A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans.

PubMed

Nahler, Gerhard; Grotenhermen, Franjo; Zuardi, Antonio Waldo; Crippa, José A S

2017-01-01

Cannabidiol (CBD), a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Under acidic conditions, CBD can be transformed to delta9-tetrahydrocannabinol (THC) and other cannabinoids. It has been argued that this may occur also after oral administration in humans. However, the experimental conversion of CBD to THC and delta8-THC in simulated gastric fluid (SGF) is a highly artificial approach that deviates significantly from physiological conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions. Unsurprisingly, the conversion of oral CBD to THC and its metabolites has not been observed to occur in vivo , even after high doses of oral CBD. In addition, the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics (e.g., dizziness, euphoria/high, thinking abnormal/concentration difficulties, nausea, tachycardia) has not been observed after treatment with CBD in double-blind, randomized, controlled clinical trials. In conclusion, the conversion of CBD to THC in SGF seems to be an in vitro artifact.

Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: A literature review.

PubMed

Steenkamp, Maria M; Blessing, Esther M; Galatzer-Levy, Isaac R; Hollahan, Laura C; Anderson, William T

2017-03-01

Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids' potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids' effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research. © 2017 Wiley Periodicals, Inc.

The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews.

PubMed

Nielsen, Suzanne; Germanos, Rada; Weier, Megan; Pollard, John; Degenhardt, Louisa; Hall, Wayne; Buckley, Nicholas; Farrell, Michael

2018-02-13

Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects. We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.

Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials.

PubMed

Fitzcharles, M-A; Baerwald, C; Ablin, J; Häuser, W

2016-02-01

In the absence of an ideal treatment for chronic pain associated with rheumatic diseases, there is interest in the potential effects of cannabinoid molecules, particularly in the context of global interest in the legalization of herbal cannabis for medicinal use. A systematic search until April 2015 was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org and clinicaltrials.gov for randomized controlled trials with a study duration of at least 2 weeks and at least ten patients per treatment arm with herbal cannabis or pharmaceutical cannabinoid products in fibromyalgia syndrome (FMS), osteoarthritis (OA), chronic spinal pain, and rheumatoid arthritis (RA) pain. Outcomes were reduction of pain, sleep problems, fatigue and limitations of quality of life for efficacy, dropout rates due to adverse events for tolerability, and serious adverse events for safety. The methodology quality of the randomized controlled trials (RCTs) was evaluated by the Cochrane Risk of Bias Tool. Two RCTs of 2 and 4 weeks duration respectively with nabilone, including 71 FMS patients, one 4-week trial with nabilone, including 30 spinal pain patients, and one 5-week study with tetrahydrocannbinol/cannabidiol, including 58 RA patients were included. One inclusion criterion was pain refractory to conventional treatment in three studies. No RCT with OA patients was found. The risk of bias was high for three studies. The findings of a superiority of cannabinoids over controls (placebo, amitriptyline) were not consistent. Cannabinoids were generally well tolerated despite some troublesome side effects and safe during the study duration. Currently, there is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases.

The pharmacologic and clinical effects of medical cannabis.

PubMed

Borgelt, Laura M; Franson, Kari L; Nussbaum, Abraham M; Wang, George S

2013-02-01

Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB(1) and CB(2) ) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ(9) -tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use. © 2013 Pharmacotherapy Publications, Inc.

Medical marijuana for cancer.

PubMed

Kramer, Joan L

2015-03-01

Answer questions and earn CME/CNE Marijuana has been used for centuries, and interest in its medicinal properties has been increasing in recent years. Investigations into these medicinal properties has led to the development of cannabinoid pharmaceuticals such as dronabinol, nabilone, and nabiximols. Dronabinol is best studied in the treatment of nausea secondary to cancer chemotherapy and anorexia associated with weight loss in patients with acquired immune deficiency syndrome, and is approved by the US Food and Drug Administration for those indications. Nabilone has been best studied for the treatment of nausea secondary to cancer chemotherapy. There are also limited studies of these drugs for other conditions. Nabiximols is only available in the United States through clinical trials, but is used in Canada and the United Kingdom for the treatment of spasticity secondary to multiple sclerosis and pain. Studies of marijuana have concentrated on nausea, appetite, and pain. This article will review the literature regarding the medical use of marijuana and these cannabinoid pharmaceuticals (with emphasis on indications relevant to oncology), as well as available information regarding adverse effects of marijuana use. © 2014 American Cancer Society.

The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial.

PubMed

Turcott, Jenny G; Del Rocío Guillen Núñez, María; Flores-Estrada, Diana; Oñate-Ocaña, Luis F; Zatarain-Barrón, Zyanya Lucia; Barrón, Feliciano; Arrieta, Oscar

2018-03-17

Over one half of the patients diagnosed with advanced lung cancer experience anorexia. In addition to its high incidence, cancer-induced anorexia promotes the development of the anorexia-cachexia syndrome, which is related to poor clinical outcomes. Recently, drugs derived from cannabinoids, such as Nabilone, have been recognized for their appetite improvement properties; however, clinical trials to support their use in cancer patients are necessary. This is a randomized, double-blind, placebo-controlled clinical trial to assess the effect of Nabilone vs. placebo on the appetite, nutritional status, and quality of life in patients diagnosed with advanced Non-small cell lung cancer (NSCLC) (NCT02802540). A total of 65 patients from the outpatient clinic at the National Institute of Cancer (INCan) were assessed for eligibility and 47 were randomized to receive Nabilone (0.5 mg/2 weeks followed by 1.0 mg/6 weeks) or placebo. After 8 weeks of treatment, patients who received Nabilone increased their caloric intake (342-kcal) and had a significantly higher intake of carbohydrates (64 g) compared to patients receiving placebo (p = 0.040). Quality of life also showed significant improvements in patients in the experimental arm of the trial, particularly in role functioning (p = 0.030), emotional functioning (p = 0.018), social functioning (p = 0.036), pain (p = 0.06), and insomnia (p = 0.020). No significant change in these scales was seen in the control group. Nabilone is an adequate and safe therapeutic option to aid in the treatment of patients diagnosed with anorexia. Larger trials are necessary in order to draw robust conclusions in regard to its efficacy in lung cancer patients.

Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

PubMed

Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

2010-01-01

For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

Clinical perspectives on medical marijuana (cannabis) for neurologic disorders

PubMed Central

Fife, Terry D.; Moawad, Heidi; Moschonas, Constantine; Hammond, Nancy

2015-01-01

Summary The American Academy of Neurology published an evidence-based systematic review of randomized controlled trials using marijuana (Cannabis sativa) or cannabinoids in neurologic disorders. Several cannabinoids showed effectiveness or probable effectiveness for spasticity, central pain, and painful spasms in multiple sclerosis. The review justifies insurance coverage for dronabinol and nabilone for these indications. Many insurance companies already cover these medications for other indications. It is unlikely that the review will alter coverage for herbal marijuana. Currently, no payers cover the costs of herbal medical marijuana because it is illegal under federal law and in most states. Cannabinoid preparations currently available by prescription may have a role in other neurologic conditions, but quality scientific evidence is lacking at this time. PMID:26336632

Clinical perspectives on medical marijuana (cannabis) for neurologic disorders.

PubMed

Fife, Terry D; Moawad, Heidi; Moschonas, Constantine; Shepard, Katie; Hammond, Nancy

2015-08-01

The American Academy of Neurology published an evidence-based systematic review of randomized controlled trials using marijuana ( Cannabis sativa ) or cannabinoids in neurologic disorders. Several cannabinoids showed effectiveness or probable effectiveness for spasticity, central pain, and painful spasms in multiple sclerosis. The review justifies insurance coverage for dronabinol and nabilone for these indications. Many insurance companies already cover these medications for other indications. It is unlikely that the review will alter coverage for herbal marijuana. Currently, no payers cover the costs of herbal medical marijuana because it is illegal under federal law and in most states. Cannabinoid preparations currently available by prescription may have a role in other neurologic conditions, but quality scientific evidence is lacking at this time.

The Changing Drug Culture: Medical and Recreational Marijuana.

PubMed

Albertson, Timothy E; Chenoweth, James A; Colby, Daniel K; Sutter, Mark E

2016-02-01

The major psychoactive compounds in marijuana (cannabis) are cannabinoids, the most significant of which is delta-9-tetrahydrocannabinol. There are also two synthetic pharmaceutical cannabinoids, nabilone and dronabinol, available by prescription in the United States. The use of marijuana has increased in the United States with passage of medical marijuana laws in many states and legalization of recreational marijuana use in several states. In addition, the potency of marijuana has increased in recent years. Marijuana has been used for a variety of medical purposes, including management of nausea and vomiting, appetite and immunologic stimulation in patients with HIV infection and AIDS, glaucoma, neurologic disorders, and pain relief. Studies on the benefits of marijuana as a treatment for various conditions have been inconsistent, except for those on pain management. Marijuana has adverse effects, and has been associated with driving impairment, psychosis, dependence and withdrawal syndromes, hyperemesis, acute cardiac events, some cancers, and impaired lung function. As with studies on the benefits of marijuana, studies of adverse effects have yielded inconsistent results. Except for impaired driving and the occurrence of dependence and withdrawal syndromes, the adverse effects of marijuana use have not been fully studied. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

[What sense in cannabinoid use as regulated by Italian DM 18/04/07? Pharmacological and legal considerations].

PubMed

Molinelli, A; Grossi, S; Bonsignore, A; Martelli, A

2008-06-01

The present article relates to the Italian Ministerial Decree (DM) 18/04/2007 referring to what was established by the Financial Law 2007 on the matter of the use of drugs for the so called ''off-label'' uses. This law introduces three cannabinoid substances, with the common name of Delta 9 and Trans-delta 9 tetrahydrocannabinol and Nabilone, within the possible therapies for the treatment of ''severe pain''. The authors underline the absence of a sufficient pharmacokinetical and pharmacodynamical knowledge supporting the use of cannabinoid substances in the ''severe pain'' therapy. Further more the professional prescriber could go against judicial consequences if the drugs causes as verified the onset of collateral effects even severe that, for the scientific knowledge in possess at the present state, the authors know could take place.

Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid.

PubMed

López-Ortíz, Manuel; Herrera-Solís, Andrea; Luviano-Jardón, Axel; Reyes-Prieto, Nidia; Castillo, Ivan; Monsalvo, Ivan; Demare, Patricia; Méndez-Díaz, Mónica; Regla, Ignacio; Prospéro-García, Oscar

2010-06-01

Endocannabinoids (eCBs) are endogenous neuromodulators of synaptic transmission. Their dysfunction may cause debilitating disorders of diverse clinical manifestation. For example, drug addiction, lack of sex desire, eating disorders, such as anorexia or bulimia and dyssomnias. eCBs also participate in the regulation of core temperature and pain perception. In this context, it is important to recognize the utility of cannabinoid receptor 1 (CB1R) agonists, natural as Delta(9)-tetrahydrocannabinol (THC) or synthetic as Nabilone as useful drugs to alleviate this kind of patients' suffering. Therefore, we have developed a new drug, (R,Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-yl phenylacetate (PhAR-DBH-Me), that appears to bind and activate the CB1R. This diazabicyclic amide was synthesized from phenylacetylricinoleic acid and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane. To test its cannabinergic properties we evaluated its effects on core temperature, pain perception, and the sleep-waking cycle of rats. Results indicate that 20 and 40mg/kg of PhAR-DBH-Me readily reduced core temperature and increased pain perception threshold. In addition, 20mg/kg increased REM sleep in otherwise normal rats. All these effects were prevented or attenuated by AM251, a CB1R antagonist. Place preference conditioning studies indicated that this molecule does not produce rewarding effects. These results strongly support that PhAR-DBH-Me possesses cannabinoid activity without the reinforcement effects. Copyright 2010 Elsevier Ltd. All rights reserved.

Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

PubMed

Davis, Mellar P

2016-07-01

Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard. Copyright © 2016 by the National Comprehensive Cancer Network.

Cannabinoids: novel medicines for the treatment of Huntington's disease.

PubMed

Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier

2012-04-01

Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists, including the phytocannabinoids present in Sativex®, and we are close to initiate a clinical trial with this cannabis-based medicine to evaluate its capability as a disease-modifying agent in a population of HD patients. The present review will address all preclinical evidence supporting the potential of Sativex® for the treatment of disease progression in HD patients. The article presents some promising patents on the cannabinoids.

Fatal overdose from synthetic cannabinoids and cathinones in Japan: demographics and autopsy findings.

PubMed

Ezaki, Jiro; Ro, Ayako; Hasegawa, Masayuki; Kibayashi, Kazuhiko

2016-09-01

Sixty-one autopsy cases involving cathinones and/or cannabinoids (synthetic cathinones/cannabinoids) use have been reported. However, little is known about the demographics and autopsy findings in fatal synthetic cathinones/cannabinoids users. To elucidate demographic and autopsy findings (i.e. major organ pathology and causes of death) in synthetic cathinones/cannabinoids cases. We reviewed forensic autopsy reports in Department of Legal Medicine of Tokyo Women's Medical University (Tokyo, Japan) between 2011 and 2015 (a total of 359). We compared demographic and autopsy findings between synthetic cathinones/cannabinoids and methamphetamine cases (as control subjects). There were 12 synthetic cathinones/cannabinoids cases and 10 methamphetamine cases. Synthetic cathinones/cannabinoids users were significantly younger than methamphetamine users (p < 0.01), and there were no cases that used both synthetic cathinones/cannabinoids and methamphetamine. Acute intoxication and cardiac ischemia were the two most prominent causes of death in both synthetic cathinones/cannabinoids users and methamphetamine users. Excited delirium syndrome and pulmonary aspiration were found only in synthetic cathinones/cannabinoids cases. The populations of synthetic cathinones/cannabinoids and methamphetamine users who died of an overdose are different in Japan. Acute intoxication, cardiac ischemia, excited delirium syndrome, pulmonary aspiration, and drowning are the major autopsy findings in synthetic cathinones/cannabinoids-related death. Clinicians shuld be aware of these potentially fatal complications in the medical management of synthetic cathinones/cannabinoids users.

The therapeutic potential of cannabis and cannabinoids.

PubMed

Grotenhermen, Franjo; Müller-Vahl, Kirsten

2012-07-01

Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany. Selective literature review. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.

Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana.

PubMed

Lauritsen, Kirstin J; Rosenberg, Harold

2016-07-01

Although initially developed for medical purposes, synthetic cannabinoids have also been consumed for recreational purposes. To evaluate whether agreement with positive and negative outcome expectancies differed for synthetic cannabinoids versus botanical marijuana, and assess reported reasons for using synthetic cannabinoids. Using a web-based recruitment and data collection procedure, 186 adults who had used both synthetic cannabinoids and botanical marijuana and 181 adults who had used botanical marijuana but not synthetic cannabinoids, completed measures of outcome expectancies and other relevant questionnaires. A significant interaction revealed that participants who had used both synthetic cannabinoids and botanical marijuana indicated lower agreement with positive expectancies for synthetic cannabinoids, and higher agreement with positive expectancies for botanical marijuana, than did those participants who used only botanical marijuana. There was no interaction between type of drug and use history on agreement with negative expectancies, and participants agreed more strongly with negative outcome expectancies for synthetic cannabinoids than for botanical marijuana whether they had used one or both types of these drugs. The most frequently provided reasons for using synthetic cannabinoids included availability, perceived legality, cost, curiosity, and social interaction. Given growing public acceptance of recreational and medical marijuana, coupled with negative perceptions and increasing regulation of synthetic cannabinoid compounds, botanical marijuana is likely to remain more available and more popular than synthetic cannabinoids.

[Therapeutic use of cannabis derivatives].

PubMed

Benyamina, Amine; Reynaud, Michel

2014-02-01

The therapeutic use of cannabis has generated a lot of interest in the past years, leading to a better understanding of its mechanisms of action. Countries like the United States and Canada have modified their laws in order to make cannabinoid use legal in the medical context. It's also the case in France now, where a recent decree was issued, authorizing the prescription of medication containing "therapeutic cannabis" (decree no. 2013-473, June 5, 2013). Cannabinoids such as dronabinol, Sativex and nabilone have been tested for the treatment of acute and chronic pain. These agents are most promising to relieve chronic pain associated with cancer, with human immunodeficiency virus infection and with multiple sclerosis. However, longer-term studies are required to determine potential long-term adverse effects and risks of misuse and addiction.

Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

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

Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

2014-01-01

The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrainmore » cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.« less

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies].

PubMed

Petzke, F; Enax-Krumova, E K; Häuser, W

2016-02-01

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2  with nabilone and 1  with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

Acute Poisonings from Synthetic Cannabinoids - 50 U.S. Toxicology Investigators Consortium Registry Sites, 2010-2015.

PubMed

Riederer, Anne M; Campleman, Sharan L; Carlson, Robert G; Boyer, Edward W; Manini, Alex F; Wax, Paul M; Brent, Jeffrey A

2016-07-15

Recent reports suggest that acute intoxications by synthetic cannabinoids are increasing in the United States (1,2). Synthetic cannabinoids, which were research compounds in the 1980s, are now produced overseas; the first shipment recognized to contain synthetic cannabinoids was seized at a U.S. border in 2008 (3). Fifteen synthetic cannabinoids are Schedule I controlled substances (3), but enforcement is hampered by the continual introduction of new chemical compounds (1,3). Studies of synthetic cannabinoids indicate higher cannabinoid receptor binding affinities, effects two to 100 times more potent than Δ(9)-tetrahydrocannabinol (the principal psychoactive constituent of cannabis), noncannabinoid receptor binding, and genotoxicity (4,5). Acute synthetic cannabinoid exposure reportedly causes a range of mild to severe neuropsychiatric, cardiovascular, renal, and other effects (4,6,7); chronic use might lead to psychosis (6,8). During 2010-2015, physicians in the Toxicology Investigators Consortium (ToxIC) treated 456 patients for synthetic cannabinoid intoxications; 277 of the 456 patients reported synthetic cannabinoids as the sole toxicologic agent. Among these 277 patients, the most common clinical signs of intoxication were neurologic (agitation, central nervous system depression/coma, and delirium/toxic psychosis). Relative to all cases logged by 50 different sites in the ToxIC Case Registry, there was a statistically significant association between reporting year and the annual proportion of synthetic cannabinoid cases. In 2015, reported cases of synthetic cannabinoid intoxication increased at several ToxIC sites, corroborating reported upward trends in the numbers of such cases (1,2) and underscoring the need for prevention.

Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

PubMed Central

Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María del Rosario; Molpeceres, Jesús

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1∶1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID:23349970

Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

PubMed

Hernán Pérez de la Ossa, Dolores; Lorente, Mar; Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María Del Rosario; Molpeceres, Jesús; Velasco, Guillermo; Torres-Suárez, Ana Isabel

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens

PubMed Central

Castaneto, Marisol S.; Scheidweiler, Karl B.; Gandhi, Adarsh; Wohlfarth, Ariane; Klette, Kevin L.; Martin, Thomas M.; Huestis, Marilyn A.

2014-01-01

Synthetic cannabinoid intake is an ongoing health issue worldwide, with new compounds continually emerging, making drug testing complex. Parent synthetic cannabinoids are rarely detected in urine, the most common matrix employed in workplace drug testing. Optimal identification of synthetic cannabinoid markers in authentic urine specimens and correlation of metabolite concentrations and toxicities would improve synthetic cannabinoid result interpretation. We screened 20,017 randomly collected US military urine specimens between July 2011 and June 2012 with a synthetic cannabinoid immunoassay yielding 1,432 presumptive positive specimens. We analyzed all presumptive positive and 1,069 negative specimens with our qualitative synthetic cannabinoid LC-MS/MS method, which confirmed 290 positive specimens. All 290 positive and 487 randomly-selected negative specimens were quantified with the most comprehensive urine quantitative LC-MS/MS method published to date. 290 specimens confirmed positive for 22 metabolites from 11 parent synthetic cannabinoids. The five most predominant metabolites were JWH-018 pentanoic acid (93%), JWH-018 N-hydroxypentyl (84%), AM2201 N-hydroxypentyl (69%), JWH-073 butanoic acid (69%), and JWH-122 N-hydroxypentyl (45%) with 11.1 (0.1–2434), 5.1 (0.1–1239), 2.0 (0.1–321), 1.1 (0.1–48.6), and 1.1 (0.1–250) μg/L median (range) concentrations, respectively. Alkyl hydroxy and carboxy metabolites provided suitable biomarkers for 11 parent synthetic cannabinoids; although, hydroxyindoles also were observed. This is by far the largest data set of synthetic cannabinoid metabolites urine concentrations from randomly collected workplace drug testing specimens rather than acute intoxications or driving under the influence of drugs. These data improve the interpretation of synthetic cannabinoid urine test results and suggest suitable urine markers of synthetic cannabinoid intake. PMID:25231213

Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry

PubMed Central

Knittel, Jessica L.; Holler, Justin M.; Chmiel, Jeffrey D.; Vorce, Shawn P.; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z.

2016-01-01

Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography–mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1–10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. PMID:26792810

76 FR 2287 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-13

...] Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I... Notice of Intent announcing its intention to temporarily place five synthetic cannabinoids into Schedule... announced its intention to temporarily place five synthetic cannabinoids into schedule I of the Controlled...

The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids.

PubMed

White, C Michael

2017-03-01

This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events. © 2016, The American College of Clinical Pharmacology.

Spicing thing up: Synthetic cannabinoids

PubMed Central

Spaderna, Max; Addy, Peter H; D’Souza, Deepak Cyril

2013-01-01

Rationale Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. Objectives The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Results Spice is sold under the guise of potpourri or incense. Unlike THC, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid-receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. Conclusions There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug-detection tests for synthetic cannabinoids need to become clinically available. PMID:23836028

The effects of synthetic cannabinoids on executive function.

PubMed

Cohen, K; Kapitány-Fövény, M; Mama, Y; Arieli, M; Rosca, P; Demetrovics, Z; Weinstein, A

2017-04-01

There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-user subjects were studied in two centers in Hungary and Israel. Computerized cognitive function tests, the classical Stroop word-color task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups. This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.

Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry.

PubMed

Knittel, Jessica L; Holler, Justin M; Chmiel, Jeffrey D; Vorce, Shawn P; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z

2016-04-01

Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography-mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1-10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Assessment of types of synthetic cannabinoids in narcotic cases assessed by the Council of Forensic Medicine between 2011-2015, Ankara, Turkey.

PubMed

Göl, Ersin; Çok, İsmet

2017-11-01

Synthetic cannabinoids mimic the effects of cannabis and are the largest and fastest growing class of newly appearing designer drugs. Reports have revealed that various types of synthetic cannabinoids are mixed with herbal substances. The present study investigated the herbal substance cases involving synthetic cannabinoids in Ankara and nearby cities in Turkey. Data were collected from the reports of synthetic cannabinoids that were analyzed between January 01, 2011 and December 31, 2015 in the Ankara Narcotic Department of the Council of Forensic Medicine at the request of the judicial authorities. In all, 4610 narcotic reports were obtained and reviewed. Among these narcotic reports during the period, 370 reports (8%) were related to synthetic cannabinoids. 28 synthetic cannabinoid compounds could be identified in herbals: 5-F-AB-PINACA, 5-F-AKB-48, 5-F-NNEI, 5-F-PB-22, AB-CHMINACA, AB-FUBINACA, AB-PINACA, ADB-CHMINACA, ADB-FUBINACA, AKB-48, AM-2201, EAM-2201, JWH-018, JWH-022, JWH-031, JWH-122, JWH-201, JWH-210, JWH-250, JWH-251, JWH-307, MAM-2201, NM-2201, PB-22, RCS-4, THJ-2201, UR-144, XLR-11. The amount of herbals was 30.72g, 329.22g, 665.89g, 4844.7g, and 5684.3g in 2011, 2012, 2013, 2014, and 2015, respectively. Generally, herbals contained more than one synthetic cannabinoids. ADB-FUBINACA was the most common synthetic cannabinoid among the herbals determined in this study, which was 3132.43g, excepting multi-synthetic cannabinoid herbals. The amount and diversity of synthetic cannabinoid compounds have increased dramatically between 2011 and 2015. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens.

PubMed

Castaneto, Marisol S; Scheidweiler, Karl B; Gandhi, Adarsh; Wohlfarth, Ariane; Klette, Kevin L; Martin, Thomas M; Huestis, Marilyn A

2015-06-01

Synthetic cannabinoid intake is an ongoing health issue worldwide, with new compounds continually emerging, making drug testing complex. Parent synthetic cannabinoids are rarely detected in urine, the most common matrix employed in workplace drug testing. Optimal identification of synthetic cannabinoid markers in authentic urine specimens and correlation of metabolite concentrations and toxicities would improve synthetic cannabinoid result interpretation. We screened 20 017 randomly collected US military urine specimens between July 2011 and June 2012 with a synthetic cannabinoid immunoassay yielding 1432 presumptive positive specimens. We analyzed all presumptive positive and 1069 negative specimens with our qualitative synthetic cannabinoid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which confirmed 290 positive specimens. All 290 positive and 487 randomly selected negative specimens were quantified with the most comprehensive urine quantitative LC-MS/MS method published to date; 290 specimens confirmed positive for 22 metabolites from 11 parent synthetic cannabinoids. The five most predominant metabolites were JWH-018 pentanoic acid (93%), JWH-N-hydroxypentyl (84%), AM2201 N-hydroxypentyl (69%), JWH-073 butanoic acid (69%), and JWH-122 N-hydroxypentyl (45%) with 11.1 (0.1-2,434), 5.1 (0.1-1,239), 2.0 (0.1-321), 1.1 (0.1-48.6), and 1.1 (0.1-250) µg/L median (range) concentrations, respectively. Alkyl hydroxy and carboxy metabolites provided suitable biomarkers for 11 parent synthetic cannabinoids; although hydroxyindoles were also observed. This is by far the largest data set of synthetic cannabinoid metabolites urine concentrations from randomly collected workplace drug testing specimens rather than acute intoxications or driving under the influence of drugs. These data improve the interpretation of synthetic cannabinoid urine test results and suggest suitable urine markers of synthetic cannabinoid intake. This article is a U.S. Government work and is in the public domain in the USA.

Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs.

PubMed

Chase, Peter B; Hawkins, Jeff; Mosier, Jarrod; Jimenez, Ernest; Boesen, Keith; Logan, Barry K; Walter, Frank G

2016-01-01

Synthetic cannabinoid use has increased in many states, and medicinal and/or recreational marijuana use has been legalized in some states. These changes present challenges to law enforcement drug recognition experts (DREs) who determine whether drivers are impaired by synthetic cannabinoids or marijuana, as well as to clinical toxicologists who care for patients with complications from synthetic cannabinoids and marijuana. Our goal was to compare what effects synthetic cannabinoids and marijuana had on performance and behavior, including driving impairment, by reviewing records generated by law enforcement DREs who evaluated motorists arrested for impaired driving. Data were from a retrospective, convenience sample of de-identified arrest reports from impaired drivers suspected of using synthetic cannabinoids (n = 100) or marijuana (n = 33). Inclusion criteria were arrested drivers who admitted to using either synthetic cannabinoids or marijuana, or who possessed either synthetic cannabinoids or marijuana; who also had a DRE evaluation at the scene; and whose blood screens were negative for alcohol and other drugs. Exclusion criteria were impaired drivers arrested with other intoxicants found in their drug or alcohol blood screens. Blood samples were analyzed for 20 popular synthetic cannabinoids by using liquid chromatography-tandem mass spectrometry. Delta-9-tetrahydrocannabinol (THC) and THC-COOH were quantified by gas chromatography-mass spectrometry. Statistical significance was determined by using Fisher's exact test or Student's t-test, where appropriate, to compare the frequency of characteristics of those in the synthetic cannabinoid group versus those in the marijuana group. 16 synthetic cannabinoid and 25 marijuana records met selection criteria; the drivers of these records were arrested for moving violations. Median age for the synthetic cannabinoid group (n = 16, 15 males) was 20 years (IQR 19-23 years). Median age for the marijuana group (n = 25, 21 males) was 20 years (IQR 19-24 years) (p = 0.46). In the synthetic cannabinoid group, 94% (15/16) admitted to using synthetic cannabinoids. In the marijuana group, 96% (24/25) admitted to using marijuana. Blood was available for testing in 96% (24/25) of the marijuana group; 21 of these 24 had quantitative levels of THC (mean + SD = 10.7 + 5 ng/mL) and THC-COOH (mean + SD = 57.8 + 3 ng/mL). Blood was available for testing in 63% (10/16) of the synthetic cannabinoid group, with 80% (8/10) of these positive for synthetic cannabinoids. Those in the synthetic cannabinoid group were more frequently confused (7/16 [44%] vs. 0/25 [0%], p ≤ 0.003) and disoriented (5/16 [31%] vs. 0/25 [0%], p ≤ 0.003), and more frequently had incoherent, slurred speech (10/16 [63%] vs. 3/25 [12%], p = 0.0014) and horizontal gaze nystagmus (8/16 [50%] vs. 3/25 [12%], p = 0.01) than those in the marijuana group. Drivers under the influence of synthetic cannabinoids were more frequently impaired with confusion, disorientation, and incoherent, slurred speech than drivers under the influence of marijuana in this population evaluated by DREs.

Synthetic cannabinoids: the hidden side of Spice drugs.

PubMed

Pintori, Nicholas; Loi, Barbara; Mereu, Maddalena

2017-09-01

Spice drugs are herbal mixtures sprayed with synthetic cannabinoids designed to mimic the psychoactive ingredient in marijuana [Δ-tetrahydrocannabinol (Δ-THC)] and synthesized by introducing modifications to the chemical structure of parental compounds aiming to circumvent legal regulations. Synthetic cannabinoid use/abuse can be devastating as toxicological effects and adverse reactions cannot be entirely predicted and may vary with the dose, route of administration, individual vulnerability and concomitant intake with other drugs. The absence of validated testing procedures in the clinical field makes difficult the adoption of a therapeutic approach effective in coping with the synthetic cannabinoid phenomenon, posing a significant challenge for prevention, treatment and public health in general. The aim of this review is to gain insights into the epidemiological, pharmacological and toxicological properties of synthetic cannabinoids, aiming to provide a reliable background needed for the management of synthetic cannabinoid-related adverse effects. Consumers, competent authorities and medical care professionals should be aware of the risks associated with synthetic cannabinoid use.

78 FR 21858 - Schedules of Controlled Substances: Temporary Placement of Three Synthetic Cannabinoids Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-12

...] Schedules of Controlled Substances: Temporary Placement of Three Synthetic Cannabinoids Into Schedule I... temporarily schedule three synthetic cannabinoids into the Controlled Substances Act (CSA) pursuant to the...). This action is based on a finding by the Deputy Administrator that the placement of these synthetic...

Health Risk Behaviors With Synthetic Cannabinoids Versus Marijuana.

PubMed

Clayton, Heather B; Lowry, Richard; Ashley, Carmen; Wolkin, Amy; Grant, Althea M

2017-04-01

Data are limited on the behavioral risk correlates of synthetic cannabinoid use. The purpose of this study was to compare the behavioral risk correlates of synthetic cannabinoid use with those among marijuana users. Data from the 2015 Youth Risk Behavior Survey, a cross-sectional survey conducted in a nationally representative sample of students in grades 9 through 12 ( N = 15 624), were used to examine the association between self-reported type of marijuana use (ie, never use of marijuana and synthetic cannabinoids, ever use of marijuana only, and ever use of synthetic cannabinoids) and self-report of 36 risk behaviors across 4 domains: substance use, injury/violence, mental health, and sexual health. Multivariable models were used to calculate adjusted prevalence ratios. Students who ever used synthetic cannabinoids had a significantly greater likelihood of engaging in each of the behaviors in the substance use and sexual risk domains compared with students who ever used marijuana only. Students who ever used synthetic cannabinoids were more likely than students who ever used marijuana only to have used marijuana before age 13 years, to have used marijuana ≥1 times during the past 30 days, and to have used marijuana ≥20 times during the past 30 days. Several injury/violence behaviors were more prevalent among students who ever used synthetic cannabinoids compared with students who ever used marijuana only. Health professionals and school-based substance use prevention programs should include strategies focused on the prevention of both synthetic cannabinoids and marijuana. Copyright © 2017 by the American Academy of Pediatrics.

What Are Synthetic Cannabinoids?

MedlinePlus

... the chemicals used in these products. How do people use synthetic cannabinoids? The most common way to use ... are some other health effects of synthetic cannabinoids? People who have ... well as kidney damage and seizures. Use of these drugs is associated with a rising ...

[The illegal synthetic cannabinoid drug market in Israel - evolution and new challenges].

PubMed

Shapira, Barak; Poperno, Alina; Berkovitz, Ronny

2016-09-01

This article represents a short review of the current knowledge on the abuse of synthetic cannabinoids from the perspective of the Division of Enforcement and Inspection of the Israeli Ministry of Health - a body in charge of providing professional assistance to law enforcement bodies in the fields of drug abuse. We describe the principal changes observed in the synthetic cannabinoid market and the Israeli legislators' and enforcement bodies' attempts to cope with these phenomena. These changes relate to the types of synthetic cannabinoids being trafficked, with many structural variations between substances, and a new legal framework which allows for the rapid, temporary scheduling of synthetic cannabinoids using both individual and generic definitions. Despite changes in legislation, we are currently witnessing the adaptation of the synthetic cannabinoid drug market to the new legal reality and enforcement practices. A considerable part of synthetic cannabinoid trafficking is carried out using phone orders, or has moved to the internet and social networks, thus making its detection difficult for enforcement bodies. Current trafficking practices represent a growing challenge for enforcement bodies. Hence, there is a need for cooperation between enforcement bodies, the Israeli Ministry of Health and health practitioners in identifying new substances, and characterizing their harms.

Purification Efficacy of Synthetic Cannabinoid Conjugates Using High-Pressure Liquid Chromatography

DTIC Science & Technology

In the current study, we successfully purified several synthetic cannabinoid (SC):dark quencher conjugates essential for the success of the synthetic... cannabinoid detection platform developed at the US Army Research Laboratorys Weapons and Materials Research Directorate. The purification was

LC/ESI-MS/MS method for quantification of 28 synthetic cannabinoids in neat oral fluid and its application to preliminary studies on their detection windows.

PubMed

Kneisel, Stefan; Speck, Michael; Moosmann, Bjoern; Corneillie, Todd M; Butlin, Nathaniel G; Auwärter, Volker

2013-05-01

Serum and urine samples are commonly used for the analysis of synthetic cannabinoids in biofluids; however, their utilization as analytical matrices for drug abstinence control features some substantial drawbacks. While for blood collection invasive sampling is inevitable, the urinary analysis of synthetic cannabinoids is limited by the lack of available reference standards of the respective major metabolites. Moreover, the long detectability of synthetic cannabinoids in both matrices hampers the identification of a recent synthetic cannabinoid use. This article describes the development, validation and application of an LC/ESI-MS/MS method for the quantification of 28 synthetic cannabinoids in neat oral fluid (OF) samples. OF samples were prepared by protein precipitation using ice-cold acetonitrile. Chromatographic separation was achieved by gradient elution on a Luna Phenyl Hexyl column (50 × 2 mm, 5 μm), while detection was carried out on a QTrap 4000 instrument in positive ionization mode. The limits of detection ranged from 0.02 to 0.40 ng/mL, whereas the lower limits of quantification ranged from 0.2 to 4.0 ng/mL. The method was applied to authentic samples collected during two preliminary studies in order to obtain insights into the general detectability and detection windows of synthetic cannabinoids in this matrix. The results indicate that synthetic cannabinoids are transferred from the blood stream into OF and vice versa only at a very low rate. Therefore, positive OF samples are due to contamination of the oral cavity during smoking. As these drug-contaminations could be detected up to approximately 2 days, neat oral fluid appears to be well suited for detection of a recent synthetic cannabinoid use.

The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids-A Systematic Review.

PubMed

Cohen, Koby; Weinstein, Aviv

2018-02-27

Background-Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method-A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., "synthetic cannabinoids AND cognition," "cannabis AND cognition" and "cannabinoids AND cognition"). Results-The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility) and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility). Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions-Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs.

Cannabis and cannabinoids: pharmacology and rationale for clinical use.

PubMed

Pertwee, R G

1999-10-01

It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists ('endocannabinoids') have also been identified. The discovery of this 'endogenous cannabinoid system' has led to the development of selective CB1 and CB2 receptor ligands and fueled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9 - tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow 'therapeutic window' (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects. Copyright 1999 S. Karger GmbH, Freiburg

Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.

