remco; Klumpers, Linda; Niesters, Marieke; Khalili-Mahani, Najmeh; Dahan, Albert; van Gerven, Joop

    2015-12-01

    This analysis examines the neuronal foundation of drug-induced psychomimetic symptoms by relating the severity of these symptoms to changes in functional connectivity for a range of different psychoactive compounds with varying degrees of psychomimetic effects. The repeated measures design included 323 resting-state functional magnetic resonance imaging time series and measures of subjective effects in 36 healthy male volunteers. Four different pharmacological challenges with ethanol, morphine, Δ(9)-tetrahydrocannabinol, and ketamine (12 subjects per drug) were applied. A set of 10 "template" resting-state networks was used to determine individual connectivity maps. Linear regression was used for each individual subject to relate these connectivity maps to three clusters of drug-induced subjective psychomimetic effects ("perception," "relaxation," and "dysphoria") as measured with visual analogue scales. Group analysis showed that the subjective effects of perception correlated significantly across drugs with the connectivity of the posterior cingulate cortex and precentral gyrus with the sensorimotor network (p < 0.005, corrected). No significant correlations were found for relaxation or dysphoria. The posterior cingulate cortex has a role in visuospatial evaluation and the precentral gyrus has been associated with auditory hallucinations. Both the posterior cingulate cortex and the precentral gyrus show changes in activation in patients with schizophrenia, which can be related to the severity of positive symptoms (i.e., hallucinations and delusions), and have previously been related to changes induced by psychoactive drugs. The similarity of functional connectivity changes for drug-induced psychomimetic effects and symptoms of psychosis provides further support for the use of pharmacological challenges with psychomimetic drugs as models for psychosis.

  20. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

    PubMed

    Elmes, Matthew W; Kaczocha, Martin; Berger, William T; Leung, KwanNok; Ralph, Brian P; Wang, Liqun; Sweeney, Joseph M; Miyauchi, Jeremy T; Tsirka, Stella E; Ojima, Iwao; Deutsch, Dale G

    2015-04-01

    Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders.

  1. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

    PubMed

    Elmes, Matthew W; Kaczocha, Martin; Berger, William T; Leung, KwanNok; Ralph, Brian P; Wang, Liqun; Sweeney, Joseph M; Miyauchi, Jeremy T; Tsirka, Stella E; Ojima, Iwao; Deutsch, Dale G

    2015-04-01

    Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders. PMID:25666611

  2. Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)*

    PubMed Central

    Elmes, Matthew W.; Kaczocha, Martin; Berger, William T.; Leung, KwanNok; Ralph, Brian P.; Wang, Liqun; Sweeney, Joseph M.; Miyauchi, Jeremy T.; Tsirka, Stella E.; Ojima, Iwao; Deutsch, Dale G.

    2015-01-01

    Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders. PMID:25666611

  3. Oral fluid cannabinoids in chronic cannabis smokers during oral Δ9-tetrahydrocannabinol therapy and smoked cannabis challenge

    PubMed Central

    Lee, Dayong; Vandrey, Ryan; Mendu, Damodara R.; Anizan, Sebastien; Milman, Garry; Murray, Jeannie A.; Barnes, Allan J.; Huestis, Marilyn A.

    2014-01-01

    BACKGROUND Oral Δ9-tetrahydrocannabinol (THC) is effective for attenuating cannabis withdrawal and may benefit treatment of cannabis use disorders. Oral fluid (OF) cannabinoid testing, increasing in forensic and workplace settings, could be valuable for monitoring during cannabis treatment. METHODS Eleven cannabis smokers resided on a closed research unit for 51 days, and received daily 0, 30, 60, and 120 mg oral THC in divided doses for 5 days. There was a 5-puff smoked cannabis challenge on the 5th day. Each medication session was separated by 9 days of ad libitum cannabis smoking. OF was collected the evening prior to and throughout oral THC sessions and analyzed by 2-dimensional GC-MS for THC, cannabidiol (CBD), cannabinol (CBN), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS During all oral THC administrations, THC OF concentrations decreased to ≤78.2, 33.2, and 1.4 μg/L by 24, 48, and 72h, respectively. CBN also decreased over time with concentrations 10-fold lower than THC, with none detected beyond 69h. CBD and 11-OH-THC were rarely detected, only within 19 and 1.6h post smoking, respectively. THCCOOH OF concentrations were dose-dependent and increased over time during 120 mg THC dosing. After cannabis smoking, THC, CBN, and THCCOOH concentrations showed a significant dose-effect and decreased significantly over time. CONCLUSIONS Oral THC dosing significantly affected OF THCCOOH but minimally contributed to THC OF concentrations; prior ad libitum smoking was the primary source of THC, CBD and CBN. Higher cannabinoid concentrations following active oral THC administrations versus placebo suggest a compensatory effect of THC tolerance on smoking topography. PMID:23938457

  4. Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (Δ(9)-tetrahydrocannabinol) discrimination for rats.

    PubMed

    Järbe, Torbjörn U C; Deng, Hongfen; Vadivel, Subramanian K; Makriyannis, Alexandros

    2011-09-01

    We examined four different cannabinergic aminoalkylindole ligands, including one drug (AM678=JWH018) found in herbal 'Spice' concoctions, for their ability to substitute for Δ(9)-tetrahydrocannabinol (THC), and the ability of the cannabinoid receptor 1-selective antagonist/inverse agonist rimonabant to block the substitution, 30 and 90 min after intraperitoneal injection. Rats trained to discriminate the effects of vehicle from those produced by 3 mg/kg of THC were used. The order of potency was: AM5983≥AM678>AM2233>WIN55212-2 at both test intervals. AM5983 and AM678 appeared eight times more potent than THC, followed by AM2233 (about twice as potent as THC), and WIN55212-2 approximately THC at the 30-min test interval. The aminoalkylindoles showed reduced potency (i.e. an increased ED50 value) at the longer injection-to-test interval of 90 min compared with testing at 30 min. The rightward shifts by coadministration of rimonabant were approximately 8-fold to 12-fold for AM5983 and AM678, compared with an approximately 3-fold rightward shift for the WIN55212-2 curve. AM2233 (1.8 mg/kg) substitution was also blocked by 1 mg/kg of rimonabant. In conclusion, AM5983 and AM678=JWH018 are potent cannabimimetics derived from an aminoalkylindole template. WIN55212-2 seemed to interact differently with rimonabant, compared with either AM5983 or AM678, indicating potential differences in the mechanism(s) of action among cannabinergic aminoalkylindoles.

  5. Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells

    PubMed Central

    Juknat, Ana; Pietr, Maciej; Kozela, Ewa; Rimmerman, Neta; Levy, Rivka; Coppola, Giovanni; Geschwind, Daniel; Vogel, Zvi

    2012-01-01

    BACKGROUND AND PURPOSE Apart from their effects on mood and reward, cannabinoids exert beneficial actions such as neuroprotection and attenuation of inflammation. The immunosuppressive activity of cannabinoids has been well established. However, the underlying mechanisms are largely unknown. We previously showed that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signalling pathways. EXPERIMENTAL APPROACH To characterize the transcriptional effects of CBD and THC, we treated BV-2 microglial cells with these compounds and performed comparative microarray analysis using the Illumina MouseRef-8 BeadChip platform. Ingenuity Pathway Analysis was performed to identify functional subsets of genes and networks regulated by CBD and/or THC. KEY RESULTS Overall, CBD altered the expression of many more genes; from the 1298 transcripts found to be differentially regulated by the treatments, 680 gene probe sets were up-regulated by CBD and 58 by THC, and 524 gene products were down-regulated by CBD and only 36 by THC. CBD-specific gene expression profile showed changes associated with oxidative stress and glutathione depletion, normally occurring under nutrient limiting conditions or proteasome inhibition and involving the GCN2/eIF2α/p8/ATF4/CHOP-TRIB3 pathway. Furthermore, CBD-stimulated genes were shown to be controlled by nuclear factors known to be involved in the regulation of stress response and inflammation, mainly via the (EpRE/ARE)-Nrf2/ATF4 system and the Nrf2/Hmox1 axis. CONCLUSIONS AND IMPLICATIONS These observations indicated that CBD, but much less than THC, induced a cellular stress response in microglial cells and suggested that this effect could underlie its anti-inflammatory activity. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012

  6. Δ9-THC exposure attenuates aversive effects and reveals appetitive effects of K2/”Spice” constituent JWH-018 in mice

    PubMed Central

    Hyatt, WS; Fantegrossi, WE

    2014-01-01

    The emergence of high efficacy synthetic cannabinoids as drugs of abuse in readily available K2/”Spice” smoking blends has exposed users to much more potent and effective substances than the phytocannabinoids present in cannabis. Increasing reports of adverse reactions, including dependence and withdrawal, are appearing in the clinical literature. Here we investigated whether the effects of one such synthetic cannabinoid, 1-pentyl-3-(1-naphthoyl)indole (JWH-018), would be altered by a prior history of Δ9-THC exposure, in assays of conditioned taste aversion (CTA) and conditioned place preference (CPP.) In the CTA procedure, JWH-018 induced dramatic and persistent aversive effects in mice with no previous cannabinoid history, but the magnitude and duration of these aversive effects were significantly blunted in mice previously treated with an ascending dose regimen of Δ9-THC. Similarly, in the CPP procedure, JWH-018 also induced dose-dependent aversive effects in mice with no previous drug history, but mice exposed to Δ9-THC prior to place conditioning exhibited reduced aversions at the high JWH-018 dose, and apparent rewarding effects at the low dose of JWH-018. These findings suggest that a history of Δ9-THC exposure “protects” against aversive effects and “unmasks” appetitive effects of the high efficacy synthetic cannabinoid JWH-018 in mice. This pattern of results implies that cannabinoid-naïve individuals administering K2/”Spice” products for the first-time may be at increased risk for adverse reactions, while those with a history of marijuana use may be particularly sensitive to the reinforcing effects of high efficacy cannabinoids present in these commercial smoking blends. PMID:24625557

  7. The Application of Voltammetric Analysis of Δ(9) -THC for the Reduction of False Positive Results in the Analysis of Suspected Marijuana Plant Matter.

    PubMed

    Balbino, Marco A; de Oliveira, Laura S; Eleotério, Izabel C; Oiye, Erica N; Ribeiro, Maria F M; McCord, Bruce R; Ipolito, Antonio J; de Oliveira, Marcelo F

    2016-07-01

    The development of methodologies using inexpensive, fast, and reliable instrumention is desirable in illicit drug analysis. The purpose of this study was based on cyclic voltammetry technique to differentiate the electrochemical behavior of ∆(9) -THC, the psychoactive substance in marijuana, and five different extract plants to yield false positive results after analysis protocol for cannabinoids using thin-layer chromatography and Fast Blue B salt. After applying a deposition potential of -0.5 V in a glassy carbon working electrode, the results indicated an anodic peak current at 0.0 V versus Ag/AgCl after addition of ∆(9) -THC solution in the electrochemical cell, and limits of detection and quantification were 1.0 ng mL(-1) and 3.5 ng mL(-1) , respectively. Other interfering plants showed distinct amperometric responses. This methodology was useful to detect ∆(9) -THC even in the presence of the Fast Blue B salt, which avoided false positive results for all the studied extract plants. PMID:27364289

  8. The Application of Voltammetric Analysis of Δ(9) -THC for the Reduction of False Positive Results in the Analysis of Suspected Marijuana Plant Matter.

    PubMed

    Balbino, Marco A; de Oliveira, Laura S; Eleotério, Izabel C; Oiye, Erica N; Ribeiro, Maria F M; McCord, Bruce R; Ipolito, Antonio J; de Oliveira, Marcelo F

    2016-07-01

    The development of methodologies using inexpensive, fast, and reliable instrumention is desirable in illicit drug analysis. The purpose of this study was based on cyclic voltammetry technique to differentiate the electrochemical behavior of ∆(9) -THC, the psychoactive substance in marijuana, and five different extract plants to yield false positive results after analysis protocol for cannabinoids using thin-layer chromatography and Fast Blue B salt. After applying a deposition potential of -0.5 V in a glassy carbon working electrode, the results indicated an anodic peak current at 0.0 V versus Ag/AgCl after addition of ∆(9) -THC solution in the electrochemical cell, and limits of detection and quantification were 1.0 ng mL(-1) and 3.5 ng mL(-1) , respectively. Other interfering plants showed distinct amperometric responses. This methodology was useful to detect ∆(9) -THC even in the presence of the Fast Blue B salt, which avoided false positive results for all the studied extract plants.

  9. Activation of Marginally Reactive Boron Enolates by MeLi for the Formation of Enol Phosphates and Synthesis of the Δ(9)-THC Intermediate.

    PubMed

    Kawada, Hiroki; Ikoma, Atsushi; Ogawa, Narihito; Kobayashi, Yuichi

    2015-09-18

    The addition of MeLi to boron enolates produced by the 1,4-addition of Ar2Cu(CN)Li2 to BF3·OEt2-activated enones was followed by the reaction with ClP(O)(OEt)2 to afford the corresponding enol phosphates in moderate to good yields. The scope of this method was examined with sterically hindered or electronically biased enones and/or reagents. This activation of boron enolates was successfully applied to the synthesis of the methyl ether of Δ(9)-tetrahydrocannabinol.

  10. Glycolytic pathway (GP), kreb's cycle (KC), and hexose monophosphate shunt (HMS) activity in myocardial subcellular fractions exposed to cannabinoids

    SciTech Connect

    Watson, A.T.; Manno, B.R.; King, J.W.; Fowler, M.R.; Dempsey, C.A.; Manno, J.E.

    1986-03-05

    Delta-9-tetrahydrocannabinol (..delta../sup 9/-THC), the primary psychoactive component of marihuana, and its active metabolite 11-hydroxy-..delta../sup 9/-tetrahydrocannabinol (11-OH-..delta../sup 9/-THC) have been reported to produce a direct cardiac depressant effect. Studies in isolated perfused rat hearts have indicated a decreased force of contraction (inotropic response) when ..delta../sup 9/-THC or 11-OH-..delta../sup 9/-THC was administered in microgram amounts. The mechanism and site of action have not been explained or correlated with associated metabolic pathways. The purpose of this study was to investigate the effects of cannabinoids on major myocardial energy producing pathways, GP and KC, and a non-energy producing pathway, HMS. Cardiac ventricular tissue from male Sprague-Dawley rats (250-300 g) was excised and homogenized for subcellular fractionation. KC, GP and HMS activity was assayed in the appropriate fractions by measuring /sup 14/CO/sub 2/ generation from /sup 14/C-2-pyruvate, /sup 14/C-6-glucose and /sup 14/C-1-glucose respectively. Duplicate assays (n=8) were performed on tissue exposed to saline (control), empty liposomes (vehicle) and four doses each of ..delta../sup 9/-THC and 11-OH-..delta../sup 9/-THC. Changes in metabolic activity and decreases in cardiac contractile performance may be associated.

  11. Determination of Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A) in whole blood and plasma by LC-MS/MS and application in authentic samples from drivers suspected of driving under the influence of cannabis.

    PubMed

    Raikos, Nikolaos; Schmid, Helene; Nussbaumer, Susanne; Ambach, Lars; Lanz, Stephan; Längin, Andreas; König, Stefan; Roth, Nadine; Auwärter, Volker; Weinmann, Wolfgang

    2014-10-01

    Delta-9-tetrahydrocannabinolic acid A (THCA-A) is the biosynthetic precursor of delta-9-tetrahydrocannabinol (THC) in cannabis plants, and has no psychotropic effects. THCA-A can be detected in blood and urine, and several metabolites have been identified. THCA-A was also shown to be incorporated in hair by side stream smoke to a minor extent, but incorporation via blood stream or sweat seems unlikely. The detection of THCA-A in biological fluids may serve as a marker for differentiating between the intake of prescribed THC medication - containing only pure THC - and cannabis products containing THC besides THC-acid A and other cannabinoids. However, the knowledge about its usefulness in forensic cases is very limited. The aim of the present work was the development of a reliable method for THCA-A determination in human blood or plasma using LC-MS/MS and application to cases of driving under the influence of drugs. Fifty eight (58) authentic whole blood and the respective plasma samples were collected from drivers suspected of driving under the influence of cannabis from the region of Bern (Switzerland). Samples were first tested for THC, 11-OH-THC and THC-COOH, and then additionally for THCA-A. For this purpose, the existing LC-MS/MS method was modified and validated, and found to be selective and linear over a range of 1.0 to 200ng/mL (the correlation coefficients were above 0.9980 in all validation runs). Limit of detection (LOD) and limit of quantification (LOQ) were 0.3ng/mL and 1.0ng/mL respectively. Intra- and inter-assay accuracy were equal or better than 90% and intra- and inter-assay precision were equal or better than 11.1%. The mean extraction efficiencies were satisfactory being equal or higher than 85.4%. THCA-A was stable in whole blood samples after 3 freeze/thaw cycles and storage at 4°C for 7 days. Re-injection (autosampler) stability was also satisfactory. THC was present in all blood samples with levels ranging from 0.7 to 51ng/mL. THCA

  12. Determination of Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A) in whole blood and plasma by LC-MS/MS and application in authentic samples from drivers suspected of driving under the influence of cannabis.

    PubMed

    Raikos, Nikolaos; Schmid, Helene; Nussbaumer, Susanne; Ambach, Lars; Lanz, Stephan; Längin, Andreas; König, Stefan; Roth, Nadine; Auwärter, Volker; Weinmann, Wolfgang

    2014-10-01

    Delta-9-tetrahydrocannabinolic acid A (THCA-A) is the biosynthetic precursor of delta-9-tetrahydrocannabinol (THC) in cannabis plants, and has no psychotropic effects. THCA-A can be detected in blood and urine, and several metabolites have been identified. THCA-A was also shown to be incorporated in hair by side stream smoke to a minor extent, but incorporation via blood stream or sweat seems unlikely. The detection of THCA-A in biological fluids may serve as a marker for differentiating between the intake of prescribed THC medication - containing only pure THC - and cannabis products containing THC besides THC-acid A and other cannabinoids. However, the knowledge about its usefulness in forensic cases is very limited. The aim of the present work was the development of a reliable method for THCA-A determination in human blood or plasma using LC-MS/MS and application to cases of driving under the influence of drugs. Fifty eight (58) authentic whole blood and the respective plasma samples were collected from drivers suspected of driving under the influence of cannabis from the region of Bern (Switzerland). Samples were first tested for THC, 11-OH-THC and THC-COOH, and then additionally for THCA-A. For this purpose, the existing LC-MS/MS method was modified and validated, and found to be selective and linear over a range of 1.0 to 200ng/mL (the correlation coefficients were above 0.9980 in all validation runs). Limit of detection (LOD) and limit of quantification (LOQ) were 0.3ng/mL and 1.0ng/mL respectively. Intra- and inter-assay accuracy were equal or better than 90% and intra- and inter-assay precision were equal or better than 11.1%. The mean extraction efficiencies were satisfactory being equal or higher than 85.4%. THCA-A was stable in whole blood samples after 3 freeze/thaw cycles and storage at 4°C for 7 days. Re-injection (autosampler) stability was also satisfactory. THC was present in all blood samples with levels ranging from 0.7 to 51ng/mL. THCA

  13. In planta imaging of Δ9-tetrahydrocannabinolic acid in Cannabis sativa L. with hyperspectral coherent anti-Stokes Raman scattering microscopy

    NASA Astrophysics Data System (ADS)

    Garbacik, Erik T.; Korai, Roza P.; Frater, Eric H.; Korterik, Jeroen P.; Otto, Cees; Offerhaus, Herman L.

    2013-04-01

    Nature has developed many pathways to produce medicinal products of extraordinary potency and specificity with significantly higher efficiencies than current synthetic methods can achieve. Identification of these mechanisms and their precise locations within plants could substantially increase the yield of a number of natural pharmaceutics. We report label-free imaging of Δ9-tetrahydrocannabinolic acid (THCa) in Cannabis sativa L. using coherent anti-Stokes Raman scattering microscopy. In line with previous observations we find high concentrations of THCa in pistillate flowering bodies and relatively low amounts within flowering bracts. Surprisingly, we find differences in the local morphologies of the THCa-containing bodies: organelles within bracts are large, diffuse, and spheroidal, whereas in pistillate flowers they are generally compact, dense, and have heterogeneous structures. We have also identified two distinct vibrational signatures associated with THCa, both in pure crystalline form and within Cannabis plants; at present the exact natures of these spectra remain an open question.

  14. An in vitro experiment on the interaction of charcoal or wheat bran with 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol and its glucuronide.

    PubMed

    Skopp, Gisela; Mikus, Gerd

    2013-11-01

    The rather long yet variable terminal half-lives and detection times since last use of urinary cannabinoids may partly be attributed to their enterohepatic circulation which generally can be interrupted or restricted by chemical adsorbents. Therefore, an in vitro experiment was performed to study the adsorption/binding of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) and its glucuronide to activated charcoal and wheat bran; remaining concentrations were determined by liquid chromatography/tandem mass spectrometry. Adsorption/binding of 1,000 ng/mL of free or conjugated THC-COOH was complete using as little as 5 mg of charcoal whereas adsorption/binding to wheat bran increased with increasing amounts. Taking of remedies affecting enterohepatic recycling of THC-COOH and its glucuronide may challenge interpretation of cannabinoid concentrations used to detect or assess frequency of drug use or the time since last drug consumption. PMID:24077855

  15. LC-MS/MS analysis of Δ9-tetrahydrocannabinolic acid A in serum after protein precipitation using an in-house synthesized deuterated internal standard.

    PubMed

    Wohlfarth, Ariane; Roth, Nadine; Auwärter, Volker

    2012-06-01

    An assay based on liquid chromatography/tandem mass spectrometry is presented for the fast, precise and sensitive quantitation of Δ9-tetrahydrocannabinolic acid A (THCA) in serum. THCA is the biogenetic precursor of Δ9-tetrahydrocannabinol in cannabis and has aroused interest in the pharmacological and forensic field especially as a potential marker for recent cannabis use. After addition of deuterated THCA, synthesized from D(3)-THC as starting material, and protein precipitation, the analytes were separated using gradient elution on a Luna C18 column (150 × 2.0 mm × 5 µm) with 0.1% formic acid and acetonitrile/0.1% formic acid. Data acquisition was performed on a triple quadrupole linear ion trap mass spectrometer in multiple reaction monitoring mode with negative electrospray ionization. After optimization, the following sample preparation procedure was used: 200 μL serum was spiked with internal standard solution and methanol and then precipitated 'in fractions' with 500 μL ice-cold acetonitrile. After storage and centrifugation, the supernatant was evaporated and the residue redissolved in mobile phase. The assay was fully validated according to international guidelines including, for the first time, the assessment of matrix effects and stability experiments. Limit of detection was 0.1 ng/mL, and limit of quantification was 1.0 ng/mL. The method was found to be selective and proved to be linear over a range of 1.0 to 100 ng/mL using a 1/x weighted calibration model with regression coefficients >0.9996. Accuracy and precision data were within the required limits (RSD ≤ 8.6%, bias: 2.4 to 11.4%), extractive yield was greater than 84%. The analytes were stable in serum samples after three freeze/thaw cycles and storage at -20 °C for one month.

  16. Development and validation of an LC-MS/MS method for quantification of Δ9-tetrahydrocannabinolic acid A (THCA-A), THC, CBN and CBD in hair.

    PubMed

    Roth, Nadine; Moosmann, Bjoern; Auwärter, Volker

    2013-02-01

    For analysis of hair samples derived from a pilot study ('in vivo' contamination of hair by sidestream marijuana smoke), an LC-MS/MS method was developed and validated for the simultaneous quantification of Δ9-tetrahydrocannabinolic acid A (THCA-A), Δ9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD). Hair samples were extracted in methanol for 4 h under occasional shaking at room temperature, after adding THC-D(3), CBN-D(3), CBD-D(3) and THCA-A-D(3) as an in-house synthesized internal standard. The analytes were separated by gradient elution on a Luna C18 column using 0.1% HCOOH and ACN + 0.1% HCOOH. Data acquisition was performed on a QTrap 4000 in electrospray ionization-multi reaction monitoring mode. Validation was carried out according to the guidelines of the German Society of Toxicological and Forensic Chemistry (GTFCh). Limit of detection and lower limit of quantification were 2.5 pg/mg for THCA-A and 20 pg/mg for THC, CBN and CBD. A linear calibration model was applicable for all analytes over a range of 2.5 pg/mg or 20 pg/mg to 1000 pg/mg, using a weighting factor 1/x. Selectivity was shown for 12 blank hair samples from different sources. Accuracy and precision data were within the required limits for all analytes (bias between -0.2% and 6.4%, RSD between 3.7% and 11.5%). The dried hair extracts were stable over a time period of one to five days in the dark at room temperature. Processed sample stability (maximum decrease of analyte peak area below 25%) was considerably enhanced by adding 0.25% lecithin (w/v) in ACN + 0.1% HCOOH for reconstitution. Extraction efficiency for CBD was generally very low using methanol extraction. Hence, for effective extraction of CBD alkaline hydrolysis is recommended.

  17. Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol

    PubMed Central

    Crippa, José A. S.; Crippa, Ana C. S.; Hallak, Jaime E. C.; Martín-Santos, Rocio; Zuardi, Antonio W.

    2016-01-01

    Animal studies and preliminary clinical trials have shown that cannabidiol (CBD)-enriched extracts may have beneficial effects for children with treatment-resistant epilepsy. However, these compounds are not yet registered as medicines by regulatory agencies. We describe the cases of two children with treatment-resistant epilepsy (Case A with left frontal dysplasia and Case B with Dravet Syndrome) with initial symptom improvement after the introduction of CBD extracts followed by seizure worsening after a short time. The children presented typical signs of intoxication by Δ9-THC (inappropriate laughter, ataxia, reduced attention, and eye redness) after using a CBD-enriched extract. The extract was replaced by the same dose of purified CBD with no Δ9-THC in both cases, which led to improvement in intoxication signs and seizure remission. These cases support pre-clinical and preliminary clinical evidence suggesting that CBD may be effective for some patients with epilepsy. Moreover, the cases highlight the need for randomized clinical trials using high-quality and reliable substances to ascertain the safety and efficacy of cannabinoids as medicines. PMID:27746737

  18. A high efficacy cannabinergic ligand (AM4054) used as a discriminative stimulus: Generalization to other adamantyl analogs and Δ(9)-THC in rats.

    PubMed

    Järbe, Torbjörn U C; LeMay, Brian J; Thakur, Ganesh A; Makriyannis, Alexandros

    2016-09-01

    In addition to endogenous lipids, the two main cloned receptors (CB1R and CB2R) of the endocannabinoid signaling system (ECS) can be activated (and blocked) by various exogenous ligands. A relatively novel template for CB1R activators contains an adamantyl moiety as a key structural subunit, the first being the cannabinergic AM411. Additional chemical optimization efforts using the classical tricyclic scaffold led to AM4054. Here we explored the in vivo consequences of novel adamantyl analogs in rats trained to recognize the effects of the potent adamantyl cannabinergic AM4054. Rats were trained to discriminate between AM4054 (0.1mg/kg) and vehicle. Three AM4054 analogs and Δ(9)-THC were tested for generalization (substitution) and antagonism was assessed with rimonabant. We found that all cannabinergics resulted in response generalization to the target stimulus AM4054. The order of potency was: AM4054≥AM4083≥AM4050>AM4089>Δ(9)-THC. The CB1R antagonist/inverse agonist rimonabant blocked the discriminative stimulus effects of AM4054. Thus the examined structural modifications affected binding affinities but did not markedly change potencies with the exception of AM4089. In vitro (cAMP assay) functional data have suggested that AM4089 behaves as a partial rather than as a full agonist at CB1R which could explain its lower potency compared to AM4054 (Thakur et al., 2013). The 9β-formyl functionality at C-9 position was identified as an important pharmacophore yielding high in vivo potency. Antagonism by rimonabant suggested CB1R mediation. PMID:27264437

  19. Chronic marijuana smoke exposure in the rhesus monkey. IV: Neurochemical effects and comparison to acute and chronic exposure to delta-9-tetrahydrocannabinol (THC) in rats.

    PubMed

    Ali, S F; Newport, G D; Scallet, A C; Paule, M G; Bailey, J R; Slikker, W

    1991-11-01

    THC is the major psychoactive constituent of marijuana and is known to produce psychopharmacological effects in humans. These studies were designed to determine whether acute or chronic exposure to marijuana smoke or THC produces in vitro or in vivo neurochemical alterations in rat or monkey brain. For the in vitro study, THC was added (1-100 nM) to membranes prepared from different regions of the rat brain and muscarinic cholinergic (MCh) receptor binding was measured. For the acute in vivo study, rats were injected IP with vehicle, 1, 3, 10, or 30 mg THC/kg and sacrificed 2 h later. For the chronic study, rats were gavaged with vehicle or 10 or 20 mg THC/kg daily, 5 days/week for 90 days and sacrificed either 24 h or 2 months later. Rhesus monkeys were exposed to the smoke of a single 2.6% THC cigarette once a day, 2 or 7 days a week for 1 year. Approximately 7 months after the last exposure, animals were sacrificed by overdose with pentobarbital for neurochemical analyses. In vitro exposure to THC produced a dose-dependent inhibition of MCh receptor binding in several brain areas. This inhibition of MCh receptor binding, however, was also observed with two other nonpsychoactive derivatives of marijuana, cannabidiol and cannabinol. In the rat in vivo study, we found no significant changes in MCh or other neurotransmitter receptor binding in hippocampus, frontal cortex or caudate nucleus after acute or chronic exposure to THC. In the monkey brain, we found no alterations in the concentration of neurotransmitters in caudate nucleus, frontal cortex, hypothalamus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.

    PubMed

    Tai, S; Hyatt, W S; Gu, C; Franks, L N; Vasiljevik, T; Brents, L K; Prather, P L; Fantegrossi, W E

    2015-12-01

    These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs.

  1. Simple quantitation of formoterol and 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid in human urine by liquid chromatography-tandem mass spectrometry in doping control.

    PubMed

    Lee, Kang Mi; Kim, Ho Jun; Son, Junghyun; Park, Ju-Hyung; Kwon, Oh-Seung; Lee, Jaeick

    2014-09-15

    11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and formoterol are newly revised prohibited threshold substances (150 ng/mL for THC-COOH and 40 ng/mL for formoterol) by the World Anti-Doping Agency (WADA). In continuation of our direct quantitation work of the prohibited threshold substances, direct LC-MS/MS methods combined with a simple sample preparation procedure have been developed and validated for the measurement of these two threshold substances in urine samples. After the enzymatic hydrolysis of urine samples, the resulting samples were diluted with acetonitrile and centrifuged. The supernatant was directly analyzed by LC-MS/MS using the selected reaction monitoring mode. The calibration curve range of the assay was ranged over 50-200% of the threshold value according to WADA guidelines. The limit of detection and limit of quantification were 6.1 and 18.4 ng/mL for THC-COOH and 2.0 and 6.2 ng/mL for formoterol, respectively. Intra- and inter-day precisions were between 2.08% and 7.28% and the accuracies ranged from 95.16% to 104.49%. The present methods were successfully applied to the analysis of the proficiency test samples. PMID:25063922

  2. Quantification of 11-Nor-9-Carboxy-Δ9-Tetrahydrocannabinol in Human Oral Fluid by Gas Chromatography–Tandem Mass Spectrometry

    PubMed Central

    Barnes, Allan J.; Scheidweiler, Karl B.; Huestis, Marilyn A.

    2015-01-01

    A sensitive and specific method for the quantification of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) in oral fluid collected with the Quantisal and Oral-Eze devices was developed and fully validated. Extracted analytes were derivatized with hexafluoroisopropanol and trifluoroacetic anhydride and quantified by gas chromatography–tandem mass spectrometry with negative chemical ionization. Standard curves, using linear least-squares regression with 1/x2 weighting were linear from 10 to 1000 ng/L with coefficients of determination >0.998 for both collection devices. Bias was 89.2%–112.6%, total imprecision 4.0%–5.1% coefficient of variation, and extraction efficiency >79.8% across the linear range for Quantisal-collected specimens. Bias was 84.6%–109.3%, total imprecision 3.6%–7.3% coefficient of variation, and extraction efficiency >92.6% for specimens collected with the Oral-Eze device at all 3 quality control concentrations (10, 120, and 750 ng/L). This effective high-throughput method reduces analysis time by 9 minutes per sample compared with our current 2-dimensional gas chromatography–mass spectrometry method and extends the capability of quantifying this important oral fluid analyte to gas chromatography–tandem mass spectrometry. This method was applied to the analysis of oral fluid specimens collected from individuals participating in controlled cannabis studies and will be effective for distinguishing passive environmental contamination from active cannabis smoking. PMID:24622724

  3. Delay- and Dose-Dependent Effects of Δ9-Tetrahydrocannabinol Administration on Spatial and Object Working Memory Tasks in Adolescent Rhesus Monkeys

    PubMed Central

    Verrico, Christopher D; Liu, Shijing; Bitler, Elizabeth J; Gu, Hong; Sampson, Allan R; Bradberry, Charles W; Lewis, David A

    2012-01-01

    Among adolescents, the perception that cannabis can cause harm has decreased and use has increased. However, in rodents, cannabinoid administration during adolescence induces working memory (WM) deficits that are more severe than if the same exposure occurs during adulthood. As both object and spatial WM mature in a protracted manner, although apparently along different trajectories, adolescent cannabis users may be more susceptible to impairments in one type of WM. Here, we evaluate the acute effects of a range of doses (30–240 μg/kg) of intravenous Δ9-tetrahydrocannabinol (THC) administration on the performance of spatial and object WM tasks in adolescent rhesus monkeys. Accuracy on the object WM task was not significantly affected by any dose of THC. In contrast, THC administration impaired accuracy on the spatial WM task in a delay- and dose-dependent manner. Importantly, the THC-induced spatial WM deficits were not because of motor or motivational impairments. These data support the idea that immature cognitive functions are more sensitive to the acute effects of THC. PMID:22218091

  4. Quantification of 11-nor-9-carboxy-δ9-tetrahydrocannabinol in human oral fluid by gas chromatography-tandem mass spectrometry.