PubMed

Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H

2017-10-01

The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Δ 9 -tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the α 1 adrenergic antagonist prazosin. Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow. Published by Elsevier B.V.

76 FR 11075 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-01

... of Abuse A ``cannabinoid'' is a class of chemical compounds in the marijuana plant that are... constituent of marijuana. ``Synthetic cannabinoids'' are a large family of chemically unrelated structures functionally (biologically) similar to THC, the active principle of marijuana. Two of the five synthetic...

Methamphetamine

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ...

Fentanyl

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ...

A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics.

PubMed

Badowski, Melissa E

2017-09-01

Oral cannabinoids (i.e., dronabinol, nabilone) containing the active component of marijuana, delta(Δ)9-tetrahydrocannabinol (THC), are available for the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer who have failed to adequately respond to conventional antiemetic therapy. The aim of this article is to provide an overview of the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of oral cannabinoids for patients with CINV. A PubMed search of the English-language literature available through 4 January 2017 was conducted to identify relevant articles for inclusion in the review. Oral cannabinoids have been shown to have similar or improved efficacy compared with conventional antiemetics for the resolution of nausea and/or vomiting in patients with cancer. However, oral THC has high PK variability, with variability in oral dronabinol peak plasma concentrations (C max ) estimated between 150 and 200%. A new oral dronabinol solution has decreased intraindividual variability (area under the curve) vs oral dronabinol capsules. Further, oral THC has a slower time to C max compared with THC administered intravenously (IV) or by smoking, and a lower systemic availability than IV or smoked THC. The PD profile (e.g., "high") of oral THC differs from that of IV or smoked THC in healthy individuals. Oral cannabinoids are associated with greater incidence of adverse effects compared with conventional antiemetic therapy or placebo (e.g., dizziness, hypotension, and dysphoria or depression). A new formulation of oral cannabinoids (i.e., dronabinol oral solution) minimized the PK/PD variability currently observed with capsule formulations.

Club Drugs

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ...

Use of synthetic cannabinoids in patients with psychotic disorders: case series.

PubMed

Celofiga, Andreja; Koprivsek, Jure; Klavz, Janez

2014-01-01

An increasing number of synthetic cannabinoids have become available on the black market in recent years, and health professionals have seen a corresponding increase in use of these compounds among patients with psychiatric disorders. Unfortunately, there is almost no research available in the literature on this topic, and what little exists is based on case reports of individuals without psychiatric disorders. Synthetic cannabinoids are functionally similar to, but structurally different from, delta-9-tetrahydrocannabinol, the active principle in cannabis, and are problematic for many reasons. The psychotropic action of synthetic cannabinoids in patients with schizophrenia is unpredictable, with very diverse clinical presentations. These drugs can be much more potent than delta-9-tetrahydrocannabinol, they are readily available and difficult to detect. The gold standard for identification of synthetic cannabinoids is gas chromatography with mass spectrometry, but even this is difficult because new formulations of these designer drugs are constantly emerging. In this manuscript, we provide an overview and discussion of synthetic cannabinoids and present four cases of patients with synthetic cannabinoid intoxication who were hospitalized in our intensive psychiatric unit at the time of intoxication. All patients had a history of schizophrenia and had been hospitalized several times previously. While hospitalized, they smoked an unknown substance brought in by a visitor, which was then confirmed using gas chromatography with mass spectrometry to be the synthetic cannabinoid AM-2201. Our patients experienced predominantly psychiatric adverse clinical effects. We observed the appearance of new psychotic phenomena, without exacerbation of their previously known psychotic symptoms, as well as the occurrence or marked worsening of mood and anxiety symptoms. Despite several similar reactions, and even though they ingested the same exact substance, the clinical picture differed markedly between individual patients. We assume that the acute effects of synthetic cannabinoids in patients with schizophrenia would be different from those in persons without psychotic disorders. The reasons for this difference could be the actual symptomatology of the presenting disorder, the impact of psychopharmacotherapy, individual patient differences and probably many, as yet unknown, factors. The long-term consequences of synthetic cannabinoid use on preexisting psychotic disorders are unclear.

The Synthetic Cannabinoids Phenomenon.

PubMed

Karila, Laurent; Benyamina, Amine; Blecha, Lisa; Cottencin, Olivier; Billieux, Joël

2016-01-01

« Spice » is generally used to describe the diverse types of herbal blends that encompass synthetic cannabinoids on the market. The emergence of smokable herbal products containing synthetic cannabinoids, which mimic the effects of cannabis, appears to become increasingly popular, in the new psychoactive substances landscape. In 2014, the existence of 134 different types of synthetic cannabinoids were reported by the European Union Early Warning System. These drugs are mainly sold online as an alternative to controlled and regulated psychoactive substances. They appear to have a life cycle of about 1-2 years before being replaced by a next wave of products. Legislation controlling these designer drugs has been introduced in many countries with the objective to limit the spread of existing drugs and control potential new analogs. The majority of the synthetic cannabinoids are full agonists at the CB1 receptor and do not contain tobacco or cannabis. They are becoming increasingly popular in adolescents, students and clubbers as an abused substance. Relatively high incidence of adverse effects associated with synthetic cannabinoids use has been documented in the literature. Numerous fatalities linked with their use and abuse have been reported. In this paper, we will review the available data regarding the use and effects of synthetic cannabinoids in humans in order to highlight their impact on public health. To reach this objective, a literature search was performed on two representative databases (Pubmed, Google Scholar), the Erowid Center website (a US non-profit educational organization that provides information about psychoactive plants and chemicals), and various governmental websites. The terms used for the database search were: "synthetic cannabinoids", "spice", "new psychoactive substances", and/or "substance use disorder", and/or "adverse effects", and/or "fatalities". The search was limited to years 2005 to 2016 due to emerging scientific literature at this period Health professionals should take into account that limited scientific evidence is available regarding the effect of synthetic cannabinoids use in humans. It thus urges to launch more systematic epidemiological studies, to develop and validate screening procedures, and to investigate the neurobiological and psychological correlates and risk factors associated to synthetic cannabinoids use and misuse. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Extraction Efficacy of Synthetic Cannabinoids From Damiana Leaf Substrates Utilizing Electrolytic Solvents

DTIC Science & Technology

2014-02-01

cannabis , delta-9-tetrahdyrocannabinol (THC) (1–5). Synthetic cannabinoid receptor agonists comprise a diverse group of chemically unrelated substances...further tested, they have been found to contain neither tobacco nor cannabis , but still produce cannabimimetic effects. As a result, these herbal...mixtures doped with synthetic cannabinoids have become widely abused as a supposed legal alternative to cannabis (12–14). Unfortunately, synthetic

Benzodiazepines and Opioid

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ...

Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids.

PubMed

Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F

2017-01-01

Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with increasingly diverse chemical structures. This chapter focuses on integration of recent results with those covered in previous reviews. Whereas most of the early compounds were derived from the prototypic naphthoylindole JWH-018, currently popular synthetic cannabinoids include tetramethylcyclopropyl ketones and indazole-derived cannabinoids (e.g., AB-PINACA, AB-CHMINACA). Despite their structural differences, psychoactive synthetic cannabinoids bind with high affinity to CB 1 receptors in the brain and, when tested, have been shown to activate these receptors and to produce a characteristic profile of effects, including suppression of locomotor activity, antinociception, hypothermia, and catalepsy, as well as Δ 9 -tetrahydrocannabinol (THC)-like discriminative stimulus effects in mice. When they have been tested, synthetic cannabinoids are often found to be more efficacious at activation of the CB 1 receptor and more potent in vivo. Further, their chemical alteration by thermolysis during use and their uncertain stability and purity may result in exposure to degradants that differ from the parent compound contained in the original product. Consequently, while their intoxicant effects may be similar to those of THC, use of synthetic cannabinoids may be accompanied by unpredicted, and sometimes harmful, effects.

Opioid Summaries by State

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ...

Heroin: Statistics and Trends

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ...

Notes from the Field: Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use - United States, January-May 2015.

PubMed

Law, Royal; Schier, Josh; Martin, Colleen; Chang, Arthur; Wolkin, Amy

2015-06-12

On April 6, 2015, CDC received notification of an increase in telephone calls to U.S. poison centers related to synthetic cannabinoid use. Monthly calls to all poison centers are tracked by the National Poison Data System, which reported that adverse health effects or concerns about possible adverse health effects related to synthetic cannabinoid use increased 330% from 349 in January 2015 to 1,501 in April 2015. Synthetic cannabinoids include various psychoactive chemicals or a mixture of such chemicals that are sprayed onto plant material, which is then often smoked or ingested to achieve a "high." These products are sold under a variety of names (e.g., synthetic marijuana, spice, K2, black mamba, and crazy clown) and can be sold in retail outlets as herbal products. Law enforcement agencies have regulated a number of these substances; however, manufacturers of synthetic cannabinoids frequently change the formulation to avoid detection and regulation. After the initial notification, CDC analyzed information from the National Poison Data System on reported adverse health effects related to synthetic cannabinoid use for the period January-May 2015.

Synthetic cannabinoid and marijuana exposures reported to poison centers.

PubMed

Forrester, M B; Kleinschmidt, K; Schwarz, E; Young, A

2012-10-01

Synthetic cannabinoids have recently gained popularity as a recreational drug because they are believed to result in a marijuana-like high. This investigation compared synthetic cannabinoids and marijuana exposures reported to a large statewide poison center system. Synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010 were identified. The distribution of exposures to the two agents with respect to various demographic and clinical factors were compared by calculating the rate ratio (RR) of the synthetic cannabinoid and marijuana percentages for each subgroup and 95% confidence interval (CI). The proportion of synthetic cannabinoid and marijuana exposures, respectively, were 87.3% and 46.5% via inhalation (RR 1.88, 95% CI 1.38-2.61), 74.9% and 65.7% in male (RR 1.14, 95% CI 0.87-1.51), 40.2% and 56.6% age ≤ 19 years (RR 0.71, 95% CI 0.52-0.98), 79.2% and 58.6% occurring at a residence (RR 1.35, 95% CI 1.02-1.82), 8.4% and 16.2% managed on-site (RR 0.52. 95% CI 0.28-1.00), and 59.3% and 41.4% with serious medical outcomes (RR 1.43, 95% CI 1.03-2.05). Compared to marijuana, synthetic cannabinoid exposures were more likely to be used through inhalation, to involve adults, to be used at a residence, and to result in serious outcomes.

Are the last grade medical students aware of the danger of synthetic cannabinoids?

PubMed

Beyhun, Nazim Ercument; Can, Gamze; Topbas, Murat; Cankaya, Sertac; Ketenci, Huseyin Cetin

2016-02-01

Synthetic cannabinoids are drugs which are increasingly used by especially adolescents and young people. In recent years hospital admissions even concluding with deaths have been observed. Therefore, the awareness of medical students, who will be in challenge with this new drug abuse, is an important issue. The aim of this study is to figure out the awareness of the last grade medical students and its correlates. This is a questionnaire based descriptive study with the participation of 148 students at Karadeniz Technical University Medical Faculty, Turkey. An awareness score was produced to measure awareness (cronbach alpha = 0.67). The 17.6% (26/148) of students who reported not knowing what synthetic cannabinoids were and hearing the name for the first time in this study. The 16.4% of students assumed that synthetic cannabinoid use was legal, and 16.2% assumed that synthetic cannabinoids are not drugs. The internet (including social media) (48.6%) and pharmacology lectures (40.5%) were identified as the most stated sources of information. The students who have synthetic cannabinoid user friends and social media account have significantly higher awareness scores (p < 0.05 for both). Last grade medical students have a lack of awareness towards synthetic cannabinoids which is an increasing threat that they have to challenge. Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids—A Systematic Review

PubMed Central

Cohen, Koby; Weinstein, Aviv

2018-01-01

Background—Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method—A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., “synthetic cannabinoids AND cognition,” “cannabis AND cognition” and “cannabinoids AND cognition”). Results—The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility) and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility). Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions—Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs. PMID:29495540

Fentanyl and Other Synthetic Opioids Drug Overdose Deaths

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... the Future 2017 Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College- ...

Understanding the Growing Threat of Synthetic Cannabinoids and Its Implications on University-Based Counselors

ERIC Educational Resources Information Center

Golubovic, Nedeljko; Dew, Brian J.

2017-01-01

The rise in synthetic cannabinoid use has been one of the nation's most alarming drug-related trends. Considering the popularity of use among young adults, college counselors are likely to be among the 1st professionals to treat clients who use these drugs. In this article, the unique aspects of synthetic cannabinoids are reviewed, implications…

Synthetic Cannabinoids: Psychopharmacology, Clinical Aspects, Psychotic Onset.

PubMed

Martinotti, Giovanni; Santacroce, Rita; Papanti, Duccio; Elgharably, Yasmine; Prilutskaya, Mariya; Corazza, Ornella

2017-01-01

Synthetic Cannabinoids (SC) are the widest and most diffused class of Novel Psychoactive Substances. The short- and long- term health risks associated with the consumption of SC are often unknown to both users and health professionals. This review aims to provide a synthesis of the most recent and relevant insights on the pharmacology, clinical and psychopathological aspects of SC. A structured search of two bibliographic databases (PubMed and Scopus) was undertaken according to inclusion/exclusion criteria. The following terms "synthetic cannabinoid*", "synthetic cannabimimetic*", "synthetic cannabis", "synthetic marijuana" and "Spice AND cannabinoid*" were used as search strings. 162 relevant results, mainly published in the past two years were revealed. Most results emerged for the keyword "synthetic cannabinoid*", followed by the combination "Spice* AND "cannabinoid*". Most papers were epidemiological, forensic, toxicologic, or analytical. The results of studies were systematized according their contribution to the comprehension of pharmacological, clinical and psychopathological effects of SC. Fifteen SC-related fatality cases were reviewed according to their histories, pathology and toxicology findings. The findings of this review confirm the importance of prompt and reliable information available for health professionals More specific analytic techniques and designed preventive strategies are required to face unprecedented SC challenge. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis.

PubMed

Meng, Howard; Johnston, Bradley; Englesakis, Marina; Moulin, Dwight E; Bhatia, Anuj

2017-11-01

There is a lack of consensus on the role of selective cannabinoids for the treatment of neuropathic pain (NP). Guidelines from national and international pain societies have provided contradictory recommendations. The primary objective of this systematic review and meta-analysis (SR-MA) was to determine the analgesic efficacy and safety of selective cannabinoids compared to conventional management or placebo for chronic NP. We reviewed randomized controlled trials that compared selective cannabinoids (dronabinol, nabilone, nabiximols) with conventional treatments (eg, pharmacotherapy, physical therapy, or a combination of these) or placebo in patients with chronic NP because patients with NP may be on any of these therapies or none if all standard treatments have failed to provide analgesia and or if these treatments have been associated with adverse effects. MEDLINE, EMBASE, and other major databases up to March 11, 2016, were searched. Data on scores of numerical rating scale for NP and its subtypes, central and peripheral, were meta-analyzed. The certainty of evidence was classified using the Grade of Recommendations Assessment, Development, and Evaluation approach. Eleven randomized controlled trials including 1219 patients (614 in selective cannabinoid and 605 in comparator groups) were included in this SR-MA. There was variability in the studies in quality of reporting, etiology of NP, type and dose of selective cannabinoids. Patients who received selective cannabinoids reported a significant, but clinically small, reduction in mean numerical rating scale pain scores (0-10 scale) compared with comparator groups (-0.65 points; 95% confidence interval, -1.06 to -0.23 points; P = .002, I = 60%; Grade of Recommendations Assessment, Development, and Evaluation: weak recommendation and moderate-quality evidence). Use of selective cannabinoids was also associated with improvements in quality of life and sleep with no major adverse effects. Selective cannabinoids provide a small analgesic benefit in patients with chronic NP. There was a high degree of heterogeneity among publications included in this SR-MA. Well-designed, large, randomized studies are required to better evaluate specific dosage, duration of intervention, and the effect of this intervention on physical and psychologic function.

Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach

PubMed Central

Niaz, Kamal; Khan, Fazlullah; Maqbool, Faheem; Momtaz, Saeideh; Ismail Hassan, Fatima; Nobakht-Haghighi, Navid; Rahimifard, Mahban; Abdollahi, Mohammad

2017-01-01

Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis. PMID:28827985

National Institute on Drug Abuse

MedlinePlus

... Drugs & Cold Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... infographic shows that synthetic cannabinoids, like K2 or Spice, are not natural drugs and can lead to ...

Teens and E-cigarettes

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... the Future 2017 Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College- ...

Buzz Juice: Neurological sequelae of synthetic cannabinoids.

PubMed

Kak, Manisha; Mikhail, Fadi; Yano, Sho T; Guan, Rui; Lukas, Rimas V

2017-03-01

The use of synthetic cannabinoids is becoming more widespread. Familiarity with the potential toxicities associated with these agents will grow in importance. We present a case of a woman who developed onset of confusion, visual hallucinations, and ataxia after vaporizing synthetic cannabinoids. MRI imaging demonstrated restricted diffusion and increased T2/FLAIR signal in the corpus callosum and cerebellar peduncles. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats.

PubMed

Wiley, Jenny L; Lefever, Timothy W; Marusich, Julie A; Craft, Rebecca M

2017-03-01

Women report greater sensitivity to the subjective effects of Δ 9 -tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. A cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure. Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes. This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC's effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantification of synthetic cannabinoids in herbal smoking blends using NMR.

PubMed

Dunne, Simon J; Rosengren-Holmberg, Jenny P

2017-05-01

Herbal smoking blends containing synthetic cannabinoids have become popular alternatives to marijuana. These products were previously sold in pre-packaged foil bags, but nowadays seizures usually contain synthetic cannabinoid powders together with unprepared plant materials. A question often raised by the Swedish police is how much smoking blend can be prepared from certain amounts of banned substance, in order to establish the severity of the crime. To address this question, information about the synthetic cannabinoid content in both the powder and the prepared herbal blends is necessary. In this work, an extraction procedure compatible with direct NMR quantification of synthetic cannabinoids in herbal smoking blends was developed. Extraction media, time and efficiency were tested for different carrier materials containing representative synthetic cannabinoids. The developed protocol utilizes a 30 min extraction step in d 4 -methanol in presence of internal standard allowing direct quantitation of the extract using NMR. The accuracy of the developed method was tested using in-house prepared herbal smoking blends. The results showed deviations less than 0.2% from the actual content, proving that the method is sufficiently accurate for these quantifications. Using this method, ten synthetic cannabinoids present in sixty-three different herbal blends seized by the Swedish police between October 2012 and April 2015 were quantified. Obtained results showed a variation in cannabinoid contents from 1.5% (w/w) for mixtures containing MDMB-CHMICA to over 5% (w/w) for mixtures containing 5F-AKB-48. This is important information for forensic experts when making theoretical calculations of production quantities in legal cases regarding "home-made" herbal smoking blends. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Validation of an ELISA Synthetic Cannabinoids Urine Assay.

PubMed

Barnes, Allan J; Spinelli, Eliani; Young, Sheena; Martin, Thomas M; Kleete, Kevin L; Huestis, Marilyn A

2015-10-01

Synthetic cannabinoids are touted as legal alternatives to cannabis, at least when first released, and routine urine cannabinoid screening methods do not detect these novel psychoactive substances. Synthetic cannabinoids are widely available, are a major public health and safety problem, and a difficult challenge for drug-testing laboratories. We evaluated performance of the National Medical Services (NMS) JWH-018 direct enzyme-linked immunosorbent assay (ELISA) kit to sensitively, selectively, and rapidly screen urinary synthetic cannabinoids. The NMS ELISA kit targeting the JWH-018 N-(5-hydroxypentyl) metabolite was used to screen 2492 urine samples with 5 and 10 mcg/L cutoffs. A fully validated liquid chromatography-tandem mass spectrometry method for 29 synthetic cannabinoids markers confirmed all presumptive positive and negative results. Performance challenges at ±25% and ±50% of cutoffs determined intraplate and interplate imprecision around proposed cutoffs. The immunoassay was linear from 1 to 500 mcg/L with intraplate and interplate imprecision of ≤8.2% and <14.0%, respectively. No interferences were present from 93 common drugs of abuse, metabolites, coadministered drugs, over-the-counter medications, or structurally similar compounds, and 19 of 73 individual synthetic cannabinoids (26%) exhibited moderate to high cross-reactivity to JWH-018 N-(5-hydroxypentyl) metabolite. Sensitivity, specificity, and efficiency results were 83.7%, 99.4%, and 97.6%, as well as 71.6%, 99.7%, and 96.4% with the 5 and 10 mcg/L urine cutoffs, respectively. This high throughput immunoassay exhibited good diagnostic efficiency and documented that the NMS JWH-018 direct ELISA is a viable method for screening synthetic cannabinoids in urine targeting the JWH-018 N-(5-hydroxypentyl) and related analytes. Optimal performance was achieved with a matrix-matched 5 mcg/L urine cutoff.

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats*

PubMed Central

Wiley, Jenny L.; Lefever, Timothy W.; Marusich, Julie A.; Craft, Rebecca M.

2017-01-01

Background Women report greater sensitivity to the subjective effects of Δ9-tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. Methods A cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure. Results Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes. Conclusions This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC’s effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology. PMID:28130989

Validation of an ELISA Synthetic Cannabinoids Urine Assay

PubMed Central

Barnes, Allan J.; Spinelli, Eliani; Young, Sheena; Martin, Thomas M.; Klette, Kevin L.; Huestis, Marilyn A.

2015-01-01

Background Synthetic cannabinoids are touted as legal alternatives to cannabis, at least when first released, and routine urine cannabinoid screening methods do not detect these novel psychoactive substances. Synthetic cannabinoids are widely available, are a major public health and safety problem, and a difficult challenge for drug testing laboratories. We evaluated performance of the NMS JWH-018 direct ELISA kit to sensitively, selectively, and rapidly screen urinary synthetic cannabinoids. Materials/ Methods The NMS ELISA kit targeting the JWH-018 N-(5-hydroxypentyl) metabolite was utilized to screen 2492 urine samples with 5 and 10µg/L cutoffs. A fully validated LC-MS/MS method for 29 synthetic cannabinoids markers confirmed all presumptive positive and negative results. Performance challenges at ±25 and ±50% of cutoffs determined intra- and inter-plate imprecision around proposed cutoffs. Result The immunoassay was linear from 1–500µg/L with intra- and inter-plate imprecision of ≤8.2% and <14.0%, respectively. No interferences were present from 93 common drugs of abuse, metabolites, co-administered drugs, over-the-counter medications or structurally similar compounds, and 19 of 73 individual, synthetic cannabinoids (26%) exhibited moderate to high cross-reactivity to JWH-018 N-(5-hydroxypentyl) metabolite. Sensitivity, specificity, and efficiency results were 83.7%, 99.4% and 97.6% and 71.6%, 99.7% and 96.4%, with the 5 and 10µg/L urine cutoffs, respectively. Conclusion This high throughput immunoassay exhibited good diagnostic efficiency and documented that the NMS JWH-018 direct ELISA is a viable method for screening synthetic cannabinoids in urine targeting the JWH-018 N-(5-hydroxypentyl) and related analytes. Optimal performance was achieved with a matrix-matched 5µg/L urine cutoff. PMID:25706046

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA.

PubMed

Gamage, Thomas F; Farquhar, Charlotte E; Lefever, Timothy W; Marusich, Julie A; Kevin, Richard C; McGregor, Iain S; Wiley, Jenny L; Thomas, Brian F

2018-05-01

Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB 1 ) receptor and produce effects similar to those of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for the potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects that include cardiotoxicity, seizure activity, and kidney damage, and they can cause death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI, and MN-18 were assessed for: 1) receptor binding affinity at the human CB 1 and human CB 2 receptors, 2) function in [ 35 S]GTP γ S and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for human cannabinoid receptors type-1 and type-2 and produced greater maximal effects than THC in [ 35 S]GTP γ S and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they probably possess subjective effects similar to those of cannabis. Notably, MDMB-FUBINACA, a methylated analog of MMB-FUBINACA, had higher affinity for CB 1 than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB 1 receptor, exhibiting greater efficacy than THC, and producing THC-like effects in models relevant to subjective effects in humans. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Rapid Identification of Synthetic Cannabinoids in Herbal Incenses with DART-MS and NMR.

PubMed

Marino, Michael A; Voyer, Brandy; Cody, Robert B; Dane, A John; Veltri, Mercurio; Huang, Ling

2016-01-01

The usage of herbal incenses containing synthetic cannabinoids has caused an increase in medical incidents and triggered legislations to ban these products throughout the world. Law enforcement agencies are experiencing sample backlogs due to the variety of the products and the addition of new and still-legal compounds. In our study, proton nuclear magnetic resonance (NMR) spectroscopy was employed to promptly screen the synthetic cannabinoids after their rapid, direct detection on the herbs and in the powders by direct analysis in real time mass spectrometry (DART-MS). A simple sample preparation protocol was employed on 50 mg of herbal sample matrices for quick NMR detection. Ten synthetic cannabinoids were discovered in fifteen herbal incenses. The combined DART-MS and NMR methods can be used to quickly screen synthetic cannabinoids in powder and herbal samples, serving as a complementary approach to conventional GC-MS or LC-MS methods. © 2015 American Academy of Forensic Sciences.

Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in vivo assays in mice

PubMed Central

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

2016-01-01

Anecdotal reports suggest that abused synthetic cannabinoids produce cannabis-like “highs,” but some of their effects may also differ from traditional cannabinoids such as Δ9-tetrahydrocannabinol (THC). This study examined the binding affinities of first-generation indole-derived synthetic cannabinoids at cannabinoid and noncannabinoid receptors and their effects in a functional observational battery (FOB) and drug discrimination in mice. All seven compounds, except JWH-391, had favorable affinity (≤ 159 nM) for both cannabinoid receptors. In contrast, binding at noncannabinoid receptors was absent or weak. In the FOB, THC and the six active compounds disrupted behaviors in CNS activation and muscle tone/equilibrium domains. Unlike THC, however, synthetic cannabinoids impaired behavior across a wider dose and domain range, producing autonomic effects and signs of CNS excitability and sensorimotor reactivity. In addition, mice acquired JWH-018 discrimination, and THC and JWH-073 produced full substitution whereas the 5-HT2B antagonist mianserin did not substitute in mice trained to discriminate JWH-018 or THC. Urinary metabolite analysis showed that the compounds were extensively metabolized, with metabolites that could contribute to their in vivo effects. Together, these results show that, while first-generation synthetic cannabinoids shared some effects that were similar to those of THC, they also possessed effects that differed from traditional cannabinoids. The high nanomolar (or absent) affinities of these compounds at receptors for most major neurotransmitters suggests that these divergent effects may be related to the greater potencies and/or efficacies at CB1 receptors; however, action(s) at noncannabinoid receptors yet to be assessed or via different signaling pathways cannot be ruled out. PMID:27449567

Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in vivo assays in mice.

PubMed

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

2016-11-01

Anecdotal reports suggest that abused synthetic cannabinoids produce cannabis-like "highs," but some of their effects may also differ from traditional cannabinoids such as Δ(9)-tetrahydrocannabinol (THC). This study examined the binding affinities of first-generation indole-derived synthetic cannabinoids at cannabinoid and noncannabinoid receptors and their effects in a functional observational battery (FOB) and drug discrimination in mice. All seven compounds, except JWH-391, had favorable affinity (≤159 nM) for both cannabinoid receptors. In contrast, binding at noncannabinoid receptors was absent or weak. In the FOB, THC and the six active compounds disrupted behaviors in CNS activation and muscle tone/equilibrium domains. Unlike THC, however, synthetic cannabinoids impaired behavior across a wider dose and domain range, producing autonomic effects and signs of CNS excitability and sensorimotor reactivity. In addition, mice acquired JWH-018 discrimination, and THC and JWH-073 produced full substitution whereas the 5-HT2B antagonist mianserin did not substitute in mice trained to discriminate JWH-018 or THC. Urinary metabolite analysis showed that the compounds were extensively metabolized, with metabolites that could contribute to their in vivo effects. Together, these results show that, while first-generation synthetic cannabinoids shared some effects that were similar to those of THC, they also possessed effects that differed from traditional cannabinoids. The high nanomolar (or absent) affinities of these compounds at receptors for most major neurotransmitters suggests that these divergent effects may be related to the greater potencies and/or efficacies at CB1 receptors; however, action(s) at noncannabinoid receptors yet to be assessed or via different signaling pathways cannot be ruled out. Copyright © 2016 Elsevier Ltd. All rights reserved.

Abuse of Prescription (Rx) Drugs Affects Young Adults Most

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... the Future 2017 Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College- ...

The Endocannabinoid System as a Target for Treatment of Breast Cancer

DTIC Science & Technology

2011-08-01

cannabinoids with radiation in MCF-7, MDA-MB-231, and 4T1 breast tumor cell lines. Interestingly, the high efficacy synthetic cannabinoid agonist...tumorgenesis in FAAH (-/-) mice vs. wild type mice; and 2) the synthetic cannabinoid receptor agonist WIN55,212-2 in combination with radiation or adriamycin...THC (the primary active psychoactive constituent present in marijuana ), cannabidiol (CBD: a marijuana -derived cannabinoid that lacks psychomimetic

Qualitative Analysis and Detection of the Pyrolytic Products of JWH-018 and 11 Additional Synthetic Cannabinoids in the Presence of Common Herbal Smoking Substrates.

PubMed

Raso, Stephen; Bell, Suzanne

2017-07-01

Synthetic cannabinoids have become a ubiquitous challenge in forensic toxicology and seized drug analysis. Thermal degradation products have yet to be identified and evaluated for toxicity in comparison to parent and metabolic compounds. An investigation into these pyrolytic products, as the major route of ingestion is inhalation, may produce additional insight to understand the toxicity of synthetic cannabinoids. The pyrolysis of JWH-018 and 11 additional synthetic cannabinoids and six herbal plant substrates were conducted using an in-house constructed smoking simulator. After pyrolysis of herbal material alone, the plant substrate was spiked with the drug compounds to 2-5% w/w concentrations. Samples were collected, filtered, evaporated under nitrogen gas, reconstituted in methanol, and analyzed via gas chromatograph-mass spectrometer. Pyrolysis of the plant material alone produced 10 consistently observed compounds between the six plant species. The pyrolysis of the synthetic cannabinoids produced a total of 52 pyrolytic compounds, where 32 were unique to a particular parent compound and the remaining 20 were common products between multiple cannabinoids. The thermal degradation followed three major pathways that are outlined to assist in producing a predictive model for new synthetic cannabinoids that may arise in case samples. The observed pyrolytic products are also viable options for analysis in post mortem samples and the evaluation of toxicity. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences.

PubMed

Thomas, Brian F; Lefever, Timothy W; Cortes, Ricardo A; Grabenauer, Megan; Kovach, Alexander L; Cox, Anderson O; Patel, Purvi R; Pollard, Gerald T; Marusich, Julie A; Kevin, Richard C; Gamage, Thomas F; Wiley, Jenny L

2017-04-01

Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal "spice" for smoking or as bulk compound for mixing with a solvent and inhalation via electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here, we show that heating synthetic cannabinoids containing tetramethylcyclopropyl-ring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds. Moreover, these degradants were formed under conditions simulating smoking. Some products of combustion retained high affinity at the cannabinoid 1 (CB 1 ) and CB 2 receptors, were more efficacious than (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB 1 receptor-mediated guanosine 5'-O-(3-thiotriphosphate) (GTPγS) binding, and were potent in producing Δ 9 -tetrahydrocannabinol-like effects in laboratory animals, whereas other compounds had low affinity and efficacy and were devoid of cannabimimetic activity. Degradants that retained affinity and efficacy also substituted in drug discrimination tests for the prototypical synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)indole (JWH-018), and are likely to produce psychotropic effects in humans. Hence, it is important to take into consideration the actual chemical exposures that occur during use of synthetic cannabinoid formulations to better comprehend the relationships between dose and effect. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Identification and quantification of synthetic cannabinoids in "spice-like" herbal mixtures: Update of the German situation for the spring of 2016.

PubMed

Langer, Nico; Lindigkeit, Rainer; Schiebel, Hans-Martin; Papke, Uli; Ernst, Ludger; Beuerle, Till

2016-12-01

In February 2016, nine "spice-like" products from German language internet shops were analyzed. In total, eight different synthetic cannabinoids were identified by gas chromatography-mass spectrometry (GC-MS), namely THJ-018, THJ-2201, MAB-CHMINACA, 5F-ADB, 5Cl-AKB48 (syn.: 5C-AKB48), 4-pentenyl-AKB48, MDMB-CHMICA and 5F-AB-PINACA. For the majority of products only one synthetic cannabinoid was identified as the active ingredient, while two products contained 2 and 5 compounds, respectively. For some of the identified cannabinoids (MAB-CHMINACA, 5Cl-AKB48 and 4-pentenyl-AKB48) no or only insufficient physico-chemical data were available in literature. To our knowledge 5Cl-AKB48 and 4-pentenyl-AKB48 were found for the first time in commercially available products, hence an in-depth characterization of these compounds by NMR, EI-MS, ESI-MS/MS, IR- and UV spectroscopy was conducted. In addition, all synthetic cannabinoids were quantified by a GC-MS method using JWH-018 as internal standard and the corresponding response factors to calculate the total amount of all synthetic cannabinoids in the commercial smoking mixtures. The content of synthetic cannabinoids in the investigated products ranged from 23 to 120mg/g (average: 57mg/g), while individual compounds ranged from 1 to 120mg/g. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Drug and Alcohol Use -- A Significant Risk Factor for HIV

MedlinePlus

... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine and E- ... the Future 2017 Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College- ...

Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

DTIC Science & Technology

2013-02-01

looking at the interaction of the synthetic cannabinoid WIN55,212-2 and ionizing radiation has led to preliminary results implicating a novel site of...we found that the various cannabinoids do not interfere with the anti-proliferative effects of either treatment; furthermore, the synthetic ...aminoalkylindole series, is one of the most highly studied synthetic cannabinoids. It has been shown to produce the full spectrum of psychoactive effects

[Cannabis and cannabinoids. Possibilities of their therapeutic use].

PubMed

Heim, M E

1982-03-04

Newer aspects of therapeutic potentials of cannabis and cannabinoids are reviewed. The major active constituent of cannabis sativa, delta-9-tetrahydrocannabinol and synthetic cannabinoids are evaluated in several clinical trials on their antiemetic efficacy in cancer chemotherapy induced vomiting. 80% of patients refractory to standard antiemetic treatment could be improved with the synthetic cannabinoid levonantradol. Other therapeutic effects, which are presently investigated in clinical trials are analgesia, antispasticity, anticonvulsion and the reduction of intraocular pressure in glaucoma. The future goal of cannabinoid research is the separation between specific pharmacologic activities and undesirable psychotropic effects.

77 FR 12508 - Schedules of Controlled Substances: Placement of Five Synthetic Cannabinoids Into Schedule I

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-01

... Final Order, a ``cannabinoid'' is a class of chemical compounds in the marijuana \\3\\ plant that are... constituent of marijuana. ``Synthetic cannabinoids'' are a large family of chemically unrelated structures functionally (biologically) similar to THC, the active principal of marijuana. \\3\\ Note that ``marihuana'' is...

Performance characteristics of an ELISA screening assay for urinary synthetic cannabinoids.

PubMed

Spinelli, Eliani; Barnes, Allan J; Young, Sheena; Castaneto, Marisol S; Martin, Thomas M; Klette, Kevin L; Huestis, Marilyn A

2015-06-01

Synthetic cannabinoids are marketed as legal alternatives to cannabis, as routine urine cannabinoid immunoassays do not detect synthetic cannabinoids. Laboratories are challenged to identify these new designer drugs that are widely available and represent a major public health and safety problem. Immunoassay testing offers rapid separation of presumptive positive and negative specimens, prior to more costly and time-consuming chromatographic confirmation. The Neogen SPICE ELISA kit targets JWH-018 N-pentanoic acid as a marker for urinary synthetic cannabinoids. Assay performance was evaluated by analyzing 2469 authentic urine samples with the Neogen immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two immunoassay cut-off concentrations, 5 and 10 µg/L, classified samples as presumptive positive or negative, followed by qualitative LC-MS/MS confirmation for 29 synthetic cannabinoids markers with limits of detection of 0.5-10 µg/L to determine the assay's sensitivity, specificity and efficacy. Challenges at ±25% of each cut-off also were investigated to determine performance around the cut-off and intra- and inter-plate imprecision. The immunoassay was linear from 1 to 250 µg/L (r(2)  = 0.992) with intra- and inter-plate imprecision of ≤5.3% and <9%, respectively. Sensitivity, specificity, and efficiency results with the 5 µg/L cut-off were 79.9%, 99.7%, and 97.4% and with the 10 µg/L cut-off 69.3%, 99.8%, and 96.3%, respectively. Cross-reactivity was shown for 18 of 73 synthetic cannabinoids markers evaluated. Good sensitivity, specificity, and efficiency, lack of sample preparation requirements, and rapid semi-automation documented that the Neogen SPICE ELISA kit is a viable method for screening synthetic cannabinoids in urine targeting JWH-018 N-pentanoic acid. Copyright © 2014 John Wiley & Sons, Ltd.