    PubMed

    Barnes, Allan J; Scheidweiler, Karl B; Huestis, Marilyn A

    2014-04-01

    A sensitive and specific method for the quantification of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) in oral fluid collected with the Quantisal and Oral-Eze devices was developed and fully validated. Extracted analytes were derivatized with hexafluoroisopropanol and trifluoroacetic anhydride and quantified by gas chromatography-tandem mass spectrometry with negative chemical ionization. Standard curves, using linear least-squares regression with 1/x weighting were linear from 10 to 1000 ng/L with coefficients of determination >0.998 for both collection devices. Bias was 89.2%-112.6%, total imprecision 4.0%-5.1% coefficient of variation, and extraction efficiency >79.8% across the linear range for Quantisal-collected specimens. Bias was 84.6%-109.3%, total imprecision 3.6%-7.3% coefficient of variation, and extraction efficiency >92.6% for specimens collected with the Oral-Eze device at all 3 quality control concentrations (10, 120, and 750 ng/L). This effective high-throughput method reduces analysis time by 9 minutes per sample compared with our current 2-dimensional gas chromatography-mass spectrometry method and extends the capability of quantifying this important oral fluid analyte to gas chromatography-tandem mass spectrometry. This method was applied to the analysis of oral fluid specimens collected from individuals participating in controlled cannabis studies and will be effective for distinguishing passive environmental contamination from active cannabis smoking. PMID:24622724

  5. Investigation of the transformation of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol during water chlorination by liquid chromatography-quadrupole-time-of-flight-mass spectrometry.

    PubMed

    González-Mariño, Iria; Rodríguez, Isaac; Quintana, José Benito; Cela, Rafael

    2013-10-15

    The stability of the main metabolite of cannabis, (±)-11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THCCOOH), during water chlorination has been investigated. THCCOOH was degraded in few seconds following a pseudo-first order kinetics. Sample pH turned out to be a significant factor, decreasing THCCOOH half-life with an increase in its values. Seven by-products could be positively identified from accurate mass measurements: three compounds resulted from electrophilic substitutions of hydrogen per chlorine (or bromine) in the aromatic ring, whereas the formation of the remaining four involved additional reactions in the C-C double bond (hydration and halogenation). The software predicted toxicity of these products towards Daphnia magna indicates that they are expected to have toxicity values similar or higher than its precursor compound. Experiments conducted with diluted urine showed that THCCOOH was stable in this matrix, probably due to a rapid and complete reaction between chlorine and other organic constituents already present in the samples. In real surface waters, the extent of the reaction was also affected by the organic matter content, and so THCCOOH was rapidly degraded in samples scarcely affected by human activities, being more stable in waters with a higher level of pollution. PMID:23995559

  6. Novel method of determination of D9-tetrahydrocannabinol(THC) in human serum by high-performance liquid chromatography with electrochemical detection.

    PubMed

    Kokubun, Hideya; Uezono, Yasuhito; Matoba, Motohiro

    2014-04-01

    In Europe and the United States, D9-tetrahydrocannabinol(THC, dronabinol), one of the psychoactive constituents of cannabis, has been used for both its anti-emetic and orexigenic effects in cancer patient receiving chemotherapy.However, dronabinol has not yet been launched in the market in Japan.In the future, it is necessary to ascertain the pharmacokinetics of dronabinol in cancer paitient.Therefore, we developed an HPLC procedure using electrochemical detection(ECD)for quan- titation of the concentrations of dronabinol in blood.An eluent of 50mM KH2PO4/CH3CN(9:16)was used as the mobile phase.The column was used the XTerra®RP18, and the voltage of the electrochemical detector in dronabinol was set at 400 mV.As a result, the calibration curve was linear in the range of 10 ng/mL to 100 ng/mL(y=964.85x -3,419, r=0.997).The lower limit of quantification was 0.5 ng/mL(S/N=3).The relative within-runs and between-runs standard deviations for the assay dronabinol were less than 4.7%. The method reported here is superior to previously reported methods in cancer patient.

  7. RNA-seq Analysis of δ9-Tetrahydrocannabinol-treated T Cells Reveals Altered Gene Expression Profiles That Regulate Immune Response and Cell Proliferation.

    PubMed

    Yang, Xiaoming; Bam, Marpe; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2016-07-22

    Marijuana has drawn significant public attention and concern both for its medicinal and recreational use. Δ9-Tetrahydrocannabinol (THC), which is the main bioactive component in marijuana, has also been shown to possess potent anti-inflammatory properties by virtue of its ability to activate cannabinoid receptor-2 (CB-2) expressed on immune cells. In this study, we used RNA-seq to quantify the transcriptomes and transcript variants that are differentially regulated by THC in super antigen-activated lymph node cells and CD4(+) T cells. We found that the expressions of many transcripts were altered by THC in both total lymph node cells and CD4(+) T cells. Furthermore, the abundance of many miRNA precursors and long non-coding RNAs was dramatically altered in THC-treated mice. For example, the expression of miR-17/92 cluster and miR-374b/421 cluster was down-regulated by THC. On the other hand miR-146a, which has been shown to induce apoptosis, was up-regulated by THC. Long non-coding RNAs that are expressed from the opposite strand of CD27 and Appbp2 were induced by THC. In addition, THC treatment also caused alternative promoter usage and splicing. The functions of those altered transcripts were mainly related to immune response and cell proliferation. PMID:27268054

  8. Changes in body temperature after administration of antipyretics, LSD, delta 9-THC, CNS depressants and stimulants, hormones, inorganic ions, gases, 2,4-DNP and miscellaneous agents.

    PubMed

    Clark, W G; Clark, Y L

    1981-01-01

    This survey concludes a series of complications of data from the literature, primarily published since 1965, on thermoregulatory effects of antipyretics in afebrile as well as in febrile subjects, LSD and other hallucinogens, cannabinoids, general CNS depressants, CNS stimulants including xanthines, hormones, inorganic ions, gases and fumes, 2,4-dinitrophenol and miscellaneous agents including capsaicin, cardiac glycosides, chemotherapeutic agents, cinchona alkaloids, cyclic nucleotides, cycloheximide, 2-deoxy-D-glucose, dimethylsulfoxide, insecticides, local anesthetics, poly I:poly C, spermidine and spermine, sugars, toxins and transport inhibitors. The information listed includes the species used, route of administration and dose of drug, the environmental temperature at which the experiments were performed, the number of tests, the direction and magnitude of body temperature change and remarks on the presence of special conditions such as age or lesions, or on the influence of other drugs, such as antagonists, on the response to the primary agents.

  9. Identification and quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-COOH-glu) in hair by ultra-performance liquid chromatography tandem mass spectrometry as a potential hair biomarker of cannabis use.

    PubMed

    Pichini, Simona; Marchei, Emilia; Martello, Simona; Gottardi, Massimo; Pellegrini, Manuela; Svaizer, Fiorenza; Lotti, Andrea; Chiarotti, Marcello; Pacifici, Roberta

    2015-04-01

    We developed and validated an ultra-high-pressure liquid chromatography-tandem mass spectrometry method to identify and quantify 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in hair of cannabis consumers. After hair washing with methyl alcohol and diethyl ether and subsequent addition of amiodarone as internal standard hair samples were treated with 500 μl VMA-T M3 buffer reagent for 1 h at 100 °C. After cooling, 10 μl VMA-T M3 extract were injected into chromatographic system. Chromatographic separation was carried out on a reversed phase column using a linear gradient elution with two solvents: 5 mM ammonium formate pH 3.0 (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The flow rate was kept constant at 0.4 ml/min during the analysis. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode via positive electrospray ionization. Linear calibration curves were obtained for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide with correlation coefficients (r(2)) of 0.99 and a limit of quantification of 0.25 pg/mg hair. Analytical recovery was between 79.6% and 100.7% and intra- and inter-assay imprecision and inaccuracy were always lower than 15%. Ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of 20 different hair samples of cannabis consumers disclosed the presence of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in the range of 0.5-8.6 pg/mg hair. These data provided a good start to consider 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide as alternative hair biomarker of cannabis consumption. PMID:25659366

  10. Identification and quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-COOH-glu) in hair by ultra-performance liquid chromatography tandem mass spectrometry as a potential hair biomarker of cannabis use.

    PubMed

    Pichini, Simona; Marchei, Emilia; Martello, Simona; Gottardi, Massimo; Pellegrini, Manuela; Svaizer, Fiorenza; Lotti, Andrea; Chiarotti, Marcello; Pacifici, Roberta

    2015-04-01

    We developed and validated an ultra-high-pressure liquid chromatography-tandem mass spectrometry method to identify and quantify 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in hair of cannabis consumers. After hair washing with methyl alcohol and diethyl ether and subsequent addition of amiodarone as internal standard hair samples were treated with 500 μl VMA-T M3 buffer reagent for 1 h at 100 °C. After cooling, 10 μl VMA-T M3 extract were injected into chromatographic system. Chromatographic separation was carried out on a reversed phase column using a linear gradient elution with two solvents: 5 mM ammonium formate pH 3.0 (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The flow rate was kept constant at 0.4 ml/min during the analysis. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode via positive electrospray ionization. Linear calibration curves were obtained for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide with correlation coefficients (r(2)) of 0.99 and a limit of quantification of 0.25 pg/mg hair. Analytical recovery was between 79.6% and 100.7% and intra- and inter-assay imprecision and inaccuracy were always lower than 15%. Ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of 20 different hair samples of cannabis consumers disclosed the presence of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in the range of 0.5-8.6 pg/mg hair. These data provided a good start to consider 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide as alternative hair biomarker of cannabis consumption.

  11. How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9-Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia

    PubMed Central

    Freeman, Daniel; Dunn, Graham; Murray, Robin M.; Evans, Nicole; Lister, Rachel; Antley, Angus; Slater, Mel; Godlewska, Beata; Cornish, Robert; Williams, Jonathan; Di Simplicio, Martina; Igoumenou, Artemis; Brenneisen, Rudolf; Tunbridge, Elizabeth M.; Harrison, Paul J.; Harmer, Catherine J.; Cowen, Philip; Morrison, Paul D.

    2015-01-01

    Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis—∆9-tetrahydrocannabinol (THC)—causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences. PMID:25031222

  12. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.

    PubMed

    Freeman, Daniel; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Antley, Angus; Slater, Mel; Godlewska, Beata; Cornish, Robert; Williams, Jonathan; Di Simplicio, Martina; Igoumenou, Artemis; Brenneisen, Rudolf; Tunbridge, Elizabeth M; Harrison, Paul J; Harmer, Catherine J; Cowen, Philip; Morrison, Paul D

    2015-03-01

    Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences.

  13. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.

    PubMed

    Freeman, Daniel; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Antley, Angus; Slater, Mel; Godlewska, Beata; Cornish, Robert; Williams, Jonathan; Di Simplicio, Martina; Igoumenou, Artemis; Brenneisen, Rudolf; Tunbridge, Elizabeth M; Harrison, Paul J; Harmer, Catherine J; Cowen, Philip; Morrison, Paul D

    2015-03-01

    Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences. PMID:25031222

  14. Development of a simple and sensitive HPLC-UV method for the simultaneous determination of cannabidiol and Δ(9)-tetrahydrocannabinol in rat plasma.

    PubMed

    Zgair, Atheer; Wong, Jonathan C M; Sabri, Akmal; Fischer, Peter M; Barrett, David A; Constantinescu, Cris S; Gershkovich, Pavel

    2015-10-10

    There has been increased interest in the medical use of cannabinoids in recent years, particularly in the predominant natural cannabinoids, cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC). The aim of the current study was to develop a sensitive and reliable method for the quantification of CBD and THC in rat plasma. A combination of protein precipitation using cold acetonitrile and liquid-liquid extraction using n-hexane was utilised to extract CBD and THC from rat plasma. Samples were then evaporated and reconstituted in acetonitrile and 30 μL was injected into an HPLC system. Separation was achieved using an ACE C18-PFP 150 mm × 4.6 mm, 3 μm column at 55 °C with isocratic elution using a mobile phase consisting of acetonitrile-water (62:38, v/v) at 1 mL/min for 20 min. Both cannabinoids, as well as the internal standard (4,4-dichlorodiphenyltrichloroethane, DDT) were detected at 220 nm. Our new method showed linearity in the range of 10-10,000 ng/mL and a lower limit of quantification (LLOQ) of 10 ng/mL for both cannabinoids, which is comparable to previously reported LC-MS/MS methods. Inter- and intra-day precision and accuracy were below 15% RSD and RE, respectively. To demonstrate the suitability of the method for in vivo studies in rats, the assay was applied to a preliminary pharmacokinetic study following IV bolus administration of 5 mg/kg CBD or THC. In conclusion, a simple, sensitive, and cost-efficient HPLC-UV method for the simultaneous determination of CBD and THC has been successfully developed, validated and applied to a pharmacokinetic study in rats.

  15. Role of the endocannabinoid system in brain functions relevant for schizophrenia: an overview of human challenge studies with cannabis or ∆9-tetrahydrocannabinol (THC).

    PubMed

    Bossong, Matthijs G; Jansma, J Martijn; Bhattacharyya, Sagnik; Ramsey, Nick F

    2014-07-01

    Accumulating evidence suggests involvement of the endocannabinoid system in the pathophysiology of schizophrenia, which signifies a potential application for this system in the treatment of this disorder. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of schizophrenia. Here we review human studies that investigated acute effects of cannabis or ∆9-tetrahydrocannabinol (THC) on brain functions that are implicated in schizophrenia. Results suggest that the impact of THC administration depends on the difficulty of the task performed. Impaired performance of cognitive paradigms is reported on more challenging tasks, which is associated with both activity deficits in temporal and prefrontal areas and a failure to deactivate regions of the default mode network. Comparable reductions in prefrontal activity and impairments in deactivation of the default mode network are seen in patients during performance of cognitive paradigms. Normal performance levels after THC administration demonstrated for less demanding tasks are shown to be related to either increased neural effort in task-specific regions ('neurophysiological inefficiency'), or recruitment of alternative brain areas, which suggests a change in strategy to meet cognitive demands. Particularly a pattern of performance and brain activity corresponding with an inefficient working memory system is consistently demonstrated in patients. These similarities in brain function between intoxicated healthy volunteers and schizophrenia patients provide an argument for a role of the endocannabinoid system in symptoms of schizophrenia, and further emphasize this system as a potential novel target for treatment of these symptoms.

  16. Regulation of Hippocampal Cannabinoid CB1 Receptor Actions by Adenosine A1 Receptors and Chronic Caffeine Administration: Implications for the Effects of Δ9-Tetrahydrocannabinol on Spatial Memory

    PubMed Central

    Sousa, Vasco C; Assaife-Lopes, Natália; Ribeiro, Joaquim A; Pratt, Judith A; Brett, Ros R; Sebastião, Ana M

    2011-01-01

    The cannabinoid CB1 receptor-mediated modulation of γ-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A1 receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A1 receptors localized in GABAergic cells do not directly influence GABA release. CB1 and A1 receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Δ9-tetrahydrocannabinol (THC, a CB1 receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A1–CB1 interaction influences GABA and glutamate release in the hippocampus. We found that A1 receptor activation attenuated the CB1-mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine–cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, >12 h before trials) led to an A1-mediated enhancement of the CB1-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB1 receptor number and an attenuation of CB1 coupling with G protein. A1 receptor levels were increased following chronic caffeine administration. This study shows that A1 receptors exert a negative modulatory effect on CB1-mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory. PMID:20927050

  17. Modulation of Gut-Specific Mechanisms by Chronic Δ9-Tetrahydrocannabinol Administration in Male Rhesus Macaques Infected with Simian Immunodeficiency Virus: A Systems Biology Analysis

    PubMed Central

    Amedee, Angela M.; LeCapitaine, Nicole J.; Zabaleta, Jovanny; Mohan, Mahesh; Winsauer, Peter J.; Vande Stouwe, Curtis; McGoey, Robin R.; Auten, Matthew W.; LaMotte, Lynn; Chandra, Lawrance C.; Birke, Leslie L.

    2014-01-01

    Abstract Our studies have demonstrated that chronic Δ9-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4- to 6-year-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 months of chronic THC administration (0.18–0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ∼5 months postinoculation showed lower viral load, increased duodenal integrin beta 7+(β7) CD4+ and CD8+ central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified six genes that were differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified as having significant participation in (1) apoptosis, (2) cell survival, proliferation, and morphogenesis, and (3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion, and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC administration modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation. PMID:24400995

  18. DELTAE

    SciTech Connect

    Ward, W.C. )

    1993-11-01

    In thermoacoustic engines and refrigerators, and in many simple acoustic systems, a one dimensional wave equation determines the spatial dependence of the acoustic pressure and velocity. DELTAE numerically integrates such wave equations in the acoustic approximation, in gases or liquids, in user-defined geometries. Boundary conditions can include conventional acoustic boundary conditions of geometry and impedance, as well as temperature and thermal power in thermoacoustic systems. DELTAE can be used easily for apparatus ranging from simple duct networks and resonators to thermoacoustic engines refrigerators and combinations thereof. It can predict how a given apparatus will perform, or can allow the user to design an apparatus to achieve desired performance. DELTAE views systems as a series of segments; twenty segment types are supported. The purely acoustic segments include ducts and cones, and lumped impedances including compliances, series impedances, and endcaps. Electroacoustics tranducer segments can be defined using either frequency-independent coefficients or the conventional parameters of loudspeaker-style drivers: mass, spring constant, magnetic field strength, etc. Tranducers can be current driven, voltage driven, or connected to an electrical load impedance. Thermoacoustic segment geometries include parallel plates, circular and rectangular pores, and pin arrays. Side branches can be defined with fixed impedances, frequency-dependent radiation impedances, or as an auxiliary series of segments of any types. The user can select working fluids from among air, helium, neon, argon, hydrogen, deuterium, carbon dioxide, nitrogen, helium-argon mixtures, helium-xenon mixtures, liquid sodium, and eutectic sodium-potassium. Additional fluids and solids can be defined by the user.

  19. Cannabinergic aminoalkylindoles, including AM678=JWH018 found in ‘Spice’, examined using drug (Δ9-THC) discrimination for rats

    PubMed Central

    Järbe, Torbjörn U.C.; Deng, Hongfeng; Vadivel, Subramanian K.; Makriyannis, Alexandros

    2011-01-01

    We examined four different cannabinergic aminoalkylindole ligands, including one drug (AM678=JWH018) found in herbal ‘Spice’ concoctions, for their ability to substitute for Δ9-tetrahydrocannabinol (THC), and the ability of the cannabinoid receptor 1 (CB1R) selective antagonist/inverse agonist rimonabant to block the substitution 30 and 90 min after i.p. injection. Rats trained to discriminate the effects of vehicle from those produced by 3 mg/kg THC were used. The order of potency was: AM5983≥AM678>AM2233>WIN55,212-2 at both test intervals. AM5983 and AM678 appeared 8 times more potent than THC, followed by AM2233 (about twice as potent as THC), and WIN55,212-2≈THCat the 30 min-test interval. The aminoalkylindoles showed reduced potency (i.e., an increased ED50 value) at the longer injection-to-test interval of 90 min compared to testing at 30 min. The rightward shifts by co-administration of rimonabant were approximately 8 to 12-fold for AM5983 and AM678, compared to an approximately 3-fold rightward shift for the WIN55,212-2 curve. AM2233 (1.8 mg/kg) substitution was also blocked by 1 mg/kg rimonabant. In conclusion, AM5983 and AM678=JWH018 are potent cannabimimetics derived from an aminoalkylindole template. WIN55,212-2 seemed to interact differently with rimonabant, compared to either AM5983 or AM678, indicating potential differences in the mechanism(s) of action between cannabinergic aminoalkylindoles. PMID:21836461

  20. Determination of main tetrahydrocannabinoids by GC-MS: impact of protein precipitation by acetonitrile on solid phase extraction of cannabinoids from human serum.

    PubMed

    Hidvégi, E; Somogyi, G P

    2014-06-01

    The analysis of delta9-tetrahydrocannabinol (delta9-THC) and its main metabolites [11-hydroxy-delta9-tetrahydrocannabinol (11-OH-delta9-THC) and 11-nor-9-carboxy-delta9-tetrahydrocannabinol] in serum is a routine assay in forensic toxicology in the case of drivers influenced by Cannabis abuse and in other cases. Analysis of the specimen may involve protein precipitation, although there are authors who do not use this step. In this study we investigated the effect of acetonitrile as protein precipitant added to the serum on the absolute extraction recoveries of the analytes. This is very important not only from a forensic point of view, but also from the aspect of impact of delta9-THC therapy. Our results showed that in the case of spiked serum (2 ml), 80-87% extraction recovery can be achieved if 4 ml of acetonitrile is added before solid phase extraction. The second best result could be reached if no acetonitrile was added (64-73%). However, in the case of physiological sera of Cannabis consumers, no precipitation may be more advantageous in some cases. Matrix effects, which were studied by comparing the detectability and relative intensities of matrix peaks within the corresponding time windows of the analytes, were less influenced if the extraction was achieved with or without acetonitrile. PMID:24974573

  1. Highly sensitive quantification of unconjugated 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol in a cannabis user's hair using micropulverized extraction.

    PubMed

    Kuwayama, Kenji; Miyaguchi, Hajime; Yamamuro, Tadashi; Tsujikawa, Kenji; Kanamori, Tatsuyuki; Iwata, Yuko T; Inoue, Hiroyuki

    2016-05-01

    We previously developed a simple and highly sensitive analytical method for 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THC-COOH) in spiked hair using micropulverized extraction (MPE) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Using this method, we were able to quantify THC-COOH at 0.2pg/mg, which is the cut-off level recommended by the Society of Hair Testing. However, it was impossible to prove the validity of the method and the presence of THC-COOH conjugated with glucuronide in hair because we did not have authentic hair containing THC-COOH at the cut-off levels at that time. In this study, the previously developed method was verified using recently obtained hair from a cannabis user. The concentrations of THC-COOH quantified using the method were 0.36±0.01pg/mg without hydrolyzation for glucuronide and 0.49±0.05pg/mg with hydrolyzation after MPE, whereas the concentration quantified using the conventional alkaline dissolution and gas chromatography/tandem mass spectrometry with negative ion chemical ionization was 0.50±0.02pg/mg. The results proved that THC-COOH could be extracted completely from authentic hair containing THC-COOH at the recommended cut-off level using MPE. In addition, MPE with and without hydrolyzation, unlike alkaline dissolution of hair, enabled the measurement of the percentage of the conjugate form in total THC-COOH. The percentage of conjugated THC-COOH in hair measured using the MPE was approximately 26%, which was greatly different from previously reported data (>75%). The discrimination between conjugated and unconjugated compounds in hair is important to understand the mechanism of drug uptakes into hair. More data obtained with our simple and highly sensitive method from the hair of cannabis users would help to understand the relationship of concentrations between THC-COOH and its conjugate in hair.

  2. Simultaneous quantification of Δ(9)-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol and cannabinol in oral fluid by microflow-liquid chromatography-high resolution mass spectrometry.

    PubMed

    Concheiro, Marta; Lee, Dayong; Lendoiro, Elena; Huestis, Marilyn A

    2013-07-01

    Δ(9)-Tetrahydrocannabinol (THC) is the primary target in oral fluid (OF) for detecting cannabis intake. However, additional biomarkers are needed to solve interpretation issues, such as the possibility of passive inhalation by identifying 11-nor-9-carboxy-THC (THCCOOH), and determining recent cannabis smoking by identifying cannabidiol (CBD) and/or cannabinol (CBN). We developed and comprehensively validated a microflow liquid chromatography (LC)-high resolution mass spectrometry method for simultaneous quantification of THC, THCCOOH, CBD and CBN in OF collected with the Oral-Eze(®) and Quantisal™ devices. One milliliter OF-buffer solution (0.25mL OF and 0.5mL of Oral-Eze buffer, 1:3 dilution, or 0.75mL Quantisal buffer, 1:4 dilution) had proteins precipitated, and the supernatant subjected to CEREX™ Polycrom™ THC solid-phase extraction (SPE). Microflow LC reverse-phase separation was achieved with a gradient mobile phase of 10mM ammonium acetate pH 6 and acetonitrile over 10min. We employed a Q Exactive high resolution mass spectrometer, with compounds identified and quantified by targeted-MSMS experiments. The assay was linear 0.5-50ng/mL for THC, CBD and CBN, and 15-500pg/mL for THCCOOH. Intra- and inter-day and total imprecision were <10.8%CV and bias 86.5-104.9%. Extraction efficiency was 52.4-109.2%, process efficiency 12.2-88.9% and matrix effect ranged from -86 to -6.9%. All analytes were stable for 24h at 5°C on the autosampler. The method was applied to authentic OF specimens collected with Quantisal and Oral-Eze devices. This method provides a rapid simultaneous quantification of THCCOOH and THC, CBD, CBN, with good selectivity and sensitivity, providing the opportunity to improve interpretation of cannabinoid OF results by eliminating the possibility of passive inhalation and providing markers of recent cannabis smoking.

  3. Highly sensitive quantification of unconjugated 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol in a cannabis user's hair using micropulverized extraction.

    PubMed

    Kuwayama, Kenji; Miyaguchi, Hajime; Yamamuro, Tadashi; Tsujikawa, Kenji; Kanamori, Tatsuyuki; Iwata, Yuko T; Inoue, Hiroyuki

    2016-05-01

    We previously developed a simple and highly sensitive analytical method for 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THC-COOH) in spiked hair using micropulverized extraction (MPE) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Using this method, we were able to quantify THC-COOH at 0.2pg/mg, which is the cut-off level recommended by the Society of Hair Testing. However, it was impossible to prove the validity of the method and the presence of THC-COOH conjugated with glucuronide in hair because we did not have authentic hair containing THC-COOH at the cut-off levels at that time. In this study, the previously developed method was verified using recently obtained hair from a cannabis user. The concentrations of THC-COOH quantified using the method were 0.36±0.01pg/mg without hydrolyzation for glucuronide and 0.49±0.05pg/mg with hydrolyzation after MPE, whereas the concentration quantified using the conventional alkaline dissolution and gas chromatography/tandem mass spectrometry with negative ion chemical ionization was 0.50±0.02pg/mg. The results proved that THC-COOH could be extracted completely from authentic hair containing THC-COOH at the recommended cut-off level using MPE. In addition, MPE with and without hydrolyzation, unlike alkaline dissolution of hair, enabled the measurement of the percentage of the conjugate form in total THC-COOH. The percentage of conjugated THC-COOH in hair measured using the MPE was approximately 26%, which was greatly different from previously reported data (>75%). The discrimination between conjugated and unconjugated compounds in hair is important to understand the mechanism of drug uptakes into hair. More data obtained with our simple and highly sensitive method from the hair of cannabis users would help to understand the relationship of concentrations between THC-COOH and its conjugate in hair. PMID:27020617

  4. Ocular hypotension, ocular toxicity, and neurotoxicity in response to marihuana extract and cannabidiol.

    PubMed

    Colasanti, B K; Brown, R E; Craig, C R

    1984-01-01

    Marihuana extract containing 21.3% delta-9-tetrahydrocannabinol (100 micrograms/hr), delta-9-tetrahydrocannabinol (20 micrograms/hr), cannabidiol (20 micrograms/hr), or the polyethylene glycol vehicle (1 microliter/hr) was delivered topically to cat eyes via osmotic minipumps over a 9-day period. Intraocular pressure differences between treated and untreated eyes of cats receiving marihuana extract remained 3-4 mmHg lower than those for vehicle controls, while differential values for the delta 9-THC-treated group remained reduced by 3-5 mmHg; data for these two groups did not differ statistically. Pressure differences between treated and untreated eyes of cats receiving cannabidiol were likewise 3-4 mmHg lower than values for controls. Ocular toxicity after delta 9-THC, consisting of conjunctival erythema and chemosis as well as corneal opacification, was quite severe. Although these changes also occurred after marihuana extract, their intensity was much reduced. In contrast, no ocular toxicity became apparent during administration of cannabidiol. While marihuana extract and delta 9-THC produced a dose-related increase in the appearance of 8-13 Hz polyspike discharges in the electrocorticograms of rats, both polyethylene glycol and cannabidiol lacked this effect. These results indicate that the ocular and central effects of marihuana extract and delta 9-THC are qualitatively similar. In addition, it appears that the ocular hypotensive effect produced by cannabidiol is relatively dissociable from both the ocular toxicity and the neurotoxicity associated with marihuana extract.

  5. Symptomatic treatment of multiple sclerosis using cannabinoids: recent advances.

    PubMed

    Smith, Paul F

    2007-09-01

    Recent years have seen a dramatic increase in the number of clinical trials investigating the potential efficacy of medicinal cannabinoids for the symptomatic treatment of chronic pain and spasticity in multiple sclerosis (MS). A number of different cannabinoids have been used, including: delta9-tetrahydrocannabinol (THC) itself; the synthetic delta9-THC, dronabinol; a 1:1 ratio of delta9-THC:cannabidiol (Sativex); and the synthetic delta9-THC metabolites CT-3 and nabilone. Other Cannabis extracts have also been tested. While 2-3 years ago there was little consensus in the literature, now the majority of studies are beginning to suggest that cannabinoids are useful in the treatment of MS in at least a subset of individuals. Their adverse side-effect profile has generally been mild compared with other drugs used for pain and spasticity; nonetheless, there is still concern about potential long-term side effects, particularly psychiatric side effects and effects on fetal development. PMID:17868014

  6. [Quantitative analysis and pharmaco-toxicity of cannabinoids in commercially available cannabis seeds].

    PubMed

    Matsunaga, T; Watanabe, K; Yoshimura, H; Yamamoto, I

    1998-09-01

    delta 9-Tetrahydrocannabinol (delta 9-THC), cannabinol, cannabidiol and cannabichromene were detected in commercially available cannabis seeds by silica gel TLC and gas chromatography. These cannabinoids existed in rather high content (0.10-2.02 mg/100 g of seeds) in the feed for birds especially bracts (82.3-441 mg/100 g). When the suspension prepared from the benzene washing solution of cannabis seeds, BenW, was administered at a dose of 3 mg/kg corresponding to delta 9-THC into a mouse, i.v., BenW caused hypothermia, catalepsy, pentobarbital-induced sleep prolongation and suppression of locomotor activity. These pharmacological activities of BenW were significantly higher than those of delta 9-THC (3 mg/kg, i.v.). These results may indicate the necessity to reconsider the present regulations on marihuana.

  7. Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

    PubMed

    Wiley, J L; Compton, D R; Gordon, P M; Siegel, C; Singer, M; Dutta, A; Lichtman, A H; Balster, R L; Razdan, R K; Martin, B R

    1996-01-01

    delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects. PMID:9076759

  8. Cannabinoid modulation of Kaposi's sarcoma-associated herpesvirus infection and transformation.

    PubMed

    Zhang, Xuefeng; Wang, Jian Feng; Kunos, George; Groopman, Jerome E

    2007-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV; also named human herpesvirus 8) is necessary but not sufficient for the development of Kaposi's sarcoma. A variety of factors may contribute to the pathogenesis of Kaposi's sarcoma in addition to KSHV. Marijuana is a widely used recreational agent, and Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major active component of marijuana, is prescribed for medicinal use. To evaluate how cannabinoids may affect the pathogenesis of Kaposi's sarcoma, we studied primary human dermal microvascular endothelial cells (HMVEC) exposed to KSHV. There was an increased efficiency of KSHV infection in the presence of low doses of Delta(9)-THC. We also found that Delta(9)-THC increased the viral load in KSHV-infected HMVEC through activation of the KSHV lytic switch gene, the open reading frame 50. Furthermore, we observed that Delta(9)-THC stimulated expression of the KSHV-encoded viral G protein-coupled receptor and Kaposi's sarcoma cell proliferation. Our results indicate that Delta(9)-THC can enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. Thus, use of cannabinoids may place individuals at greater risk for the development and progression of Kaposi's sarcoma. PMID:17671191

  9. Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats.

    PubMed

    Leitl, Michael D; Negus, S Stevens

    2016-06-01

    Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32-3.2 mg/kg), ketoprofen (0.1-10 mg/kg), bupropion (3.2-32 mg/kg), and [INCREMENT]9-tetrahydrocannabinol (THC; 0.32-3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin-induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain.

  10. Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences.

    PubMed

    Tunbridge, Elizabeth M; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Stumpenhorst, Katharina; Harrison, Paul J; Morrison, Paul D; Freeman, Daniel

    2015-11-01

    Cannabis use can induce cognitive impairments and psychotic experiences. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val(158)Met) appears to influence the immediate cognitive and psychotic effects of cannabis, or ∆(9)-tetrahydrocannabinol (THC), its primary psychoactive ingredient. This study investigated the moderation of the impact of experimentally administered THC by COMT. Cognitive performance and psychotic experiences were studied in participants without a psychiatric diagnosis, using a between-subjects design (THC vs. placebo). The effect of COMT Val(158)Met genotype on the cognitive and psychotic effects of THC, administered intravenously in a double-blind, placebo-controlled manner to 78 participants who were vulnerable to paranoia, was examined. The results showed interactive effects of genotype and drug group (THC or placebo) on working memory, assayed using the Digit Span Backwards task. Specifically, THC impaired performance in COMT Val/Val, but not Met, carriers. In contrast, the effect of THC on psychotic experiences, measured using the Community Assessment of Psychic Experiences (CAPE) positive dimension, was unaffected by COMT genotype. This study is the largest to date examining the impact of COMT genotype on response to experimentally administered THC, and the first using a purely non-clinical cohort. The data suggest that COMT genotype moderates the cognitive, but not the psychotic, effects of acutely administered THC.

  11. Cannabinoid findings in children hair - what do they really tell us? An assessment in the light of three different analytical methods with focus on interpretation of Δ9-tetrahydrocannabinolic acid A concentrations.

    PubMed

    Moosmann, Bjoern; Roth, Nadine; Hastedt, Martin; Jacobsen-Bauer, Andrea; Pragst, Fritz; Auwärter, Volker

    2015-05-01

    Hair analysis for drugs and drugs of abuse is increasingly applied in child protection cases. To determine the potential risk to a child living in a household where drugs are consumed, not only can the hair of the parents be analyzed but also the hair of the child. In the case of hair analysis for cannabinoids, the differentiation between external contamination and systemic uptake is particularly difficult, since the drug is quite often handled extensively prior to consumption (e.g. when preparing a joint) and smoke causes a further risk for an external contamination. Δ9-tetrahydrocannabinolic acid A (THCA-A), the non-psychoactive biogenetic precursor of Δ9-tetrahydrocannabinol (THC), is a suitable marker for external contamination since it is not incorporated into the hair matrix through the bloodstream in relevant amounts. In the presented study, hair samples from 41 children, 4 teenagers, and 34 drug-consuming parents were analyzed for THCA-A, THC and cannabinol (CBN) applying methanolic extraction and a fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (Method 1). For comparison, a part of the samples was also analyzed applying alkaline hydrolysis followed by liquid/liquid extraction and gas chromatography-mass spectrometry (GC-M)S (Method 2), or by headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) (Method 3). Furthermore, 458 seized marihuana samples and 180 seized hashish samples were analyzed for the same cannabinoids by gas-chromatography-flame ionization detector (GC-FID). In all but one of the hair samples, the concentration of THCA-A was higher than the concentration of THC and in 14 cases no THC could be detected despite the presence of THCA-A, suggesting that in almost all cases a significant external contamination had occurred. Within-family comparison showed a higher THCA-A/THC ratio in hair of children than of their consuming caregivers. Mean and median of this ratio of all

  12. Simultaneous LC-MS/MS determination of JWH-210, RCS-4, ∆(9)-tetrahydrocannabinol, and their main metabolites in pig and human serum, whole blood, and urine for comparing pharmacokinetic data.

    PubMed

    Schaefer, Nadine; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Peters, Benjamin; Bregel, Dietmar; Menger, Michael D; Maurer, Hans H; Ewald, Andreas H; Schmidt, Peter H

    2015-05-01

    A series of new synthetic cannabinoids (SC) has been consumed without any toxicological testing. For example, pharmacokinetic data have to be collected from forensic toxicological case work and/or animal studies. To develop a corresponding model for assessing such data, samples of controlled pig studies with two selected SC (JWH-210, RCS-4) and, as reference, ∆(9)-tetrahydrocannabinol (THC) should be analyzed as well as those of human cases. Therefore, a method for determination of JWH-210, RCS-4, THC, and their main metabolites in pig and human serum, whole blood, and urine samples is presented. Specimens were analyzed by liquid-chromatography tandem mass spectrometry and multiple-reaction monitoring with three transitions per compound. Full validation was carried out for the pig specimens and cross-validation for the human specimens concerning precision and bias. For the pig studies, the limits of detection were between 0.05 and 0.50 ng/mL in serum and whole blood and between 0.05 and 1.0 ng/mL in urine, the lower limits of quantification between 0.25 and 1.0 ng/mL in serum and 0.50 and 2.0 ng/mL in whole blood and urine, and the intra- and interday precision values lower than 15% and bias values within ±15%. The applicability was tested with samples taken from a pharmacokinetic pilot study with pigs following intravenous administration of a mixture of 200 μg/kg body mass dose each of JWH-210, RCS-4, and THC. The cross-validation data for human serum, whole blood, and urine showed that this approach should also be suitable for human specimens, e.g., of clinical or forensic cases. PMID:25772567

  13. Simultaneous Quantification of Δ9-Tetrahydrocannabinol, 11-nor-9-carboxy-Tetrahydrocannabinol, Cannabidiol and Cannabinol in Oral Fluid by MicroFlow-Liquid Chromatography-High Resolution Mass Spectrometry

    PubMed Central

    Concheiro, Marta; Lee, Dayong; Lendoiro, Elena; Huestis, Marilyn A.

    2014-01-01

    Δ9-tetrahydrocannabinol (THC) is the primary target in oral fluid (OF) for detecting cannabis intake. However, additional biomarkers are needed to solve interpretation issues, such as the possibility of passive inhalation by identifying 11-nor-9-carboxy-THC (THCCOOH), and determining recent cannabis smoking by identifying cannabidiol (CBD) and/or cannabinol (CBN). We developed and comprehensively validated a microflow liquid chromatography (LC)–high resolution mass spectrometry method for simultaneous quantification of THC, THCCOOH, CBD and CBN in OF collected with the Oral-Eze® and Quantisal™ devices. One mL OF-buffer solution (0.25mL OF and 0.5mL of Oral-Eze buffer,1:3 dilution, or 0.75mL Quantisal buffer, 1:4 dilution) had proteins precipitated, and the supernatant subjected to CEREX™ Polycrom™ THC solid-phase extraction (SPE). Microflow LC reverse-phase separation was achieved with a gradient mobile phase of 10mM ammonium acetate pH 6 and acetonitrile over 10 min. We employed a Q Exactive high resolution mass spectrometer, with compounds identified and quantified by targeted-MSMS experiments. The assay was linear 0.5–50 ng/mL for THC, CBD and CBN, and 15–500 pg/mL for THCCOOH. Intra- and inter-day and total imprecision were <10.8%CV and bias 86.5–104.9%. Extraction efficiency was 52.4–109.2%, process efficiency 12.2– 88.9% and matrix effect ranged from −86 to −6.9%. All analytes were stable for 24h at 5°C on the autosampler. The method was applied to authentic OF specimens collected with Quantisal and Oral-Eze devices. This method provides a rapid simultaneous quantification of THCCOOH and THC, CBD, CBN, with good selectivity and sensitivity, providing the opportunity to improve interpretation of cannabinoid OF results by eliminating the possibility of passive inhalation and providing markers of recent cannabis smoking. PMID:23726246

  14. Effect of cannabis on glutamate signalling in the brain: A systematic review of human and animal evidence.

    PubMed

    Colizzi, Marco; McGuire, Philip; Pertwee, Roger G; Bhattacharyya, Sagnik

    2016-05-01

    Use of cannabis or delta-9-tetrahydrocannabinol9-THC), its main psychoactive ingredient, is associated with psychotic symptoms or disorder. However, the neurochemical mechanism that may underlie this psychotomimetic effect is poorly understood. Although dopaminergic dysfunction is generally recognized as the final common pathway in psychosis, evidence of the effects of Δ9-THC or cannabis use on dopaminergic measures in the brain is equivocal. In fact, it is thought that cannabis or Δ9-THC may not act on dopamine firing directly but indirectly by altering glutamate neurotransmission. Here we systematically review all studies examining acute and chronic effects of cannabis or Δ9-THC on glutamate signalling in both animals and man. Limited research carried out in humans tends to support the evidence that chronic cannabis use reduces levels of glutamate-derived metabolites in both cortical and subcortical brain areas. Research in animals tends to consistently suggest that Δ9-THC depresses glutamate synaptic transmission via CB1 receptor activation, affecting glutamate release, inhibiting receptors and transporters function, reducing enzyme activity, and disrupting glutamate synaptic plasticity after prolonged exposure. PMID:26987641

  15. Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol.

    PubMed

    Lile, Joshua A; Wesley, Michael J; Kelly, Thomas H; Hays, Lon R

    2016-04-01

    The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating [INCREMENT]-tetrahydrocannabinol ([INCREMENT]-THC) using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral [INCREMENT]-THC from placebo and then received gabapentin (600 and 1200 mg), [INCREMENT]-THC (5, 15, and 30 mg), and placebo alone and in combination. Self-report, task performance, and physiological measures were also collected. [INCREMENT]-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate, and impaired psychomotor performance. Both doses of gabapentin substituted for the [INCREMENT]-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of [INCREMENT]-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of [INCREMENT]-THC leftward/upward, and combinations of [INCREMENT]-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to [INCREMENT]-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids.

  16. Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol.

    PubMed

    Lile, Joshua A; Wesley, Michael J; Kelly, Thomas H; Hays, Lon R

    2016-04-01

    The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating [INCREMENT]-tetrahydrocannabinol ([INCREMENT]-THC) using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral [INCREMENT]-THC from placebo and then received gabapentin (600 and 1200 mg), [INCREMENT]-THC (5, 15, and 30 mg), and placebo alone and in combination. Self-report, task performance, and physiological measures were also collected. [INCREMENT]-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate, and impaired psychomotor performance. Both doses of gabapentin substituted for the [INCREMENT]-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of [INCREMENT]-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of [INCREMENT]-THC leftward/upward, and combinations of [INCREMENT]-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to [INCREMENT]-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids. PMID:26313650

  17. St8sia2 deficiency plus juvenile cannabis exposure in mice synergistically affect higher cognition in adulthood.

    PubMed

    Tantra, Martesa; Kröcher, Tim; Papiol, Sergi; Winkler, Daniela; Röckle, Iris; Jatho, Jasmin; Burkhardt, Hannelore; Ronnenberg, Anja; Gerardy-Schahn, Rita; Ehrenreich, Hannelore; Hildebrandt, Herbert

    2014-12-15

    The neural cell adhesion molecule (NCAM) and its functionally linked polysialyltransferases, ST8SIA2 and ST8SIA4, are crucial for synaptic plasticity. Variations in encoding genes have been associated with mental illness. Since cannabinoids can alter NCAM polysialylation, we hypothesized that delta-9-tetrahydrocannabinol9-THC) might act as environmental 'second hit' regarding cognition of St8sia2(-/-) mice. These mice show per se minor behavioral abnormalities, consisting of reduced anxiety and mild cognitive deficits. Chronic Δ9-THC treatment of juvenile male wildtype mice (St8sia2(+/+)) (7mg/kg every other day over 3 weeks) did not appreciably affect cognition. St8sia2(-/-) mice, however, displayed a synergistic negative consequence of Δ9-THC on learning/memory, accompanied by polysialic acid-free NCAM-180 reduction in hippocampus and polysialic acid increase in dentate outer molecular layer. These synergistic effects became obvious only months after the last Δ9-THC. We conclude that juvenile cannabis exposure may cause delayed but lasting damage on cognition in subjects genetically predisposed to altered NCAM polysialylation.

  18. Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain.

    PubMed

    Polissidis, Alexia; Chouliara, Olga; Galanopoulos, Andreas; Rentesi, Georgia; Dosi, Maria; Hyphantis, Thomas; Marselos, Marios; Papadopoulou-Daifoti, Zeta; Nomikos, George G; Spyraki, Christina; Tzavara, Eleni T; Antoniou, Katerina

    2010-10-01

    This study explored the behavioural, neurochemical and molecular effects of Delta9-tetrahydrocannabinol (Delta9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following Delta9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of Delta9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse.

  19. Cannabinoids in the treatment of pain and spasticity in multiple sclerosis.

    PubMed

    Smith, Paul F

    2002-06-01

    There is a large amount of evidence to support the view that the psychoactive ingredient in cannabis, delta9-tetrahydrocannabinol (delta9-THC), and cannabinoids in general, can reduce muscle spasticity and pain under some circumstances. Cannabinoid (CB1) receptors in the CNS appear to mediate both of these effects and endogenous cannabinoids may fulfil these functions to some extent under normal circumstances. However, in the context of multiple sclerosis (MS), it is still questionable whether cannabinoids are superior to existing, conventional medicationsfor the treatment of spasticity and pain. In the case of spasticity, there are too few controlled clinical trials to draw any reliable conclusion at this stage. In the case of pain, most of the available trials suggest that cannabinoids are not superior to existing treatments; however, few trials have examined chronic pain syndromes that are relevant to MS. Whether or not cannabinoids do have therapeutic potential in the treatment of MS, a further issue will be whether synthetic cannabinoids should be used in preference to cannabis itself. Smoking cannabis is associated with significant risks of lung cancer and other respiratory dysfunction. Furthermore, delta9-THC, as a broad-spectrum cannabinoid receptor agonist, will activate both CB1 and CB2 receptors. Synthetic cannabinoids, which target specific cannabinoid receptor subtypes in specific parts of the CNS, are likely to be of more therapeutic use than delta9-THC itself. If rapid absorption is necessary, such synthetic drugs could be delivered via aerosol formulations.

  20. Current status of cannabis treatment of multiple sclerosis with an illustrative case presentation of a patient with MS, complex vocal tics, paroxysmal dystonia, and marijuana dependence treated with dronabinol.

    PubMed

    Deutsch, Stephen I; Rosse, Richard B; Connor, Julie M; Burket, Jessica A; Murphy, Mary E; Fox, Fiona J

    2008-05-01

    Pain, spasticity, tremor, spasms, poor sleep quality, and bladder and bowel dysfunction, among other symptoms, contribute significantly to the disability and impaired quality of life of many patients with multiple sclerosis (MS). Motor symptoms referable to the basal ganglia, especially paroxysmal dystonia, occur rarely and contribute to the experience of distress. A substantial percentage of patients with MS report subjective benefit from what is often illicit abuse of extracts of the Cannabis sativa plant; the main cannabinoids include delta-9-tetrahydrocannabinol (delta9-THC) and cannabidiol. Clinical trials of cannabis plant extracts and synthetic delta9-THC provide support for therapeutic benefit on at least some patient self-report measures. An illustrative case is presented of a 52-year-old woman with MS, paroxysmal dystonia, complex vocal tics, and marijuana dependence. The patient was started on an empirical trial of dronabinol, an encapsulated form of synthetic delta9-THC that is usually prescribed as an adjunctive medication for patients undergoing cancer chemotherapy. The patient reported a dramatic reduction of craving and illicit use; she did not experience the "high" on the prescribed medication. She also reported an improvement in the quality of her sleep with diminished awakenings during the night, decreased vocalizations, and the tension associated with their emission, decreased anxiety and a decreased frequency of paroxysmal dystonia.

  1. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside.

    PubMed

    Rahn, Elizabeth J; Hohmann, Andrea G

    2009-10-01

    Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB(1)/CB(2) agonists, CB(2) selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Delta(9)-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Delta(9)-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research. PMID:19789075

  2. Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis.

    PubMed

    Bhattacharyya, Sagnik; Atakan, Z; Martin-Santos, R; Crippa, J A; Kambeitz, J; Malhi, S; Giampietro, V; Williams, S; Brammer, M; Rubia, K; Collier, D A; McGuire, P K

    2015-01-01

    Cannabis use can induce acute psychotic symptoms and increase the risk of schizophrenia. Impairments in inhibitory control and processing are known to occur both under the influence of cannabis and in schizophrenia. Whether cannabis-induced impairment in inhibitory processing is related to the acute induction of psychotic symptoms under its influence is unclear. We investigated the effects of acute oral administration of 10mg of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on inhibitory control and regional brain activation during inhibitory processing in humans and examined whether these effects are related to the induction of psychotic symptoms under its influence using a repeated-measures, placebo-controlled, double-blind, within-subject design. We studied thirty-six healthy, English-speaking, right-handed men with minimal previous exposure to cannabis and other illicit drugs twice using functional magnetic resonance imaging (fMRI) while they performed a response inhibition (Go/No-Go) task. Relative to placebo, delta-9-THC caused transient psychotic symptoms, anxiety, intoxication and sedation, inhibition errors and impaired inhibition efficiency. Severity of psychotic symptoms was directly correlated with inhibition error frequency and inversely with inhibition efficiency under the influence of delta-9-THC. Delta-9-THC attenuated left inferior frontal activation which was inversely correlated with the frequency of inhibition errors and severity of psychotic symptoms and positively with inhibition efficiency under its influence. These results provide experimental evidence that impairments in cognitive processes involved in the inhibitory control of thoughts and actions and inferior frontal function under the influence of cannabis may have a role in the emergence of transient psychotic symptoms under its influence.

  3. Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis.

    PubMed

    Bhattacharyya, Sagnik; Atakan, Z; Martin-Santos, R; Crippa, J A; Kambeitz, J; Malhi, S; Giampietro, V; Williams, S; Brammer, M; Rubia, K; Collier, D A; McGuire, P K

    2015-01-01

    Cannabis use can induce acute psychotic symptoms and increase the risk of schizophrenia. Impairments in inhibitory control and processing are known to occur both under the influence of cannabis and in schizophrenia. Whether cannabis-induced impairment in inhibitory processing is related to the acute induction of psychotic symptoms under its influence is unclear. We investigated the effects of acute oral administration of 10mg of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on inhibitory control and regional brain activation during inhibitory processing in humans and examined whether these effects are related to the induction of psychotic symptoms under its influence using a repeated-measures, placebo-controlled, double-blind, within-subject design. We studied thirty-six healthy, English-speaking, right-handed men with minimal previous exposure to cannabis and other illicit drugs twice using functional magnetic resonance imaging (fMRI) while they performed a response inhibition (Go/No-Go) task. Relative to placebo, delta-9-THC caused transient psychotic symptoms, anxiety, intoxication and sedation, inhibition errors and impaired inhibition efficiency. Severity of psychotic symptoms was directly correlated with inhibition error frequency and inversely with inhibition efficiency under the influence of delta-9-THC. Delta-9-THC attenuated left inferior frontal activation which was inversely correlated with the frequency of inhibition errors and severity of psychotic symptoms and positively with inhibition efficiency under its influence. These results provide experimental evidence that impairments in cognitive processes involved in the inhibitory control of thoughts and actions and inferior frontal function under the influence of cannabis may have a role in the emergence of transient psychotic symptoms under its influence. PMID:25532865

  4. Nile Delta

    Atmospheric Science Data Center

    2013-04-15

    article title:  The Nile River Delta     View Larger Image ... of eastern Africa. At the apex of the fertile Nile River Delta is the Egyptian capital city of Cairo. To the west are the Great Pyramids ...

  5. Mississippi Delta

    Atmospheric Science Data Center

    2014-05-15

    article title:  The Mississippi Delta     Left: True Color Image ... Imaging SpectroRadiometer (MISR) images of the Mississippi delta were acquired on April 26, 2000. The true color image displays the ...

  6. Mutation of putative GRK phosphorylation sites in the cannabinoid receptor 1 (CB1R) confers resistance to cannabinoid tolerance and hypersensitivity to cannabinoids in mice.

    PubMed

    Morgan, Daniel J; Davis, Brian J; Kearn, Chris S; Marcus, David; Cook, Alex J; Wager-Miller, Jim; Straiker, Alex; Myoga, Michael H; Karduck, Jeffrey; Leishman, Emma; Sim-Selley, Laura J; Czyzyk, Traci A; Bradshaw, Heather B; Selley, Dana E; Mackie, Ken

    2014-04-01

    For many G-protein-coupled receptors (GPCRs), including cannabinoid receptor 1 (CB1R), desensitization has been proposed as a principal mechanism driving initial tolerance to agonists. GPCR desensitization typically requires phosphorylation by a G-protein-coupled receptor kinase (GRK) and interaction of the phosphorylated receptor with an arrestin. In simple model systems, CB1R is desensitized by GRK phosphorylation at two serine residues (S426 and S430). However, the role of these serine residues in tolerance and dependence for cannabinoids in vivo was unclear. Therefore, we generated mice where S426 and S430 were mutated to nonphosphorylatable alanines (S426A/S430A). S426A/S430A mutant mice were more sensitive to acutely administered delta-9-tetrahydrocannabinol (Δ(9)-THC), have delayed tolerance to Δ(9)-THC, and showed increased dependence for Δ(9)-THC. S426A/S430A mutants also showed increased responses to elevated levels of endogenous cannabinoids. CB1R desensitization in the periaqueductal gray and spinal cord following 7 d of treatment with Δ(9)-THC was absent in S426A/S430A mutants. Δ(9)-THC-induced downregulation of CB1R in the spinal cord was also absent in S426A/S430A mutants. Cultured autaptic hippocampal neurons from S426A/S430A mice showed enhanced endocannabinoid-mediated depolarization-induced suppression of excitation (DSE) and reduced agonist-mediated desensitization of DSE. These results indicate that S426 and S430 play major roles in the acute response to, tolerance to, and dependence on cannabinoids. Additionally, S426A/S430A mice are a novel model for studying pathophysiological processes thought to involve excessive endocannabinoid signaling such as drug addiction and metabolic disease. These mice also validate the approach of mutating GRK phosphorylation sites involved in desensitization as a general means to confer exaggerated signaling to GPCRs in vivo.

  7. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  8. Volga Delta

    Atmospheric Science Data Center

    2013-04-17

    article title:  Volga Delta and the Caspian Sea     View ... appear reddish. A small cloud near the center of the delta separates into red, green, and blue components due to geometric parallax ... include several linear features located near the Volga Delta shoreline. These long, thin lines are artificially maintained shipping ...

  9. Excretion of cannabinoids in urine after ingestion of cannabis seed oil.

    PubMed

    Lehmann, T; Sager, F; Brenneisen, R

    1997-09-01

    Gas chromatographic-mass spectrometric (GC-MS) quantitation of 25 cannabis sed oils determined delta 9-tetrahydrocannabinol (THC) concentrations from 3 to 1500 micrograms/g oil. In a pilot study, the morning urine of six volunteers who had ingested 11 or 22 g of the oil, which contained the highest THC content (1500 micrograms/g), was collected for six days. The urine samples were screened by immunoassay, and the content of 11-nor-9-carboxy-delta 9-THC (THCCOOH) was determined by GC-MS. Urine samples were found cannabis positive for up to six days with THCCOOH-equivalent concentrations up to 243 ng/mL. by the Abuscreen OnLine immunoassay and THCCOOH contents from 5 to 431 ng/mL by the GC-MS method. All subjects reported THC-specific psychotropic effects.

  10. The endocannabinoid nervous system: unique opportunities for therapeutic intervention.

    PubMed

    Porter, A C; Felder, C C

    2001-04-01

    The active principle in marijuana, Delta(9)-tetrahydrocannabinol (THC), has been shown to have wide therapeutic application for a number of important medical conditions, including pain, anxiety, glaucoma, nausea, emesis, muscle spasms, and wasting diseases. Delta(9)-THC binds to and activates two known cannabinoid receptors found in mammalian tissue, CB1 and CB2. The development of cannabinoid-based therapeutics has focused predominantly on the CB1 receptor, based on its predominant and abundant localization in the CNS. Like most of the known cannabinoid agonists, Delta(9)-THC is lipophilic and relatively nonselective for both receptor subtypes. Clinical studies show that nonselective cannabinoid agonists are relatively safe and provide therapeutic efficacy, but that they also induce psychotropic side effects. Recent studies of the biosynthesis, release, transport, and disposition of anandamide are beginning to provide an understanding of the role of lipid transmitters in the CNS. This review attempts to link current understanding of the basic biology of the endocannabinoid nervous system to novel opportunities for therapeutic intervention. This new knowledge may facilitate the development of cannabinoid receptor-targeted therapeutics with improved safety and efficacy profiles.

  11. Medical cannabis vs. synthetic cannabinoids: What does the future hold?

    PubMed

    Bolognini, D; Ross, R A

    2015-06-01

    The medical use of cannabis has an intricate therapeutic history that finds its roots in ancient China (∼2700 BC). The main psychoactive component of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), was discovered in 1964. This was a significant breakthrough, as it allowed the generation of synthetic analogs of Δ(9) -THC, the discovery of cannabinoid receptors, and the generation of synthetic small molecules. Despite this, today there is still a paucity of drugs that target the cannabinoid system.

  12. Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018.

    PubMed

    Su, M K; Seely, K A; Moran, J H; Hoffman, R S

    2015-06-01

    Although the putative pharmacological targets of synthetic cannabinoids (SCBs) abused in "K2" and "Spice" are similar to Δ(9) -tetrahydrocannabinol (Δ(9) -THC), it remains unclear why SCB toxicity is similar yet different from marijuana. There are obvious potency and efficacy differences, but also important metabolic differences that help explain the unique adverse reactions associated with SCBs. This brief review discusses the limited research on the metabolism of the SCB JWH-018 and contrasts that with the metabolism of Δ(9) -THC.

  13. Medical cannabis vs. synthetic cannabinoids: What does the future hold?

    PubMed

    Bolognini, D; Ross, R A

    2015-06-01

    The medical use of cannabis has an intricate therapeutic history that finds its roots in ancient China (∼2700 BC). The main psychoactive component of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), was discovered in 1964. This was a significant breakthrough, as it allowed the generation of synthetic analogs of Δ(9) -THC, the discovery of cannabinoid receptors, and the generation of synthetic small molecules. Despite this, today there is still a paucity of drugs that target the cannabinoid system. PMID:25761845

  14. Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory

    PubMed Central

    Ballinger, Michael D.; Saito, Atsushi; Abazyan, Bagrat; Taniguchi, Yu; Huang, Ching-Hsun; Ito, Koki; Zhu, Xiaolei; Segal, Hadar; Jaaro-Peled, Hanna; Sawa, Akira; Mackie, Ken; Pletnikov, Mikhail V.; Kamiya, Atsushi

    2015-01-01

    Cannabis is an increasingly popular and controversial drug used worldwide. Cannabis use often begins during adolescence, a highly susceptible period for environmental stimuli to alter functional and structural organization of the developing brain. Given that adolescence is a critical time for the emergence of mental illnesses before full-onset in early adulthood, it is particularly important to investigate how genetic insults and adolescent cannabis exposure interact to affect brain development and function. Here we show for the first time that a perturbation in Disrupted in Schizophrenia 1 (DISC1) exacerbates the response to adolescent exposure to delta-9-tetrahydrocannabinol9-THC), a major psychoactive ingredient of cannabis, consistent with the concept that gene-environment interactions may contribute to the pathophysiology of psychiatric conditions. We found that chronic adolescent treatment with Δ9-THC exacerbates deficits in fear-associated memory in adult mice that express a putative dominant-negative mutant of DISC1 (DN-DISC1). Synaptic expression of cannabinoid receptor 1 (CB1R) is down-regulated in the prefrontal cortex, hippocampus, and amygdala, critical brain regions for fear-associated memory, by either expression of DN-DISC1 or adolescent Δ9-THC treatment. Notably, elevation of c-Fos expression evoked by context-dependent fear memory retrieval is impaired in these brain regions in DN-DISC1 mice. We also found a synergistic reduction of c-Fos expression induced by cue-dependent fear memory retrieval in DN-DISC1 with adolescent Δ9-THC exposure. These results suggest that alteration of CB1R-mediated signaling in DN-DISC1 mice may underlie susceptibility to detrimental effects of adolescent cannabis exposure on adult behaviors. PMID:26093170

  15. Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory.

    PubMed

    Ballinger, Michael D; Saito, Atsushi; Abazyan, Bagrat; Taniguchi, Yu; Huang, Ching-Hsun; Ito, Koki; Zhu, Xiaolei; Segal, Hadar; Jaaro-Peled, Hanna; Sawa, Akira; Mackie, Ken; Pletnikov, Mikhail V; Kamiya, Atsushi

    2015-10-01

    Cannabis is an increasingly popular and controversial drug used worldwide. Cannabis use often begins during adolescence, a highly susceptible period for environmental stimuli to alter functional and structural organization of the developing brain. Given that adolescence is a critical time for the emergence of mental illnesses before full-onset in early adulthood, it is particularly important to investigate how genetic insults and adolescent cannabis exposure interact to affect brain development and function. Here we show for the first time that a perturbation in disrupted in schizophrenia 1 (DISC1) exacerbates the response to adolescent exposure to delta-9-tetrahydrocannabinol (Δ(9)-THC), a major psychoactive ingredient of cannabis, consistent with the concept that gene-environment interaction may contribute to the pathophysiology of psychiatric conditions. We found that chronic adolescent treatment with Δ(9)-THC exacerbates deficits in fear-associated memory in adult mice that express a putative dominant-negative mutant of DISC1 (DN-DISC1). Synaptic expression of cannabinoid receptor 1 (CB1R) is down-regulated in the prefrontal cortex, hippocampus, and amygdala, critical brain regions for fear-associated memory, by either expression of DN-DISC1 or adolescent Δ(9)-THC treatment. Notably, elevation of c-Fos expression evoked by context-dependent fear memory retrieval is impaired in these brain regions in DN-DISC1 mice. We also found a synergistic reduction of c-Fos expression induced by cue-dependent fear memory retrieval in DN-DISC1 with adolescent Δ(9)-THC exposure. These results suggest that alteration of CB1R-mediated signaling in DN-DISC1 mice may underlie susceptibility to detrimental effects of adolescent cannabis exposure on adult behaviors.

  16. Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory.

    PubMed

    Ballinger, Michael D; Saito, Atsushi; Abazyan, Bagrat; Taniguchi, Yu; Huang, Ching-Hsun; Ito, Koki; Zhu, Xiaolei; Segal, Hadar; Jaaro-Peled, Hanna; Sawa, Akira; Mackie, Ken; Pletnikov, Mikhail V; Kamiya, Atsushi

    2015-10-01

    Cannabis is an increasingly popular and controversial drug used worldwide. Cannabis use often begins during adolescence, a highly susceptible period for environmental stimuli to alter functional and structural organization of the developing brain. Given that adolescence is a critical time for the emergence of mental illnesses before full-onset in early adulthood, it is particularly important to investigate how genetic insults and adolescent cannabis exposure interact to affect brain development and function. Here we show for the first time that a perturbation in disrupted in schizophrenia 1 (DISC1) exacerbates the response to adolescent exposure to delta-9-tetrahydrocannabinol (Δ(9)-THC), a major psychoactive ingredient of cannabis, consistent with the concept that gene-environment interaction may contribute to the pathophysiology of psychiatric conditions. We found that chronic adolescent treatment with Δ(9)-THC exacerbates deficits in fear-associated memory in adult mice that express a putative dominant-negative mutant of DISC1 (DN-DISC1). Synaptic expression of cannabinoid receptor 1 (CB1R) is down-regulated in the prefrontal cortex, hippocampus, and amygdala, critical brain regions for fear-associated memory, by either expression of DN-DISC1 or adolescent Δ(9)-THC treatment. Notably, elevation of c-Fos expression evoked by context-dependent fear memory retrieval is impaired in these brain regions in DN-DISC1 mice. We also found a synergistic reduction of c-Fos expression induced by cue-dependent fear memory retrieval in DN-DISC1 with adolescent Δ(9)-THC exposure. These results suggest that alteration of CB1R-mediated signaling in DN-DISC1 mice may underlie susceptibility to detrimental effects of adolescent cannabis exposure on adult behaviors. PMID:26093170

  17. Effects of ultraviolet-B radiation on the growth, physiology and cannabinoid production of Cannabis sativa L

    SciTech Connect

    Lydon, J.

    1986-01-01

    The concentration of cannabinoids in Cannabis sativa L. is correlated with high ultraviolet-B (UV-B) radiation environments. ..delta../sup 9/-Tetrahydrocannabinolic acid and cannabidiolic acid, both major secondary products of C. sativa, absorb UV-B radiation and may function as solar screens. The object of this study was to test the effects of UV-B radiation on the physiology and cannabinoid production of C. sativa. Drug and fiber-type C. sativa were irradiated with three levels of UV-B radiation for 40 days in greenhouse experiments. Physiological measurements on leaf tissues were made by infra-red gas analysis. Drug and fiber-type control plants had similar CO/sub 2/ assimilation rates from 26 to 32/sup 0/C. Drug-type control plant had higher dark respiration rates and stomatal conductances than fiber-type control plants. The concentration of ..delta../sup 9/-THC, but not of other cannabinoids) in both vegetative and reproductive tissues increased with UV-B dose in drug-type plants. None of the cannabinoids in fiber-type plants were affected by UV-B radiation. The increased level of ..delta../sup 9/-THC found in leaves after irradiation may account for the physiological and morphological insensitivity to UV-B radiation in the drug-type plants. However, fiber plants showed no comparable change in the level of cannabidoil (CBD). Resin stripped form fresh fiber-type floral tissue by sonication was spotted on filter paper and irradiated continuously for 7 days. Cannabidiol (CBD) gradually decreased when irradiated but ..delta../sup 9/-THC and cannabichromene did not.

  18. Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops.

    PubMed

    Pijlman, F T A; Rigter, S M; Hoek, J; Goldschmidt, H M J; Niesink, R J M

    2005-06-01

    The total concentration of THC has been monitored in cannabis preparations sold in Dutch coffee shops since 1999. This annual monitoring was issued by the Ministry of Health after reports of increased potency. The level of the main psychoactive compound, Delta9-tetrahydrocannabinol (THC), is measured in marijuana and hashish. A comparison is made between imported and Dutch preparations, and between seasons. Samples of cannabis preparations from randomly selected coffee shops were analyzed using gas chromatography (GC-FID) for THC, CBD and CBN. In 2004, the average THC level of Dutch home-grown marijuana (Nederwiet) (20.4% THC) was significantly higher than that of imported marijuana (7.0% THC). Hashish derived from Dutch marijuana (Nederhasj) contained 39.3% THC in 2004, compared with 18.2% THC in imported hashish. The average THC percentage of Dutch marijuana, Dutch hashish and imported hashish was significantly higher than in previous years. It nearly doubled over 5 years. During this period, the THC percentage in imported marijuana remained unchanged. A higher price had to be paid for cannabis with higher levels of THC. Whether the increase in THC levels causes increased health risks for users can only be concluded when more data are available on adjusted patterns of use, abuse liability, bioavailability and levels of THC in the brain. PMID:16191670

  19. Mississippi Delta

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The streamers of clouds draped over the Gulf of Mexico in this true-color MODIS image from February 27, 2002, suggest that a cold, dry wind was blowing southward over the United States and began to pick up moisture over the Gulf, causing these strips of clouds. That the clouds didn't pick up until some distance from the coastline allowed MODIS to get a perfect view of the dynamic Gulf Coast environment spanning (left to right) Texas, Louisiana, Mississippi, Alabama, and Florida's Western Panhandle. The Mississippi River runs roughly down the center of the image, and is joined in Louisiana by the Red River coming in from the northwest. Over the past 7000 years, the actual delta, where the main river channel empties into the Gulf, has wandered around what we now think of as the Louisiana coast. Considering all the sediment visible in this image, it's not hard to imagine that the river carries about 2.4 billion kilograms of sediment into the Gulf each year. Deposition of some of this sediment has been building up the current delta, called the Birdfoot Delta, for obvious reasons, for about 700 years. The coastal waters are alive with microscopic organisms called phytoplankton, which contain colorful pigments, including chlorophyll, for harvesting sunlight. Beyond the sediment plume off Louisiana, the waters are very dark, which could indicate that a large amount of chlorophyll is present, absorbing lots of sunlight and causing the water to appear dark. Farther south, the waters appear bright blue, which could be a signature of coccolithophores, which use highly reflective calcium carbonate to build scaly coverings for themselves. The brighter offshore waters could also be caused by a blue-green algae called Trichodesmium, an organism that can not only harness carbon dioxide for photosynthesis, but can also take nitrogen from the air and turn it into a form that can be used by living organisms. Credit: Jacques Descloitres, MODIS Land Rapid Response Team, NASA/GSFC

  20. Hair analysis in order to evaluate drug abuse in driver's license regranting procedures.

    PubMed

    Tassoni, G; Mirtella, D; Zampi, M; Ferrante, L; Cippitelli, M; Cognigni, E; Froldi, R; Cingolani, M

    2014-11-01

    In Italy, driving under the influence of drugs determines the suspension of the offender's driver's license. To regain the license the person must be drug free during an observation period. People whose license has been revoked or suspended can obtain, or re-obtain their driver's license subject to the judgment of a medical commission. The exclusion of illicit drug use is determined by means of toxicological analysis, mainly on urine or hair matrices. We reported the results of several years of experience of the forensic toxicology laboratory of the University of Macerata in the use of hair analysis for the assessment of past exposure to drugs in people suspected of driving under the influence of drugs. From 2004 to 2013, 8612 hair samples, were analyzed for opiates, cocaine and delta-9-tetrahydrocannabinol (Δ(9)-THC) using gas chromatography/mass spectrometry (GC/MS) method. We used a cutoff (SoHT or national guidelines) to determine the positive data, regardless of the hair sample concentrations. 1213 samples resulted positive, 71.7% were positive for cocaine and metabolites, 19.8% for morphine and metabolites, 8.5% for Δ(9)-THC. We also studied the timeframe of the abuse, as well as gender and age distribution of positive subjects. Moreover, we analyzed the possible deterrent effect of the hair analysis on driving under the influence of psychoactive substances. PMID:25151106

  1. Hair analysis in order to evaluate drug abuse in driver's license regranting procedures.

    PubMed

    Tassoni, G; Mirtella, D; Zampi, M; Ferrante, L; Cippitelli, M; Cognigni, E; Froldi, R; Cingolani, M

    2014-11-01

    In Italy, driving under the influence of drugs determines the suspension of the offender's driver's license. To regain the license the person must be drug free during an observation period. People whose license has been revoked or suspended can obtain, or re-obtain their driver's license subject to the judgment of a medical commission. The exclusion of illicit drug use is determined by means of toxicological analysis, mainly on urine or hair matrices. We reported the results of several years of experience of the forensic toxicology laboratory of the University of Macerata in the use of hair analysis for the assessment of past exposure to drugs in people suspected of driving under the influence of drugs. From 2004 to 2013, 8612 hair samples, were analyzed for opiates, cocaine and delta-9-tetrahydrocannabinol (Δ(9)-THC) using gas chromatography/mass spectrometry (GC/MS) method. We used a cutoff (SoHT or national guidelines) to determine the positive data, regardless of the hair sample concentrations. 1213 samples resulted positive, 71.7% were positive for cocaine and metabolites, 19.8% for morphine and metabolites, 8.5% for Δ(9)-THC. We also studied the timeframe of the abuse, as well as gender and age distribution of positive subjects. Moreover, we analyzed the possible deterrent effect of the hair analysis on driving under the influence of psychoactive substances.