Synthetic cannabinoids 2015: An update for pediatricians in clinical practice

PubMed Central

Castellanos, Daniel; Gralnik, Leonard M

2016-01-01

Synthetic cannabinoids are a group of substances in the world of designer drugs that have become increasingly popular over the past few years. Synthetic cannabinoids are a chemically diverse group of compounds functionally similar to THC. Since first appearing on the world market a few years ago these compounds have evolved rapidly. Newer more potent analogues have been developed. Identifying youth who abuse these substances can be difficult. Newer forms of consumption have also evolved. These products are now manufactured in products that look like natural cannabis resin and in liquid cartridges used in electronic cigarettes. Synthetic cannabinoids appear to be associated with potentially dangerous health effects that are more severe than that of marijuana. Some synthetic cannabinoid compounds have been associated with serious physical consequences, such as, seizures, myocardial infarction and renal damage. In addition, psychoactive effects, such as aggression, confusion, anxiety and psychosis have also been reported. The diagnosis remains primarily clinical with toxicological confirmation difficult due to manufacturers constantly developing new analogues to avoid detection. Pediatricians are urged to familiarize themselves with these drugs and the typical presentations of patients who use them. PMID:26862498

Retrospective analysis of synthetic cannabinoids in serum samples--epidemiology and consumption patterns.

PubMed

Jaenicke, Nathalie J; Pogoda, Werner; Paulke, Alexander; Wunder, Cora; Toennes, Stefan W

2014-09-01

Herbal mixtures contain synthetic cannabinoids, which can cause severe intoxications. Due to the great variety and the changing spectrum of substances on the drug market, prevalence data are limited, and data on prevalence rates of synthetic cannabinoids in forensic cases are not available. The present study was performed to survey the prevalence of synthetic cannabinoids in cases of traffic and criminal offences in the German state Hesse in 2010. The applied analytical method covered all synthetic cannabinoids on the drug market at that time, and with 20% of the blood samples (422 out of 2201) a representative number was reanalyzed. In twelve samples synthetic cannabinoids were identified and a prevalence of 2.8% was estimated. Consumption patterns showed predominantly cases of multi-drug consumption (10 cases); the combination with cannabis or alcohol was frequent (four cases each). The observed deficits were moderate with the exception of aggravation of paranoia in one case. The symptoms were either compatible with the effects of cannabinoid agonists or attributable to alcohol or other drugs found in the blood samples. Our current analytical strategy is to perform such analyses only in cases where use is suspected or where symptoms are not explained by routine toxicological analyses. Hence, the positive rate is rather low highlighting the need to keep up with the developments on the drug market and to establish sensitive screening methods covering a broad range of substances that can be updated fast, e.g., relying on collections of mass spectrometric reference data. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[Drug Dependence and Cytotoxicity of Law-evading Drugs: Their Identities Explored from Basic Research].

PubMed

Funada, Masahiko

2016-01-01

  Cases of people experiencing disturbed consciousness or dyspnea, causing traffic accidents, or requiring ambulance transport to hospital due to abuse of law-evading chemical substances have become a serious social problem in Japan. Most law-evading herbal products are marketed as incense or herbs and consist of finely chopped, dry vegetative matter mixed with chemical substances (drugs). Analysis of the chemical substances in these herbal products has demonstrated that they contain synthetic cannabinoids. Because there are many cannabinoid compounds, even if a particular drug is regulated, similar compounds that differ only slightly in structure may be added in their place. Therefore a cat-and-mouse game exists between regulations on chemical substances and their propagation. This paper summarizes the pharmacological actions and dangers of chemical substances contained in law-evading herbal products by focusing on synthetic cannabinoids, as a group of chemical substances contained in these products. Furthermore, comprehensive designations of synthetic cannabinoids have been introduced as a new method of regulation that emphasizes the similarity of chemical structures; this paper also outlines the comprehensive designations. We established a psychic-dependence liability and cytotoxicity screening system for synthetic cannabinoids using animals (behavioral analysis in vivo) and cell cultures (cytotoxicity analysis in vitro). With our drug-screening system, we were able rapidly to evaluate and quantify psychic-dependence liabilities and cytotoxicity of synthetic cannabinoids contained in law-evading herbal products. These scientific data using our screening system contributed to the establishment of legislation for comprehensive designations of synthetic cannabinoids.

Acute intoxication caused by synthetic cannabinoids 5F-ADB and MMB-2201: A case series.

PubMed

Barceló, Bernardino; Pichini, Simona; López-Corominas, Victoria; Gomila, Isabel; Yates, Christopher; Busardò, Francesco Paolo; Pellegrini, Manuela

2017-04-01

Synthetic cannabinoids are relatively new substances of abuse. Recently, abuse of synthetic cannabinoids has been increasingly reported in the lay press and medical literature. When new compounds are introduced, their use is initially not restricted by prohibition therefore their consumption cannot be verified by standard drug tests. The use of these compounds among adolescents and young adults is constantly growing, making it important for emergency services to be familiar with the signs and symptoms of intoxication present. Overdose and chronic use of these substances can cause adverse effects including altered mental status, tachycardia, and loss of consciousness. Here, we report five cases of acute intoxication by synthetic cannabinoids 5F-ADB and MMB-2201 with analytical confirmation. Copyright © 2017 Elsevier B.V. All rights reserved.

DART - LTQ ORBITRAP as an expedient tool for the identification of synthetic cannabinoids.

PubMed

Habala, Ladislav; Valentová, Jindra; Pechová, Iveta; Fuknová, Mária; Devínsky, Ferdinand

2016-05-01

Synthetic cannabinoids as designer drugs constitute a major problem due to their rapid increase in number and the difficulties connected with their identification in complex mixtures. DART (Direct Analysis in Real Time) has emerged as an advantageous tool for the direct and rapid analysis of complex samples by mass spectrometry. Here we report on the identification of six synthetic cannabinoids originating from seized material in various matrices, employing the combination of ambient pressure ion source DART and hybrid ion trap - LTQ ORBITRAP mass spectrometer. This report also describes the sampling techniques for the provided herbal material containing the cannabinoids, either directly as plant parts or as an extract in methanol and their influence on the outcome of the analysis. The high resolution mass spectra supplied by the LTQ ORBITRAP instrument allowed for an unambiguous assignment of target compounds. The utilized instrumental coupling proved to be a convenient way for the identification of synthetic cannabinoids in real-world samples. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

PubMed Central

Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

2017-01-01

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana”) in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance. PMID:28469427

Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

PubMed

Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

2017-01-01

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

Investigating correlates of synthetic marijuana and Salvia use in light and intermittent smokers and college students in a predominantly Hispanic sample.

PubMed

Gutierrez, Kevin M; Cooper, Theodore V

2014-12-01

Few studies have examined correlates related to the use of synthetic cannabinoids (e.g., Spice, K2) and Salvia divinorum. Two studies were conducted to investigate whether demographic, smoking-related, and substance-related variables were associated with the use of synthetic cannabinoids and Salvia. In Study 1, 185 participants (50% female; 83% Hispanic; Mage = 32 years; SD = 13.68) were recruited from a local health clinic and a university on the U.S./Mexico border for a smoking-cessation study targeting light and intermittent smokers. In Study 2, 675 participants (62.4% female; 89.1% Hispanic; Mage = 21.0, SD = 8.56) were recruited from a university on the U.S./Mexico border for an online study. In Study 1, 10% of the sample indicated they had ever used either synthetic cannabinoids or Salvia in their lifetime. Being male and dual/multiple use of tobacco products were significantly associated with having ever used synthetic cannabinoids or Salvia. In Study 2, 9%, 5%, and 3% of the sample indicated lifetime, past-year, and past 30-day use of synthetic cannabinoids, respectively. Five percent, 2%, and 1% of the sample indicated lifetime, past-year, and past 30-day use of Salvia, respectively. Logistic regression analyses revealed that past 30-day marijuana use and past 30-day ecstasy use were significantly associated with use of synthetic cannabinoids and Salvia in one's lifetime. These findings suggest that the assessment of synthetic marijuana and Salvia use is warranted in studies of other addictive behaviors, particularly among current marijuana and ecstasy users. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Evaluation of cognitive functions in individuals with synthetic cannabinoid use disorder and comparison to individuals with cannabis use disorder.

PubMed

Cengel, Hanife Yilmaz; Bozkurt, Muge; Evren, Cuneyt; Umut, Gokhan; Keskinkilic, Cahit; Agachanli, Ruken

2018-04-01

The use of synthetic cannabinoid has been increasing throughout the world and has become a major public health problem. The present study aims to investigate the attention, memory, visuospatial and executive functions in individuals with synthetic cannabinoid use disorder and compare the results with findings obtained from individuals with cannabis use disorder and healthy volunteers with no substance use. Fifty-two patients with synthetic cannabinoid use disorder, 45 patients with cannabis use disorder and 48 healthy control group males were included in the study. The neuropsychological test battery was designed to involve ten studies evaluating a large series of cognitive functions. Impairments in attention, memory, executive and visuospatial functions were identified in individuals with synthetic cannabinoid use disorder and these impairments were found to be significantly greater than in individuals with cannabis use disorder and healthy controls. In line with the data obtained from this study; the evaluation of each cognitive function with more comprehensive test batteries and supporting these evaluations with sensitive brain imaging studies are important topics for future research. Copyright © 2018 Elsevier B.V. All rights reserved.

Analysis of 62 synthetic cannabinoids by gas chromatography-mass spectrometry with photoionization.

PubMed

Akutsu, Mamoru; Sugie, Ken-Ichi; Saito, Koichi

2017-01-01

Gas chromatography-mass spectrometry (GC-MS) in electron ionization (EI) mode is one of the most commonly used techniques for analysis of synthetic cannabinoids, because the GC-EI-MS spectra contain characteristic fragment ions for identification of a compound; however, the information on its molecular ions is frequently lacking. To obtain such molecular ion information, GC-MS in chemical ionization (CI) mode is frequently used. However, GC-CI-MS requires a relatively tedious process using reagent gas such as methane or isobutane. In this study, we show that GC-MS in photoionization (PI) mode provided molecular ions in all spectra of 62 synthetic cannabinoids, and 35 of the 62 compounds showed only the molecular radical cations. Except for the 35 compounds, the PI spectra showed very simple patterns with the molecular peak plus only a few fragment peak(s). An advantage is that the ion source for GC-PI-MS can easily be used for GC-EI-MS as well. Therefore, GC-EI/PI-MS will be a useful tool for the identification of synthetic cannabinoids contained in a dubious product. To the best of our knowledge, this is the first report to use GC-PI-MS for analysis of synthetic cannabinoids.

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. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Novel psychoactive substance use by US adolescents: Characteristics associated with use of synthetic cannabinoids and synthetic cathinones.

PubMed

Patrick, Megan E; O'Malley, Patrick M; Kloska, Deborah D; Schulenberg, John E; Johnston, Lloyd D; Miech, Richard A; Bachman, Jerald G

2016-09-01

The current study documents the characteristics associated with the use of two novel psychoactive substances: synthetic cannabinoids and synthetic cathinones. Nationally representative samples of students in 8th (n = 9665), 10th (n = 10 655) and 12th (n = 10 057) grades across the US were included in the Monitoring the Future study from 2012 to 2014. There were relatively few differences in prevalence based on sociodemographic characteristics, although boys were at greater risk for use of synthetic cannabinoids in 12th grade (used by 10.3% of boys and 6.4% of girls) and for use of synthetic cathinones in 10th grade (used by 1.0% of boys and 0.4% of girls). Synthetic drug use was also associated with truancy and use of cigarettes, alcohol, and marijuana. Prevention and intervention efforts for novel psychoactive substance use should focus primarily on polysubstance users and youth who are disengaged from school.[Patrick M, O'Malley P, Kloska D, Schulenberg J, Johnston L, Miech R, Bachman J. Novel psychoactive substance use by US adolescents: Characteristics associated with use of synthetic cannabinoids and synthetic cathinones. Drug Alcohol Rev 2016;35:586-590]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

Analytical confirmation of synthetic cannabinoids in a cohort of 179 presentations with acute recreational drug toxicity to an Emergency Department in London, UK in the first half of 2015.

PubMed

Abouchedid, Rachelle; Hudson, Simon; Thurtle, Natalie; Yamamoto, Takahiro; Ho, James H; Bailey, George; Wood, Michelle; Sadones, Nele; Stove, Christophe P; Dines, Alison; Archer, John R H; Wood, David M; Dargan, Paul I

2017-06-01

Synthetic cannabinoid receptor agonists are the largest group of new psychoactive substances reported in the last decade; in this study we investigated how commonly these drugs are found in patients presenting to the Emergency Department with acute recreational drug toxicity. We conducted an observational cohort study enrolling consecutive adult patients presenting to an Emergency Department (ED) in London (UK) January-July 2015 (6 months) with acute recreational drug toxicity. Residual serum obtained from a serum sample taken as part of routine clinical care was analyzed using high-resolution accurate mass-spectrometry with liquid-chromatography (HRAM-LCMSMS). Minimum clinical data were obtained from ED medical records. 18 (10%) of the 179 patient samples were positive for synthetic cannabinoid receptor agonists. The most common was 5F AKB-48 (13 samples, concentration 50-7600 pg/ml), followed by 5F PB-22 (7, 30-400 pg/mL), MDMB-CHMICA (7, 80-8000 pg/mL), AB-CHMINACA (3, 50-1800 pg/mL), Cumyl 5F-PINACA (1, 800 pg/mL) and BB-22 (1, 60 pg/mL). Only 9/18 (50%) in whom synthetic cannabinoid receptor agonists were detected self-reported synthetic cannabinoid receptor agonist use. The most common clinical features were seizures and agitation, both recorded in four (22%) individuals. Fourteen patients (78%) were discharged from the ED, one of the four admitted to hospital was admitted to critical care. Synthetic cannabinoid receptor agonists were found in 10% of this cohort with acute recreational drug toxicity but self-reported in only half of these. This suggests that presentations to the ED with acute synthetic cannabinoid receptor agonist toxicity may be more common than reported.

Three fatalities associated with the synthetic cannabinoids 5F-ADB, 5F-PB-22, and AB-CHMINACA.

PubMed

Angerer, V; Jacobi, S; Franz, F; Auwärter, V; Pietsch, J

2017-12-01

The use of synthetic cannabinoids (SC) has been widespread in certain groups of drug users for many years. In the scientific literature many intoxication cases and a number of fatalities after the use of synthetic cannabinoids were reported. In this paper three death cases are described with involvement of the synthetic cannabinoids 5F-PB-22, AB-CHMINACA, and 5F-ADB. The three cases occurred in the eastern region of Germany, which is known as a region of high methamphetamine abuse. All decedents were male, between 25 and 41 years old, and had a known history of drug use. Femoral blood concentrations of the synthetic cannabinoids were measured using a validated LC-MS/MS method. The concentration of 5F-PB-22 in the first case was 0.37ng/mL, the concentration of AB-CHMINACA in the second case was approximately 4.1ng/mL (extrapolated) and the 5F-ADB concentration in the third case was 0.38ng/mL. Compared to other published cases the concentrations in the here presented cases seem to be in the lower range. However, taking into account the scene of death, the results of the forensic autopsy and the full toxicological analysis, the deaths can be explained as a direct consequence of consumption of synthetic cannabinoids, although in case one and two relevant amounts of ethanol were found, and in case three trimipramine and olanzapine were present in non-toxic concentrations. It has to be noted that concentrations of synthetic cannabinoids in femoral blood cannot directly be judged as toxic or lethal due to the possibility of postmortem redistribution and the development of tolerance after frequent use. Therefore, all available information has to be considered carefully before stating SC use as the cause of death. Copyright © 2017 Elsevier B.V. All rights reserved.

Adding Spice to the Porridge: The development of a synthetic cannabinoid market in an English prison.

PubMed

Ralphs, Rob; Williams, Lisa; Askew, Rebecca; Norton, Anna

2017-02-01

In 2014, the annual report of the Her Majesty's Chief Inspector of Prisons (HMIP) for England and Wales raised concerns regarding New Psychoactive Substance (NPS) use in custody, specifically the consumption of synthetic cannabinoids. To date, however, the use of these substances in prison populations, and the markets that have emerged to facilitate it, have been under-researched. Our research was conducted in an English adult male prison using multi-method techniques. These included: in-depth interviews and focus groups with prison staff and prisoners; observations of prisoner-led focus groups, workshops and restorative justice circles involving discussion of synthetic cannabinoid use and markets; and analysis of routinely collected prison data measuring drug seizures, incidents of violence and incidents of self-harm. The findings highlight: (1) the scale and nature of synthetic cannabinoid markets in a custodial setting and the motivations for establishing them; (2) the nature and motivations for synthetic cannabinoids use in prison; and (3) the impact synthetic cannabinoid markets in this setting have upon prisoners, the prison system and the wider criminal justice system. The policy implications of the stated motivations for use and reported problems are discussed in relation to both prison and community settings, and the recently implemented Psychoactive Substance Act (2016). The paper concludes that the rise in synthetic cannabinoid use in custody and the size of the drug market are posing significant challenges to the management of offenders; including healthcare, appropriate detection techniques, license recall and sanctions for both use and supply. We argue that the primary motivation for consumption in this setting is the avoidance of drug use detection, and that this is likely to supersede other motivations for consumption in the future. We propose a revision of the use of mandatory drug tests (MDTs) both in prisons and in the management of offenders in the community. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Focus on cannabinoids and synthetic cannabinoids.