  2. Mississippi Delta

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The Mississippi River delta teems with sediment deposited by the river as it flows into the Gulf of Mexico in this true-color image captured by MODIS on October 15, 2001. The sediment, which is marked by brown swirls in the Gulf, provides nutrients for the bloom of phytoplankton visible as blue-green swirls off the coastline. In the high-resolution image the city of Memphis can be seen in the southwest corner of Tennessee, which is just to left of center at the top of the image. The brown coloration that encompasses Memphis and either side of the river, as flows north to south along the left side of the image, is the river's flood plain. Also visible, in the upper-right hand corner of the image is the southern end of the Appalachian Mountains.

  3. Delta III—an evolutionary delta growth

    NASA Astrophysics Data System (ADS)

    Arvesen, R. J.; Simpson, J. S.

    1996-03-01

    In order to remain competitive in the future and expand the McDonnell Douglas Aerospace market share, MDA has developed an expendable launch system strategy that devices cost-effective launch systems from the Delta II with a growth vehicle configuration called Delta III. The Delta III evolves from the Delta II launch system through development of a larger payload fairing (4-meter diameter), new cryogenically propelled upper stage, new first stage fuel tank, and larger strap-on solid rocket motors. We are developing the Delta III using Integrated Product Development Teams that capitalize on the experience base that has led us to a world record breaking mission success of 49 consecutive Delta II missions. The Delta III first-launch capability is currently planned for the spring of 1998 in support of our first spacecraft customer, Hughes Space and Communications International.

  4. The effect of cannabis use on memory function: an update.

    PubMed

    Schoeler, Tabea; Bhattacharyya, Sagnik

    2013-01-01

    Investigating the effects of cannabis use on memory function appears challenging. While early observational investigations aimed to elucidate the longer-term effects of cannabis use on memory function in humans, findings remained equivocal and pointed to a pattern of interacting factors impacting on the relationship between cannabis use and memory function, rather than a simple direct effect of cannabis. Only recently, a clearer picture of the chronic and acute effects of cannabis use on memory function has emerged once studies have controlled for potential confounding factors and started to investigate the acute effects of delta-9-tetrahydrocannabinol9-THC) and cannabidiol (CBD), the main ingredients in the extract of the cannabis plant in pharmacological challenge experiments. Relatively consistent findings have been reported regarding the acute impairments induced by a single dose of Δ9-THC on verbal and working memory. It is unclear whether they may persist beyond the intoxication state. In the long-term, these impairments seem particularly likely to manifest and may also persist following abstinence if regular and heavy use of cannabis strains high in Δ9-THC is started at an early age. Although still at an early stage, studies that employed advanced neuroimaging techniques have started to model the neural underpinnings of the effects of cannabis use and implicate a network of functional and morphological alterations that may moderate the effects of cannabis on memory function. Future experimental and epidemiological studies that take into consideration individual differences, particularly previous cannabis history and demographic characteristics, but also the precise mixture of the ingredients of the consumed cannabis are necessary to clarify the magnitude and the mechanisms by which cannabis-induced memory impairments occur and to elucidate underlying neurobiological mechanisms.

  5. The effect of cannabis use on memory function: an update

    PubMed Central

    Schoeler, Tabea; Bhattacharyya, Sagnik

    2013-01-01

    Investigating the effects of cannabis use on memory function appears challenging. While early observational investigations aimed to elucidate the longer-term effects of cannabis use on memory function in humans, findings remained equivocal and pointed to a pattern of interacting factors impacting on the relationship between cannabis use and memory function, rather than a simple direct effect of cannabis. Only recently, a clearer picture of the chronic and acute effects of cannabis use on memory function has emerged once studies have controlled for potential confounding factors and started to investigate the acute effects of delta-9-tetrahydrocannabinol9-THC) and cannabidiol (CBD), the main ingredients in the extract of the cannabis plant in pharmacological challenge experiments. Relatively consistent findings have been reported regarding the acute impairments induced by a single dose of Δ9-THC on verbal and working memory. It is unclear whether they may persist beyond the intoxication state. In the long-term, these impairments seem particularly likely to manifest and may also persist following abstinence if regular and heavy use of cannabis strains high in Δ9-THC is started at an early age. Although still at an early stage, studies that employed advanced neuroimaging techniques have started to model the neural underpinnings of the effects of cannabis use and implicate a network of functional and morphological alterations that may moderate the effects of cannabis on memory function. Future experimental and epidemiological studies that take into consideration individual differences, particularly previous cannabis history and demographic characteristics, but also the precise mixture of the ingredients of the consumed cannabis are necessary to clarify the magnitude and the mechanisms by which cannabis-induced memory impairments occur and to elucidate underlying neurobiological mechanisms. PMID:24648785

  6. The Delta 2 launcher

    NASA Astrophysics Data System (ADS)

    Ousley, Gilbert W., Sr.

    1991-12-01

    The utilization of the Delta 2 as the vehicle for launching Aristoteles into its near Sun synchronous orbit is addressed. Delta is NASA's most reliable launch vehicle and is well suited for placing the present Aristoteles spacecraft into a 400 m circular orbit. A summary of some of the Delta 2 flight parameters is presented. Diagrams of a typical Delta 2 two stage separation are included along with statistics on delta reliability and launch plans.

  7. Fan deltas and braid deltas: conceptual problems

    SciTech Connect

    McPherson, J.G.; Shanmugam, G.; Moiola, R.J.

    1986-05-01

    The concept of fan deltas has been widely misinterpreted in the geologic literature. A true fan delta is defined as an alluvial fan deposited into a standing body of water. Such sequences are of limited areal extent and are, as expected, uncommon in the rock record. By contrast, braid deltas (herein defined), formed by progradation of a braided fluvial system into a standing body of water, are a common geomorphic feature in many modern settings, and their deposits are common in the geologic record. Braid-delta sequences are often identified as fan deltas, on the false premise that coarse-grained deposits in a deltaic setting are always part of an alluvial fan complex. The authors find that most published examples of so called fan deltas contain no direct evidence for the presence of an alluvial fan. Even in examples where an alluvial fan could be documented, the authors found that, in many cases, the alluvial fan complex was far removed from the shoreline, separated by an extensive braid plain. The authors suggest that such systems are better classified as braid deltas. They consider that it is essential to distinguish the environmental setting of true fan deltas from that of braid deltas. Misclassification will lead to incorrect interpretations of expected facies, sandstone geometry, reservoir quality, and tectonic settings. Criteria based on geometry, vertical and lateral lithofacies associations, and paleocurrent patterns should be used to correctly identify and distinguish these depositional systems.

  8. High-affinity cannabinoid binding site in brain: A possible marijuana receptor

    SciTech Connect

    Nye, J.S.

    1988-01-01

    The mechanism by which delta{sup 9} tetrahydrocannabinol (delta{sup 9}THC), the major psychoactive component of marijuana or hashish, produces its potent psychological and physiological effects is unknown. To find receptor binding sites for THC, we designed a water-soluble analog for use as a radioligand. 5{prime}-Trimethylammonium-delta{sup 8}THC (TMA) is a positively charged analog of delta-{sup 8}THC modified on the 5{prime} carbon, a portion of the molecule not important for its psychoactivity. We have studied the binding of ({sup 3}H)-5{prime}-trimethylammonium-delta-{sup 8}THC (({sup 3}H)TMA) to rat neuronal membranes. ({sup 3}H)TMA binds saturably and reversibly to brain membranes with high affinity to apparently one class of sites. Highest binding site density occurs in brain, but several peripheral organs also display specific binding. Detergent solubilizes the sites without affecting their pharmacologial properties. Molecular sieve chromatography reveals a bimodal peak of ({sup 3}H)TMA binding activity of approximately 60,000 daltons apparent molecular weight.

  9. delta-Hexachlorocyclohexane (delta-HCH)

    Integrated Risk Information System (IRIS)

    delta - Hexachlorocyclohexane ( delta - HCH ) ; CASRN 319 - 86 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Ass

  10. 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.

  11. Delta launcher enhanced

    NASA Astrophysics Data System (ADS)

    1987-08-01

    The next-generation, 'Delta II' version of the Delta expendable launch vehicle will be able to launch over 4000 lbs into geosynchronous transfer orbit (GTO), as required by the USAF's Navstar GPS; the current Delta 3920 configuration can loft only 2800 lbs into GEO. Three distinct growth configurations of the Delta II are planned: the 6925, whose booster propellant tanks will be extended by 12 ft; the 7925, whose improved booster engine will increase nozzle expansion ratio from 8:1 to 12:1; and the 'enhanced ' Delta II, with stretched graphite-epoxy solid rocket motor cases. In this final form, Delta II will boost 4010 lbs into GTO, or 11,110 lbs into LEO.

  12. Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats.

    PubMed

    Bruijnzeel, Adriaan W; Qi, Xiaoli; Guzhva, Lidia V; Wall, Shannon; Deng, Jie V; Gold, Mark S; Febo, Marcelo; Setlow, Barry

    2016-01-01

    Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol9-THC) is the main psychoactive component of cannabis and its effects have been well-studied. However, cannabis contains many other cannabinoids that affect brain function. Therefore, these studies investigated the effect of cannabis smoke exposure on locomotor activity, rearing, anxiety-like behavior, and the development of dependence in rats. It was also investigated if cannabis smoke exposure leads to tolerance to the locomotor-suppressant effects of the endogenous cannabinoid anandamide. Cannabis smoke was generated by burning 5.7% Δ9-THC cannabis cigarettes in a smoking machine. The effect of cannabis smoke on the behavior of rats in a small and large open field and an elevated plus maze was evaluated. Cannabis smoke exposure induced a brief increase in locomotor activity followed by a prolonged decrease in locomotor activity and rearing in the 30-min small open field test. The cannabinoid receptor type 1 (CB1) receptor antagonist rimonabant increased locomotor activity and prevented the smoke-induced decrease in rearing. Smoke exposure also increased locomotor activity in the 5-min large open field test and the elevated plus maze test. The smoke exposed rats spent more time in the center zone of the large open field, which is indicative of a decrease in anxiety-like behavior. A high dose of anandamide decreased locomotor activity and rearing in the small open field and this was not prevented by rimonabant or pre-exposure to cannabis smoke. Serum Δ9-THC levels were 225 ng/ml after smoke exposure, which is similar to levels in humans after smoking cannabis. Exposure to cannabis smoke led to dependence as indicated by more rimonabant-precipitated somatic withdrawal signs in the cannabis smoke exposed rats than in the air-control rats. In conclusion, chronic cannabis smoke exposure in rats leads to clinically relevant Δ9-THC levels, dependence, and has a biphasic effect

  13. Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats

    PubMed Central

    Bruijnzeel, Adriaan W.; Qi, Xiaoli; Guzhva, Lidia V.; Wall, Shannon; Deng, Jie V.; Gold, Mark S.; Febo, Marcelo; Setlow, Barry

    2016-01-01

    Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol9-THC) is the main psychoactive component of cannabis and its effects have been well-studied. However, cannabis contains many other cannabinoids that affect brain function. Therefore, these studies investigated the effect of cannabis smoke exposure on locomotor activity, rearing, anxiety-like behavior, and the development of dependence in rats. It was also investigated if cannabis smoke exposure leads to tolerance to the locomotor-suppressant effects of the endogenous cannabinoid anandamide. Cannabis smoke was generated by burning 5.7% Δ9-THC cannabis cigarettes in a smoking machine. The effect of cannabis smoke on the behavior of rats in a small and large open field and an elevated plus maze was evaluated. Cannabis smoke exposure induced a brief increase in locomotor activity followed by a prolonged decrease in locomotor activity and rearing in the 30-min small open field test. The cannabinoid receptor type 1 (CB1) receptor antagonist rimonabant increased locomotor activity and prevented the smoke-induced decrease in rearing. Smoke exposure also increased locomotor activity in the 5-min large open field test and the elevated plus maze test. The smoke exposed rats spent more time in the center zone of the large open field, which is indicative of a decrease in anxiety-like behavior. A high dose of anandamide decreased locomotor activity and rearing in the small open field and this was not prevented by rimonabant or pre-exposure to cannabis smoke. Serum Δ9-THC levels were 225 ng/ml after smoke exposure, which is similar to levels in humans after smoking cannabis. Exposure to cannabis smoke led to dependence as indicated by more rimonabant-precipitated somatic withdrawal signs in the cannabis smoke exposed rats than in the air-control rats. In conclusion, chronic cannabis smoke exposure in rats leads to clinically relevant Δ9-THC levels, dependence, and has a biphasic effect

  14. Pen Branch delta expansion

    SciTech Connect

    Nelson, E.A.; Christensen, E.J.; Mackey, H.E.; Sharitz, R.R.; Jensen, J.R.; Hodgson, M.E.

    1984-02-01

    Since 1954, cooling water discharges from K Reactor ({anti X} = 370 cfs {at} 59 C) to Pen Branch have altered vegetation and deposited sediment in the Savannah River Swamp forming the Pen Branch delta. Currently, the delta covers over 300 acres and continues to expand at a rate of about 16 acres/yr. Examination of delta expansion can provide important information on environmental impacts to wetlands exposed to elevated temperature and flow conditions. To assess the current status and predict future expansion of the Pen Branch delta, historic aerial photographs were analyzed using both basic photo interpretation and computer techniques to provide the following information: (1) past and current expansion rates; (2) location and changes of impacted areas; (3) total acreage presently affected. Delta acreage changes were then compared to historic reactor discharge temperature and flow data to see if expansion rate variations could be related to reactor operations.

  15. Date-rape drugs scene in Poland.

    PubMed

    Adamowicz, Piotr; Kała, Maria

    2005-01-01

    Since the beginnings of twenty-first century in Poland increasing number of reports about the drug-facilitated sexual assaults have been observed. Many drugs have been identified as so-called "date-rape drugs", because of their pharmacological properties, especially inducing amnesia. These drugs are used for the purpose of "drugging" unsuspected victims and than raping them. In a typical scenario, the perpetrator surreptitiously adds "date-rape drug" to the alcoholic or non-alcoholic beverage of an unsuspecting person, who is subsequently sexually assaulted while under the influence of this substance. Many victims do not report the incident until several days after the event or even do not report it at all. They report the incident so late after the events because they often have problems with remember the course of incident. It causes that victim is not reliable witness for justice. Detection of "date-rape drugs" in biological fluids is unequivocal evidence of perpetration. Analysis of biological fluids collected from victims of rapes for presence of drugs was rare in Poland up to now. The aim of this study is to show the use of "date-rape drugs" in Poland. Materials for this study were from the routine casework elaborated at the Institute of Forensic Research in Kraków. APCI-LC-MS methods were applied for screening of biological fluids (blood and/or urine) for amphetamine and its 6 analogues, for 12 substances from benzodiazepine group and for quantification of the detected drugs. HPLC-DAD was used as a screening method for wide range of medicinal drugs, and NCI-GC-MS methods for determination of ketamine and tetrahydrocannabinols (delta9-tetrahydrocannabinol, 9THC) and its metabolite (11-nor-carboxy-delta9-tetrahydrocannabinol, THCCOOH). In 2000-2004, the biological fluids taken from 33 persons, both sexually assaulted or perpetrators were analysed. In 2000 and 2002 not any case of this type was registered, in 2001 only two cases were recorded. After 2003

  16. Delta hepatitis in Malaysia.

    PubMed

    Sinniah, M; Dimitrakakis, M; Tan, D S

    1986-06-01

    Sera from one hundred and fifty nine Malaysian individuals were screened for the prevalence of delta markers. These included 15 HBsAg positive homosexuals, 16 acute hepatitis B cases, 9 chronic hepatitis B patients, 13 healthy HBsAg carriers and 106 intravenous (i.v.) drug abusers, of whom 27 were positive for HBsAg only and the rest were anti-HBc IgG positive but HBsAg negative. The prevalence of delta markers in the homosexuals was found to be 6.7%, in the HBsAg positive drug abusers 17.8%, in acute hepatitis B cases 12.5%. No evidence of delta infection was detected in healthy HBsAg carriers, chronic hepatitis B cases and HBsAg negative i.v. drug abusers. With reference to i.v. drug abusers, the prevalence of delta markers was higher in Malays (23%) than in Chinese (7%) although the latter had a higher HBsAg carrier rate. Although the HBsAg carrier rate in the homosexuals was high, their delta prevalence rate was low as compared to drug abusers. In Malaysia, as in other non-endemic regions, hepatitis delta virus transmission appeared to occur mainly via the parenteral and sexual routes. This is the first time in Malaysia that a reservoir of delta infection has been demonstrated in certain groups of the population at high risk for hepatitis B. PMID:3787309

  17. Delta Scuti stars: Theory

    SciTech Connect

    Guzik, J.A.

    1998-03-01

    The purpose of asteroseismology is not only to derive the internal structure of individual stars from their observed oscillation frequencies, but also to test and extend one`s understanding of the physics of matter under the extremes of temperature, density, and pressure found in stellar interiors. In this review, the author hopes to point out what one can learn about the Sun by studying {delta} Scuti stars, as well as what one can learn about stars more massive or evolved than the Sun. He discusses some of the difficulties in theoretical approaches to asteroseismology for {delta} Scuti stars, using FG Vir, {delta} Scuti, and CD-24{degree} 7599 as examples.

  18. Nile Delta, Egypt

    NASA Technical Reports Server (NTRS)

    1982-01-01

    The Nile Delta of Egypt (30.0N, 31.0E) irrigated by the Nile River and its many distributaries, is some of the richest farm land in the world and home to some 45 million people, over half of Egypt's population of 57 million. The capital city of Cairo is at the apex of the delta in the middle of the scene. Across the river from Cairo can be seen the three big pyramids and sphinx at Giza and the Suez Canal is just to the right of the delta.

  19. Nile River Delta, Egypt

    NASA Technical Reports Server (NTRS)

    1984-01-01

    The Nile River Delta of Egypt (30.0N, 31.0E) irrigated by the Nile River and its many distributaries, is some of the richest farm land in the world and home to some 45 million people, over half of Egypt's population. The capital city of Cairo is at the apex of the delta. Just across the river from Cairo can be seen the ancient three big pyramids and sphinx at Giza and the Suez Canal is just to the right of the delta.

  20. Modeling river delta formation.

    PubMed

    Seybold, Hansjörg; Andrade, José S; Herrmann, Hans J

    2007-10-23

    A model to simulate the time evolution of river delta formation process is presented. It is based on the continuity equation for water and sediment flow and a phenomenological sedimentation/erosion law. Different delta types are reproduced by using different parameters and erosion rules. The structures of the calculated patterns are analyzed in space and time and compared with real data patterns. Furthermore, our model is capable of simulating the rich dynamics related to the switching of the mouth of the river delta. The simulation results are then compared with geological records for the Mississippi River. PMID:17940031

  1. Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice.

    PubMed

    Gatch, Michael B; Forster, Michael J

    2014-12-01

    A number of cannabinoid compounds are being sold in the form of incense as 'legal' alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Δ-tetrahydrocannabinol (Δ-THC), the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH-200, JWH-203, JWH-250, AM-2201, and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Δ-THC (3 mg/kg, intraperitoneally). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for 1-2 h. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8-homolog suppressed response rates at doses that fully substituted for Δ-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Δ-THC, and the effects of three of the compounds lasted substantially longer (JWH-073, JWH-250, and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable with those of Δ-THC, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards among humans.

  2. Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice.

    PubMed

    Gatch, Michael B; Forster, Michael J

    2014-12-01

    A number of cannabinoid compounds are being sold in the form of incense as 'legal' alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Δ-tetrahydrocannabinol (Δ-THC), the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH-200, JWH-203, JWH-250, AM-2201, and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Δ-THC (3 mg/kg, intraperitoneally). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for 1-2 h. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8-homolog suppressed response rates at doses that fully substituted for Δ-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Δ-THC, and the effects of three of the compounds lasted substantially longer (JWH-073, JWH-250, and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable with those of Δ-THC, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards among humans. PMID:25325289

  3. Influence of ethanol on the pharmacokinetic properties of Δ9-tetrahydrocannabinol in oral fluid.

    PubMed

    Toennes, Stefan W; Schneider, Kirsten; Wunder, Cora; Kauert, Gerold F; Moeller, Manfred R; Theunissen, Eef L; Ramaekers, Johannes G

    2013-04-01

    Oral fluid (OF) tests aid in identifying drivers under the influence of drugs. In this study, 17 heavy cannabis users consumed alcohol to achieve steady blood alcohol concentrations of 0 to 0.7 g/L and smoked cannabis 3 h afterward. OF samples were obtained before and up to 4 h after smoking and on-site tests were performed (Dräger DrugTest 5000 and Securetec DrugWipe 5+). Maximum concentrations of tetrahydrocannabinol (THC) immediately after smoking (up to 44,412 ng/g) were below 4,300 (median 377) ng/g 1 h after smoking and less than 312 (median 88) ng/g 3 h later with 5 of 49 samples negative, suggesting that recent cannabis use might occasionally not be detectable. An influence of alcohol was not observed. Drinking 300 mL variably influenced THC concentrations (median only -29.6%), which suggests that drinking does not markedly affect on-site test performance. Many (92%) Dräger tests performed 4 h after smoking were still positive, indicating sufficient sensitivity for recent cannabis use. Differences in the results of a roadside study with DrugTest 5000 (sensitivity 84.8%, specificity 96.0%, accuracy 84.3%) could be explained by a higher number of true negatives, differences between OF and serum and differences between occasional and chronic users.

  4. Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

    PubMed

    Gatch, Michael B; Forster, Michael J

    2015-08-01

    When synthetic cannabinoid compounds became controlled by state and federal governments, different, noncontrolled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Δ-tetrahydrocannabinol (Δ-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F-PB-22, and AB-FUBINACA were tested for locomotor depressant effects in male Swiss-Webster mice and subsequently for their ability to substitute for Δ-THC (3 mg/kg, intraperitoneally) in drug discrimination experiments with male Sprague-Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability. PMID:26061356

  5. The discovery of a cannabinoid receptor

    SciTech Connect

    Devane, W.A.

    1989-01-01

    A tritiated form of CP-55,940, a Pfizer cannabinoid analog that is 20- to 100-fold more potent than {Delta}{sup 9}-tetrahydrocannabinol in various in vivo and in vitro models of cannabimimetric activity, was used as the tool with which to probe for a cannabinoid receptor in rat cortical membranes. The bound and free ligand were successfully separated using a centrifugation assay. Specific binding was saturable, rapidly attained, and completely reversible. The K{sub D}'s derived from kinetic analysis of binding agreed well with the K{sub D}'s derived from saturation and displacement analysis. The ({sup 3}H)CP-55,940 binding site exhibited high affinity with a K{sub D} of 68 pM as determined by LIGAND analysis of homologous displacement studies. The ability of other cannabinoid drugs to displace ({sup 3}H)CP-55,940 binding correlated well with the potency of these drugs in in vivo and in vitro models of cannabimimetic activity. The K{sub i} of {Delta}{sup 9}-THC was 1.6 nM. Cannabidiol and cannabigerol, which both lack psychoactivity in man, displaced specific binding by less than 50% at 1 {mu}M.

  6. Cannabis coadministration potentiates the effects of "ecstasy" on heart rate and temperature in humans.

    PubMed

    Dumont, G J; Kramers, C; Sweep, F C; Touw, D J; van Hasselt, J G; de Kam, M; van Gerven, J M; Buitelaar, J K; Verkes, R J

    2009-08-01

    This study assessed the acute physiologic effects over time of (co)administration of Delta9-tetrahydrocannabinol (Delta9-THC) (the main psychoactive compound of cannabis) and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") in 16 healthy volunteers. Pharmacokinetics and cardiovascular, temperature, and catecholamine responses were assessed over time. Both single-drug conditions robustly increased heart rate, and coadministration showed additive effects. MDMA increased epinephrine and norepinephrine concentrations, whereas THC did not affect the catecholamine response. Coadministration of MDMA and THC attenuated the increase of norepinephrine concentrations relative to administration of MDMA alone. These results show that THC mediates heart rate increase independent of sympathetic (catecholaminergic) activity, probably through direct cannabinoid receptor type 1 (CB(1)) agonism in cardiac tissue. Furthermore, THC coadministration did not prevent MDMA-induced temperature increase, but it delayed the onset and prolonged the duration of temperature elevation. These effects may be of particular relevance for the cardiovascular safety of ecstasy users who participate in energetic dancing in nightclubs with high ambient temperature. PMID:19440186

  7. Comparison of three advanced chromatographic techniques for cannabis identification.

    PubMed

    Debruyne, D; Albessard, F; Bigot, M C; Moulin, M

    1994-01-01

    The development of chromatography technology, with the increasing availability of easier-to-use mass spectrometers combined with gas chromatography (GC), the use of diode-array or programmable variable-wavelength ultraviolet absorption detectors in conjunction with high-performance liquid chromatography (HPLC), and the availability of scanners capable of reading thin-layer chromatography (TLC) plates in the ultraviolet and visible regions, has made for easier, quicker and more positive identification of cannabis samples that standard analytical laboratories are occasionally required to undertake in the effort to combat drug addiction. At laboratories that do not possess the technique of GC combined with mass spectrometry, which provides an irrefutable identification, the following procedure involving HPLC or TLC techniques may be used: identification of the chromatographic peaks corresponding to each of the three main cannabis constituents-cannabidiol (CBD), delta-9-tetrahydrocannabinol (delta-9-THC) and cannabinol (CBN)-by comparison with published data in conjunction with a specific absorption spectrum for each of those constituents obtained between 200 and 300 nm. The collection of the fractions corresponding to the three major cannabinoids at the HPLC system outlet and the cross-checking of their identity in the GC process with flame ionization detection can further corroborate the identification and minimize possible errors due to interference.

  8. Man made deltas

    PubMed Central

    Maselli, Vittorio; Trincardi, Fabio

    2013-01-01

    The review of geochronological and historical data documents that the largest southern European deltas formed almost synchronously during two short intervals of enhanced anthropic pressure on landscapes, respectively during the Roman Empire and the Little Ice Age. These growth phases, that occurred under contrasting climatic regimes, were both followed by generalized delta retreat, driven by two markedly different reasons: after the Romans, the fall of the population and new afforestation let soil erosion in river catchments return to natural background levels; since the industrial revolution, instead, flow regulation through river dams overkill a still increasing sediment production in catchment basins. In this second case, furthermore, the effect of a reduced sediment flux to the coasts is amplified by the sinking of modern deltas, due to land subsidence and sea level rise, that hampers delta outbuilding and increases the vulnerability of coastal zone to marine erosion and flooding. PMID:23722597

  9. Man made deltas.

    PubMed

    Maselli, Vittorio; Trincardi, Fabio

    2013-01-01

    The review of geochronological and historical data documents that the largest southern European deltas formed almost synchronously during two short intervals of enhanced anthropic pressure on landscapes, respectively during the Roman Empire and the Little Ice Age. These growth phases, that occurred under contrasting climatic regimes, were both followed by generalized delta retreat, driven by two markedly different reasons: after the Romans, the fall of the population and new afforestation let soil erosion in river catchments return to natural background levels; since the industrial revolution, instead, flow regulation through river dams overkill a still increasing sediment production in catchment basins. In this second case, furthermore, the effect of a reduced sediment flux to the coasts is amplified by the sinking of modern deltas, due to land subsidence and sea level rise, that hampers delta outbuilding and increases the vulnerability of coastal zone to marine erosion and flooding. PMID:23722597

  10. Turbulent heat exchanger {Delta}T and {Delta}P

    SciTech Connect

    Steinmeyer, D.

    1996-12-31

    Optimum pressure drop ({Delta}P) and temperature difference ({Delta}T) in turbulent flow heat exchangers are presented in three frameworks: as quantitatively defined by fluid properties, the value of energy and the cost of heat exchange surface (with a little help from a relationship between [power/mass] and heat transfer); as the energy cost for heat recovery (with the {Delta}T cost being about equal to the heat exchanger cost and the {Delta}P cost being about 1/3 as great); and as the second law lost work inherent in heat exchange (with the {Delta}T loss being {approximately}3 times the {Delta}T loss).

  11. Ganges River Delta

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The Ganges River forms an extensive delta where it empties into the Bay of Bengal. The delta is largely covered with a swamp forest known as the Sunderbans, which is home to the Royal Bengal Tiger. It is also home to most of Bangladesh, one of the world's most densely populated countries. Roughly 120 million people live on the Ganges Delta under threat of repeated catastrophic floods due to heavy runoff of meltwater from the Himalayas, and due to the intense rainfall during the monsoon season. This image was acquired by Landsat 7's Enhanced Thematic Mapper plus (ETM+) sensor on February 28, 2000. This is a false-color composite image made using green, infrared, and blue wavelengths. Image provided by the USGS EROS Data Center Satellite Systems Branch

  12. Delta II Mars Pathfinder

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Final preparations for lift off of the DELTA II Mars Pathfinder Rocket are shown. Activities include loading the liquid oxygen, completing the construction of the Rover, and placing the Rover into the Lander. After the countdown, important visual events include the launch of the Delta Rocket, burnout and separation of the three Solid Rocket Boosters, and the main engine cutoff. The cutoff of the main engine marks the beginning of the second stage engine. After the completion of the second stage, the third stage engine ignites and then cuts off. Once the third stage engine cuts off spacecraft separation occurs.

  13. DELTA PHASE PLUTONIUM ALLOYS

    DOEpatents

    Cramer, E.M.; Ellinger, F.H.; Land. C.C.

    1960-03-22

    Delta-phase plutonium alloys were developed suitable for use as reactor fuels. The alloys consist of from 1 to 4 at.% zinc and the balance plutonium. The alloys have good neutronic, corrosion, and fabrication characteristics snd possess good dimensional characteristics throughout an operating temperature range from 300 to 490 deg C.

  14. The Devil's in the Delta

    ERIC Educational Resources Information Center

    Luyben, William L.

    2007-01-01

    Students frequently confuse and incorrectly apply the several "deltas" that are used in chemical engineering. The deltas come in three different flavors: "out minus in", "big minus little" and "now versus then." The first applies to a change in a stream property as the stream flows through a process. For example, the "[delta]H" in an energy…

  15. Delta-ALA urine test

    MedlinePlus

    Delta-aminolevulinic acid ... This test looks for an increased level of delta-ALA. It may be used to help diagnose ... An increased level of urinary delta-ALA may indicate: Lead poisoning ... level may occur with chronic (long-term) liver disease .

  16. DELTAS: A new Global Delta Sustainability Initiative (Invited)

    NASA Astrophysics Data System (ADS)

    Foufoula-Georgiou, E.

    2013-12-01

    Deltas are economic and environmental hotspots, food baskets for many nations, home to a large part of the world population, and hosts of exceptional biodiversity and rich ecosystems. Deltas, being at the land-water interface, are international, regional, and local transport hubs, thus providing the basis for intense economic activities. Yet, deltas are deteriorating at an alarming rate as 'victims' of human actions (e.g. water and sediment reduction due to upstream basin development), climatic impacts (e.g. sea level rise and flooding from rivers and intense tropical storms), and local exploration (e.g. sand or aggregates, groundwater and hydrocarbon extraction). Although many efforts exist on individual deltas around the world, a comprehensive global delta sustainability initiative that promotes awareness, science integration, data and knowledge sharing, and development of decision support tools for an effective dialogue between scientists, managers and policy makers is lacking. Recently, the international scientific community proposed to establish the International Year of Deltas (IYD) to serve as the beginning of such a Global Delta Sustainability Initiative. The IYD was proposed as a year to: (1) increase awareness and attention to the value and vulnerability of deltas worldwide; (2) promote and enhance international and regional cooperation at the scientific, policy, and stakeholder level; and (3) serve as a launching pad for a 10-year committed effort to understand deltas as complex socio-ecological systems and ensure preparedness in protecting and restoring them in a rapidly changing environment. In this talk, the vision for such an international coordinated effort on delta sustainability will be presented as developed by a large number of international experts and recently funded through the Belmont Forum International Opportunities Fund. Participating countries include: U.S., France, Germany, U.K., India, Japan, Netherlands, Norway, Brazil, Bangladesh

  17. Behavioral effects in monkeys of racemates of two biologically active marijuana constituents.

    PubMed

    Scheckel, C L; Boff, E; Dahlen, P; Smart, T

    1968-06-28

    Both dl-Delta(8)- and dl-Delta(9)-tetrahydrocannabinol produced marked alterations of behavior in rhesus and squirrel monkeys. Squirrel monkeys appeared to have visual hallucinations. Continuous avoidance behavior of squirrel monkeys was stimulated by both drugs, but high doses of dl-Delta(9)-tetrahydrocannabinol also caused depression after the stimulant phase. Complex behavior involving memory and visual discrimination in rhesus monkeys was markedly disrupted by both drugs.

  18. Understanding pesticides in California's Delta

    USGS Publications Warehouse

    Kuivila, Kathryn M.; Orlando, James L.

    2012-01-01

    The Sacramento-San Joaquin River Delta (Delta) is the hub of California’s water system and also an important habitat for imperiled fish and wildlife. Aquatic organisms are exposed to mixtures of pesticides that flow through the maze of Delta water channels from sources including agricultural, landscape, and urban pest-control applications. While we do not know all of the effects pesticides have on the ecosystem, there is evidence that they cause some damage to organisms in the Delta. Decades of USGS research have provided a good understanding of when, where, and how pesticides enter the Delta. However, pesticide use is continually changing. New field studies and methods are needed so that scientists can analyze which pesticides are present in the Delta, and at what concentrations, enabling them to estimate exposure and ultimate effects on organisms. Continuing research will provide resource managers and stakeholders with crucial information to manage the Delta wisely.

  19. Mississippi River Delta

    NASA Technical Reports Server (NTRS)

    2002-01-01

    As the Mississippi River enters the Gulf of Mexico, it loses energy and dumps its load of sediment that it has carried on its journey through the mid continent. This pile of sediment, or mud, accumulates over the years building up the delta front. As one part of the delta becomes clogged with sediment, the delta front will migrate in search of new areas to grow. The area shown on this image is the currently active delta front of the Mississippi. The migratory nature of the delta forms natural traps for oil. Most of the land in the image consists of mud flats and marsh lands. There is little human settlement in this area due to the instability of the sediments. The main shipping channel of the Mississippi River is the broad stripe running northwest to southeast.

    This image was acquired on May 24, 2001 by the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) on NASA's Terra satellite. With its 14 spectral bands from the visible to the thermal infrared wavelength region, and its high spatial resolution of 15 to 90 meters (about 50 to 300 feet), ASTER will image Earth for the next 6 years to map and monitor the changing surface of our planet.

    ASTER is one of five Earth-observing instruments launched December 18,1999, on NASA's Terra satellite. The instrument was built by Japan's Ministry of Economy, Trade and Industry. A joint U.S./Japan science team is responsible for validation and calibration of the instrument and the data products. Dr. Anne Kahle at NASA's Jet Propulsion Laboratory, Pasadena, California, is the U.S. Science team leader; Bjorn Eng of JPL is the project manager. The Terra mission is part of NASA's Earth Science Enterprise, a long-term research and technology program designed to examine Earth's land, oceans, atmosphere, ice and life as a total integrated system.

    The broad spectral coverage and high spectral resolution of ASTER will provide scientists in numerous disciplines with critical information for surface mapping

  20. Natural processes in delta restoration: application to the Mississippi Delta.

    PubMed

    Paola, Chris; Twilley, Robert R; Edmonds, Douglas A; Kim, Wonsuck; Mohrig, David; Parker, Gary; Viparelli, Enrica; Voller, Vaughan R

    2011-01-01

    Restoration of river deltas involves diverting sediment and water from major channels into adjoining drowned areas, where the sediment can build new land and provide a platform for regenerating wetland ecosystems. Except for local engineered structures at the points of diversion, restoration mainly relies on natural delta-building processes. Present understanding of such processes is sufficient to provide a basis for determining the feasibility of restoration projects through quantitative estimates of land-building rates and sustainable wetland area under different scenarios of sediment supply, subsidence, and sea-level rise. We are not yet to the point of being able to predict the evolution of a restored delta in detail. Predictions of delta evolution are based on field studies of active deltas, deltas in mine-tailings ponds, experimental deltas, and countless natural experiments contained in the stratigraphic record. These studies provide input for a variety of mechanistic delta models, ranging from radially averaged formulations to more detailed models that can resolve channels, topography, and ecosystem processes. Especially exciting areas for future research include understanding the mechanisms by which deltaic channel networks self-organize, grow, and distribute sediment and nutrients over the delta surface and coupling these to ecosystem processes, especially the interplay of topography, network geometry, and ecosystem dynamics. PMID:21329199

  1. Pioneer Launch on Delta Vehicle

    NASA Technical Reports Server (NTRS)

    1969-01-01

    NASA launches the last in the series of interplanetary Pioneer spacecraft, Pioneer 10 from Cape Kennedy, Florida. The long-tank Delta launch vehicle placed the spacecraft in a solar orbit along the path of Earth's orbit. The spacecraft then passed inside and outside Earth's orbit, alternately speeding up and slowing down relative to Earth. The Delta launch vehicle family started development in 1959. The Delta was composed of parts from the Thor, an intermediate-range ballistic missile, as its first stage, and the Vanguard as its second. The first Delta was launched from Cape Canaveral on May 13, 1960 and was powerful enough to deliver a 100-pound spacecraft into geostationary transfer orbit. Delta has been used to launch civil, commercial, and military satellites into orbit. For more information about Delta, please see Chapter 3 in Roger Launius and Dennis Jenkins' book To Reach the High Frontier published by The University Press of Kentucky in 2002.

  2. Delta in Eberswalde

    NASA Technical Reports Server (NTRS)

    2006-01-01

    This HiRISE image covers a portion of a delta that partially fills Eberswalde crater in Margaritifer Sinus. The delta was first recognized and mapped using MOC images that revealed various features whose presence required sustained flow and deposition into a lake that once occupied the crater. The HiRISE image resolves meter-scale features that record the migration of channels and delta distributaries as the delta grew over time. Differences in grain-size of sediments within the environments on the delta enable differential erosion of the deposits. As a result, coarser channel deposits are slightly more resistant and stand in relief relative to finer-grained over-bank and more easily eroded distal delta deposits. Close examination of the relict channel deposits confirms the presence of some meter-size blocks that were likely too coarse to have been transported by water flowing within the channels. These blocks may be formed of the sand and gravel that more likely moved along the channels that was lithified and eroded. Numerous meter-scale polygonal structures are common on many surfaces, but mostly those associated with more quiescent depositional environments removed from the channels. The polygons could be the result of deposition of fine-grained sediments that were either exposed and desiccated (dried out), rich in clays that shrunk when the water was removed, turned into rock and then fractured and eroded, or some combination of these processes.

    Image PSP_001336_1560 was taken by the High Resolution Imaging Science Experiment (HiRISE) camera onboard the Mars Reconnaissance Orbiter spacecraft on November 8, 2006. The complete image is centered at -23.8 degrees latitude, 326.4 degrees East longitude. The range to the target site was 256.3 km (160.2 miles). At this distance the image scale is 25.6 cm/pixel (with 1 x 1 binning) so objects 77 cm across are resolved. The image shown here has been map-projected to 25 cm/pixel and north is up. The image was

  3. Delta II commercial space transportation

    NASA Astrophysics Data System (ADS)

    Meyers, J. F.

    1988-07-01

    Delta II is an upgraded variant of the Delta family of launch vehicles that has been in use by NASA since 1960. Among the design improvements incorporated by Delta II is a cryogenic-propellant second stage, a 2.89-m diameter satellite-protecting nose fairing, graphite/epoxy solid rocket motor cases, and 12:1 main engine expansion nozzle. The manufacturer/operator offers Delta II customers a dedicated, single satellite launch capability fully tailored to the given spacecraft's unique mission requirements.

  4. Shanghai Delta Complex

    SciTech Connect

    Hart, R.E.; Hoffman, P.F.; Parker, R.W.

    1988-01-01

    The upper Eocene Yegua Formation expands dramatically across a regional system of growth faults into an area generally 12-15 km wide, extending at least from the western edge of the Houston sale dome basin to the San Marcos arch. Within this area, the expanded Yegua trend has yielded, since 1982, at least seven noteworthy discoveries: Toro Grande and Lost Bridge fields in Jackson County, and Black Owl, Shanghai, Shanghai East, El Campo, and Phase Four fields in Wharton County. During each of several postulated Yegua sea level drops, this flexure became a focal point for deltaic deposition of excellent reservoir-quality sands. Shanghai, Shanghai East, and El Campo fields are located within what the writers have labeled the ''Shanghai delta complex.'' Integration of seismic and well data in this vicinity shows a marked increase in the expansion indices of growth faults, and moderately thick progradational sand sequences have accumulated immediately downthrow. This structural-stratigraphic pattern, as well as internal bedding characteristics and other lithologic data observed, is believed typical of deltas deposited along the Yegua shelf margin.

  5. Holden Crater Delta

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Context image for PIA03694 Holden Crater Delta

    This fan-shaped delta deposit is located in Holden Crater.

    Image information: VIS instrument. Latitude -27.3N, Longitude 324.5E. 17 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  6. Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ⁹-THC.

    PubMed

    Coskun, Zeynep Mine; Bolkent, Sema

    2014-10-01

    The objectives of study were (a) to determine alteration of feeding, glucose level and oxidative stress and (b) to investigate expression and localization of cannabinoid receptors in type-2 diabetic rat pancreas treated with Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Rats were randomly divided into four groups: control, Δ(9)-THC, diabetes and diabetes + Δ(9)-THC groups. Diabetic rats were treated with a single dose of nicotinamide (85 mg/kg) 15 min before injection of streptozotocin (65 mg/kg). Δ(9)-THC was administered intraperitoneally at 3 mg/kg/day for 7 days. Body weights and blood glucose level of rats in all groups were measured on days 0, 7, 14 and 21. On day 15 after the Δ(9)-THC injections, pancreatic tissues were removed. Blood glucose levels and body weights of diabetic rats treated with Δ(9)-THC did not show statistically significant changes when compared with the diabetic animals on days 7, 14 and 21. Treatment with Δ(9)-THC significantly increased pancreas glutathione levels, enzyme activities of superoxide dismutase and catalase in diabetes compared with non-treatment diabetes group. The cannabinoid 1 receptor was found in islets, whereas the cannabinoid 2 receptor was found in pancreatic ducts. Their localization in cells was both nuclear and cytoplasmic. We can suggest that Δ(9) -THC may be an important agent for the treatment of oxidative damages induced by diabetes. However, it must be supported with anti-hyperglycaemic agents. Furthermore, the present study for the first time emphasizes that Δ(9)-THC may improve pancreatic cells via cannabinoid receptors in diabetes. The aim of present study was to elucidate the effects of Δ(9)-THC, a natural cannabinoid receptor agonist, on the expression and localization of cannabinoid receptors, and oxidative stress statue in type-2 diabetic rat pancreas. Results demonstrate that the cannabinoid receptors are presented in both Langerhans islets and duct regions. The curative effects

  7. Delta Electroproduction in 12-C

    SciTech Connect

    Steven McLauchlan

    2003-01-31

    The Delta-nucleus potential is a crucial element in the understanding of the nuclear system. Previous electroexcitation measurements in the delta region reported a Q2 dependence of the delta mass indicating that this potential is dependent on the momentum of the delta. Such a dependence is not observed for protons and neutrons in the nuclear medium. This thesis presents the experimental study of the electroexcitation of the delta resonance in 12C, performed using the high energy electron beam at the Thomas Jefferson National Accelerator Facility, and the near 4(pie) acceptance detector CLAS that enables the detection of the full reaction final state. Inclusive, semi inclusive, and exclusive cross sections were measured with an incident electron beam energy of 1.162GeV over the Q2 range 0.175-0.475 (GeV/c)2. A Q2 dependence of the delta mass was only observed in the exclusive measurements indicating that the delta-nucleus potential is affected by the momentum of the delta.

  8. Mackenzie River Delta, Canada

    NASA Technical Reports Server (NTRS)

    2007-01-01

    The Mackenzie River in the Northwest Territories, Canada, with its headstreams the Peace and Finley, is the longest river in North America at 4241 km, and drains an area of 1,805,000 square km. The large marshy delta provides habitat for migrating Snow Geese, Tundra Swans, Brant, and other waterfowl. The estuary is a calving area for Beluga whales. The Mackenzie (previously the Disappointment River) was named after Alexander Mackenzie who travelled the river while trying to reach the Pacific in 1789.

    The image was acquired on August 4, 2005, covers an area of 55.8 x 55.8 km, and is located at 68.6 degrees north latitude, 134.7 degrees west longitude.

    The U.S. science team is located at NASA's Jet Propulsion Laboratory, Pasadena, Calif. The Terra mission is part of NASA's Science Mission Directorate.

  9. Notes from the Field: Death Following Ingestion of an Edible Marijuana Product--Colorado, March 2014.

    PubMed

    Hancock-Allen, Jessica B; Barker, Lisa; VanDyke, Michael; Holmes, Dawn B

    2015-07-24

    In March 2014, the Colorado Department of Public Health and Environment (CDPHE) learned of the death of a man aged 19 years after consuming an edible marijuana product. CDPHE reviewed autopsy and police reports to assess factors associated with his death and to guide prevention efforts. The decedent's friend, aged 23 years, had purchased marijuana cookies and provided one to the decedent. A police report indicated that initially the decedent ate only a single piece of his cookie, as directed by the sales clerk. Approximately 30-60 minutes later, not feeling any effects, he consumed the remainder of the cookie. During the next 2 hours, he reportedly exhibited erratic speech and hostile behaviors. Approximately 3.5 hours after initial ingestion, and 2.5 hours after consuming the remainder of the cookie, he jumped off a fourth floor balcony and died from trauma. The autopsy, performed 29 hours after time of death, found marijuana intoxication as a chief contributing factor. Quantitative toxicologic analyses for drugs of abuse, synthetic cannabinoid, and cathinones ("bath salts") were performed on chest cavity blood by gas chromatography and mass spectrometry. The only confirmed findings were cannabinoids (7.2 ng/mL delta-9 tetrahydrocannabinol [THC] and 49 ng/mL delta-9 carboxy-THC, an inactive marijuana metabolite). The legal whole blood limit of delta-9 THC for driving a vehicle in Colorado is 5.0 ng/mL. This was the first reported death in Colorado linked to marijuana consumption without evidence of polysubstance use since the state approved recreational use of marijuana in 2012. PMID:26203632

  10. Cannabinoid CB1 Receptor Agonists Do Not Decrease, but may Increase Acoustic Trauma-Induced Tinnitus in Rats

    PubMed Central

    Zheng, Yiwen; Reid, Peter; Smith, Paul F.

    2015-01-01

    Tinnitus has been suggested to arise from neuronal hyperactivity in auditory areas of the brain, and anti-epileptic drugs are sometimes used to provide relief from tinnitus. Recently, the anti-epileptic properties of the cannabinoid drugs have gained increasing interest; however, the use of cannabinoids as a form of treatment for tinnitus is controversial. In this study, we tested whether a combination of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), delivered in a 1:1 ratio, could affect tinnitus perception in a rat model of acoustic trauma-induced tinnitus. Following sham treatment or acoustic trauma, the animals were divided into the following groups: (1) sham (i.e., no acoustic trauma) with vehicle treatment; (2) sham with drug treatment (i.e., delta-9-THC + CBD); (3) acoustic trauma-exposed exhibiting tinnitus, with drug treatment; and (4) acoustic trauma-exposed exhibiting no tinnitus, with drug treatment. The animals received either the vehicle or the cannabinoid drugs every day, 30 min before the tinnitus behavioral testing. Acoustic trauma caused a significant increase in the auditory brainstem response (ABR) thresholds in the exposed animals, indicating hearing loss; however, there was a partial recovery over 6 months. Acoustic trauma did not always result in tinnitus; however, among those that did exhibit tinnitus, some of them had tinnitus at multiple frequencies while others had it only at a single frequency. The cannabinoids significantly increased the number of tinnitus animals in the exposed-tinnitus group, but not in the sham group. The results suggest that cannabinoids may promote the development of tinnitus, especially when there is pre-existing hearing damage. PMID:25852639

  11. Artificial delta growth

    NASA Astrophysics Data System (ADS)

    Mikeš, Daniel

    2010-05-01

    A deltaic sedimentary system has a point source; sediment is carried over the delta plain by distributary channels away from the point source and deposited at the delta front by distributary mouth bars. The established methods to describe such a sedimentary system are "bedding analysis", "facies analysis", and "basin analysis". We shall call the ambient conditions "input" and the rock record "output". There exist a number of methods to deduce input from output, e.g. "Sequence stratigraphy" (a.o. Vail et al. 1977, Catuneanu et al. 2009), "Shoreline trajectory" (a.o. Helland-Hansen & Martinsen 1996, Helland-Hansen & Hampson 2009) on the one hand and the complex use of established techniques on the other (a.o. Miall & Miall 2001, Miall & Miall 2002). None of these deductive methods seems to be sufficient. I claim that the common errors in all these attempts are the following: (1) a sedimentary system is four-dimensional (3+1) and a lesser dimensional analysis is insufficient; (2) a sedimentary system is complex and any empirical/deductive analysis is non-unique. The proper approach to the problem is therefore the theoretical/inductive analysis. To that end we performed six scenarios of a scaled version of a passive margin delta in a flume tank. The scenarios have identical stepwise tectonic subsidence and semi-cyclic sealevel, but different supply curves, i.e. supply is: constant, highly-frequent, proportional to sealevel, inversely proportional to sealevel, lagging to sealevel, ahead of sealevel. The preliminary results are indicative. Lobe-switching occurs frequently and hence locally sedimentation occurs shortly and hiatuses are substantial; therefore events in 2D (+1) cross-sections don't correlate temporally. The number of sedimentary cycles disequals the number of sealevel cycles. Lobe-switching and stepwise tectonic subsidence cause onlap/transgression. Erosional unconformities are local diachronous events, whereas maximum flooding surfaces are regional

  12. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

    PubMed Central

    Rodriguez, Jesse S.; McMahon, Lance R.

    2014-01-01

    SUMMARY Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50 = 0.01 mg/kg) and decreased response rate (ED50 = 0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940 = JWH-018 > Δ9-THC = WIN-55212-2 = JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and 9-THC decreased rectal temperature by 2.2 and 2.8 °C, respectively; the doses decreasing temperature by 2 °C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and 9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoid on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects. PMID:24972243

  13. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects.

    PubMed

    Rodriguez, Jesse S; McMahon, Lance R

    2014-10-01

    Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8°C, respectively; the doses decreasing temperature by 2°C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.

  14. The DELTA Synchrotron Light Interferometer

    SciTech Connect

    Berges, U.

    2004-05-12

    Synchrotron radiation sources like DELTA, the Dortmund Electron Accelerator, a third generation synchrotron light source, need an optical monitoring system to measure the beam size at different points of the ring with high resolution and accuracy. These measurements also allow an investigation of the emittance of the storage ring, an important working parameter for the efficiency of working beamlines with experiments using the synchrotron radiation. The resolution limits of the different types of optical synchrotron light monitors at DELTA are investigated. The minimum measurable beamsize with the normal synchrotron light monitor using visible light at DELTA is about 80 {mu}m. Due to this a synchrotron light interferometer was built up and tested at DELTA. The interferometer uses the same beamline in the visible range. The minimum measurable beamsize is with about 8 {mu}m one order of magnitude smaller. This resolution is sufficient for the expected small vertical beamsizes at DELTA. The electron beamsize and emittance were measured with both systems at different electron beam energies of the storage ring. The theoretical values of the present optics are smaller than the measured emittance. So possible reasons for beam movements are investigated.

  15. Multifractal analysis of information processing in hippocampal neural ensembles during working memory under Δ9-tetrahydrocannabinol administration

    PubMed Central

    Fetterhoff, Dustin; Opris, Ioan; Simpson, Sean L.; Deadwyler, Sam A.; Hampson, Robert E.; Kraft, Robert A.

    2014-01-01

    Background Multifractal analysis quantifies the time-scale-invariant properties in data by describing the structure of variability over time. By applying this analysis to hippocampal interspike interval sequences recorded during performance of a working memory task, a measure of long-range temporal correlations and multifractal dynamics can reveal single neuron correlates of information processing. New method Wavelet leaders-based multifractal analysis (WLMA) was applied to hippocampal interspike intervals recorded during a working memory task. WLMA can be used to identify neurons likely to exhibit information processing relevant to operation of brain–computer interfaces and nonlinear neuronal models. Results Neurons involved in memory processing (“Functional Cell Types” or FCTs) showed a greater degree of multifractal firing properties than neurons without task-relevant firing characteristics. In addition, previously unidentified FCTs were revealed because multifractal analysis suggested further functional classification. The cannabinoid-type 1 receptor partial agonist, tetrahydrocannabinol (THC), selectively reduced multifractal dynamics in FCT neurons compared to non-FCT neurons. Comparison with existing methods WLMA is an objective tool for quantifying the memory-correlated complexity represented by FCTs that reveals additional information compared to classification of FCTs using traditional z-scores to identify neuronal correlates of behavioral events. Conclusion z-Score-based FCT classification provides limited information about the dynamical range of neuronal activity characterized by WLMA. Increased complexity, as measured with multifractal analysis, may be a marker of functional involvement in memory processing. The level of multifractal attributes can be used to differentially emphasize neural signals to improve computational models and algorithms underlying brain–computer interfaces. PMID:25086297

  16. The endocannabinoid system as a target for the treatment of cannabis dependence.

    PubMed

    Clapper, Jason R; Mangieri, Regina A; Piomelli, Daniele

    2009-01-01

    The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain

  17. Driving Under the Influence of Marijuana Versus Driving and Dying Under the Influence of Marijuana: A Comparison of Blood Concentrations of Δ9-Tetrahydrocannabinol, 11-Hydroxy-Δ9-Tetrahydrocannabinol, 11-Nor-9-Carboxy-Δ9-Tetrahydrocannabinol and Other Cannabinoids in Arrested Drivers Versus Deceased Drivers.

    PubMed

    Lemos, Nikolas P; San Nicolas, Alexander C; Volk, Justin A; Ingle, Eric A; Williams, Chinyere M

    2015-10-01

    Cannabis intoxication in living and deceased drivers is an important medico-legal topic, but only a limited number of studies examine cannabinoids in living and deceased humans. This study compares cannabinoid concentrations (in ng/mL) in driving under the influence of drug (DUID) drivers with blood cannabinoids to those in drivers who died while driving with cannabinoids in their postmortem (PM) peripheral blood. From 2010 to 2013, there were 318 cannabis-positive DUID cases (mean, median THC: 4.9, 3); 88 had cannabis-only in their bloods (mean, median THC: 5.8, 4). In 23 DUID cases, Huestis' Predictive Models with 95% confidence intervals were applied and evaluated, demonstrating that the actual case time points in all 23 cases fell within the predicted time ranges. Among deceased drivers, 19 had cannabis-positive toxicology (mean, median THC: 11.7, 4.5) and 8 had cannabis-only (mean, median THC: 20.3, 19.5). Motorcyclists and bicyclists comprised the majority of deceased vehicle operators, with bicyclists averaging the highest mean and median THC concentrations overall. The analysis of variance between living and deceased drivers' cannabinoid concentrations showed that THC-OH and THC-COOH concentrations are not statistically different between the two groups, but that THC concentrations are statistically different, making it difficult to directly correlate PM with antemortem THC concentrations between living and deceased drivers. PMID:26378132

  18. Delta launch vehicle inertial guidance system (DIGS)

    NASA Technical Reports Server (NTRS)

    Duck, K. I.

    1973-01-01

    The Delta inertial guidance system, part of the Delta launch vehicle improvement effort, has been flown on three launches and was found to perform as expected for a variety of mission profiles and vehicle configurations.

  19. Delta nitrogen tetroxide fueling operations

    NASA Technical Reports Server (NTRS)

    Grigsby, R. B.; Cross, T. M.; Rucci, T. D.

    1978-01-01

    The development of the Delta second stage nitrogen tetroxide fueling system is briefly summarized. The nitrogen tetroxide fueling system and the equipment used to protect the spacecraft environment from the toxic nitrogen tetroxide fumes are described. Topics covered include: the nitrogen tetroxide transfer system; loading operations; safety precautions; and chemical treatment of all toxic vapors.

  20. Spongeplant Spreading in the Delta

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Invasive, exotic aquatic plants impact a range of important economic and ecological functions in the Sacramento-San Joaquin Delta of California, and the state now spends over $5 million to control water hyacinth and Brazilian waterweed. In 2007, a new exotic floating plant South American Spongeplan...

  1. Delta launch vehicle accident investigation

    NASA Astrophysics Data System (ADS)

    1986-03-01

    The text of the testimony given by several witnesses during the House hearings on the Delta launch vehicle accident of May 3, 1986 is given. Pre-launch procedures, failure analysis, the possibility of sabotage, and design and testing are among the topics discussed.

  2. N-{Delta} weak transition

    SciTech Connect

    Graczyk, Krzysztof M.

    2011-11-23

    A short review of the Rein-Sehgal and isobar models is presented. The attention is focused on the nucleon-{Delta}(1232) weak transition form-factors. The results of the recent re-analyses of the ANL and BNL bubble chamber neutrino-deuteron scattering data are discussed.

  3. Phytoplankton fuels Delta food web

    USGS Publications Warehouse

    Jassby, Alan D.; Cloern, James E.; Muller-Solger, A. B.

    2003-01-01

    Populations of certain fishes and invertebrates in the Sacramento-San Joaquin Delta have declined in abundance in recent decades and there is evidence that food supply is partly responsible. While many sources of organic matter in the Delta could be supporting fish populations indirectly through the food web (including aquatic vegetation and decaying organic matter from agricultural drainage), a careful accounting shows that phytoplankton is the dominant food source. Phytoplankton, communities of microscopic free-floating algae, are the most important food source on a Delta-wide scale when both food quantity and quality are taken into account. These microscopic algae have declined since the late 1960s. Fertilizer and pesticide runoff do not appear to be playing a direct role in long-term phytoplankton changes; rather, species invasions, increasing water transparency and fluctuations in water transport are responsible. Although the potential toxicity of herbicides and pesticides to plank- ton in the Delta is well documented, the ecological significance remains speculative. Nutrient inputs from agricultural runoff at current levels, in combination with increasing transparency, could result in harmful al- gal blooms. 

  4. Revisiting double Dirac delta potential

    NASA Astrophysics Data System (ADS)

    Ahmed, Zafar; Kumar, Sachin; Sharma, Mayank; Sharma, Vibhu

    2016-07-01

    We study a general double Dirac delta potential to show that this is the simplest yet still versatile solvable potential to introduce double wells, avoided crossings, resonances and perfect transmission (T = 1). Perfect transmission energies turn out to be the critical property of symmetric and anti-symmetric cases wherein these discrete energies are found to correspond to the eigenvalues of a Dirac delta potential placed symmetrically between two rigid walls. For well(s) or barrier(s), perfect transmission (or zero reflectivity, R(E)) at energy E=0 is non-intuitive. However, this has been found earlier and called the ‘threshold anomaly’. Here we show that it is a critical phenomenon and we can have 0≤slant R(0)\\lt 1 when the parameters of the double delta potential satisfy an interesting condition. We also invoke a zero-energy and zero curvature eigenstate (\\psi (x)={Ax}+B) of the delta well between two symmetric rigid walls for R(0)=0. We resolve that the resonant energies and the perfect transmission energies are different and they arise differently.

  5. Maintenance of large deltas through channelization

    NASA Astrophysics Data System (ADS)

    Giosan, L.; Constatinescu, S.; Filip, F.

    2013-12-01

    A new paradigm for delta restoration is currently taking shape using primarily Mississippi delta examples. Here we propose an alternative for delta maintenance primarily envisioned for wave-influenced deltas based on Danube delta experiences. Over the last half century, while the total sediment load of the Danube dramatically decreased due to dam construction on tributaries and its mainstem, a grand experiment was inadvertently run in the Danube delta: the construction of a dense network of canals, which almost tripled the water discharge toward the interior of the delta plain. We use core-based and chart-based sedimentation rates and patterns to explore the delta transition from the natural to an anthropogenic regime, to understand the effects of far-field damming and near-field channelization, and to construct a conceptual model for delta development as a function sediment partition between the delta plain and the delta coastal fringe. We show that sediment fluxes increased to the delta plain due to channelization, counteracting sea level rise. In turn, the delta coastal fringe was most impacted by the Danube's sediment load collapse. Furthermore, we show that morphodynamic feedbacks at the river mouth are crucial in trapping sediment near the coast and constructing wave-dominated deltas or lobes or delaying their destruction. As a general conclusion, we suggest that increased channelization that mimics and enhances natural processes may provide a simple solution for keeping delta plains above sea level and that abandonment of wave-dominated lobes may be the most long term efficient solution for protecting the internal fluvial regions of deltas and provide new coastal growth downcoast.

  6. 27 CFR 9.96 - Mississippi Delta.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Mississippi Delta. 9.96... Mississippi Delta. (a) Name. The name of the viticultural area described in this section is “Mississippi Delta.” (b) Approved maps. The appropriate maps for determining the boundaries of the Mississippi...

  7. 27 CFR 9.96 - Mississippi Delta.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Mississippi Delta. 9.96... Mississippi Delta. (a) Name. The name of the viticultural area described in this section is “Mississippi Delta.” (b) Approved maps. The appropriate maps for determining the boundaries of the Mississippi...

  8. 27 CFR 9.96 - Mississippi Delta.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Mississippi Delta. 9.96... Mississippi Delta. (a) Name. The name of the viticultural area described in this section is “Mississippi Delta.” (b) Approved maps. The appropriate maps for determining the boundaries of the Mississippi...

  9. 27 CFR 9.96 - Mississippi Delta.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Mississippi Delta. 9.96... Mississippi Delta. (a) Name. The name of the viticultural area described in this section is “Mississippi Delta.” (b) Approved maps. The appropriate maps for determining the boundaries of the Mississippi...

  10. 27 CFR 9.96 - Mississippi Delta.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Mississippi Delta. 9.96... Mississippi Delta. (a) Name. The name of the viticultural area described in this section is “Mississippi Delta.” (b) Approved maps. The appropriate maps for determining the boundaries of the Mississippi...

  11. Potential effects of cannabidiol as a wake-promoting agent.

    PubMed

    Murillo-Rodríguez, Eric; Sarro-Ramírez, Andrea; Sánchez, Daniel; Mijangos-Moreno, Stephanie; Tejeda-Padrón, Alma; Poot-Aké, Alwin; Guzmán, Khalil; Pacheco-Pantoja, Elda; Arias-Carrión, Oscar

    2014-05-01

    Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆(9)-tetrahydrocannabinol (∆(9)-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug. PMID:24851090

  12. Potential Effects of Cannabidiol as a Wake-Promoting Agent

    PubMed Central

    Murillo-Rodríguez, Eric; Sarro-Ramírez, Andrea; Sánchez, Daniel; Mijangos-Moreno, Stephanie; Tejeda-Padrón, Alma; Poot-Aké, Alwin; Guzmán, Khalil; Pacheco-Pantoja, Elda; Arias-Carrión, Oscar

    2014-01-01

    Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆9-tetrahydrocannabinol (∆9-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug. PMID:24851090

  13. Early phytocannabinoid chemistry to endocannabinoids and beyond.

    PubMed

    Mechoulam, Raphael; Hanuš, Lumír O; Pertwee, Roger; Howlett, Allyn C

    2014-11-01

    Isolation and structure elucidation of most of the major cannabinoid constituents--including Δ(9)-tetrahydrocannabinol (Δ(9)-THC), which is the principal psychoactive molecule in Cannabis sativa--was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders. PMID:25315390

  14. Marijuana-based Drugs: Innovative Therapeutics or Designer Drugs of Abuse?

    PubMed Central

    Seely, Kathryn A.; Prather, Paul L.; James, Laura P.; Moran, Jeffery H.

    2011-01-01

    Marijuana has been used recreationally and medicinally for centuries. The principle psychoactive component, Δ9-tetrahydrocannabinol9-THC), activates CB1 cannabinoid receptors (CB1Rs). CB1R agonists and antagonists could potentially treat a wide variety of diseases; unfortunately, therapeutic doses produce unacceptable psychiatric effects. “K2” or “Spice” (K2/Spice), an emerging drug of abuse, exhibits psychotropic actions via CB1R activation. Because of structural dissimilarity to Δ9-THC, these drugs are widely unregulated and touted as “legal” marijuana. This review summarizes current and future therapeutic uses of CB1R ligands and provides a historical perspective of the K2/Spice “phenomenon” so the reader can decide if marijuana-based drugs will truly provide innovative therapeutics or instead perpetuate drug abuse. PMID:21441120

  15. Shoreline change in 48 river deltas: towards indexing erosion as a criterion of delta vulnerability

    NASA Astrophysics Data System (ADS)

    Besset, Manon; Anthony, Edward; Dussouillez, Philippe; Sabatier, François

    2016-04-01

    River deltas are considered as increasingly vulnerable to environmental modifications resulting from climate change and human activities. Delta vulnerability is associated with a number of drivers, chief among which are depleted sediment supply, changes in water discharge, and pumping of underground fluids. These activities lead to accelerated subsidence and erosion, the twin mechanisms of delta destruction. A lot of attention has been focused on vulnerability resulting from accelerated subsidence. Here, we address the problem of delta erosion based on the analysis of 48 deltas, including 30 of the world's largest deltas. Using satellite images (Landsat, Spot 5, Spot 6) and aerial photographs, we determined for each delta, the change in delta protruberance area over a 30-year period, this being defined as the area of delta protrusion relative to a straight shoreline running across the delta plain and linking the delta to the adjacent non-protruding non-deltaic shoreline. We classified the deltas in terms of net area loss, gain, or stability, the last corresponding to an uncertainty threshold of _0.3% of the delta's protruberance over the 30-year period. The results show that 25 (52%) of the studied set of deltas show area loss, 11 (23%) stability, and 12 (25%) gain. Area loss is more important in deltas with a protruberance area <500 km2 (67% of small deltas) than in the largest deltas (23%), with a protruberance area >500 km2. Besides sediment supply conditions, which are a primary factor in delta erosion, eroding deltas tend to be more commonly subjected to relatively significant levels of wave energy.

  16. [delta-Aminolevulinate dehydratase deficiency].

    PubMed

    Fujita, H; Ishida, N; Akagi, R

    1995-06-01

    delta-Aminolevulinate dehydratase (ALAD: E. C. 4.2.1.24), the second enzyme in the heme biosynthetic pathway, condenses two moles of delta-aminolevulinic acid to form porphobilinogen. ALAD deficiency is well known to develop signs and symptoms of typical hepatic porphyria, and classified into three categories as follows: (i) ALAD porphyria, a genetic defect of the enzyme, (ii) tyrosinemia type I, a genetic defect of fumarylacetoacetase in the tyrosine catabolic pathway, producing succinylacetone (a potent inhibitor of ALAD), and (iii) ALAD inhibition by environmental hazards, such as lead, trichloroethylene, and styrene. In the present article, we will describe molecular and biochemical mechanisms to cause the enzyme defect to discuss the significance of ALAD defect on human health.