PubMed

Le Boisselier, R; Alexandre, J; Lelong-Boulouard, V; Debruyne, D

2017-02-01

The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids. © 2016 American Society for Clinical Pharmacology and Therapeutics.

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

PubMed Central

2014-01-01

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

75 FR 71635 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-24

... have similar properties to delta-9- tetrahydrocannabinol (THC) found in marijuana and have been found... these THC-like synthetic cannabinoids are marketed as ``legal'' alternatives to marijuana and are being...

High times, low sats: diffuse pulmonary infiltrates associated with chronic synthetic cannabinoid use.

PubMed

Alhadi, Sameir; Tiwari, Anupama; Vohra, Rais; Gerona, Roy; Acharya, Janak; Bilello, Kathryn

2013-06-01

In recent years, cases of severe adverse effects from recreational use of synthetic cannabinoids (SC) have established that these agents represent a novel toxicologic hazard. A 21-year-old male presenting as a vehicular trauma victim was noted with diffuse pulmonary infiltrates related to chronic inhalation of multiple synthetic cannabinoid-containing products. Chest imaging revealed bilateral, subacute lung infiltrates; histopathological analysis of bronchial and alveolar tissues revealed an inflammatory process. An extensive workup failed to identify infectious, malignant, autoimmune, or hematologic causes of the syndrome, and toxicological analysis of the blood and body fluids confirmed the presence of multiple synthetic cannabinoids and metabolites. The patient recovered after an 8-day ICU course, wherein he received antibiotics, steroids, and mechanical ventilation. This case contributes to the currently evolving knowledge about SC agents, adding a rarely described pulmonary complication to the growing list of adverse effects associated with these products.

Cannabinoids and brain injury: therapeutic implications.

PubMed

Mechoulam, Raphael; Panikashvili, David; Shohami, Esther

2002-02-01

Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.

[Effect and occurrence of synthetic cannabinoids].

PubMed

Tuv, Silja Skogstad; Strand, Maren Cecilie; Karinen, Ritva; Øiestad, Elisabeth Leere; Christophersen, Asbjørg S; Vindenes, Vigdis

2012-10-30

''Spice'' is the term used for various products that contain synthetic cannabinoids. In recent years a growing number of products have been reported on the illegal market, also in Norway. The substances are sold over the internet as 'legal' cannabis. A number of the substances have gradually been classified as narcotics, also in Norway, but new variants continue to be developed. An overview is provided here of current knowledge of the efficacy and occurrence of synthetic cannabinoids. The article is based on a discretionary selection of relevant articles found by means of a literature search in PubMed and on reports from Norwegian and European authorities and research institutions. Synthetic cannabinoids are a large group of drugs of abuse that have an effect similar to cannabis, but may be considerably more potent. The contents of the various Spice products vary with respect to potency, purity and the number and types of additives, and this implies a risk of unintentional overdose. There are reports from abroad of cardiac infarction in teenagers, severe psychoses, anxiety, unconsciousness and deaths following use. Synthetic cannabinoids are marketed over the internet as legal and harmless cannabis, but can cause severe intoxication and death. There is a considerable need for more knowledge about the action and harmful effects of these substances.

Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

DTIC Science & Technology

2012-02-01

maximally efficacious synthetic cannabinoid that would ensure full activation of the cannabinoid receptors (1,2). We also expanded the spectrum of...of the data failed to demonstrate significance (fig 2A, B and C). We then expanded these experiments to the synthetic cannabinoid CP55,940 (CP55...radiation treatment in various breast cancer cell lines has the capacity to enhance the inhibition of tumor growth. Marijuana and its related

Implementation of a generic SFC-MS method for the quality control of potentially counterfeited medicinal cannabis with synthetic cannabinoids.

PubMed

Jambo, Hugues; Dispas, Amandine; Avohou, Hermane T; André, Sébastien; Hubert, Cédric; Lebrun, Pierre; Ziemons, Éric; Hubert, Philippe

2018-06-05

In this study, we describe the development of a SFC-MS method for the quality control of cannabis plants that could be potentially adulterated with synthetic cannabinoids. Considering the high number of already available synthetic cannabinoids and the high rate of development of novel structures, we aimed to develop a generic method suitable for the analysis of a large panel of substances using seventeen synthetic cannabinoids from multiple classes as model compounds. Firstly, a suitable column was chosen after a screening phase. Secondly, optimal operating conditions were obtained following a robust optimization strategy based on a design of experiments and design space methodology (DoE-DS). Finally, the quantitative performances of the method were assessed with a validation according to the total error approach. The developed method has a run time of 9.4 min. It uses a simple modifier composition of methanol with 2% H 2 O and requires minimal sample preparation. It can chromatographically separate natural cannabinoids (except THC-A and CBD-A) from the synthetics assessed. Also, the use of mass spectrometry provides sensitivity and specificity. Moreover, this quality by design (QbD) approach permits the tuning of the method (within the DS) during routine analysis to achieve a desirable separation since the future compounds that should be analyzed could be unknown. The method was validated for the quantitation of a selected synthetic cannabinoid in fiber-type cannabis matrix over the range of 2.5% - 7.5% (w/w) with LOD value as low as 14.4 ng/mL. This generic method should be easy to implement in customs or QC laboratories in the context of counterfeit drugs tracking. Copyright © 2018 Elsevier B.V. All rights reserved.

An outbreak of acute delirium from exposure to the synthetic cannabinoid AB-CHMINACA.

PubMed

Tyndall, Joseph A; Gerona, Roy; De Portu, Giuliano; Trecki, Jordan; Elie, Marie-Carmelle; Lucas, Judith; Slish, John; Rand, Kenneth; Bazydlo, Lindsay; Holder, Martina; Ryan, Matthew F; Myers, Paul; Iovine, Nicole; Plourde, Michelle; Weeks, Emily; Hanley, James R; Endres, Greg; St Germaine, Danielle; Dobrowolski, Paul J; Schwartz, Michael

2015-01-01

Synthetic cannabinoid containing products are a public health threat as reflected by a number of outbreaks of serious adverse health effects over the past 4 years. The designer drug epidemic is characterized by the rapid turnover of synthetic cannabinoid compounds on the market which creates a challenge in identifying the particular etiology of an outbreak, confirming exposure in cases, and providing current information to law enforcement. Between 28 May 2014 and 8 June 2014, 35 patients were evaluated and treated at the University of Florida Health Medical Center in Gainesville following reported exposure to a synthetic cannabinoid containing product obtained from a common source. Patients demonstrated acute delirium (24) and seizures (14), and five required ventilator support and ICU-level care; none died. The presence of N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (AB-CHMINACA), or one of its predicted metabolites was confirmed in 15 of 21 cases. A rapid public health response and aggressive public messaging prevented further morbidity, identified the source, and led to law enforcement seizure of the implicated product. The significance of this outbreak lies as much in the rapid occurrence of unpredictable, life-threatening adverse health effects from a newly identified synthetic cannabinoid compound as it does in the multidisciplinary investigation and novel partnership between local public health, the laboratory, and the chemical industry, resulting in termination of the outbreak. A coordinated response and collaboration between law enforcement, the local public health, emergency medical services and Health Center staff, were all key interventions in preventing a more substantial public health outbreak resulting from use of a novel synthetic cannabinoid compound. Real time collaborations between toxicology laboratories, suppliers of analytical standards and the public health system may be useful in the face of future novel chemical exposures.

The role of cannabinoid signaling in acute and chronic kidney diseases.

PubMed

Barutta, Federica; Bruno, Graziella; Mastrocola, Raffaella; Bellini, Stefania; Gruden, Gabriella

2018-04-26

The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid-induced AKI. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

The chemistry and pharmacology of synthetic cannabinoid SDB-006 and its regioisomeric fluorinated and methoxylated analogs.

PubMed

Banister, Samuel D; Olson, Alexander; Winchester, Matthew; Stuart, Jordyn; Edington, Amelia R; Kevin, Richard C; Longworth, Mitchell; Herrera, Marco; Connor, Mark; McGregor, Iain S; Gerona, Roy R; Kassiou, Michael

2018-01-19

Synthetic cannabinoids are the largest and most structurally diverse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogs of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CB 1 EC 50 = 19 nM). All methoxy- and fluorine-substituted analogs showed reduced potency compared to SDB-006, although the 2-fluorinated analog (EC 50 = 166 nM) was comparable to known synthetic cannabinoid RCS-4 (EC 50 = 146 nM). Using biotelemetry in rats, SDB-006 and RCS-4 evoked comparable reduction in body temperature (~0.7°C at a dose of 10 mg/kg), suggesting lower potency than the recent synthetic cannabinoid AB-CHMINACA (>2°C, 3 mg/kg). Copyright © 2018 John Wiley & Sons, Ltd.

Identification and analytical characterization of six synthetic cannabinoids NNL-3, 5F-NPB-22-7N, 5F-AKB-48-7N, 5F-EDMB-PINACA, EMB-FUBINACA, and EG-018.

PubMed

Liu, Cuimei; Jia, Wei; Hua, Zhendong; Qian, Zhenhua

2017-08-01

Clinical and forensic toxicology laboratories are continuously confronted by analytical challenges when dealing with the new psychoactive substances phenomenon. The number of synthetic cannabinoids, the chemical diversity, and the speed of emergence make this group of compounds particularly challenging in terms of detection, monitoring, and responding. Three indazole 7N positional isomer synthetic cannabinoids, two ethyl 2-amino-3-methylbutanoate-type synthetic cannabinoids, and one 9H-carbazole substituted synthetic cannabinoid were identified in seized materials. These six synthetic cannabinoid derivatives included: 1H-benzo[d] [1,2,3]triazol-1-yl 1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (NNL-3, 1), quinolin-8-yl 1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (5F-NPB-22-7N, 2), N-((1 s,3 s)-adamantan-1-yl)-1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (5F-AKB-48-7N, 3), ethyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (5F-EDMB-PINACA, 4), ethyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (EMB-FUBINACA, 5), and naphthalen-1-yl(9-pentyl-9H-carbazol-3-yl)methanone (EG-018, 6). The identification was based on ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance spectroscopy (NMR). The analytical characterization of these six synthetic cannabinoids was described, so as to assist forensic laboratories in identifying these compounds or other substances with similar structure in their case work. To our knowledge, no analytical data about the compounds 1-5 have appeared until now, making this the first report on these compounds. The GC-MS data of 6 has been reported, but this study added the LC-MS, NMR, and Fourier transform infrared (FTIR), data to render the analytical data collection process more complete. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Speckle-tracking strain assessment of left ventricular dysfunction in synthetic cannabinoid and heroin users.

PubMed

Demirkıran, Aykut; Albayrak, Neslihan; Albayrak, Yakup; Zorkun, Cafer Sadık

2018-06-01

There is growing evidence regarding the numerous adverse effects of synthetic cannabinoids (SCBs) on the cardiovascular system; however, no studies have shown the cardiovascular effects of opioids using strain echocardiography. This study examines the cardiac structure and function using echocardiographic strain imaging in heroin and synthetic cannabinoid users. This double-blind study included patients who were admitted or referred to a rehabilitation center for heroin (n=31) and synthetic cannabinoid users (n=30). Heroin users and synthetic cannabinoid users were compared with healthy volunteers (n=32) using two-dimensional (2D) speckle-tracking (ST) echocardiography. No differences were found in the baseline characteristics and 2D echocardiography values. The mean global longitudinal strain value was -20.5%±2.4% for SCB users, -22.3%±2.4% for opioid users, and -22.5%±2.2% for healthy volunteers (p=0.024). The mean apical 2-chamber (AP2C) L-strain values were -20.1%±3.1%, -22.4%±3.0%, and -22.3%±2.8% for SCB users, opioid users, and healthy volunteers, respectively (p=0.032). The mean apical 4-chamber (AP4C) L-strain values were -20.7%±2.5% for SCB users, -23.2%±3.2% for opioid users, and -23.8%±3.1% for healthy volunteers (p<0.001). SCBs are potential causes of subclinical left ventricular dysfunction.

A synthetic cannabinoid FDU-NNEI, two 2H-indazole isomers of synthetic cannabinoids AB-CHMINACA and NNEI indazole analog (MN-18), a phenethylamine derivative N-OH-EDMA, and a cathinone derivative dimethoxy-α-PHP, newly identified in illegal products.

PubMed

Uchiyama, Nahoko; Shimokawa, Yoshihiko; Kikura-Hanajiri, Ruri; Demizu, Yosuke; Goda, Yukihiro; Hakamatsuka, Takashi

Six new psychoactive substances were identified together with two other substances (compounds 1 - 8 ) in illegal products by our ongoing survey in Japan between January and July 2014. A new synthetic cannabinoid, FDU-NNEI [1-(4-fluorobenzyl)- N -(naphthalen-1-yl)-1 H -indole-3-carboxamide, 2 ], was detected with the newly distributed synthetic cannabinoid FDU-PB-22 ( 1 ). Two 2 H -indazole isomers of synthetic cannabinoids, AB-CHMINACA 2 H -indazole analog ( 3 ) and NNEI 2 H -indazole analog ( 4 ), were newly identified with 1 H -indazoles [AB-CHMINACA and NNEI indazole analog (MN-18)]. In addition, 2-methylpropyl N -(naphthalen-1-yl) carbamate ( 5 ) and isobutyl 1-pentyl-1 H -indazole-3-carboxylate ( 6 ) were detected in illegal products. Compound 6 is considered to be a by-product of the preparation of NNEI indazole analog from compound 5 and 1-pentyl-1 H -indazole. A phenethylamine derivative, N -OH-EDMA [ N -hydroxy-3,4-ethylenedioxy- N -methylamphetamine, 7 ], and a cathinone derivative, dimethoxy-α-PHP (dimethoxy-α-pyrrolidinohexanophenone, 8 ), were newly identified in illegal products. Among them, compounds 1 and 8 have been controlled as designated substances (Shitei-Yakubutsu) under the Pharmaceutical Affairs Law in Japan since August and November 2014, respectively.

[Testing the pharmacological activity of some synthetic cannabinoids in mice (author's transl)].

PubMed

Ganz, A J; Waser, P G

1980-01-01

A series of synthetic cannabinoids were tested in mice for analgesic, anticonvulsant, sedative and reserpine antagonistic properties as well as for influence on body temperature and on motor coordination and compared with the natural delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC) and cannabidiol (CBD). All cannabinoids were injected s.c. or i.p. in mice as solutions in olive oil. The synthetic cannabinoids, with the exception of the lipophilic ones, were less active than the natural delta 9-THC. 1',1'-dimethyl-delta 8-tetrahydrocannabinol (DM-delta 8-THC) has an analgesic ED 50 of 16 mg/kg s.c. (writhing test) and is three times more active than delta 9-THC, but also eight times less active than morphine. The lipophilic derivatives of delta 8-THC prolonged pentobarbitone narcosis and diminished locomotor activity in mice. Anticonvulsant activities could never be detected; all cannabinoids slightly diminished body temperature and antagonized weakly the hypothermia induced by reserpine. The trained capacity of remaining on the rotating rod was severely shortened for a long time after application of all cannabinoids but mainly by the lipophilic ones. The influence of derivation on the activity of delta 9-THC is discussed.

The Use of Cannabinoids in Treating Dementia.

PubMed

Weier, Megan; Hall, Wayne

2017-08-01

To review and summarise the current evidence on the safety and efficacy of using cannabinoids to treat behavioural and neuropsychiatric symptoms of dementia. Two randomised controlled trials testing a synthetic form of tetrahydrocannabinol have shown that while well tolerated, there was no significant therapeutic effect, based on changes to scores on the neuropsychiatric inventory (NPI). Case reports and open label trials have indicated that there may be some therapeutic benefit of adding synthetic cannabinoids as an adjunctive therapy to reduce agitation, aberrant motor behaviour and nighttime behaviour. More well-controlled clinical trials in older populations with varying severity of dementia are needed to evaluate the effectiveness of cannabinoids in treating behaviour symptoms of dementia. We provide suggestions for designing such trials and evaluating possible adverse effects of cannabinoids on cognitive and neuropsychiatric functioning.

Rapid and sensitive detection of synthetic cannabinoids AMB-FUBINACA and α-PVP using surface enhanced Raman scattering (SERS)

NASA Astrophysics Data System (ADS)

Islam, Syed K.; Cheng, Yin Pak; Birke, Ronald L.; Green, Omar; Kubic, Thomas; Lombardi, John R.

2018-04-01

The application of surface enhanced Raman scattering (SERS) has been reported as a fast and sensitive analytical method in the trace detection of the two most commonly known synthetic cannabinoids AMB-FUBINACA and alpha-pyrrolidinovalerophenone (α-PVP). FUBINACA and α-PVP are two of the most dangerous synthetic cannabinoids which have been reported to cause numerous deaths in the United States. While instruments such as GC-MS, LC-MS have been traditionally recognized as analytical tools for the detection of these synthetic drugs, SERS has been recently gaining ground in the analysis of these synthetic drugs due to its sensitivity in trace analysis and its effectiveness as a rapid method of detection. This present study shows the limit of detection of a concentration as low as picomolar for AMB-FUBINACA while for α-PVP, the limit of detection is in nanomolar concentration using SERS.

Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health

PubMed Central

Weinstein, Aviv M.; Rosca, Paola; Fattore, Liana; London, Edythe D.

2017-01-01

As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment. PMID:28878698

Molecularly imprinted polymer based quartz crystal microbalance sensor system for sensitive and label-free detection of synthetic cannabinoids in urine.

PubMed

Battal, Dilek; Akgönüllü, Semra; Yalcin, M Serkan; Yavuz, Handan; Denizli, Adil

2018-07-15

Herein, we prepared a novel quartz crystal microbalance (QCM) sensor for synthetic cannabinoids (JWH-073, JWH-073 butanoic acid, JWH-018 and JWH-018 pentanoic acid,) detection. Firstly, the synthetic cannabinoid (SCs) imprinted (MIP) and non-imprinted (NIP) nanoparticles were synthesized by mini-emulsion polymerization system. The SCs-imprinted nanoparticles were first characterized by SEM, TEM, zeta-size and FTIR-ATR analysis and then were dropped onto the gold QCM surface. The SCs-imprinted QCM sensor was characterized by an ellipsometer, contact angle, and AFM. The limit of detection was found as 0.3, 0.45, 0.4, 0.2 pg/mL JWH-018, JWH-073, JWH-018 pentanoic acid and JWH-073 butanoic acid, respectively. The selectivity of the SCs-imprinted QCM sensor was shown by using JWH-018, JWH-018 pentanoic acid, JWH-073 and JWH-073 butanoic acid. According to the results, the SCs-imprinted QCM sensors show highly selective and sensitive in a broad range of synthetic cannabinoid concentrations (0.0005-1.0 ng/mL) in both aqueous and synthetic urine solutions. Copyright © 2018 Elsevier B.V. All rights reserved.

Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

PubMed

Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

2016-03-14

The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Separation and structural characterization of the new synthetic cannabinoid JWH-018 cyclohexyl methyl derivative "NE-CHMIMO" using flash chromatography, GC-MS, IR and NMR spectroscopy.

PubMed

Angerer, Verena; Bisel, Philippe; Moosmann, Bjoern; Westphal, Folker; Auwärter, Volker

2016-09-01

Synthetic cannabinoids have become an integral part of the drugs of abuse market since many years. The most frequent form of consumption for this class of substances is smoking of herbal mixtures purchased via the Internet. In this article the identification and structure elucidation of a new synthetic cannabinoid, [1-(cyclohexylmethyl)-1H-indol-3-yl](naphthalen-1-yl)methanone, is described. The compound was found along with 5F-ADB in a 'herbal mixture' called 'Jamaican Gold Extreme', which was sent to our laboratory in the context of a suspected intoxication. For isolation of the substance a flash chromatography separation was applied. Structure elucidation was performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography solid-state infrared (GC-sIR) and nuclear magnetic resonance (NMR) analysis. The new compound can be described as the cyclohexyl methyl derivative of the first generation synthetic cannabinoid JWH-018, and the authors suggest to use "NE-CHMIMO" as a semisystematic name. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Spice: A New Legal Herbal Mixture Abused by Young Active Duty Military Personnel

DTIC Science & Technology

2012-01-01

ABSTRACT. Spice is an herbal mixture smoked for euphoria and mixed with synthetic cannabinoids that are undetected on urine drug screens. Spice use has...more paranoia and hallucinations, and may differ for each brand. KEYWORDS. Cannabinoid, military, spice, substance abuse INTRODUCTION Use of synthetic ...regu- lations in an attempt to decrease the use of such synthetic psychoactive substances (1). There are few reports of Spice use and its potential

Looking back at Cannabis research.

PubMed

Mechoulam, R

2000-09-01

Research leading to the isolation of the plant cannabinoids during the 1960 s and to the endogenous cannabinoids, during the 1990 s is described. Investigations on two non-psychotropic, synthetic cannabinoids, HU-211, a neuroprotective agent and HU-308, a specific CB2 agonist are presented.

Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry.

PubMed

Scheidweiler, Karl B; Jarvis, Michael J Y; Huestis, Marilyn A

2015-01-01

Clandestine laboratories constantly produce new synthetic cannabinoids to circumvent legislative scheduling efforts, challenging and complicating toxicological analysis. Sundstrom et al. (Anal Bioanal Chem 405(26):8463-8474, [9]) and Kronstrand et al. (Anal Bioanal Chem 406(15):3599-3609, [10]) published nontargeted liquid chromatography, high-resolution, quadrupole/time-of-flight mass spectrometric (LC-QTOF) assays with validated detection of 18 and 38 urinary synthetic cannabinoid metabolites, respectively. We developed and validated a LC-QTOF urine method for simultaneously identifying the most current 47 synthetic cannabinoid metabolites from 21 synthetic cannabinoid families (5-fluoro AB-PINACA, 5-fluoro-AKB48, 5-fluoro PB-22, AB-PINACA, ADB-PINACA, AKB48, AM2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, JWH-398, MAM2201, PB-22, RCS-4, UR-144, and XLR11). β-Glucuronidase-hydrolyzed urine was extracted with 1-mL Biotage SLE+ columns. Specimens were reconstituted in 150-μL mobile phase consisting of 80% A (0.1% formic acid in water) and 20% B (0.1% formic acid in acetonitrile). Fifty microliters was injected, and SWATH™ MS data were acquired in positive electrospray mode. The LC-QTOF instrument consisted of a Shimadzu UFLCxr system and an ABSciex 5600+ TripleTOF® mass spectrometer. Gradient chromatographic separation was achieved with a Restek Ultra Biphenyl column with a 0.5-mL/min flow rate and an overall run time of 15 min. Identification criteria included molecular ion mass error, isotopic profiles, retention time, and library fit criteria. Limits of detection were 0.25-5 μg/L (N = 10 unique fortified urine samples), except for two PB-22 metabolites with limits of 10 and 20 μg/L. Extraction efficiencies and matrix effects (N = 10) were 55-104 and -65-107%, respectively. We present a highly useful novel LC-QTOF method for simultaneously confirming 47 synthetic cannabinoid metabolites in human urine.

Endocannabinoid System: A Multi-Facet Therapeutic Target.

PubMed

Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

2016-01-01

Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve "protective role" in many medical conditions. Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists. One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that act selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted. Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids. In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as "protective" and "disease inducing substance", time-dependent changes in the expression of cannabinoid receptors.

Cannabinoid-based medicines for neurological disorders--clinical evidence.

PubMed

Wright, Stephen

2007-08-01

Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU.

Intraperirhinal cortex administration of the synthetic cannabinoid, HU210, disrupts object recognition memory in rats.

PubMed

Sticht, Martin A; Jacklin, Derek L; Mechoulam, Raphael; Parker, Linda A; Winters, Boyer D

2015-03-25

Cannabinoids disrupt learning and memory in human and nonhuman participants. Object recognition memory, which is particularly susceptible to the impairing effects of cannabinoids, relies critically on the perirhinal cortex (PRh); however, to date, the effects of cannabinoids within PRh have not been assessed. In the present study, we evaluated the effects of localized administration of the synthetic cannabinoid, HU210 (0.01, 1.0 μg/hemisphere), into PRh on spontaneous object recognition in Long-Evans rats. Animals received intra-PRh infusions of HU210 before the sample phase, and object recognition memory was assessed at various delays in a subsequent retention test. We found that presample intra-PRh HU210 dose dependently (1.0 μg but not 0.01 μg) interfered with spontaneous object recognition performance, exerting an apparently more pronounced effect when memory demands were increased. These novel findings show that cannabinoid agonists in PRh disrupt object recognition memory. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Clinical and financial implications of emergency department visits for synthetic marijuana.

PubMed

Rowley, Eric; Benson, David; Tiffee, Aaron; Hockensmith, Adam; Zeng, Henry; Jones, Glenn N; Musso, Mandi W

2017-10-01

Many users believe that synthetic cannabinoids offer a safe and legal means of getting high. However, spikes in emergency department visits have been associated with use of synthetic cannabinoids. The purpose of the current study was to document emergency department visits from three large hospitals in one metropolitan area over a two month period. This was a retrospective chart review examining 218 patients presenting to three inner city emergency departments between March and April 2014. Data collected included demographic information, information regarding ED diagnosis and treatment, signs and symptoms, ancillary testing, ED disposition, and cost of the medical treatment. The majority of patients (75.7%) were discharged after ED workup, but 12.4% were admitted for medical treatment and 11.5% were admitted for psychiatric treatment. Ten patients (4.6%) were admitted to the ICU. Symptoms experienced most frequently include: hypertension, tachycardia, agitation, drowsiness, nausea, and confusion. Cluster analysis revealed four symptom clusters of individuals presenting after using synthetic cannabinoids: 1) confusion, hostility, agitation, 2) nausea, vomiting, abdominal pain, 3) drowsiness, and 4) the absence of these symptoms. This study has three important findings. First, significant ED resources are being used to treat individuals presenting due to effects of synthetic cannabis. Second, synthetic cannabis is not a benign substance. Third, while the hostile and agitated user is generally presented in the media, this study finds significant heterogeneity in presentation. Further research is needed to fully understand the implications of synthetic cannabinoid use. Copyright © 2017 Elsevier Inc. All rights reserved.

"Zombie" Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York.

PubMed

Adams, Axel J; Banister, Samuel D; Irizarry, Lisandro; Trecki, Jordan; Schwartz, Michael; Gerona, Roy

2017-01-19

New psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a "zombie" outbreak because of the appearance of the intoxicated persons. We obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal "incense" product "AK-47 24 Karat Gold," which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography-quadrupole time-of-flight mass spectrometry. The synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB) was identified in AK-47 24 Karat Gold at a mean (±SD) concentration of 16.0±3.9 mg per gram. The de-esterified acid metabolite was found in the serum or whole blood of all eight patients, with concentrations ranging from 77 to 636 ng per milliliter. The potency of the synthetic cannabinoid identified in these analyses is consistent with strong depressant effects that account for the "zombielike" behavior reported in this mass intoxication. AMB-FUBINACA is an example of the emerging class of "ultrapotent" synthetic cannabinoids and poses a public health concern. Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action.

Toward drugs derived from cannabis.

PubMed

Mechoulam, R; Carlini, E A

1978-04-01

Recent work aimed at the introduction of natural and synthetic cannabinoids as drugs is reviewed. Delta1-Tetrahydrocannabinol (delta1-THC) is mainly investigated as a potential drug against glaucoma and asthma, and as an antiemetic agent in cancer chemotherapy. Cannabidiol is being tried in the clinic against epilepsy and as a hypnotic. Numerous synthetic cannabinoids are currently being investigated as analgetics and as sedative-relaxants.

Identification of Eight Synthetic Cannabinoids, Including 5F-AKB48 in Seized Herbal Products Using DART-TOF-MS and LC-QTOF-MS as Nontargeted Screening Methods.

PubMed

Moore, Katherine N; Garvin, Demetra; Thomas, Brian F; Grabenauer, Megan

2017-09-01

Synthetic cannabinoids are sprayed onto plant material and smoked for their marijuana-like effects. Clandestine manufacturers modify synthetic cannabinoid structures by creating closely related analogs. Forensic laboratories are tasked with detection of these analog compounds, but targeted analytical methods are often thwarted by the structural modifications. Here, direct analysis in real time coupled to accurate mass time-of-flight mass spectrometry (DART-TOF-MS) in combination with liquid chromatography quadruple time-of-flight mass spectrometry (LC-QTOF-MS) are presented as a screening and nontargeted confirmation method, respectively. Methanol extracts of herbal material were run using both methods. Spectral data from four different herbal products were evaluated by comparing fragmentation pattern, accurate mass and retention time to available reference standards. JWH-018, JWH-019, AM2201, JWH-122, 5F-AKB48, AKB48-N-(4-pentenyl) analog, UR144, and XLR11 were identified in the products. Results demonstrate that DART-TOF-MS affords a useful approach for rapid screening of herbal products for the presence and identification of synthetic cannabinoids. © 2017 American Academy of Forensic Sciences.

Schedules of controlled substances: temporary placement of three synthetic cannabinoids into Schedule I. Final order.

PubMed

2013-05-16

The Deputy Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule three synthetic cannabinoids under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144), [1-(5-fluoro-pentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (5-fluoro-UR-144, XLR11) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA, AKB48). This action is based on a finding by the Deputy Administrator that the placement of these synthetic cannabinoids and their salts, isomers and salts of isomers into Schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the full effect of the CSA and the Controlled Substances Import and Export Act (CSIEA) and their implementing regulations including criminal, civil and administrative penalties, sanctions and regulatory controls of Schedule I substances will be imposed on the manufacture, distribution, possession, importation, and exportation of these synthetic cannabinoids.

Metabolome disruption of the rat cerebrum induced by the acute toxic effects of the synthetic cannabinoid MAM-2201.

PubMed

Zaitsu, Kei; Hayashi, Yumi; Suzuki, Kei; Nakayama, Hiroshi; Hattori, Nanpei; Takahara, Rina; Kusano, Maiko; Tsuchihashi, Hitoshi; Ishii, Akira

2015-09-15

The aim of this study is to investigate the metabolome disruption in the rat cerebrum induced by the recently abused synthetic cannabinoid MAM-2201. MAM-2201 was intraperitoneally administered to 6-week Wistar rats at 5 or 15mg/kg (n=5), and the cerebrum metabolome alteration was investigated using a gas chromatography/tandem mass spectrometry (GC/MS/MS)-based metabolomics technique. MAM-2201 induced oligopnea and hypokinesia at the 5mg/kg dose, while more abnormal symptoms like rotational and seizure-like behaviors were observed at the 15mg/kg dose, suggesting that MAM-2201 induced neurofunctional disruptions. GC/MS/MS detected 72 metabolites in the rat cerebrum. The cerebrum levels of 12 of these metabolites, including intermediates of the tricarboxylic acid cycle (malic acid and succinic acid) and glutamic acid (Glu), were significantly changed in MAM-2201 administered groups compared to the control group. The synthetic cannabinoid MAM-2201 can disrupt not only glutamatergic neurotransmission but also energy metabolism in the rat cerebrum. Such disruption may contribute to the abnormal symptoms induced by synthetic cannabinoids. Copyright © 2015 Elsevier Inc. All rights reserved.

Sickle Cell Crisis Complicated by Synthetic Cannabinoid Abuse: A Case Report.

PubMed

Zheng, Crystal Y; Minniti, Caterina P; Chaitowitz, Mark H

2016-06-01

We describe a case of delirium occurring in a hospitalized sickle cell patient. Following admission for a typical pain crisis, the patient continued to report unrelieved pain with marked agitation for several days, despite escalating doses of opioid analgesia, and ultimately required intubation following development of acute chest syndrome (ACS). After some delay, it was discovered that he had been using a synthetic cannabinoid (K2) which may have precipitated his pain crisis and, with hindsight, explained his prolonged period of delirium. Delayed recognition was due to multiple factors, notably the absence of an index of suspicion for this novel drug, the presence of alternate explanations for the patient's altered mental status, and the fact that reliable laboratory screening for synthetic cannabinoids is currently not widely available.

Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial.

PubMed

Côté, Mathieu; Trudel, Mathieu; Wang, Changshu; Fortin, André

2016-04-01

Patients treated for head and neck carcinomas experience a significant deterioration of their quality of life during treatments because of severe side effects. Nabilone has many properties that could alleviate symptoms caused by radiotherapy and improve patients' quality of life. The aim of the present study was to compare the effects of nabilone versus placebo on the quality of life and side effects during radiotherapy for head and neck carcinomas. Fifty-six patients were randomized to nabilone or placebo. Patients filled the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H&N35; three independent questionnaires assessing appetite, nausea, and toxicity; and a visual analog scale for pain. These data were collected before radiotherapy, each week during radiotherapy, and 4 weeks after radiotherapy. Patients were weighed every week. Nabilone did not lengthen the time necessary for a 15% deterioration of quality of life (P = .4279), and it was not better than placebo for relieving symptoms like pain (P = .6048), nausea (P = .7105), loss of appetite (P = .3295), weight (P = .1454), mood (P = .3214), and sleep (P = .4438). At the dosage used, nabilone was not potent enough to improve the patients' quality of life over placebo. © The Author(s) 2015.

Simultaneous determination of five naphthoylindole-based synthetic cannabinoids and metabolites and their deposition in human and rat hair.

PubMed

Kim, Jihyun; Park, Yuran; Park, Meejung; Kim, Eunmi; Yang, Wonkyung; Baeck, Seungkyung; Lee, Sooyeun; Han, Sangbeom

2015-01-01

The continuing appearance of new synthetic cannabinoids has been a major issue in the field of forensic and clinical toxicology. In response to that, analytical methods for synthetic cannabinoids have been increasingly established in a variety of biological matrices. Since most of synthetic cannabinoids with structure similarity share some enzymatic metabolites, making the interpretation of analytical results and the discovery of the parent drug actually ingested very complicated, the investigation on metabolites of the first generation of synthetic cannabinoids with their relatively short side chains in chemical structure could be more important. Therefore, in the present study, we developed the analytical method for AM-2201, JWH-122 and MAM-2201 with JWH-018 as a precursor and their monohydroxylated metabolites in hair matrix. Also, using a rat model, AM-2201 and its monohydroxylated metabolites were identified and then the ratios of metabolite-to-parent drug were estimated to be used as criteria on external contamination. All analytes were extracted with methanol from washed and cut hair samples and the extracts were injected into LC-MS/MS with electrospray ion source in the positive ionization mode. Matrix effect and recovery were evaluated in hair matrices and no significant variations were observed. The validation results for precision and accuracy were satisfactory in both human and rat hair. The LOD and LOQ were 0.5 pg/10mg and 1.0 pg/10mg in human hair and 0.5 pg/20mg and 1.0 pg/20mg in pigmented and non-pigmented rat hair, respectively. Additionally, as a result of the animal study, there were not significant differences in the effect of pigmentation on the distribution of AM-2201 and its monohydroxylated metabolites in hair. Wide variations were observed for the concentrations of the naphthoylindole-based synthetic cannabinoids and metabolites in authentic hair samples from nine cases; those were 0.4-59.2 pg/mg for JWH-018, 0.1-0.8 pg/mg for JWH-073, 1.7-739.0 pg/mg for AM-2201, 0.1-402.0 pg/mg for JWH-122, 0.2-276.0 pg/mg for MAM-2201, 0.2-1.1 pg/mg for JWH-018 N-COOH, 0.3-37.2 pg/mg for JWH-018 N-5-OH, 0.3 pg/mg for JWH-073 N-COOH, 0.4 pg/mg for AM-2201 N-4-OH, 0.2-3.1 pg/mg for AM-2201 N-6-OHindole and 0.1-3.5 pg/mg for JWH-122 N-5-OH. This quantitative LC-MS/MS analytical method for five naphthoylindole-based synthetic cannabinoids and their metabolites was very useful to be applied to authentic hair samples, of which their analytical results suggested the incorporation of synthetic cannabinoids in the hair matrix and provided the information on ingested parent drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds.