  17. Parana River Delta in Argentina

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The Parana River delta is a huge forested marshland about 20 miles northeast of Buenos Aires, Argentina. The area is a very popular tour destination. Guided boat tours can be taken into this vast labyrinth of marsh and trees. The Parana River delta is one of the world's greatest bird-watching destinations. This image highlights the striking contrast between dense forest and wetland marshes, and the deep blue ribbon of the Parana River. This image was acquired by Landsat 7's Enhanced Thematic Mapper plus (ETM+) sensor on May 26, 2000. This is a false-color composite image made using shortwave infrared, near infrared, and green wavelengths. Image provided by the USGS EROS Data Center Satellite Systems Branch.

  18. The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse

    PubMed Central

    2013-01-01

    Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure–activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB1 (EC50 = 16–43 nM) and CB2 (EC50 = 29–216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ9-tetrahydrocannabinol9-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ9-tetrahydrocannabinol9-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Δ9-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ9-THC, JWH-018, and SDB-001. PMID:23551277

  19. Deformation characteristics of {delta} phase in the delta-processed Inconel 718 alloy

    SciTech Connect

    Zhang, H.Y.; Zhang, S.H.; Cheng, M.; Li, Z.X.

    2010-01-15

    The hot working characteristics of {delta} phase in the delta-processed Inconel 718 alloy during isothermal compression deformation at temperature of 950 deg. C and strain rate of 0.005 s{sup -1}, were studied by using optical microscope, scanning electron microscope and quantitative X-ray diffraction technique. The results showed that the dissolution of plate-like {delta} phase and the precipitation of spherical {delta} phase particles coexisted during the deformation, and the content of {delta} phase decreased from 7.05 wt.% to 5.14 wt.%. As a result of deformation breakage and dissolution breakage, the plate-like {delta} phase was spheroidized and transferred to spherical {delta} phase particles. In the center with largest strain, the plate-like {delta} phase disappeared and spherical {delta} phase appeared in the interior of grains and grain boundaries.

  20. Effects of synthetic cannabinoids on electroencephalogram power spectra in rats.

    PubMed

    Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Matsumoto, Naomi; Huang, Zhi-Li; Goda, Yukihiro; Urade, Yoshihiro

    2012-02-10

    Several synthetic cannabinoids have recently been distributed as psychoactive adulterants in many herbal products on the illegal drug market around the world. However, there is little information on pharmacology and toxicology of such compounds. Although Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a psychoactive cannabinoid of marijuana, was reported to affect electroencephalograms (EEG) of rats, the effects of synthetic cannabinoids are unknown. We examined the pharmacological activities of three synthetic cannabinoids; cannabicyclohexanol (CCH), CP-47,497 and JWH-018; by analyzing EEG power spectra and locomotor activity after intraperitoneal administration to rats and compared them with those of Δ(9)-THC. The three compounds significantly increased the EEG power in the frequency range of 5.0-6.0 Hz for the first 3h, while Δ(9)-THC decreased the power spectra in the wide range of 7.0-20.0 Hz during the first hour. These results indicate that the effect of the three compounds on EEG is different from that of Δ(9)-THC. Additionally, CCH, CP-47,497 and JWH-018 significantly decreased the locomotor activity for 11.5h, 11h and 4.5h, respectively, after administration which was longer than that of Δ(9)-THC (3.5h). Furthermore, all three compounds significantly reduced the total amounts of locomotor activity during a 3-h, 6-h and 12-h period after injection, whereas no statistical difference was observed for the Δ(9)-THC injection. Among the three compounds, CCH and CP-47,497 exerted a longer duration of the change in the EEG power spectra and suppression of the locomotor activity than JWH-018.

  1. Synthetic Cannabinoids: Pharmacology, Behavioral Effects, and Abuse Potential

    PubMed Central

    Tai, Sherrica; Fantegrossi, William E.

    2015-01-01

    Cannabis has been used throughout the world for centuries. The psychoactive effects of cannabis are largely attributable to Δ9-tetrahydrocannabinol9-THC), the prototypical cannabinoid that occurs naturally in the plant. More recently, chemically- and pharmacologically-distinct synthetic cannabinoids (SCBs) have emerged as drugs of abuse. As compared to Δ9-THC, the distinct structures of these compounds allow them to avoid legal restrictions (at least initially) and detection in standard drug screens. This has contributed to the popularity of SCBs among drug users who seek to avoid positive drug screens. Importantly, the distinct structures of the SCBs also typically result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be responsible for the psychoactive effects of Δ9-THC and its analogues. Accordingly, it seems likely that these more powerful cannabimimetic effects could result in increased adverse reactions and toxicities not elicited by Δ9-THC in cannabis. Animal models useful for the study of emerging SCBs include the cannabinoid tetrad, drug discrimination, and assays of tolerance, dependence, and withdrawal. However, these in vivo procedures have not been particularly informative with regards to drug efficacy, where the majority of SCB effects are comparable to those of Δ9-THC. In contrast, essentially all in vitro measures of drug efficacy confirm Δ9-THC as a relatively weak CB1 partial agonist, while the majority of the SCBs detected in commercial preparations are full agonists at the CB1 receptor. As use of these emerging SCBs continues to rise, there is an urgent need to better understand the pharmacology and toxicology of these novel compounds. PMID:26413452

  2. Phytocannabinoids as novel therapeutic agents in CNS disorders.

    PubMed

    Hill, Andrew J; Williams, Claire M; Whalley, Benjamin J; Stephens, Gary J

    2012-01-01

    The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines. PMID:21924288

  3. The interaction of cannabinoid receptor agonists, CP55940 and WIN55212-2 with membranes using solid state 2H NMR

    PubMed Central

    Tian, Xiaoyu; Pavlopoulos, Spiro; Yang, De-Ping; Makriyannis, Alexandros

    2013-01-01

    Two key commonly used cannabinergic agonists, CP55940 and WIN55212-2, are investigated for their effects on the lipid membrane bilayer using 2H solid state NMR, and the results are compared with our earlier work with delta-9-tetrahydrocannabinol9-THC). To study the effects of these ligands we used hydrated bilayers of dipalmitoylphosphatidylcholine (DPPC) deuterated at the 2′ and 16′ positions of both acyl chains with deuterium atoms serving as probes for the dynamic and phase changes at the membrane interface and at the bilayer center respectively. All three cannabinergic ligands lower the phospholipid membrane phase transition temperature, increase the lipid sn-2 chain order parameter at the membrane interface and decrease the order at the center of the bilayer. Our studies show that the cannabinoid ligands induce lateral phase separation in the lipid membrane at physiological temperatures. During the lipid membrane phase transition, the cooperative dynamic process whereby the C-2H segments at the interface and center of the bilayer spontaneously reach the fast exchange regime (2H NMR timescale) is distinctively modulated by the two cannabinoids. Specifically, CP55940 is slightly more efficient at inducing liquid crystalline-type 2H NMR spectral features at the membrane interface compared to WIN55212-2. In contrast, WIN55212-2 has a far superior ability to induce liquid crystalline-type spectral features at the center of the bilayer, and it increases the order parameter of the sn-1 chain in addition to the sn-2 chain of the lipids. These observations suggest the cannabinoid ligands may influence lipid membrane domain formations and there may be contributions to their cannabinergic activities through lipid membrane microdomain related mechanisms. Our work demonstrates that experimental design strategies utilizing specifically deuterium labeled lipids yield more detailed insights concerning the properties of lipid bilayers. PMID:21129361

  4. COMMD1 regulates the delta epithelial sodium channel ({delta}ENaC) through trafficking and ubiquitination

    SciTech Connect

    Chang, Tina; Ke, Ying; Ly, Kevin; McDonald, Fiona J.

    2011-08-05

    Highlights: {yields} The COMM domain of COMMD1 mediates binding to {delta}ENaC. {yields} COMMD1 reduces the cell surface population of {delta}ENaC. {yields} COMMD1 increases the population of {delta}ENaC-ubiquitin. {yields} Both endogenous and transfected {delta}ENaC localize with COMMD1 and transferrin suggesting they are located in early/recycling endosomes. -- Abstract: The delta subunit of the epithelial sodium channel ({delta}ENaC) is a member of the ENaC/degenerin family of ion channels. {delta}ENaC is distinct from the related {alpha}-, {beta}- and {gamma}ENaC subunits, known for their role in sodium homeostasis and blood pressure control, as {delta}ENaC is expressed in brain neurons and activated by external protons. COMMD1 (copper metabolism Murr1 domain 1) was previously found to associate with and downregulate {delta}ENaC activity. Here, we show that COMMD1 interacts with {delta}ENaC through its COMM domain. Co-expression of {delta}ENaC with COMMD1 significantly reduced {delta}ENaC surface expression, and led to an increase in {delta}ENaC ubiquitination. Immunocytochemical and confocal microscopy studies show that COMMD1 promoted localization of {delta}ENaC to the early/recycling endosomal pool where the two proteins were localized together. These results suggest that COMMD1 downregulates {delta}ENaC activity by reducing {delta}ENaC surface expression through promoting internalization of surface {delta}ENaC to an intracellular recycling pool, possibly via enhanced ubiquitination.

  5. Delta hepatitis agent: structural and antigenic properties of the delta-associated particle.

    PubMed Central

    Bonino, F; Hoyer, B; Shih, J W; Rizzetto, M; Purcell, R H; Gerin, J L

    1984-01-01

    Delta agent (delta) was serially passaged to a second and third hepatitis B surface antigen (HBsAg) carrier chimpanzee, using as inoculum the peak delta antigen (delta Ag) serum of an animal previously infected with human serum. The characteristics of serially transmitted delta Ag were similar to those described in first-passage animals. It was consistently detected before the development of anti-delta, in association with a 35- to 37-nm subpopulation of HBsAg particles and a unique low-molecular-weight (5.5 X 10(5)) RNA. RNase susceptibility of the delta-associated RNA and release of delta Ag activity upon treatment of delta-associated particles with detergent revealed that this particle is organized into a virion-like form with the RNA and delta Ag as internal components within a coat of HBsAg. Surface determinants of the delta-associated particle other than HBsAg were not detected by radioimmunoprecipitation experiments, using sera of humans and chimpanzees convalescent from delta hepatitis. The HBsAg-associated particle is the "candidate agent" of delta hepatitis. Images PMID:6698598

  6. Delta II development and flight results

    NASA Astrophysics Data System (ADS)

    Mihara, S. K.

    An account is given of the design modifications of the Delta launch vehicle which have resulted in its Delta II variant, together with flight results obtained with the Delta II to date. Delta II launchers feature a stretched LX tank, a larger-diameter satellite-payload fairing, and an expansion of first-stage nozzle expansion ratio from 8:1 to 12:1. The thrust-augmenting solid rocket boosters use graphite/epoxy composite motor cases. Both two-stage and three-stage launches are discussed, with attention to flights for the Navstar satellites.

  7. From Natural to Design River Deltas

    NASA Astrophysics Data System (ADS)

    Giosan, Liviu

    2016-04-01

    Productive and biologically diverse, deltaic lowlands attracted humans since prehistory and may have spurred the emergence of the first urban civilizations. Deltas continued to be an important nexus for economic development across the world and are currently home for over half a billion people. But recently, under the double whammy of sea level rise and inland sediment capture behind dams, they have become the most threatened coastal landscape. Here I will address several deceptively simple questions to sketch some unexpected answers using example deltas from across the world from the Arctic to the Tropics, from the Danube to the Indus, Mississippi to Godavari and Krishna, Mackenzie to Yukon. What is a river delta? What is natural and what is not in a river delta? Are the geological and human histories of a delta important for its current management? Is maintaining a delta the same to building a new one? Can we design better deltas than Nature? These answers help us see clearly that survival of deltas in the next century depends on human intervention and is neither assured nor simple to address or universally applicable. Empirical observations on the hydrology, geology, biology and biochemistry of deltas are significantly lagging behind modeling capabilities endangering the applicability of numerical-based reconstruction solutions and need to be ramped up significantly and rapidly across the world.

  8. Comments on the slip factor and the relation Delta phi = -h Delta theta

    SciTech Connect

    Ng, K.Y.; /Fermilab

    2009-09-01

    The definition of the slip factor can be obtained from the phase equation. However, a derivation using the relation {Delta}{phi} = -h{Delta}{theta} leads to a different slip-factor definition. This apparent paradox is examined in detail and resolved. Here {Delta}{phi} is the rf phase difference and {Delta}{theta} is the azimuthal phase difference around the accelerator ring between an off-momentum particle and the synchronous particle, while h is the rf harmonic.

  9. The hepatitis delta virus and its infection

    SciTech Connect

    Rizzeto, M.; Gerin, J.L.; Purcell, R.H.

    1987-01-01

    This book contains over 50 papers. Some of the titles are: Structure and Replication of the Genome of Hepatitis Delta Virus; Clinical Significance of HDV RNA in HDV Disease; HBV DNA in Delta Chronic Carriers; Prevalance of HBV-DNA Among Anti-Hd Positive Patients; and Characterization of LKM/sub 1/ and LKM/sub 2/ Antigens.

  10. Wave-angle control of delta evolution

    NASA Astrophysics Data System (ADS)

    Ashton, Andrew D.; Giosan, Liviu

    2011-07-01

    Wave-influenced deltas, with large-scale arcuate shapes and demarcated beach ridge complexes, often display an asymmetrical form about their river channel. Here, we use a numerical model to demonstrate that the angles from which waves approach a delta can have a first-order influence upon its plan-view morphologic evolution and sedimentary architecture. The directional spread of incoming waves plays a dominant role over fluvial sediment discharge in controlling the width of an active delta lobe, which in turn affects the characteristic rates of delta progradation. Oblique wave approach (and a consequent net alongshore sediment transport) can lead to the development of morphologic asymmetry about the river in a delta's plan-view form. This plan-form asymmetry can include the development of discrete breaks in shoreline orientation and the appearance of self-organized features arising from shoreline instability along the downdrift delta flank, such as spits and migrating shoreline sand waves—features observed on natural deltas. Somewhat surprisingly, waves approaching preferentially from one direction tend to increase sediment deposition updrift of the river. This ‘morphodynamic groin effect’ occurs when the delta's plan-form aspect ratio is sufficiently large such that the orientation of the shoreline on the downdrift flank is rotated past the angle of maximum alongshore sediment transport, resulting in preferential redirection of fluvial sediment updrift of the river mouth.

  11. Electromagnetic excitation of the Delta(1232) resonance

    SciTech Connect

    V. Pascalutsa; M. Vanderhaeghen; Shin Nan Yang

    2006-09-05

    We review the description of the lowest-energy nucleon excitation--the Delta(1232)-resonance. Much of the recent effort has been focused on the precision measurements of the nucleon to Delta transition by means of electromagnetic probes. We review the results of those measurements and confront them with the state-of-the-art calculations based on chiral effective-field theories (EFT), lattice QCD, and QCD-inspired models. Some of the theoretical approaches are reviewed in detail. In particular, we describe the chiral EFT of QCD in the energy domain of the Delta-resonance, and its applications to the electromagnetic nucleon-to-Delta transition (gamma N Delta). We also describe the recent dynamical and unitary-isobar models of pion electroproduction which are extensively used in the extraction of the gamma* N Delta form factors from experiment. Furthermore, we discuss the link of the gamma* N Delta form factors to generalized parton distributions (GPDs), as well as the predictions of perturbative QCD for these transition form factors. The present status of understanding the Delta-resonance properties and the nature of its excitation is summarized.

  12. The determination of equilibrium constants, DeltaG, DeltaH and DeltaS for vapour interaction with a pharmaceutical drug, using gravimetric vapour sorption.

    PubMed

    Willson, Richard J; Beezer, Anthony E

    2003-06-01

    The application of gravimetric vapour sorption (GVS) to the characterisation of pharmaceutical drugs is often restricted to the study of gross behaviour such as a measure of hygroscopicity. Although useful in early development of a drug substance, for example, in salt selection screening exercises, such types of analysis may not contribute to a fundamental understanding of the properties of the material. This paper reports a new methodology for GVS experimentation that will allow specific sorption parameters to be calculated; equilibrium constant (K), van't Hoff enthalpy change (DeltaH(v)), Gibbs free energy for sorption (DeltaG) and the entropy change for sorption (DeltaS). Unlike other reports of such type of analysis that require the application of a specific model, this method is model free. The analysis does require that over the narrow temperature range of the study DeltaH(v) is constant and there is no change in interaction mechanism.

  13. Delta connected resonant snubber circuit

    DOEpatents

    Lai, J.S.; Peng, F.Z.; Young, R.W. Sr.; Ott, G.W. Jr.

    1998-01-20

    A delta connected, resonant snubber-based, soft switching, inverter circuit achieves lossless switching during dc-to-ac power conversion and power conditioning with minimum component count and size. Current is supplied to the resonant snubber branches solely by the dc supply voltage through the main inverter switches and the auxiliary switches. Component count and size are reduced by use of a single semiconductor switch in the resonant snubber branches. Component count is also reduced by maximizing the use of stray capacitances of the main switches as parallel resonant capacitors. Resonance charging and discharging of the parallel capacitances allows lossless, zero voltage switching. In one embodiment, circuit component size and count are minimized while achieving lossless, zero voltage switching within a three-phase inverter. 36 figs.

  14. Delta connected resonant snubber circuit

    DOEpatents

    Lai, Jih-Sheng; Peng, Fang Zheng; Young, Sr., Robert W.; Ott, Jr., George W.

    1998-01-01

    A delta connected, resonant snubber-based, soft switching, inverter circuit achieves lossless switching during dc-to-ac power conversion and power conditioning with minimum component count and size. Current is supplied to the resonant snubber branches solely by the dc supply voltage through the main inverter switches and the auxiliary switches. Component count and size are reduced by use of a single semiconductor switch in the resonant snubber branches. Component count is also reduced by maximizing the use of stray capacitances of the main switches as parallel resonant capacitors. Resonance charging and discharging of the parallel capacitances allows lossless, zero voltage switching. In one embodiment, circuit component size and count are minimized while achieving lossless, zero voltage switching within a three-phase inverter.

  15. 78 FR 53127 - Delta-Bienville Resource Advisory Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-28

    ...; ] DEPARTMENT OF AGRICULTURE Forest Service Delta-Bienville Resource Advisory Committee AGENCY: Forest Service, USDA. ACTION: Notice of meeting. Date change. SUMMARY: The Delta-Bienville Resource Advisory...

  16. Differentiation of Boc-protected alpha,delta-/delta,alpha- and beta,delta-/delta,beta-hybrid peptide positional isomers by electrospray ionization tandem mass spectrometry.

    PubMed

    Raju, G; Ramesh, V; Srinivas, R; Sharma, G V M; Shoban Babu, B

    2010-06-01

    Two new series of Boc-N-alpha,delta-/delta,alpha- and beta,delta-/delta,beta-hybrid peptides containing repeats of L-Ala-delta(5)-Caa/delta(5)-Caa-L-Ala and beta(3)-Caa-delta(5)-Caa/delta(5)-Caa-beta(3)-Caa (L-Ala = L-alanine, Caa = C-linked carbo amino acid derived from D-xylose) have been differentiated by both positive and negative ion electrospray ionization (ESI) ion trap tandem mass spectrometry (MS/MS). MS(n) spectra of protonated isomeric peptides produce characteristic fragmentation involving the peptide backbone, the Boc-group, and the side chain. The dipeptide positional isomers are differentiated by the collision-induced dissociation (CID) of the protonated peptides. The loss of 2-methylprop-1-ene is more pronounced for Boc-NH-L-Ala-delta-Caa-OCH(3) (1), whereas it is totally absent for its positional isomer Boc-NH-delta-Caa-L-Ala-OCH(3) (7), instead it shows significant loss of t-butanol. On the other hand, second isomeric pair shows significant loss of t-butanol and loss of acetone for Boc-NH-delta-Caa-beta-Caa-OCH(3) (18), whereas these are insignificant for its positional isomer Boc-NH-beta-Caa-delta-Caa-OCH(3) (13). The tetra- and hexapeptide positional isomers also show significant differences in MS(2) and MS(3) CID spectra. It is observed that 'b' ions are abundant when oxazolone structures are formed through five-membered cyclic transition state and cyclization process for larger 'b' ions led to its insignificant abundance. However, b(1)(+) ion is formed in case of delta,alpha-dipeptide that may have a six-membered substituted piperidone ion structure. Furthermore, ESI negative ion MS/MS has also been found to be useful for differentiating these isomeric peptide acids. Thus, the results of MS/MS of pairs of di-, tetra-, and hexapeptide positional isomers provide peptide sequencing information and distinguish the positional isomers.

  17. Influence of different organic fertilizers on quality parameters and the delta(15)N, delta(13)C, delta(2)H, delta(34)S, and delta(18)O values of orange fruit (Citrus sinensis L. Osbeck).

    PubMed

    Rapisarda, Paolo; Camin, Federica; Fabroni, Simona; Perini, Matteo; Torrisi, Biagio; Intrigliolo, Francesco

    2010-03-24

    To investigate the influence of different types of fertilizers on quality parameters, N-containing compounds, and the delta(15)N, delta(13)C, delta(2)H, delta (34)S, and delta(18)O values of citrus fruit, a study was performed on the orange fruit cv. 'Valencia late' (Citrus sinensis L. Osbeck), which was harvested in four plots (three organic and one conventional) located on the same farm. The results demonstrated that different types of organic fertilizers containing the same amount of nitrogen did not effect important changes in orange fruit quality parameters. The levels of total N and N-containing compounds such as synephrine in fruit juice were not statistically different among the different treatments. The delta(15)N values of orange fruit grown under fertilizer derived from animal origin as well as from vegetable compost were statistically higher than those grown with mineral fertilizer. Therefore, delta(15)N values can be used as an indicator of citrus fertilization management (organic or conventional), because even when applied organic fertilizers are of different origins, the natural abundance of (15)N in organic citrus fruit remains higher than in conventional ones. These treatments also did not effect differences in the delta(13)C, delta(2)H, delta(34)S, and delta(18)O values of fruit.

  18. Understand {Delta}P and {Delta}T in turbulent flow heat exchangers

    SciTech Connect

    Steinmeyer, D.

    1996-06-01

    This article attempts to lead the reader down a clear path to the approximate optimum pressure drop ({Delta}P) and temperature difference ({Delta}T) for the most important class of heat exchangers--those with turbulent flow, no phase change, and fluids and flow rates that are similar on both the hot and cold sides. The optimum {Delta}P and {Delta}T are presented in two frameworks: equations for quantitatively estimating the {Delta}P and {Delta}T from fluid properties, the price of energy, the price of heat exchange surface, and the equivalent diameter; and ratios of the bills (i.e., costs) for the {Delta}P and {Delta}T in an optimized design to the bill (i.e., value) for incremental heat exchanger area. The equations can be used in heat exchanger specification. The ratios provide a guide for the designer when the process flowsheet is constructed. As discussed later, these ratios suggest that the engineer should consider the {Delta}P and {Delta}T costs as more important than the capital spent on the heat exchanger.

  19. Identifying hazards associated with lava deltas

    USGS Publications Warehouse

    Poland, Michael P.; Orr, Tim R.

    2014-01-01

    Lava deltas, formed where lava enters the ocean and builds a shelf of new land extending from the coastline, represent a significant local hazard, especially on populated ocean island volcanoes. Such structures are unstable and prone to collapse—events that are often accompanied by small explosions that can deposit boulders and cobbles hundreds of meters inland. Explosions that coincide with collapses of the East Lae ‘Apuki lava delta at Kīlauea Volcano, Hawai‘i, during 2005–2007 followed an evolutionary progression mirroring that of the delta itself. A collapse that occurred when the lava–ocean entry was active was associated with a blast of lithic blocks and dispersal of spatter and fine, glassy tephra. Shortly after delta growth ceased, a collapse exposed hot rock to cold ocean water, resulting in an explosion composed entirely of lithic blocks and lapilli. Further collapse of the delta after several months of inactivity, by which time it had cooled significantly, resulted in no recognizable explosion deposit. Seaward displacement and subsidence of the coastline immediately inland of the delta was measured by both satellite and ground-based sensors and occurred at rates of several centimeters per month even after the lava–ocean entry had ceased. The anomalous deformation ended only after complete collapse of the delta. Monitoring of ground deformation may therefore provide an indication of the potential for delta collapse, while the hazard associated with collapse can be inferred from the level of activity, or the time since the last activity, on the delta.

  20. Niger Delta play types, Nigeria

    SciTech Connect

    Akinpelu, A.O.

    1995-08-01

    Exploration databases can be more valuable when sorted by play type. Play specific databases provide a system to organize E & P data used in evaluating the range of values of parameters for reserve estimation and risk assessment. It is important both in focusing the knowledge base and in orienting research effort. A play in this context is any unique combination of trap, reservoir and source properties with the right dynamics of migration and preservation that results in hydrocarbon accumulation. This definitions helps us to discriminate the subtle differences found with these accumulation settings. About 20 play types were identified around the Niger Delta oil province in Nigeria. These are grouped into three parts: (1) The proven plays-constituting the bulk of exploration prospects in Nigeria today. (2) The unproven or semi-proven plays usually with some successes recorded in a few tries but where knowledge is still inadequate. (3) The unproven or analogous play concept. These are untested but geologically sound ideas which may or may not have been tried elsewhere. With classification and sub grouping of these play types into specific databases, intrinsic attributes and uniqueness of each of them with respect to the four major risk elements and the eight parameters for reserve estimation can be better understood.

  1. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  2. Delta-nucleus dynamics: proceedings of symposium

    SciTech Connect

    Lee, T.S.H.; Geesaman, D.F.; Schiffer, J.P.

    1983-10-01

    The appreciation of the role in nuclear physics of the first excited state of the nucleon, the delta ..delta..(1232), has grown rapidly in the past decade. The delta resonance dominates nuclear reactions induced by intermediate energy pions, nucleons, and electromagnetic probes. It is also the most important non-nucleonic degree of freedom needed to resolve many fundamental problems encountered in the study of low-energy nuclear phenomena. Clearly, a new phase of nuclear physics has emerged and conventional thinking must be extended to account for this new dimension of nuclear dynamics. The most challenging problem we are facing is how a unified theory can be developed to describe ..delta..-nucleus dynamics at all energies. In exploring this new direction, it is important to have direct discussions among researchers with different viewpoints. Separate entries were prepared for the 49 papers presented. (WHK)

  3. Contemporary depositional environments of the Omo delta.

    PubMed

    Butzer, K W

    1970-05-01

    Geomorphological and sedimentological studies of depositional environments of the modern Omo River delta and floodplain are essential to an understanding of the Pliocene to Pleistocene Mursi, Nkalabong and Kibish Formations of the Lower Omo Basin (southwestern Ethiopia).

  4. delta(13)C and delta(2)H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane.

    PubMed

    Collins, Michael; Salouros, Helen; Cawley, Adam T; Robertson, James; Heagney, Aaron C; Arenas-Queralt, Andrea

    2010-06-15

    Previous work in these laboratories and by Butzenlechner et al. and Culp et al. has demonstrated that the delta(2)H isotope value of industrial benzaldehyde produced by the catalytic oxidation of toluene is profoundly positive, usually in the range +300 per thousand to +500 per thousand. Synthetic routes leading to amphetamine, methylamphetamine or their precursors and commencing with such benzaldehyde may be expected to exhibit unusually positive delta(2)H values. Results are presented for delta(13)C and delta(2)H isotope values of 1-phenyl-2-nitropropene synthesized from an industrial source of benzaldehyde, having a positive delta(2)H isotope value, by a Knoevenagel condensation with nitroethane. Results are also presented for delta(13)C and delta(2)H isotope values for amphetamine prepared from the resulting 1-phenyl-2-nitropropene. The values obtained were compared with delta(13)C and delta(2)H isotope values obtained for an amphetamine sample prepared using a synthetic route that did not involve benzaldehyde. Finally, results are presented for samples of benzaldehyde, 1-phenyl-2-nitropropene and amphetamine that had been seized at a clandestine amphetamine laboratory.

  5. Migration in Vulnerable Deltas: A Research Strategy

    NASA Astrophysics Data System (ADS)

    Hutton, C.; Nicholls, R. J.; Allan, A.

    2015-12-01

    C. Hutton1, & R. J. Nicholls1, , 1 University of Southampton, University Road, Southampton, Hampshire, United Kingdom, SO17 1BJ. cwh@geodata. soton.ac.ukAbstractGlobally, deltas contain 500 million people and with rising sea levels often linked to large number of forced migrants are expected in the coming century. However, migration is already a major process in deltas, such as the growth of major cities such as Dhaka and Kolkata. Climate and environmental change interacts with a range of catchment and delta level drivers, which encompass a nexus of sea-level rise, storms, freshwater and sediment supply from the catchment, land degradation, subsidence, agricultural loss and socio-economic stresses. DECCMA (Deltas, Vulnerability and Climate Change: Migration and Adaptation/CARRIA) is investigating migration in the Ganges-Brahmaputra-Meghna (GBM), Mahanadi and Volta Deltas, including the influence of climate change. The research will explore migration from a range of perspectives including governance and stakeholder analysis, demographic analysis, household surveys of sending and receiving areas, macro-economic analysis, and hazards and hotspot analysis both historically and into the future. Migration under climate change will depend on other adaptation in the deltas and this will be examined. Collectively, integrated analysis will be developed to examine migration, other adaptation and development pathways with a particular focus on the implications for the poorest. This will require the development of input scenarios, including expert-derived exogenous scenarios (e.g., climate change) and endogenous scenarios of the delta developed in a participatory manner. This applied research will facilitate decision support methods for the development of deltas under climate change, with a focus on migration and other adaptation strategies.

  6. Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

    PubMed

    Fasinu, Pius S; Phillips, Sarah; ElSohly, Mahmoud A; Walker, Larry A

    2016-07-01

    States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.

  7. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease.

    PubMed

    Sagredo, Onintza; Pazos, M Ruth; Satta, Valentina; Ramos, José A; Pertwee, Roger G; Fernández-Ruiz, Javier

    2011-09-01

    We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies. PMID:21674569

  8. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

    PubMed

    Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David

    2015-06-01

    Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

  9. Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

    PubMed

    Fasinu, Pius S; Phillips, Sarah; ElSohly, Mahmoud A; Walker, Larry A

    2016-07-01

    States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain

  10. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  11. Lena River Delta formation during the Holocene

    NASA Astrophysics Data System (ADS)

    Bolshiyanov, D.; Makarov, A.; Savelieva, L.

    2014-03-01

    The Lena River Delta, the largest delta of the Arctic Ocean, differs from other deltas because it consists mainly of organomineral sediments, commonly called peat, that contain a huge organic carbon reservoir. The analysis of Delta sediment radiocarbon ages showed that they could not have formed as peat during floodplain bogging, but accumulated when Laptev Sea water level was high and green mosses and sedges grew and were deposited on the surface of flooded marshes. The Lena River Delta formed as organomineral masses and layered sediments accumulated during transgressive phases when sea level rose. In regressive phases, the islands composed of these sediments and other, more ancient islands were eroded. Each new sea transgression led to further accumulation of layered sediments. As a result of alternating transgressive and regressive phases the first alluvial-marine terrace formed, consisting of geological bodies of different ages. Determining the formation age of different areas of the first terrace and other marine terraces on the coast allowed the periods of increasing (8-6 Ka, 4.5-4 Ka, 2.5-1.5 Ka, 0.4-0.2 Ka) and decreasing (5 Ka, 3 Ka, 0.5 Ka) Laptev Sea levels to be distinguished in the Lena Delta area.

  12. Lena River delta formation during the Holocene

    NASA Astrophysics Data System (ADS)

    Bolshiyanov, D.; Makarov, A.; Savelieva, L.

    2015-01-01

    The Lena River delta, the largest delta of the Arctic Ocean, differs from other deltas because it consists mainly of organomineral sediments, commonly called peat, that contain a huge organic carbon reservoir. The analysis of delta sediment radiocarbon ages showed that they could not have formed as peat during floodplain bogging; rather, they accumulated when Laptev Sea water level was high and green mosses and sedges grew and were deposited on the surface of flooded marshes. The Lena River delta formed as organomineral masses and layered sediments accumulated during transgressive phases when sea level rose. In regressive phases, the islands composed of these sediments and other, more ancient islands were eroded. Each new sea transgression led to further accumulation of layered sediments. As a result of alternating transgressive and regressive phases, the first alluvial-marine terrace formed, consisting of geological bodies of different ages. Determining the formation age of different areas of the first terrace and other marine terraces on the coast allowed the periods of increasing (8000-6000 BP (years before present), 4500-4000, 2500-1500, and 400-200 BP) and decreasing (5000, 3000, and 500 BP) Laptev Sea levels to be distinguished in the Lena Delta area.

  13. Preparing Nimbus E on Delta Vehicle

    NASA Technical Reports Server (NTRS)

    1972-01-01

    Nimbus E, the sixth spacecraft in the Nimbus series, is shown preparing for launch on December 12, 1972 from the Western Test Range (WTR), Space Launch Complex SLC-2, West, by the Thrust- Augmented Delta vehicle. The satellite was placed in an 1100-kilometer run-synchronous nearly circular polar orbit. The spacecraft was designated Nimbus 5 upon confirmation that it had achieved successful orbit. The Delta launch vehicle family started development in 1959. The Delta is composed of parts from the Thor, an intermediate-range ballistic missile, as its first stage, and the Vanguard as its second. The first Delta was launched from Cape Canaveral on May 13, 1960 and was powerful enough to deliver a 100-pound spacecraft into geostationary transfer orbit. Delta has been used to launch civil, commercial, and military satellites into orbit. For more information about Delta, please see Chapter 3 in Roger Launius and Dennis Jenkins' book To Reach the High Frontier published by The University Press of Kentucky in 2002.

  14. Phytotaphonomy in subtropical to temperate bayhead delta

    SciTech Connect

    Gastaldo, R.A.

    1986-05-01

    Deltaic regimes act as sinks for hydrocarbon precursors of various organic origin. Most organic detritus incorporated into deltaic sediments is contributed by vegetation established in wetland environments. Processes that incorporate vegetational components in deltaic subenvironments vary, depending on the climate and geography of the sediment-receiving basin. Understanding the phytotaphonomy within the sedimentologic context of different deltas will help workers develop criteria to identify ancient deltaic subenvironments. Some subenvironments are richer in accumulated plant detritus than others; therefore, to plan exploration and exploitation programs, the relationships between sources and reservoirs must be understood. The Mobile delta, Alabama, is a bayhead delta that began prograding through a drowned Pleistocene river valley before 9.5 k.y.B.P. Plant detritus accumulated - and is presently accumulating - in parts of the upper and lower delta flood basins. In the upper delta, large quantities of detritus are deposited in abandoned distributary channels, whereas litter is recycled in clastic swamps. Organic detritus is concentrated in the lower delta in interdistributary bays and marshes. These latter sites contain more productive source sediments for future hydrocarbon resources.

  15. A novel mouse PKC{delta} splice variant, PKC{delta}IX, inhibits etoposide-induced apoptosis

    SciTech Connect

    Kim, Jung D.; Seo, Kwang W.; Lee, Eun A.; Quang, Nguyen N.; Cho, Hong R.; Kwon, Byungsuk

    2011-07-01

    Highlights: {yields} A novel PKC{delta} isoform, named PKC{delta}IX, that lacks the C1 domain and the ATP-binding site is ubiquitously expressed. {yields} PKC{delta}IX inhibits etoposide-induced apoptosis. {yields} PKC{delta}IX may function as an endogenous dominant negative isoform for PKC{delta}. -- Abstract: Protein kinase C (PKC) {delta} plays an important role in cellular proliferation and apoptosis. The catalytic fragment of PKC{delta} generated by caspase-dependent cleavage is essential for the initiation of etoposide-induced apoptosis. In this study, we identified a novel mouse PKC{delta} isoform named PKC{delta}IX (Genebank Accession No. (HQ840432)). PKC{delta}IX is generated by alternative splicing and is ubiquitously expressed, as seen in its full-length PKC{delta}. PKC{delta}IX lacks the C1 domain, the caspase 3 cleavage site, and the ATP binding site but preserves an almost intact c-terminal catalytic domain and a nuclear localization signal (NLS). The structural characteristics of PKC{delta}IX provided a possibility that this PKC{delta} isozyme functions as a novel dominant-negative form for PKC{delta} due to its lack of the ATP-binding domain that is required for the kinase activity of PKC{delta}. Indeed, overexpression of PKC{delta}IX significantly inhibited etoposide-induced apoptosis in NIH3T3 cells. In addition, an in vitro kinase assay showed that recombinant PKC{delta}IX protein could competitively inhibit the kinase activity of PKC{delta}. We conclude that PKC{delta}IX can function as a natural dominant-negative inhibitor of PKC{delta}in vivo.

  16. The Okavango: Whose Delta is it?

    NASA Astrophysics Data System (ADS)

    Magole, Lapologang; Magole, Lefatshe Innocent

    The Okavango Delta is amongst the largest Ramsar sites ( http://www.ramsar.org/sitelist.pdf) in the world and an important wetland for community livelihoods, conservation and tourism in Botswana. Over the years, the utilization of the delta has shifted from communal use to state control, with an increased use for conservation and tourism. This increased use for conservation and tourism has manifested in the physical expansion of the conservation area - Moremi Game Reserve and the formation of Wildlife Management Areas (WMAs) around the reserve, whose primary land use is wildlife utilization. The expansion of the conservation area has translated into several practical matters, including expansion of the area for non-hunting activities or photographic areas. The livelihoods of local communities of the Okavango delta who depended on fishing, hunter-gathering, livestock rearing, rain-fed agriculture and flood recession farming have been negatively affected by the expansion of conservation and tourism in the delta. The livelihoods alternatives in the form of Community Based Natural Resource Management (CBNRM) and tourism have not provided substitutes for the people as the communities are still reliant on the same old livelihood sources as in the past, albeit within smaller and restricted areas. This paper explores the ownership of the natural resources within the Okavango Delta. It asks and attempts to answer the following questions: Who owns and controls the use of the land? Who has access to other resources there in? Who makes the decisions on how the delta resources should be managed and used? Who benefits from the delta resources? We argue firstly that ownership of the delta as defined by legal parameters and demonstrated in natural resource management practice is vested on government. Secondly, government, after assuming ownership of the delta continues to sell its stake to the international community, at the expense of local ownership and access to resources. We

  17. Model for the {Delta}(1600) resonance and {gamma}N{yields}{Delta}(1600) transition

    SciTech Connect

    Ramalho, G.; Tsushima, K.

    2010-10-01

    A covariant spectator constituent quark model is applied to study the {gamma}N{yields}{Delta}(1600) transition. Two processes are important in the transition: a photon couples to the individual quarks of the {Delta}(1600) core (quark core), and a photon couples to the intermediate pion-baryon states (pion cloud). While the quark core contributions are estimated assuming {Delta}(1600) as the first radial excitation of {Delta}(1232), the pion cloud contributions are estimated based on an analogy with the {gamma}N{yields}{Delta}(1232) transition. To estimate the pion cloud contributions in the {gamma}N{yields}{Delta}(1600) transition, we include the relevant intermediate states, {pi}N, {pi}{Delta}, {pi}N(1440) and {pi}{Delta}(1600). Dependence on the four-momentum transfer squared, Q{sup 2}, is predicted for the magnetic dipole transition form factor, G{sub M}*(Q{sup 2}), as well as the helicity amplitudes, A{sub 1/2}(Q{sup 2}) and A{sub 3/2}(Q{sup 2}). The results at Q{sup 2}=0 are compared with the existing data.

  18. A model for the Delta(1600) resonance and gamma N -> Delta(1600) transition

    SciTech Connect

    G. Ramalho, K. Tsushima

    2010-10-01

    A covariant spectator constituent quark model is applied to study the gamma N -> Delta(1600) transition. Two processes are important in the transition: a photon couples to the individual quarks of the Delta(1600) core (quark core), and a photon couples to the intermediate pion-baryon states (pion cloud). While the quark core contributions are estimated assuming Delta(1600) as the first radial excitation of Delta(1232), the pion cloud contributions are estimated based on an analogy with the gamma N -> Delta(1232) transition. To estimate the pion cloud contributions in the gamma N -> Delta(1600) transition, we include the relevant intermediate states, pi-N, pi-Delta, pi-N(1440) and pi-Delta(1600). Dependence on the four-momentum transfer squared, Q2, is predicted for the magnetic dipole transition form factor, GM*(Q2), as well as the helicity amplitudes, A_1/2(Q2) and A_3/2(Q2). The results at Q2=0 are compared with the existing data.

  19. Holocene evolution of a wave-dominated fan-delta: Godavari delta, India

    NASA Astrophysics Data System (ADS)

    Saito, Y.; Nageswara Rao, K.; Nagakumar, K.; Demudu, G.; Rajawat, A.; Kubo, S.; Li, Z.

    2013-12-01

    The Godavari delta is one of the world's largest wave-dominated deltas. The Godavari River arises in the Western Ghats near the west coast of India and drains an area of about 3.1x10^5 km^2, flowing about 1465 km southeast across the Indian peninsula to the Bay of Bengal. The Godavari delta consists of a gentle seaward slope from its apex (12 m elevation) at Rajahmundry and a coastal beach-ridge plain over a distance of about 75 km and covers ~5200 km^2 as a delta plain. The river splits into two major distributary channels, the Gautami and the Vasishta, at a barrage constructed in the mid-1800s. The coastal environment of the deltaic coast is microtidal (~1 m mean tidal range) and wave-dominated (~1.5 m mean wave height in the June-September SW monsoon season, ~0.8 m in the NE monsoon season). Models of the Holocene evolution of the Godavari delta have changed from a zonal progradation model (e.g. Nageswara Rao & Sadakata, 1993) to a truncated cuspate delta model (Nageswara Rao et al., 2005, 2012). Twelve borehole cores (340 m total length), taken in the coastal delta plain during 2010-2013, yielded more than 100 C-14 dates. Sediment facies and C-14 dates from these and previous cores and remote-sensing data support a new delta evolution model. The Holocene coastal delta plain is divided into two parts by a set of linear beach ridges 12-14 km landward from the present shoreline in the central part of the delta. The location of the main depocenter (lobe) has shifted during the Holocene from 1) the center to 2) the west, 3) east, 4) center, 5) west, and 6) east. The linear beach ridges separate the first three from the last three stages. These lobe shifts are controlled by river channel shifts near the apex. Just as the current linear shoreline of the central part of the delta and the concave-up nearshore topography are the result of coastal erosion of a cuspate delta, the linear beach ridges indicate a former eroded shoreline. An unconformity within the deltaic

  20. The DELTA MONSTER: An RPV designed to investigate the aerodynamics of a delta wing platform

    NASA Technical Reports Server (NTRS)

    Connolly, Kristen; Flynn, Mike; Gallagher, Randy; Greek, Chris; Kozlowski, Marc; Mcdonald, Brian; Mckenna, Matt; Sellar, Rich; Shearon, Andy

    1989-01-01

    The mission requirements for the performance of aerodynamic tests on a delta wind planform posed some problems, these include aerodynamic interference; structural support; data acquisition and transmission instrumentation; aircraft stability and control; and propulsion implementation. To eliminate the problems of wall interference, free stream turbulence, and the difficulty of achieving dynamic similarity between the test and actual flight aircraft that are associated with aerodynamic testing in wind tunnels, the concept of the remotely piloted vehicle which can perform a basic aerodynamic study on a delta wing was the main objective for the Green Mission - the Delta Monster. The basic aerodynamic studies were performed on a delta wing with a sweep angle greater than 45 degrees. These tests were performed at various angles of attack and Reynolds numbers. The delta wing was instrumented to determine the primary leading edge vortex formation and location, using pressure measurements and/or flow visualization. A data acquisition system was provided to collect all necessary data.

  1. Tracking Nile Delta vulnerability to Holocene change.

    PubMed

    Marriner, Nick; Flaux, Clément; Morhange, Christophe; Stanley, Jean-Daniel

    2013-01-01

    Understanding deltaic resilience in the face of Holocene climate change and human impacts is an important challenge for the earth sciences in characterizing the full range of present and future wetland responses to global warming. Here, we report an 8000-year mass balance record from the Nile Delta to reconstruct when and how this sedimentary basin has responded to past hydrological shifts. In a global Holocene context, the long-term decrease in Nile Delta accretion rates is consistent with insolation-driven changes in the 'monsoon pacemaker', attested throughout the mid-latitude tropics. Following the early to mid-Holocene growth of the Nile's deltaic plain, sediment losses and pronounced erosion are first recorded after ~4000 years ago, the corollaries of falling sediment supply and an intensification of anthropogenic impacts from the Pharaonic period onwards. Against the backcloth of the Saharan 'depeopling', reduced river flow underpinned by a weakening of monsoonal precipitation appears to have been particularly conducive to the expansion of human activities on the delta by exposing productive floodplain lands for occupation and irrigation agriculture. The reconstruction suggests that the Nile Delta has a particularly long history of vulnerability to extreme events (e.g. floods and storms) and sea-level rise, although the present sediment-starved system does not have a direct Holocene analogue. This study highlights the importance of the world's deltas as sensitive archives to investigate Holocene geosystem responses to climate change, risks and hazards, and societal interaction.

  2. {delta}-mediated pion production in nuclei

    SciTech Connect

    Praet, C.; Lalakulich, O.; Jachowicz, N.; Ryckebusch, J.

    2009-04-15

    We present a fully relativistic formalism for describing neutrino-induced {delta}-mediated single-pion production in nuclei. We assess the ambiguities stemming from the {delta} interactions and quantify the uncertainties in the axial form-factor parameters by comparing with the available bubble-chamber neutrino-scattering data. To include nuclear effects, we turn to a relativistic plane-wave impulse approximation (RPWIA) using realistic bound-state wave functions derived in the Hartree approximation to the {sigma}-{omega} Walecka model. For neutrino energies larger than 1 GeV, we show that a relativistic Fermi-gas model with appropriate binding-energy correction produces results that are comparable to the RPWIA that naturally includes Fermi motion, nuclear-binding effects, and the Pauli exclusion principle. Including {delta} medium modifications roughly halves the RPWIA cross section. Calculations for primary (prior to undergoing final-state interactions) pion production are presented for both electron- and neutrino-induced processes, and a comparison with electron-scattering data and other theoretical approaches is included. We infer that the total {delta}-production strength is underestimated by about 20 to 25%, a fraction that is due to the pionless decay modes of the {delta} in a medium. The model presented in this work can be naturally extended to include the effect of final-state interactions in a relativistic and quantum-mechanical way.

  3. The ecology of the Sacramento-San Joaquin Delta

    SciTech Connect

    Herbold, B.; Moyle, P.B. . Dept. of Wildlife and Fisheries Biology)

    1989-09-01

    This report describes an ecosystem significantly different from other delta ecosystems in North America. The Sacramento-San Joaquin Delta is one of the 60 largest river deltas in the world and is the largest river delta on the west coast. As the hub of California's water system, the delta is of immense municipal, agricultural, and industrial importance. The amount of freshwater that flows through the delta controls the delta's productivity and regulates the life cycles of many of its organisms. The vast estuary of the Sacramento and San Joaquin Rivers is one of the most highly modified and intensively managed estuaries in the world. Biological processes in the delta are obscured by the temporal dynamics of the system. Many of the most significant alterations, such as leveeing, diking, and agricultural practices, are not now recognized as such by most citizens, making conservation and protection of the delta difficult. 308 refs., 43 figs., 11 tabs.

  4. Delta capability for launch of communications satellites

    NASA Technical Reports Server (NTRS)

    Grimes, D. W.; Russell, W. A., Jr.; Kraft, J. D.

    1982-01-01

    The evolution of capabilities and the current performance levels of the Delta launch vehicle are outlined. The first payload was the Echo I passive communications satellite, weighing 179 lb, and placed in GEO in 1960. Emphasis since then has been to use off-the-shelf hardware where feasible. The latest version in the 3924 first stage, 3920 second stage, and Pam D apogee kick motor third stage. The Delta is presently equipped to place 2800 lb in GEO, as was proven with the 2717 lb Anik-D1 satellite. The GEO payload placement performance matches the Shuttle's, and work is therefore under way to enhance the Delta performance to handle more massive payloads. Installation of the Castor-IV solid motor separation system, thereby saving mass by utilizing compressed nitrogen, rather than mechanical thrusters to remove the strap-on boosters, is indicated, together with use of a higher performance propellant and a wider nose fairing.

  5. NATO-3C/Delta launch

    NASA Technical Reports Server (NTRS)

    1978-01-01

    NATO-3C, the third in a series of NATO defense-related communication satellites, is scheduled to be launched on a delta vehicle from the Eastern Test Range no earlier than November 15, 1978. NATO-3A and -3B were successfully launched by Delta vehicles in April 1976 and January 1977, respectively. The NATO-3C spacecraft will be capable of transmitting voice, data, facsimile, and telex messages among military ground stations. The launch vehicle for the NATO-3C mission will be the Delta 2914 configuration. The launch vehicle is to place the spacecraft in a synchronous transfer orbit. The spacecraft Apogee Kick motor is to be fired at fifth transfer orbit apogee to circularize its orbit at geosynchronous altitude of 35,900 km(22,260 miles) above the equator over the Atlantic Ocean somewhere between 45 and 50 degrees W longitude.

  6. Mutagenesis of the borage Delta(6) fatty acid desaturase.

    PubMed

    Sayanova, O; Beaudoin, F; Libisch, B; Shewry, P; Napier, J

    2000-12-01

    The consensus sequence of the third histidine box of a range of Delta(5), Delta(6), Delta(8) and sphingolipid desaturases differs from that of the membrane-bound non-fusion Delta(12) and Delta(15) desaturases in the presence of glutamine instead of histidine. We have used site-directed mutagenesis to determine the importance of glutamine and other residues of the third histidine box and created a chimaeric enzyme to determine the ability of the Cyt b(5) fusion domain from the plant sphingolipid desaturase to substitute for the endogenous domain of the Delta(6) desaturase. PMID:11171152

  7. DNA polymerase III accessory proteins. I. holA and holB encoding delta and delta'.

    PubMed

    Dong, Z; Onrust, R; Skangalis, M; O'Donnell, M

    1993-06-01

    The genes encoding the delta and delta' subunits of the 10-subunit Escherichia coli replicase, DNA polymerase III holoenzyme, have been identified and sequenced. The holA gene encoding delta is located downstream of rlpB at 15.2 min and predicts a 38.7 kda protein. The holB gene encoding delta' is located at 24.3 min and predicts a 36.9-kDa protein. Hence the delta and delta' subunits are unrelated proteins encoded by separate genes. The genes have been used to express and purify delta and delta' in quantity. The predicted amino acid sequence of delta' is homologous to the sequences of the tau and gamma subunits revealing a large amount of structural redundancy within the holoenzyme.

  8. Gamma-delta t-cell lymphomas.

    PubMed

    Foppoli, Marco; Ferreri, Andrés J M

    2015-03-01

    Gamma-delta T-cell lymphomas are aggressive and rare diseases originating from gamma-delta lymphocytes. These cells, which naturally play a role in the innate, non-specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for <1% of all primary cutaneous lymphomas, occurring in adults with relevant comorbidities. Cutaneous lesions may vary, but its clinical behaviour is usually aggressive and long-term survival is anecdotal. Available literature on gamma-delta T-cell lymphomas is fractioned, mostly consisting of case reports or small cumulative series. Therefore, clinical suspicion and diagnosis are usually delayed, and therapeutic management remains to be established. This review critically analyses available evidence on diagnosis, staging and behaviour of gamma-delta T-cell lymphomas, provides recommendations for therapeutic management in routine practice and discusses relevant unmet clinical needs for future studies.

  9. A reduced-complexity model for river delta formation - Part 1: Modeling deltas with channel dynamics

    NASA Astrophysics Data System (ADS)

    Liang, M.; Voller, V. R.; Paola, C.

    2014-07-01

    We develop a reduced-complexity model (RCM) delta formation model, in contrast to reductionist models based on high-resolution computational fluid dynamics. The basic framework of this model (referred in this paper as "DeltaRCM") consists of stochastic parcel-based cellular routing schemes for water and sediment and a set of phenomenological rules for sediment deposition and erosion. The outputs of the model include flow field, water surface topography and bed topography that evolves in time. Results show that DeltaRCM is able to: (1) resolve a wide range of channel dynamics, including elongation, bifurcation, avulsion and migration; (2) in response to the changes in input parameters, produce different types of deltas such as alluvial fan deltas at experimental scale. We also identify three key areas of particular model sensitivity, even at the RCM level: (1) avulsion dynamics is sensitive to dynamic free-surface topography; (2) channel network structure is sensitive to instability at channel mouths which creates bars; and (3) out-of-channel sedimentation is sensitive to water surface slope along channel margins. We also demonstrate a simple stratigraphy tracking component which can display the structure of the deposit in terms of distribution of coarse and fine materials along with the age of the deposit. DeltaRCM is a useful tool for understanding the dynamics of river deltas within a relatively simple cellular representation of water and sediment transport.

  10. All optical binary delta-sigma modulator

    NASA Astrophysics Data System (ADS)

    Sayeh, Mohammad R.; Siahmakoun, Azad

    2005-09-01

    This paper describes a novel A/D converter called "Binary Delta-Sigma Modulator" (BDSM) which operates only with nonnegative signal with positive feedback and binary threshold. This important modification to the conventional delta-sigma modulator makes the high-speed (>100GHz) all-optical implementation possible. It has also the capability to modify its own sampling frequency as well as its input dynamic range. This adaptive feature helps designers to optimize the system performance under highly noisy environment and also manage the power consumption of the A/D converters.

  11. The sensitivity of the ESA DELTA model

    NASA Astrophysics Data System (ADS)

    Martin, C.; Walker, R.; Klinkrad, H.

    2004-01-01

    The debris environment long term analysis (DELTA) model, developed by QinetiQ for the European Space Agency (ESA), allows the future projection of the debris environment throughout Earth orbit. To ensure a sound basis for such future projections, and consequently for assessing the effectiveness of various mitigation measures, it is essential that the sensitivity of the model is examined. This paper discusses the sensitivity of the DELTA model to changes in key model parameters and assumptions. Specifically, the variation in future traffic rates, including the deployment of satellite constellations, and the variation in the break-up model and criteria used to simulate future explosion and collision events.

  12. How Deltas Die - a Case Study of the End of Sedimentation in Two Giant Deltas

    NASA Astrophysics Data System (ADS)

    Macdonald, D.; Robinson, P.; Nicholson, U.

    2013-12-01

    Most well-studied deltas are on passive margins (e.g. Mississippi, Rhone, Ebro), where the main tectonic control on accommodation space is thermal subsidence. As long as the main river in the sediment routing system keeps flowing, there is no particular reason for sedimentation to end, and some deltas have a history extending more than 100 Ma (e.g. Niger at 130 Ma). However, some very large deltas can build out over active margins. For example, the Amur, Orinoco, and Colorado (US) deltas all straddle strike-slip plate boundaries and are much less long-lived than their passive margin counterparts. This paper looks in detail at the end of the deltaic sedimentation in the Pliocene deltas of the Amur River on the island of Sakhalin, and the Colorado River in the Fish Creek-Vallecito Basin of southern California. In both cases the deltas are sand-rich with distant provenances in East Asia and the Colorado Plateau respectively; also they both coexist with locally derived clastic sedimentation. Despite these similarities, there are significant differences between the two deltas as a direct result of the differences in plate boundary movement rates and tectonic state. On Sakhalin, the plate boundary has moved at about 1.95 mm a-1 during the Pliocene and has been in a transpressional state. Primary deltaic sedimentation ended by a three main mechanisms: uplift of the island along the transpressional plate boundary detached the delta from the trunk stream; growth of anticlines over strands of the plate boundary disrupted the consequent delta-top drainage; and late sedimentation involved reworking of the far-travelled deltaic material. In California, where the plate boundary has moved at about 50 mm a-1 in the Pliocene, deltaic sedimentation ceased by translation of the receiving basin from the river mouth. New field and mineralogical data suggest that Colorado River sedimentation waned over a period of about 1 Ma in the Late Pliocene, and was gradually overwhelmed by locally

  13. Modeling delta growth and channel geometry on Wax Lake Delta, Louisiana. Preliminary results

    NASA Astrophysics Data System (ADS)

    Viparelli, E.; Czapiga, M. J.; Li, C.; Shaw, J. B.; Parker, G.

    2013-12-01

    A numerical model of delta growth, in which the distributary channels are assumed to have self-constructed their cross sections, is validated on Wax Lake Delta, Louisiana. As in previous laterally averaged models of delta growth, the delta is divided in a low slope delta top, a steep delta front and a low slope basement. The flow on the delta top is assumed steady, and a backwater formulation is implemented. Since one or more channels can actively transport water and sediment on the delta top during floods, we simplify the problem by assuming that the bed material is transported in one rectangular channel, with width and depth roughly equal to the sum of the active channel widths, and to the average depth of the active channels. The problem is characterized by one equation (i.e. the backwater equation) in two unknowns, the channel width and depth. Another equation is thus needed to close the problem. Under the assumptions that 1) the system is at bankfull flow, and 2) the Shields number in the channels is equal to its channel formative value, our closure relation is a channel-formative criterion. In particular, a recently derived relation to estimate the formative (bankfull) Shields number as a function of the friction slope is implemented. Recent field work on Wax Lake Delta shows that the distributary channels are incising into a relatively stiff basement. In our model we do not attempt to directly model channel incision, but we implicitly account for it with a modified formulation to compute the shoreline migration rate. In this formulation the bed material at the shoreline is trapped in the non-channelized portion of the delta front only. Measured and numerical shoreline migration rates, longitudinal profiles of delta elevation, and channel geometry, i.e. width and depth, are compared. In the relatively near future we plan to 1) use our model to estimate land-building potential of engineered diversions of the Mississippi River, and 2) couple the present model

  14. The PVH as a site of CB1-mediated stimulation of thermogenesis by MC4R agonism in male rats.

    PubMed

    Monge-Roffarello, Boris; Labbe, Sebastien M; Roy, Marie-Claude; Lemay, Marie-Laurence; Coneggo, Estelle; Samson, Pierre; Lanfray, Damien; Richard, Denis

    2014-09-01

    The present study was designed to investigate the involvement of the cannabinoid receptor 1 (CB1) in the stimulating effects of the melanocortin-4 receptor (MC4R) agonism on whole-body and brown adipose tissue (BAT) thermogenesis. In a first series of experiments, whole-body and BAT thermogenesis were investigated in rats infused in the third ventricle of the brain with the MC4R agonist melanotan II (MTII) and the CB1 agonist δ9-tetrahydrocannabinol (δ(9)-THC) or the CB1 antagonist AM251. Whole-body thermogenesis was measured by indirect calorimetry and BAT thermogenesis assessed from interscapular BAT (iBAT) temperature. δ(9)-THC blunted the effects of MTII on energy expenditure and iBAT temperature, whereas AM251 tended to potentiate the MTII effects. δ(9)-THC also blocked the stimulating effect of MTII on (14)C-bromopalmitate and (3)H-deoxyglucose uptakes in iBAT. Additionally, δ(9)-THC attenuated the stimulating effect of MTII on the expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (Pgc1α), type II iodothyronine deiodinase (Dio2), carnitine palmitoyltransferase 1B (Cpt1b), and uncoupling protein 1 (Ucp1). In a second series of experiments, we addressed the involvement of the paraventricular hypothalamic nucleus (PVH) in the CB1-mediated effects of MTII on iBAT thermogenesis, which were assessed following the infusion of MTII in the PVH and δ(9)-THC or AM251 in the fourth ventricle of the brain. We demonstrated the ability of δ(9)-THC to blunt MTII-induced iBAT temperature elevation. δ(9)-THC also blocked the PVH effect of MTII on (14)C-bromopalmitate uptake as well as on Pgc1α and Dio2 expression in iBAT. Altogether the results of this study demonstrate the involvement of the PVH in the CB1-mediated stimulating effects of the MC4R agonist MTII on whole-body and BAT thermogenesis.

  15. Assembly of hepatitis delta virus particles.

    PubMed Central

    Ryu, W S; Bayer, M; Taylor, J

    1992-01-01

    Hepatitis delta virus (HDV) is a subviral satellite of hepatitis B virus (HBV). Since the RNA genome of HDV can replicate in cultured cells in the absence of HBV, it has been suggested that the only helper function of HBV is to supply HBV coat proteins in the assembly process of HDV particles. To examine the factors involved in such virion assembly, we transiently cotransfected cells with various hepadnavirus constructs and cDNAs of HDV and analyzed the particles released into the medium. We report that the HDV genomic RNA and the delta antigen can be packaged by coat proteins of either HBV or the related hepadnavirus woodchuck hepatitis virus (WHV). Among the three co-carboxy-terminal coat proteins of WHV, the smallest form was sufficient to package the HDV genome; even in the absence of HDV RNA, the delta antigen could be packaged by this WHV coat protein. Also, of the two co-amino-terminal forms of the delta antigen, only the larger form was essential for packaging. Images PMID:1548764

  16. Delta Scorpii unusual brightening to first magnitude

    NASA Astrophysics Data System (ADS)

    Sigismondi, Costantino

    2016-01-01

    The Be star delta Scorpii with a range of variability between 2.35 and 1.65 in visible light is having an unusual brightening to magnitude mV=0.8, as measured on 31 Jan 2016 at 3:56 UT and 5:36 UT from Lanciano, Italy.

  17. Applications of Dirac's Delta Function in Statistics

    ERIC Educational Resources Information Center

    Khuri, Andre

    2004-01-01

    The Dirac delta function has been used successfully in mathematical physics for many years. The purpose of this article is to bring attention to several useful applications of this function in mathematical statistics. Some of these applications include a unified representation of the distribution of a function (or functions) of one or several…

  18. Phi Delta Kappa at the Threshold

    ERIC Educational Resources Information Center

    Walling, Donovan R.

    2006-01-01

    Since its fraternal origins a century ago, Phi Delta Kappa (PDK) International has been foremost a society of individuals joined together in professional collegiality and dedicated to tenets of leadership, service, and research in education. As PDK crosses the threshold into its second century, that early spirit of association lit in 1906, like…

  19. Definition of the {delta} mass and width

    SciTech Connect

    Djukanovic, D.; Scherer, S.; Gegelia, J.

    2007-08-01

    In the framework of effective field theory we show that, at two-loop order, the mass and width of the {delta} resonance defined via the (relativistic) Breit-Wigner parametrization both depend on the choice of field variables. In contrast, the complex-valued position of the pole of the propagator is independent of this choice.

  20. Backwater controls of avulsion location on deltas

    NASA Astrophysics Data System (ADS)

    Chatanantavet, Phairot; Lamb, Michael P.; Nittrouer, Jeffrey A.

    2012-01-01

    River delta complexes are built in part through repeated river-channel avulsions, which often occur about a persistent spatial node creating delta lobes that form a fan-like morphology. Predicting the location of avulsions is poorly understood, but it is essential for wetland restoration, hazard mitigation, reservoir characterization, and delta morphodynamics. Following previous work, we show that the upstream distance from the river mouth where avulsions occur is coincident with the backwater length, i.e., the upstream extent of river flow that is affected by hydrodynamic processes in the receiving basin. To explain this observation we formulate a fluvial morphodynamic model that is coupled to an offshore spreading river plume and subject it to a range of river discharges. Results show that avulsion is less likely in the downstream portion of the backwater zone because, during high-flow events, the water surface is drawn down near the river mouth to match that of the offshore plume, resulting in river-bed scour and a reduced likelihood of overbank flow. Furthermore, during low-discharge events, flow deceleration near the upstream extent of backwater causes enhanced deposition locally and a reduced channel-fill timescale there. Both mechanisms favor preferential avulsion in the upstream part of the backwater zone. These dynamics are fundamentally due to variable river discharges and a coupled offshore river plume, with implications for predicting delta response to climate and sea level change, and fluvio-deltaic stratigraphy.

  1. The Delta Team: Empowering Adolescent Girls.

    ERIC Educational Resources Information Center

    Hood, Marian White

    1994-01-01

    In response to adolescent girls' concerns about teen violence, rumors, grooming, careers, and equity, four women teachers and a woman administrator at a Maryland middle school developed the Delta Program. The program provides positive learning experiences, teaches social skills and conflict management techniques, empowers girls through mentoring…

  2. Quantitative Metrics of Robustness in River Deltas

    NASA Astrophysics Data System (ADS)

    Foufoula-Georgiou, E.; Tejedor, A.; Longjas, A.; Zaliapin, I. V.

    2014-12-01

    Deltas are landforms with channels that deliver water, sediment and nutrient fluxes from rivers to oceans or inland water bodies via multiple pathways. We conceptualize a delta channel network as a rooted acyclic directed graph where channels are modeled by edges and junctions by vertices. We use spectral graph theory - mainly the geometry of the null space of the directed weighted graph Laplacian - to establish a quantitative framework for extracting important structural and dynamics-related information from river deltas. Using this information, we introduce refined metrics of system complexity, such as entropy. Entropy has been proven to be an important measure of the amount of uncertainty in stochastic systems, and therefore a surrogate of the capacity of the system to undergo changes. Here we present an entropic approach to evaluate the robustness of deltas, showing how the two components of entropy: mutual information and conditional entropy can be interpreted in this framework. We also present other metrics that include, among others, resistance distance and number of alternative paths, which quantify the structural complexity of the system. We use these metrics to better classify deltaic systems, quantify their resilience and propose possible management scenarios.

  3. Alkoxy radicals: Delta proton hyperfine couplingsa)

    NASA Astrophysics Data System (ADS)

    Budzinski, Edwin E.; Box, Harold C.

    1985-04-01

    Single crystals of rhamnose were x irradiated at 4.2 K and the ESR and ENDOR spectra taken at 1.6 K. A component of the ESR absorption arises from an alkoxy radical exhibiting an unusual delta proton hyperfine coupling. Parallels between the radiation-induced oxidation of certain carbohydrates and that of amino acids are pointed out.

  4. Faculty Salaries at Delta College. Research Report.

    ERIC Educational Resources Information Center

    Evans, John W.

    In 1989, a study was conducted of faculty salaries at California's San Joaquin Delta Community College (SJDCC). Salary results were compared with community college districts in the State of California, with two specially selected subgroups of colleges comparable to SJDCC, and with all of California's major public and private four-year…

  5. San Joaquin Delta College Student Athlete Study.

    ERIC Educational Resources Information Center

    Lewis, Merrilee R.; Marcopulos, Ernest

    In spring 1988, a study was conducted of students who participated in college athletics at San Joaquin Delta College (SJDC) between 1983-84 and 1987-88. Data collected on each student athlete included ethnicity, sport, place of residence, initial and current reading level, total grade point average (GPA), GPA in athletics and physical education…

  6. {Delta}G and {Delta}q-bar measurements at PHENIX

    SciTech Connect

    Okada, Kensuke; Collaboration: PHENIX Collaboration

    2011-12-14

    RHIC provides a unique opportunity to address the components of the proton spin. In comparison to deep inelastic scattering experiments, the gluon is the main player in proton-proton collisions. PHENIX has measured double spin asymmetries of various processes. Those contain the information of the gluon spin component ({Delta}G). In addition high energy collisions open the unique channel to access flavor dependent information of quark polarization through the real W boson production. Because of the feature of weak interaction, the parity violating process defines the helicity of quarks in the interaction. The single spin asymmetry is the observable. It is especially interesting to probe anti-quark components ({Delta}q-bar). In this article, we report the recent progress of {Delta}G and {Delta}q-bar measurements at PHENIX.

  7. Hard breakup of the deuteron into two {Delta} isobars

    SciTech Connect

    Granados, Carlos G.; Sargsian, Misak M.

    2011-05-15

    We study high-energy photodisintegration of the deuteron into two {Delta} isobars at large center of mass angles within the QCD hard rescattering model (HRM). According to the HRM, the process develops in three main steps: the photon knocks a quark from one of the nucleons in the deuteron; the struck quark rescatters off a quark from the other nucleon sharing the high energy of the photon; then the energetic quarks recombine into two outgoing baryons which have large transverse momenta. Within the HRM, the cross section is expressed through the amplitude of pn{yields}{Delta}{Delta} scattering which we evaluated based on the quark-interchange model of hard hadronic scattering. Calculations show that the angular distribution and the strength of the photodisintegration is mainly determined by the properties of the pn{yields}{Delta}{Delta} scattering. We predict that the cross section of the deuteron breakup to {Delta}{sup ++}{Delta}{sup -} is 4-5 times larger than that of the breakup to the {Delta}{sup +}{Delta}{sup 0} channel. Also, the angular distributions for these two channels are markedly different. These can be compared with the predictions based on the assumption that two hard {Delta} isobars are the result of the disintegration of the preexisting {Delta}{Delta} components of the deuteron wave function. In this case, one expects the angular distributions and cross sections of the breakup in both {Delta}{sup ++}{Delta}{sup -} and {Delta}{sup +}{Delta}{sup 0} channels to be similar.

  8. SDO Delta H Mode Design and Analysis

    NASA Technical Reports Server (NTRS)

    Mason, Paul A.; Starin, Scott R.

    2007-01-01

    While on orbit, disturbance torques on a three axis stabilized spacecraft tend to increase the system momentum, which is stored in the reaction wheels. Upon reaching the predefined momentum capacity (or maximum wheel speed) of the reaction wheel, an external torque must be used to unload the momentum. The purpose of the Delta H mode is to manage the system momentum. This is accomplished by driving the reaction wheels to a target momentum state while the attitude thrusters, which provide an external torque, are used to maintain the attitude. The Delta H mode is designed to meet the mission requirements and implement the momentum management plan. Changes in the requirements or the momentum management plan can lead to design changes in the mode. The momentum management plan defines the expected momentum buildup trend, the desired momentum state and how often the system is driven to the desired momentum state (unloaded). The desired momentum state is chosen based on wheel capacity, wheel configuration, thruster layout and thruster sizing. For the Solar Dynamics Observatory mission, the predefined wheel momentum capacity is a function of the jitter requirements, power, and maximum momentum capacity. Changes in jitter requirements or power limits can lead to changes in the desired momentum state. These changes propagate into the changes in the momentum management plan and therefore the Delta H mode design. This paper presents the analysis and design performed for the Solar Dynamics Observatory Delta H mode. In particular, the mode logic and processing needed to meet requirements is described along with the momentum distribution formulation. The Delta H mode design is validated using the Solar Dynamics Observatory High Fidelity simulator. Finally, a summary of the design is provided along with concluding remarks.

  9. Tracking Nile Delta Vulnerability to Holocene Change

    PubMed Central

    Marriner, Nick; Flaux, Clément; Morhange, Christophe; Stanley, Jean-Daniel

    2013-01-01

    Understanding deltaic resilience in the face of Holocene climate change and human impacts is an important challenge for the earth sciences in characterizing the full range of present and future wetland responses to global warming. Here, we report an 8000-year mass balance record from the Nile Delta to reconstruct when and how this sedimentary basin has responded to past hydrological shifts. In a global Holocene context, the long-term decrease in Nile Delta accretion rates is consistent with insolation-driven changes in the ‘monsoon pacemaker’, attested throughout the mid-latitude tropics. Following the early to mid-Holocene growth of the Nile’s deltaic plain, sediment losses and pronounced erosion are first recorded after ~4000 years ago, the corollaries of falling sediment supply and an intensification of anthropogenic impacts from the Pharaonic period onwards. Against the backcloth of the Saharan ‘depeopling’, reduced river flow underpinned by a weakening of monsoonal precipitation appears to have been particularly conducive to the expansion of human activities on the delta by exposing productive floodplain lands for occupation and irrigation agriculture. The reconstruction suggests that the Nile Delta has a particularly long history of vulnerability to extreme events (e.g. floods and storms) and sea-level rise, although the present sediment-starved system does not have a direct Holocene analogue. This study highlights the importance of the world’s deltas as sensitive archives to investigate Holocene geosystem responses to climate change, risks and hazards, and societal interaction. PMID:23922692

  10. Genetics Home Reference: activated PI3K-delta syndrome

    MedlinePlus

    ... Health Conditions activated PI3K-delta syndrome activated PI3K-delta syndrome Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Activated PI3K-delta syndrome is a disorder that impairs the immune ...

  11. 78 FR 45592 - DeltaPoint Capital IV, LP;

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-29

    ... ADMINISTRATION DeltaPoint Capital IV, LP; Notice Seeking Exemption Under Section 312 of the Small Business Investment Act, Conflicts of Interest Notice is hereby given that DeltaPoint Capital IV, L.P., 45 East Avenue... Business Administration (``SBA'') Rules and Regulations (13 CFR 107.730). DeltaPoint Capital IV,...

  12. De-Mystifying the Dirac [delta]-Function

    ERIC Educational Resources Information Center

    Lutzer, Carl V.

    2007-01-01

    In this article, we discuss an alternative method of teaching students about the Dirac [delta]-function. The method provides students with the mechanical tools they need in order to work with the [delta]-function in practice, while also fostering a sense of cohesion in the calculus curriculum by presenting the [delta]-function as an evolution of…

  13. The Niger Delta petroleum system; Niger Delta Province, Nigeria, Cameroon, and equatorial Guinea, Africa

    USGS Publications Warehouse

    Tuttle, Michele L.W.; Charpentier, Ronald R.; Brownfield, Michael E.

    1999-01-01

    In the Niger Delta province, we have identified one petroleum system--the Tertiary Niger Delta (Akata-Agbada) petroleum system. The delta formed at the site of a rift triple junction related to the opening of the southern Atlantic starting in the Late Jurassic and continuing into the Cretaceous. The delta proper began developing in the Eocene, accumulating sediments that now are over 10 kilometers thick. The primary source rock is the upper Akata Formation, the marine-shale facies of the delta, with possibly contribution from interbedded marine shale of the lowermost Agbada Formation. Oil is produced from sandstone facies within the Agbada Formation, however, turbidite sand in the upper Akata Formation is a potential target in deep water offshore and possibly beneath currently producing intervals onshore. Known oil and gas resources of the Niger Delta rank the province as the twelfth largest in the world. To date, 34.5 billion barrels of recoverable oil and 93.8 trillion cubic feet of recoverable gas have been discovered. In 1997, Nigeria was the fifth largest crude oil supplier to the United States, supplying 689,000 barrels/day of crude.

  14. Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol

    PubMed Central

    Cluny, Nina L.; Keenan, Catherine M.; Reimer, Raylene A.; Le Foll, Bernard; Sharkey, Keith A.

    2015-01-01

    Objective Acute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users. Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice. Methods Adult male DIO and lean mice were treated daily with vehicle or THC (2mg/kg for 3 weeks and 4 mg/kg for 1 additional week). Body weight, fat mass, energy intake, locomotor activity, whole gut transit and gut microbiota were measured longitudinally. Results THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC. THC had no effect on locomotor activity or whole gut transit in either lean or DIO mice. Conclusions Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity. PMID:26633823

  15. A study on the concentrations of 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in hair root and whole hair.

    PubMed

    Han, Eunyoung; Choi, Hwakyung; Lee, Sangki; Chung, Heesun; Song, Joon Myong

    2011-07-15

    In this study, we investigated the patterns of cannabis users (n=412) according to their sex, age, and the results of urinalysis and hair analysis, and classified the concentrations of THCCOOH in hair into three categories to examine the levels of cannabis use. We also compared the concentrations of THCCOOH in hair root, hair without the hair root and whole hair and examined the relationship among them according to the results of urinalysis. The hair samples were washed, digested with 1ml of 1M NaOH at 85°C for 30min and extracted with 2ml of n-hexane:ethyl acetate (9:1) two times after adding 1ml of 0.1N sodium acetate buffer (pH 4.5) and 200μl of acetic acid. The final mixture was derivatized with 50μl of PFPA and 25μl of PFPOH for 30min at 70°C. The solution was evaporated, and the residue was reconstituted in 40μl of ethyl acetate and transferred to an autosampler vial. One microlitre was injected into the GC/MS/MS-NCI system. The concentrations of THCCOOH ranged from 0.06 to 33.44pg/mg (mean 2.96; median 1.32) in hair from cannabis users who had positive urine results and ranged from 0.05 to 7.24pg/mg (mean 1.35; median 0.37) in hair from cannabis users who had negative urine results. The average concentration of THCCOOH in hair from cannabis users who had positive urine results was higher than that from cannabis users who had negative urine results. Male cannabis users in their forties were predominant. We classified the concentrations of THCCOOH in hair into three groups (low, medium and high), and could use the grouping of THCCOOH in hair as a guide for determining the level of use. The low, medium and high concentration ranges for THCCOOH in hair were 0.05-0.24, 0.25-2.60 and 2.63-33.44pg/mg, respectively. We also investigated 28 hair samples with the root. The highest concentrations of THCCOOH were seen in the hair root from 18 out of the 28 hair samples. The average concentrations of THCCOOH in hair root, hair without hair root and whole hair from cannabis users who had positive urine results were higher than those who had negative urine results.

  16. A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes.

    PubMed

    Rockwell, Cheryl E; Kaminski, Norbert E

    2004-11-01

    Arachidonyl ethanolamine, which is commonly known as anandamide, was the first endogenous compound to be identified that binds to the cannabinoid receptors. Anandamide mimics many of the physiological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including hypothermia, antinociception, immobility, catalepsy, and immune modulation. In the present studies, we show that anandamide caused a concentration-dependent inhibition of interleukin-2 in primary splenocytes. The CB1 and CB2 antagonists, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride] and SR144528 [N-[(1S)-endo-1,3,3,-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], when used in combination, did not antagonize the inhibition of interleukin-2 by anandamide. Additionally, neither UCM707 [N-(3-furanylmethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide], the inhibitor of the putative anandamide membrane transporter (AMT), nor methyl arachidonoyl fluorophosphonate (MAFP), the inhibitor of fatty acid amidohydrolase (FAAH), were able to affect the inhibitory activity of anandamide upon interleukin-2. Interestingly, arachidonic acid caused a concentration-dependent inhibition of interleukin-2 secretion (IC(50) = 10.3 microM), which was similar to that of structurally related anandamide (IC(50) = 11.4 microM). The inhibition of interleukin-2 by anandamide and arachidonic acid was partially reversed by pretreatment with the nonspecific cyclooxygenase inhibitors, flurbiprofen and piroxicam. Moreover, NS398 [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide], a cyclooxygenase-2-specific inhibitor, also attenuated the inhibitory effects of anandamide and arachidonic acid upon interleukin-2 secretion. Finally, pretreatment with a peroxisome proliferator-activated receptor gamma (PPARgamma)-specific antagonist, T0070907 [2-chloro-5-nitro-N-4-pyridinyl-benzamide], partially antagonized

  17. 78 FR 22911 - Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Seatac, WA; Delta Air...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-17

    ... Employment and Training Administration Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Seatac, WA; Delta Air Lines, Inc., Reservation Sales and Customer Care Call Center, Sioux City, IA... workers and former workers of Delta Air Lines, Inc., Reservation Sales and Customer Care Call...

  18. BCAS2 Regulates Delta-Notch Signaling Activity through Delta Pre-mRNA Splicing in Drosophila Wing Development

    PubMed Central

    Huang, Chu-Wei; Chen, Po-Han; Chan, Shih-Peng; Tsao, Yeou-Ping; Lee, Hsiu-Hsiang; Wu, June-Tai; Chen, Show-Li

    2015-01-01

    Previously, we showed that BCAS2 is essential for Drosophila viability and functions in pre-mRNA splicing. In this study, we provide strong evidence that BCAS2 regulates the activity of Delta-Notch signaling via Delta pre-mRNA splicing. Depletion of dBCAS2 reduces Delta mRNA expression and leads to accumulation of Delta pre-mRNA, resulting in diminished transcriptions of Delta-Notch signaling target genes, such as cut and E(spl)m8. Furthermore, ectopic expression of human BCAS2 (hBCAS2) and Drosophila BCAS2 (dBCAS2) in a dBCAS2-deprived fly can rescue dBCAS2 depletion-induced wing damage to the normal phenotypes. These rescued phenotypes are correlated with the restoration of Delta pre-mRNA splicing, which affects Delta-Notch signaling activity. Additionally, overexpression of Delta can rescue the wing deformation by deprivation of dBCAS2; and the depletion of dBCAS2 can restore the aberrant eye associated with Delta-overexpressing retinas; providing supporting evidence for the regulation of Delta-Notch signaling by dBCAS2. Taken together, dBCAS2 participates in Delta pre-mRNA splicing that affects the regulation of Delta-Notch signaling in Drosophila wing development. PMID:26091239

  19. Interaction of cannabis and general anaesthetic agents in mice.

    PubMed

    Chesher, G B; Jackson, D M; Starmer, G A

    1974-04-01

    1 A cannabis extract (I) (in a concentration equivalent to 10 mg Delta(9)-tetrahydro-cannabinol(THC)/kg) prolonged pentobarbitone anaesthesia in mice maximally 20 min to 2 h after medication. The effect was still significant after 8 h, but less than at 2 hours.2 The cannabis extract (I) (equivalent to 10 mg Delta(9)-THC/kg) prolonged both pentobarbitone and ether anaesthesia in mice when administered 20 min before the anaesthetic. After eight consecutive daily doses of cannabis, the pentobarbitone anaesthesia was still significantly longer than a control group, while ether anaesthesia was not significantly prolonged.3 A second cannabis extract (II) with a different ratio of cannabinoids (also administered in dosage equivalent to 10 mg Delta(9)-THC/kg) failed to affect pentobarbitone anaesthesia in mice. This extract presented about 4% the dose of cannabidiol as extract I.4 Delta(8)-THC, Delta(9)-THC and cannabidiol prolonged pentobarbitone anaesthesia with cannabidiol being generally more active than Delta(9)-THC. Cannabinol (10 mg/kg) was inactive.5 The effects of cannabidiol and Delta(9)-THC were found to be additive, and there was a consistent trend for cannabinol to reduce the effectiveness of Delta(9)-THC and cannabidiol when given in combination.6 Premedication with phenoxybenzamine, phentolamine, propranolol, iproniazid, protriptyline, desipramine, reserpine, alpha-methyl tyrosine or parachlorophenylalanine did not affect the extract I-induced prolongation of pentobarbitone anaesthesia.7 It is concluded that cannabis may affect pentobarbitone and ether anaesthesia in mice at least partially by a direct depressant effect, and that the cannabis-induced prolongation of anaesthesia is probably unrelated to any effect on central 5-hydroxytryptamine or catecholamine neurones.

  20. 78 FR 21491 - DeltaPoint Capital IV, L.P., DeltaPoint Capital IV (New York), L.P.; Notice Seeking Exemption...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-10

    ... ADMINISTRATION DeltaPoint Capital IV, L.P., DeltaPoint Capital IV (New York), L.P.; Notice Seeking Exemption... that DeltaPoint Capital IV, L.P. and DeltaPoint Capital IV (New York), L.P., 45 East Avenue, 6th Floor... Business Administration (``SBA'') Rules and Regulations (13 CFR 107.730). DeltaPoint Capital IV,...

  1. Clostridium perfringens Delta-Toxin Induces Rapid Cell Necrosis.

    PubMed

    Seike, Soshi; Miyamoto, Kazuaki; Kobayashi, Keiko; Takehara, Masaya; Nagahama, Masahiro

    2016-01-01

    Clostridium perfringens delta-toxin is a β-pore-forming toxin and a putative pathogenic agent of C. perfringens types B and C. However, the mechanism of cytotoxicity of delta-toxin remains unclear. Here, we investigated the mechanisms of cell death induced by delta-toxin in five cell lines (A549, A431, MDCK, Vero, and Caco-2). All cell lines were susceptible to delta-toxin. The toxin caused rapid ATP depletion and swelling of the cells. Delta-toxin bound and formed oligomers predominantly in plasma membrane lipid rafts. Destruction of the lipid rafts with methyl β-cyclodextrin inhibited delta-toxin-induced cytotoxicity and ATP depletion. Delta-toxin caused the release of carboxyfluorescein from sphingomyelin-cholesterol liposomes and formed oligomers; toxin binding to the liposomes declined with decreasing cholesterol content in the liposomes. Flow cytometric assays with annexin V and propidium iodide revealed that delta-toxin treatment induced an elevation in the population of annexin V-negative and propidium iodide-positive cells. Delta-toxin did not cause the fragmentation of DNA or caspase-3 activation. Furthermore, delta-toxin caused damage to mitochondrial membrane permeability and cytochrome c release. In the present study, we demonstrate that delta-toxin produces cytotoxic activity through necrosis.

  2. Clostridium perfringens Delta-Toxin Induces Rapid Cell Necrosis

    PubMed Central

    Seike, Soshi; Miyamoto, Kazuaki; Kobayashi, Keiko; Takehara, Masaya; Nagahama, Masahiro

    2016-01-01

    Clostridium perfringens delta-toxin is a β-pore-forming toxin and a putative pathogenic agent of C. perfringens types B and C. However, the mechanism of cytotoxicity of delta-toxin remains unclear. Here, we investigated the mechanisms of cell death induced by delta-toxin in five cell lines (A549, A431, MDCK, Vero, and Caco-2). All cell lines were susceptible to delta-toxin. The toxin caused rapid ATP depletion and swelling of the cells. Delta-toxin bound and formed oligomers predominantly in plasma membrane lipid rafts. Destruction of the lipid rafts with methyl β-cyclodextrin inhibited delta-toxin-induced cytotoxicity and ATP depletion. Delta-toxin caused the release of carboxyfluorescein from sphingomyelin-cholesterol liposomes and formed oligomers; toxin binding to the liposomes declined with decreasing cholesterol content in the liposomes. Flow cytometric assays with annexin V and propidium iodide revealed that delta-toxin treatment induced an elevation in the population of annexin V-negative and propidium iodide-positive cells. Delta-toxin did not cause the fragmentation of DNA or caspase-3 activation. Furthermore, delta-toxin caused damage to mitochondrial membrane permeability and cytochrome c release. In the present study, we demonstrate that delta-toxin produces cytotoxic activity through necrosis. PMID:26807591

  3. Clostridium perfringens Delta-Toxin Induces Rapid Cell Necrosis.

    PubMed

    Seike, Soshi; Miyamoto, Kazuaki; Kobayashi, Keiko; Takehara, Masaya; Nagahama, Masahiro

    2016-01-01

    Clostridium perfringens delta-toxin is a β-pore-forming toxin and a putative pathogenic agent of C. perfringens types B and C. However, the mechanism of cytotoxicity of delta-toxin remains unclear. Here, we investigated the mechanisms of cell death induced by delta-toxin in five cell lines (A549, A431, MDCK, Vero, and Caco-2). All cell lines were susceptible to delta-toxin. The toxin caused rapid ATP depletion and swelling of the cells. Delta-toxin bound and formed oligomers predominantly in plasma membrane lipid rafts. Destruction of the lipid rafts with methyl β-cyclodextrin inhibited delta-toxin-induced cytotoxicity and ATP depletion. Delta-toxin caused the release of carboxyfluorescein from sphingomyelin-cholesterol liposomes and formed oligomers; toxin binding to the liposomes declined with decreasing cholesterol content in the liposomes. Flow cytometric assays with annexin V and propidium iodide revealed that delta-toxin treatment induced an elevation in the population of annexin V-negative and propidium iodide-positive cells. Delta-toxin did not cause the fragmentation of DNA or caspase-3 activation. Furthermore, delta-toxin caused damage to mitochondrial membrane permeability and cytochrome c release. In the present study, we demonstrate that delta-toxin produces cytotoxic activity through necrosis. PMID:26807591

  4. Space Radar Image of Mississippi Delta

    NASA Technical Reports Server (NTRS)

    1999-01-01

    This is a radar image of the Mississippi River Delta where the river enters into the Gulf of Mexico along the coast of Louisiana. This multi-frequency image demonstrates the capability of the radar to distinguish different types of wetlands surfaces in river deltas. This image was acquired by the Spaceborne Imaging Radar-C/X-Band Synthetic Aperture Radar (SIR-C/X-SAR) aboard the space shuttle Endeavour on October 2, 1995. The image is centered on latitude 29.3 degrees North latitude and 89.28 degrees West longitude. The area shown is approximately 63 kilometers by 43 kilometers (39 miles by 26 miles). North is towards the upper right of the image. As the river enters the Gulf of Mexico, it loses energy and dumps its load of sediment that it has carried on its journey through the mid-continent. This pile of sediment, or mud, accumulates over the years building up the delta front. As one part of the delta becomes clogged with sediment, the delta front will migrate in search of new areas to grow. The area shown on this image is the currently active delta front of the Mississippi. The migratory nature of the delta forms natural traps for oil and the numerous bright spots along the outside of the delta are drilling platforms. Most of the land in the image consists of mud flats and marsh lands. There is little human settlement in this area due to the instability of the sediments. The main shipping channel of the Mississippi River is the broad red stripe running northwest to southeast down the left side of the image. The bright spots within the channel are ships. The colors in the image are assigned to different frequencies and polarizations of the radar as follows: red is L-band vertically transmitted, vertically received; green is C-band vertically transmitted, vertically received; blue is X-band vertically transmitted, vertically received. Spaceborne Imaging Radar-C and X-band Synthetic Aperture Radar (SIR-C/X-SAR) is part of NASA's Mission to Planet Earth. The radars

  5. On regularizations of the Dirac delta distribution

    NASA Astrophysics Data System (ADS)

    Hosseini, Bamdad; Nigam, Nilima; Stockie, John M.

    2016-01-01

    In this article we consider regularizations of the Dirac delta distribution with applications to prototypical elliptic and hyperbolic partial differential equations (PDEs). We study the convergence of a sequence of distributions SH to a singular term S as a parameter H (associated with the support size of SH) shrinks to zero. We characterize this convergence in both the weak-* topology of distributions and a weighted Sobolev norm. These notions motivate a framework for constructing regularizations of the delta distribution that includes a large class of existing methods in the literature. This framework allows different regularizations to be compared. The convergence of solutions of PDEs with these regularized source terms is then studied in various topologies such as pointwise convergence on a deleted neighborhood and weighted Sobolev norms. We also examine the lack of symmetry in tensor product regularizations and effects of dissipative error in hyperbolic problems.

  6. Resurveys of active mudslides, Mississippi Delta

    NASA Astrophysics Data System (ADS)

    Prior, David B.; Coleman, James M.

    1981-03-01

    A survey procedure using digitally acquired, scale-corrected sidescan sonar has been applied to document active submarine landslides in the Mississippi Delta region. Periodic resurveys have been completed for a 70-km2 area in water depths of 10 to 50 m. Sufficient resurvey precision allowed short-term changes in seafloor mapping to be observed. Mudslides showed enlargement by retrogression and downslope surging within a single 5-month period.

  7. Adaptive Delta Management: cultural aspects of dealing with uncertainty

    NASA Astrophysics Data System (ADS)

    Timmermans, Jos; Haasnoot, Marjolijn; Hermans, Leon; Kwakkel, Jan

    2016-04-01

    Deltas are generally recognized as vulnerable to climate change and therefore a salient topic in adaptation science. Deltas are also highly dynamic systems viewed from physical (erosion, sedimentation, subsidence), social (demographic), economic (trade), infrastructures (transport, energy, metropolization) and cultural (multi-ethnic) perspectives. This multi-faceted dynamic character of delta areas warrants the emergence of a branch of applied adaptation science, Adaptive Delta Management, which explicitly focuses on climate adaptation of such highly dynamic and deeply uncertain systems. The application of Adaptive Delta Management in the Dutch Delta Program and its active international dissemination by Dutch professionals results in the rapid dissemination of Adaptive Delta Management to deltas worldwide. This global dissemination raises concerns among professionals in delta management on its applicability in deltas with cultural conditions and historical developments quite different from those found in the Netherlands and the United Kingdom where the practices now labelled as Adaptive Delta Management first emerged. This research develops an approach and gives a first analysis of the interaction between the characteristics of different approaches in Adaptive Delta Management and their alignment with the cultural conditions encountered in various delta's globally. In this analysis, first different management theories underlying approaches to Adaptive Delta Management as encountered in both scientific and professional publications are identified and characterized on three dimensions: The characteristics dimensions used are: orientation on today, orientation on the future, and decision making (Timmermans, 2015). The different underlying management theories encountered are policy analysis, strategic management, transition management, and adaptive management. These four management theories underlying different approaches in Adaptive Delta Management are connected to

  8. WESTAR-V launch on delta

    NASA Astrophysics Data System (ADS)

    1982-01-01

    The WESTAR-V, the second in a series of second-generation, large, 24-transponder communications satellites developed for the Space Communications Company is discussed. It is scheduled to be launched on a Delta vehicle from the Eastern Space and Missile Center no earlier than June 8, 1982. The launch support for this mission will be provided by NASA, on a reimbursable basis, to the Space Communications Company for a fixed price of $25.OM. The launch vehicle for the WESTAR-V mission will be the Delta 3910 configuration which incorporates an extended long tank Thor booster, nine Castor IV strap-on motors, a TR-201 second stage, and an 8-foot fairing. The Delta launch vehicle will place the spacecraft along a suborbital trajectory. The PAM-D stage will then thrust it to a synchronous transfer orbit. Three days after launch, the spacecraft apogee kick motor will be fired to circularize its orbit at geosynchronous altitude of 19,300 NM above the equator at approxmately 75 degrees west longitude.

  9. Delta: Data Reduction for Integrated Application Workflows.

    SciTech Connect

    Lofstead, Gerald Fredrick; Jean-Baptiste, Gregory; Oldfield, Ron A.

    2015-06-01

    Integrated Application Workflows (IAWs) run multiple simulation workflow components con- currently on an HPC resource connecting these components using compute area resources and compensating for any performance or data processing rate mismatches. These IAWs require high frequency and high volume data transfers between compute nodes and staging area nodes during the lifetime of a large parallel computation. The available network band- width between the two areas may not be enough to efficiently support the data movement. As the processing power available to compute resources increases, the requirements for this data transfer will become more difficult to satisfy and perhaps will not be satisfiable at all since network capabilities are not expanding at a comparable rate. Furthermore, energy consumption in HPC environments is expected to grow by an order of magnitude as exas- cale systems become a reality. The energy cost of moving large amounts of data frequently will contribute to this issue. It is necessary to reduce the volume of data without reducing the quality of data when it is being processed and analyzed. Delta resolves the issue by addressing the lifetime data transfer operations. Delta removes subsequent identical copies of already transmitted data during transfers and restores those copies once the data has reached the destination. Delta is able to identify duplicated information and determine the most space efficient way to represent it. Initial tests show about 50% reduction in data movement while maintaining the same data quality and transmission frequency.

  10. Quantitative expression patterns of peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) protein in mice

    SciTech Connect

    Girroir, Elizabeth E.; Hollingshead, Holly E.; He Pengfei; Zhu Bokai; Perdew, Gary H.; Peters, Jeffrey M.

    2008-07-04

    The expression patterns of PPAR{beta}/{delta} have been described, but the majority of these data are based on mRNA data. To date, there are no reports that have quantitatively examined the expression of PPAR{beta}/{delta} protein in mouse tissues. In the present study, a highly specific PPAR{beta}/{delta} antibody was developed, characterized, and used to examine tissue expression patterns of PPAR{beta}/{delta}. As compared to commercially available anti-PPAR{beta}/{delta} antibodies, one of six polyclonal anti-PPAR{beta}/{delta} antibodies developed was significantly more effective for immunoprecipitation of in vitro-translated PPAR{beta}/{delta}. This antibody was used for quantitative Western blot analysis using radioactive detection methods. Expression of PPAR{beta}/{delta} was highest in colon, small intestine, liver, and keratinocytes as compared to other tissues including heart, spleen, skeletal muscle, lung, brain, and thymus. Interestingly, PPAR{beta}/{delta} expression was localized in the nucleus and RXR{alpha} can be co-immunoprecipitated with nuclear PPAR{beta}/{delta}. Results from these studies demonstrate that PPAR{beta}/{delta} expression is highest in intestinal epithelium, liver, and keratinocytes, consistent with significant biological roles in these tissues.

  11. Explanation of the {delta}{sub 5/2{sup -}}(1930) as a {rho}{delta} bound state

    SciTech Connect

    Gonzalez, P.; Oset, E.; Vijande, J.

    2009-02-15

    We use the {rho}{delta} interaction in the hidden gauge formalism to dynamically generate N* and {delta}* resonances. We show, through a comparison of the results from this analysis and from a quark model study with data, that the {delta}{sub 5/2{sup -}}(1930), {delta}{sub 3/2{sup -}}(1940), and {delta}{sub 1/2{sup -}}(1900) resonances can be assigned to {rho}{delta} bound states. More precisely the {delta}{sub 5/2{sup -}}(1930) can be interpreted as a {rho}{delta} bound state whereas the {delta}{sub 3/2{sup -}}(1940) and {delta}{sub 1/2{sup -}}(1900) may contain an important {rho}{delta} component. This interpretation allows for a solution of a long-standing puzzle concerning the description of these resonances in constituent quark models. In addition we also obtain degenerate J{sup P}=1/2{sup -},3/2{sup -},5/2{sup -} N* states but their assignment to experimental resonances is more uncertain.

  12. GW-1000. GW Pharmaceuticals.

    PubMed

    Smith, Paul F

    2004-07-01

    GW Pharmaceuticals is developing GW-1000 (Sativex), a narrow ratio delta9-tetrahydrocannabinol:cannabidiol product for the potential treatment of multiple sclerosis, spinal cord injury, neurogenic pain and peripheral neuropathy. In March 2003, the company filed for approval for the treatment of MS with the UK Medicines Control Agency, and in May 2004, filed for new drug submission with Health Canada. PMID:15298072

  13. Cannabinoid and Cholinergic Systems Interact during Performance of a Short-Term Memory Task in the Rat

    ERIC Educational Resources Information Center

    Goonawardena, Anushka V.; Robinson, Lianne; Hampson, Robert E.; Riedel, Gernot

    2010-01-01

    It is now well established that cannabinoid agonists such as [delta][superscript 9]-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such…

  14. 21 CFR 862.3870 - Cannabinoid test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cannabinoid test system. 862.3870 Section 862.3870....3870 Cannabinoid test system. (a) Identification. A cannabinoid test system is a device intended to..., saliva, and urine. Cannabinoid compounds include delta-9-tetrahydrocannabinol, cannabidiol,...

  15. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

    PubMed

    Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

    2014-09-01

    Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs. PMID:25118789

  16. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

    PubMed

    Devinsky, Orrin; Cilio, Maria Roberta; Cross, Helen; Fernandez-Ruiz, Javier; French, Jacqueline; Hill, Charlotte; Katz, Russell; Di Marzo, Vincenzo; Jutras-Aswad, Didier; Notcutt, William George; Martinez-Orgado, Jose; Robson, Philip J; Rohrback, Brian G; Thiele, Elizabeth; Whalley, Benjamin; Friedman, Daniel

    2014-06-01

    To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in

  17. Chronic cannabinoid CB2 activation reverses paclitaxel neuropathy without tolerance or CB1-dependent withdrawal

    PubMed Central

    Deng, Liting; Guindon, Josée; Cornett, Benjamin L.; Makriyannis, Alexandros; Mackie, Ken; Hohmann, Andrea G.

    2014-01-01

    Background Mixed cannabinoid CB1/CB2 agonists such as Δ9-tetrahydrocannabinol9-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. Methods We evaluated anti-allodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1KO, CB2KO, and WT mice. Comparisons were made with the prototypic classical cannabinoid Δ9-THC. We also explored the site and possible mechanism of action of AM1710. Results Paclitaxel-induced mechanical and cold allodynia developed equivalently in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ9-THC suppressed established paclitaxel-induced allodynia in WT mice. Unlike Δ9-THC, chronic AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Anti-allodynic efficacy of systemic AM1710 was absent in CB2KO mice or WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal AM1710 also attenuated paclitaxel-induced allodynia in WT but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 anti-allodynic efficacy. Finally, both acute and chronic treatment with AM1710 decreased mRNA levels of tumor necrosis factor alpha and monocyte chemoattractant protein-1 in lumbar spinal cord of paclitaxel-treated WT mice. Conclusions Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects. PMID:24853387

  18. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

    PubMed

    Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

    2014-09-01

    Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

  19. Analysis, testing, and evaluation of faulted and unfaulted Wye, Delta, and open Delta connected electromechanical actuators

    NASA Technical Reports Server (NTRS)

    Nehl, T. W.; Demerdash, N. A.

    1983-01-01

    Mathematical models capable of simulating the transient, steady state, and faulted performance characteristics of various brushless dc machine-PSA (power switching assembly) configurations were developed. These systems are intended for possible future use as primemovers in EMAs (electromechanical actuators) for flight control applications. These machine-PSA configurations include wye, delta, and open-delta connected systems. The research performed under this contract was initially broken down into the following six tasks: development of mathematical models for various machine-PSA configurations; experimental validation of the model for failure modes; experimental validation of the mathematical model for shorted turn-failure modes; tradeoff study; and documentation of results and methodology.

  20. Analysis, testing, and evaluation of faulted and unfaulted Wye, Delta, and open Delta connected electromechanical actuators

    NASA Astrophysics Data System (ADS)

    Nehl, T. W.; Demerdash, N. A.

    1983-07-01

    Mathematical models capable of simulating the transient, steady state, and faulted performance characteristics of various brushless dc machine-PSA (power switching assembly) configurations were developed. These systems are intended for possible future use as primemovers in EMAs (electromechanical actuators) for flight control applications. These machine-PSA configurations include wye, delta, and open-delta connected systems. The research performed under this contract was initially broken down into the following six tasks: development of mathematical models for various machine-PSA configurations; experimental validation of the model for failure modes; experimental validation of the mathematical model for shorted turn-failure modes; tradeoff study; and documentation of results and methodology.

  1. Dual regulation of the {delta}Np63 transcriptional activity by {delta}Np63 in human nasopharyngeal carcinoma cell

    SciTech Connect

    Chu, W.-K.; Lee, K.-C.; Chow, S.-E.; Chen, J.-K. . E-mail: jkc508@mail.cgu.edu.tw

    2006-04-21

    p63 splicing variants lacking NH{sub 2}-terminal transactivating domain, known as {delta}Np63, are thought to antagonize p53 and p63 functions and are suggested to play roles in keratinocyte differentiation. Here, we show that {delta}Np63 has a dual-regulatory effect on the activity of its own promoter in NPC-076 cell. Down-regulation of the transcriptional activity is observed when {delta}Np63 is present in low levels. In contrast, up-regulation of {delta}Np63 transcriptional activity is observed when {delta}Np63 is expressed at higher levels. The down-regulation effect is abolished when the p53-binding site of the {delta}Np63 promoter is mutated. In sharp contrast, similar mutation does not affect the up-regulation of the {delta}Np63 transcriptional activity under the same experimental conditions. Further study shows that the up-regulation is correlated with the activation of the STAT3, as the blockade of STAT3 nuclear translocation abolishes the up-regulation by {delta}Np63. Thus, {delta}Np63 exerts a bidirectional regulation of the {delta}Np63 transcriptional activity in NPC-076 cell.

  2. Delta channel networks: 2. Metrics of topologic and dynamic complexity for delta comparison, physical inference, and vulnerability assessment

    NASA Astrophysics Data System (ADS)

    Tejedor, Alejandro; Longjas, Anthony; Zaliapin, Ilya; Foufoula-Georgiou, Efi

    2015-06-01

    Deltas are landforms that deliver water, sediment and nutrient fluxes from upstream rivers to the deltaic surface and eventually to oceans or inland water bodies via multiple pathways. Despite their importance, quantitative frameworks for their analysis lack behind those available for tributary networks. In a companion paper, delta channel networks were conceptualized as directed graphs and spectral graph theory was used to design a quantitative framework for exploring