PubMed

Dresen, Sebastian; Ferreirós, Nerea; Pütz, Michael; Westphal, Folker; Zimmermann, Ralf; Auwärter, Volker

2010-10-01

Herbal mixtures like 'Spice' with potentially bioactive ingredients were available in many European countries since 2004 and are still widely used as a substitute for cannabis, although merchandized as 'herbal incense'. After gaining a high degree of popularity in 2008, big quantities of these drugs were sold. In December 2008, synthetic cannabinoids were identified in the mixtures which were not declared as ingredients: the C(8) homolog of the non-classical cannabinoid CP-47,497 (CP-47,497-C8) and a cannabimimetic aminoalkylindole called JWH-018. In February 2009, a few weeks after the German legislation put these compounds and further pharmacologically active homologs of CP-47,497 under control, another cannabinoid appeared in 'incense' products: the aminoalkylindole JWH-073. In this paper, the results of monitoring of commercially available 'incense' products from June 2008 to September 2009 are presented. In this period of time, more than 140 samples of herbal mixtures were analyzed for bioactive ingredients and synthetic cannabimimetic substances in particular. The results show that the composition of many products changed repeatedly over time as a reaction to prohibition and prosecution of resellers. Therefore neither the reseller nor the consumer of these mixtures can predict the actual content of the 'incense' products. As long as there is no possibility of generic definitions in the controlled substances legislation, further designer cannabinoids will appear on the market as soon as the next legal step has been taken. This is affirmed by the recent identification of the aminoalkylindoles JWH-250 and JWH-398. As further cannabinoids can be expected to occur in the near future, a continuous monitoring of these herbal mixtures is required. The identification of the synthetic opioid O-desmethyltramadol in a herbal mixture declared to contain 'kratom' proves that the concept of selling apparently natural products spiked with potentially dangerous synthetic chemicals/pharmaceuticals is a continuing trend on the market of 'legal highs'. Copyright © 2010 John Wiley & Sons, Ltd.

Evidence for the use of "medical marijuana" in psychiatric and neurologic disorders.

PubMed

Noel, Christopher

2017-01-01

Cannabis is listed as a Schedule I substance under the Controlled Substances Act of 1970, meaning the US federal government defines it as an illegal drug that has high potential for abuse and no established medical use; however, half of the states in the nation have enacted "medical marijuana" (MM) laws. Clinicians must be aware of the evidence for and against the use of MM in their patients who may consider using this substance. A PubMed database search was performed using the text string: "Cannabis"[Mesh] OR "Marijuana Abuse"[Mesh] OR "Medical Marijuana"[Mesh] OR "Marijuana Smoking"[Mesh] OR "cannabi*" OR "tetrahydrocannabinol." The search was further limited to randomized clinical trial publications in English on human subjects to identify articles regarding the therapeutic use of phytocannabinoids for psychiatric and neurologic disorders. Commercially available products (ie, dronabinol, nabilone, nabiximols) and synthetic cannabinoids were excluded from the review. Publications were identified that included patients with dementia, multiple sclerosis, Parkinson disease, Huntington disease, schizophrenia, social anxiety disorder, depression, tobacco use disorder, and neuropathic pain. There is great variety concerning which medical conditions are approved for treatment with MM for either palliative or therapeutic benefit, depending on the state law. It is important to keep an evidence-based approach in mind, even with substances considered to be illegal under US federal law. Clinicians must weigh risks and benefits of the use of MM in their patients and should ensure that patients have tried other treatment modalities with higher levels of evidence for use when available and appropriate.

A comprehensive library-based, automated screening procedure for 46 synthetic cannabinoids in serum employing liquid chromatography-quadrupole ion trap mass spectrometry with high-temperature electrospray ionization.

PubMed

Huppertz, Laura M; Kneisel, Stefan; Auwärter, Volker; Kempf, Jürgen

2014-02-01

Considering the vast variety of synthetic cannabinoids and herbal mixtures - commonly known as 'Spice' or 'K2' - on the market and the resulting increase of severe intoxications related to their consumption, there is a need in clinical and forensic toxicology for comprehensive up-to-date screening methods. The focus of this project aimed at developing and implementing an automated screening procedure for the detection of synthetic cannabinoids in serum using a liquid chromatography-ion trap-MS (LC-MS(n)) system and a spectra library-based approach, currently including 46 synthetic cannabinoids and 8 isotope labelled analogues. In the process of method development, a high-temperature ESI source (IonBooster(TM), Bruker Daltonik) and its effects on the ionization efficiency of the investigated synthetic cannabinoids were evaluated and compared to a conventional ESI source. Despite their structural diversity, all investigated synthetic cannabinoids benefitted from high-temperature ionization by showing remarkably higher MS intensities compared to conventional ESI. The employed search algorithm matches retention time, MS and MS(2)/MS(3) spectra. With the utilization of the ionBooster source, limits for the automated detection comparable to cut-off values of routine MRM methods were achieved for the majority of analytes. Even compounds not identified when using a conventional ESI source were detected using the ionBooster-source. LODs in serum range from 0.1 ng/ml to 0.5 ng/ml. The use of parent compounds as analytical targets offers the possibility of instantly adding new emerging compounds to the library and immediately applying the updated method to serum samples, allowing the rapid adaptation of the screening method to ongoing forensic or clinical requirements. The presented approach can also be applied to other specimens, such as oral fluid or hair, and herbal mixtures and was successfully applied to authentic serum samples. Quantitative MRM results of samples with analyte concentrations above the determined LOD were confirmed as positive findings by the presented method. Copyright © 2014 John Wiley & Sons, Ltd.

Immunomodulatory properties of kappa opioids and synthetic cannabinoids in HIV-1 neuropathogenesis.

PubMed

Hu, Shuxian; Sheng, Wen S; Rock, Robert Bryan

2011-12-01

Anti-retroviral therapy (ART) has had a tremendous impact on the clinical outcomes of HIV-1 infected individuals. While ART has produced many tangible benefits, chronic, long-term consequences of HIV infection have grown in importance. HIV-1-associated neurocognitive disorder (HAND) represents a collection of neurological syndromes that have a wide range of functional cognitive impairments. HAND remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Based upon work in other models of neuroinflammation, kappa opioid receptors (KOR) and synthetic cannabinoids have emerged as having neuroprotective properties and the ability to dampen pro-inflammatory responses of glial cells; properties that may have a positive influence in HIV-1 neuropathogenesis. The ability of KOR ligands to inhibit HIV-1 production in human microglial cells and CD4 T lymphocytes, demonstrate neuroprotection, and dampen chemokine production in astrocytes provides encouraging data to suggest that KOR ligands may emerge as potential therapeutic agents in HIV neuropathogenesis. Based upon findings that synthetic cannabinoids inhibit HIV-1 expression in human microglia and suppress production of inflammatory mediators such as nitric oxide (NO) in human astrocytes, as well as a substantial literature demonstrating neuroprotective properties of cannabinoids in other systems, synthetic cannabinoids have also emerged as potential therapeutic agents in HIV neuropathogenesis. This review focuses on these two classes of compounds and describes the immunomodulatory and neuroprotective properties attributed to each in the context of HIV neuropathogenesis.

From "herbal highs" to the "heroin of cannabis": Exploring the evolving discourse on synthetic cannabinoid use in a Norwegian Internet drug forum.

PubMed

Bilgrei, Ola Røed

2016-03-01

In the early 2000s, online vendors began selling an array of so-called "legal highs"--apparently organic produce made from exotic herbs. Simultaneously, members of online drug discussion forums began to debate the alleged effects of the new drugs, creating an enormous base of user-derived information based on personal experiences. This study combines the historical data spanning a seven-year period derived from a Norwegian drug discussion forum about synthetic cannabinoids and interviews with 14 male forum members who all had experience with the drug. By combining the two sources, this study reveals not only the evolving discourse on synthetic cannabinoid use but also how forum members related to the online information that they gathered and co-produced. Analysis of the evolving online discourse revealed three distinct phases. The first was an enthusiastic phase, with users embracing the new drugs. The second was a phase characterized by growing ambivalence and scepticism towards use of the drugs. The third was one in which members of the community rejected the new drugs based on negative reviews from users. The analysis displays the communal process whereby members co-operate in the exchange of an extensive body of knowledge accumulated about synthetic cannabinoids, and the way in which this evolving discourse influences members of the forum in their views and representations of the drugs. Paradoxically, the online discussions of synthetic cannabinoids, which had great significance for their proliferation when they were initially introduced to the market, now seem to be a deterrent. The role of online drug communities in the development of new drug trends should receive renewed attention. Copyright © 2016 Elsevier B.V. All rights reserved.

Oral fluid vs. Urine Analysis to Monitor Synthetic Cannabinoids and Classic Drugs Recent Exposure

PubMed Central

Blandino, Vincent; Wetzel, Jillian; Kim, Jiyoung; Haxhi, Petrit; Curtis, Richard; Concheiro, Marta

2018-01-01

Background Urine is a common biological sample to monitor recent drug exposure, and oral fluid is an alternative matrix of increasing interest in clinical and forensic toxicology. Limited data are available about oral fluid vs. urine drug disposition, especially for synthetic cannabinoids. Objective To compare urine and oral fluid as biological matrices to monitor recent drug exposure among HIV-infected homeless individuals. Methods Seventy matched urine and oral fluid samples were collected from 13 participants. Cannabis, amphetamines, benzodiazepines, cocaine and opiates were analyzed in urine by the enzyme-multiplied-immunoassay-technique and in oral fluid by liquid chromatography tandem mass spectrometry (LC-MSMS). Eleven synthetic cannabinoids were analyzed in urine and in oral fluid by LC-MSMS. Results Five oral fluid samples were positive for AB-FUBINACA. In urine, 4 samples tested positive for synthetic cannabinoids PB-22, 5-Fluoro-PB-22, AB-FUBINACA, and metabolites UR-144 5-pentanoic acid and UR-144 4-hydroxypentyl. In only one case, oral fluid and urine results matched, both specimens being AB-FUBINACA positive. For cannabis, 40 samples tested positive in urine and 30 in oral fluid (85.7% match). For cocaine, 37 urine and 52 oral fluid samples were positive (75.7% match). Twenty-four urine samples were positive for opiates, and 25 in oral fluid (81.4% match). For benzodiazepines, 23 samples were positive in urine and 25 in oral fluid (85.7% match). Conclusion/Discussion These results offer new information about drugs disposition between urine and oral fluid. Oral fluid is a good alternative matrix to urine for monitoring cannabis, cocaine, opiates and benzodiazepines recent use; however, synthetic cannabinoids showed mixed results. PMID:29173162

Oral Fluid vs. Urine Analysis to Monitor Synthetic Cannabinoids and Classic Drugs Recent Exposure.

PubMed

Blandino, Vincent; Wetzel, Jillian; Kim, Jiyoung; Haxhi, Petrit; Curtis, Richard; Concheiro, Marta

2017-01-01

Urine is a common biological sample to monitor recent drug exposure, and oral fluid is an alternative matrix of increasing interest in clinical and forensic toxicology. Limited data are available about oral fluid vs. urine drug disposition, especially for synthetic cannabinoids. To compare urine and oral fluid as biological matrices to monitor recent drug exposure among HIV-infected homeless individuals. Seventy matched urine and oral fluid samples were collected from 13 participants. Cannabis, amphetamines, benzodiazepines, cocaine and opiates were analyzed in urine by the enzyme-multipliedimmunoassay- technique and in oral fluid by liquid chromatography tandem mass spectrometry (LCMSMS). Eleven synthetic cannabinoids were analyzed in urine and in oral fluid by LC-MSMS. Five oral fluid samples were positive for AB-FUBINACA. In urine, 4 samples tested positive for synthetic cannabinoids PB-22, 5-Fluoro-PB-22, AB-FUBINACA, and metabolites UR-144 5-pentanoic acid and UR-144 4-hydroxypentyl. In only one case, oral fluid and urine results matched, both specimens being AB-FUBINACA positive. For cannabis, 40 samples tested positive in urine and 30 in oral fluid (85.7% match). For cocaine, 37 urine and 52 oral fluid samples were positive (75.7% match). Twenty-four urine samples were positive for opiates, and 25 in oral fluid (81.4% match). For benzodiazepines, 23 samples were positive in urine and 25 in oral fluid (85.7% match). These results offer new information about drugs disposition between urine and oral fluid. Oral fluid is a good alternative matrix to urine for monitoring cannabis, cocaine, opiates and benzodiazepines recent use; however, synthetic cannabinoids showed mixed results. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users.

PubMed

Herrmann, Evan S; Cooper, Ziva D; Bedi, Gillinder; Ramesh, Divya; Reed, Stephanie C; Comer, Sandra D; Foltin, Richard W; Haney, Margaret

2016-07-01

Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ(9)-tetrahydrocannabinol (THC)). On days 2-8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3-4, when only inactive cannabis (0.0 % THC) was available for self-administration. "Relapse" was measured on days 5-8, when participants could self-administer active cannabis. Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users

PubMed Central

Herrmann, Evan S.; Cooper, Ziva D.; Bedi, Gillinder; Ramesh, Divya; Reed, Stephanie C.; Comer, Sandra D.; Foltin, Richard W.; Haney, Margaret

2017-01-01

Rationale Each year over 300,000 individuals in the U.S. enter treatment for Cannabis Use Disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. Objective This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Methods Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6% THC). On days 2–8, participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300), zolpidem (0 mg at 0900 and 1800 and 12.5 mg at 2300) or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3–4, when only inactive cannabis (0.0% THC) was available for self-administration. ‘Relapse’ was measured on days 5–8, when participants could self-administer active cannabis. Results Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Conclusions Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted. PMID:27085870

Spice, bath salts, and the U.S. military: the emergence of synthetic cannabinoid receptor agonists and cathinones in the U.S. Armed Forces.

PubMed

Loeffler, George; Hurst, Donald; Penn, Ashley; Yung, Kathryn

2012-09-01

Designer drugs are synthetic compounds that contain modified molecular structures of illegal or controlled substances. They are produced clandestinely with the intent to elicit effects similar to controlled substances while circumventing existing drug laws. Two classes of designer drugs that have risen to recent prominence are "spice," synthetic cannabinoid receptor agonists that mimic the effect of tetrahydrocannabinol, the active ingredient in cannabis, and "bath salts," synthetic cathinones, stimulants structurally related to amphetamines that have effects similar to cocaine and methamphetamine. Although these substances have only gained prominence recently, service members of the U.S. armed forces have not been immune to spice and bath salt abuse. These substances are often perceived as safe and are available via the Internet, in head shops and from dealers. Spice and bath salt abuse is increasingly associated with serious medical and psychiatric problems. Military health care providers must be familiar with these important new classes of drugs. This article discusses the background, current civilian and military legal status, clinical effects, pharmacology, and clinical management of synthetic cannabinoid receptor agonists and synthetic cathinones.

Chest pain, troponin rise, and ST-elevation in an adolescent boy following the use of the synthetic cannabis product K2.

PubMed

Zaleta, Sona; Kumar, Prashant; Miller, Sarah

2016-01-01

"Legal highs" such as K2, which typically contain synthetic cannabinoids, are increasingly popular with adolescents around the world. We have limited knowledge concerning their toxicity or adverse effects and their mechanism of action is poorly understood. While synthetic cannabinoids have been linked to adverse cardiovascular effects, cases of ST-elevation myocardial infarction (STEMI) associated with K2 use are exceedingly rare. We report a case of a 14-year-old boy who suffered an STEMI after smoking K2. To our knowledge, this is not only the youngest case of an STEMI associated with K2 use, but also the first case to be reported outside of the United States of America. Pediatricians worldwide must be aware of the clinical significance and potential harm associated with the use of synthetic cannabinoids, to better educate patients and their families regarding the dangers of using such "legal" substances.

[Pharmacological properties of law-evading chemical substances].

PubMed

Funada, Masahiko

2015-09-01

In recent years, frequent cases of people suffering disturbed consciousness, dyspnea, etc. due to abuse of synthetic cannabis and being transported by ambulance or causing traffic accidents are occurring and are becoming a serious social problem in Japan. Most law-evading herbal products have colorful illustrations and logos and are sold as incense or herbs. Law-evading herbal products consist of finely chopped dry vegetative matter mixed with chemical substances (drugs), and the drugs are injurious to health. Analysis of chemical substances in herbal products clarified that they contain synthetic cannabinoid, a chemical component that exhibits action similar to that of hemp. There are many affinity compounds of cannabinoid, so presently, even if a particular drug is regulated, similar compounds that partially differ in structure will propagate. There is thus a cat-and-mouse game between regulations on chemical substances and their propagation. This paper summarizes the pharmacological actions and danger of chemical substances contained in law-evading herbal products by focusing on synthetic cannabinoid or synthetic cathinone, a chemical substance it contains.

Metabolite profiling of RCS-4, a novel synthetic cannabinoid designer drug, using human hepatocyte metabolism and TOF-MS

PubMed Central

Gandhi, Adarsh S; Zhu, Mingshe; Pang, Shaokun; Wohlfarth, Ariane; Scheidweiler, Karl B; Huestis, Marilyn A

2014-01-01

Background Since 2009, scheduling legislation of synthetic cannabinoids prompted new compound emergence to circumvent legal restrictions. 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) is a potent cannabinoid receptor agonist sold in herbal smoking blends. Absence of parent synthetic cannabinoids in urine suggests the importance of metabolite identification for detecting RCS-4 consumption in clinical and forensic investigations. Materials & methods & Results With 1 h human hepatocyte incubation and TOF high-resolution MS, we identified 18 RCS-4 metabolites, many not yet reported. Most metabolites were hydroxylated with or without demethylation, carboxylation and dealkylation followed by glucuronidation. One additional sulfated metabolite was also observed. O-demethylation was the most common biotransformation and generated the major metabolite. Conclusion For the first time, we present a metabolic scheme of RCS-4 obtained from human hepatocytes, including Phase I and II metabolites. Metabolite structural information and associated high-resolution mass spectra can be employed for developing clinical and forensic laboratory RCS-4 urine screening methods. PMID:25046048

The Endocannabinoid System as a Target for Treatment of Breast Cancer

DTIC Science & Technology

2010-08-01

psychoactive constituent of marijuana (Gaoni and Mechoulam, 1964), as well as other naturally occurring and synthetically derived cannabinoids bind to and...the primary psychoactive constituent present in marijuana , and WIN55,212-2, a highly potent, full CB1 receptor agonist. Female mice implanted with...potent and highly efficacious synthetic cannabinoid receptor agonist originally developed as a nonsteroidal anti-inflammatory drug (Ward et al., 1991

Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids

PubMed Central

Seely, Kathryn A.; Lapoint, Jeff; Moran, Jeffery H.; Fattore, Liana

2014-01-01

“K2” and “Spice” drugs (collectively hereafter referred to as Spice) represent a relatively new class of designer drugs that have recently emerged as popular alternatives to marijuana, otherwise characterized as “legal highs”. These drugs are readily available on the Internet and sold in many head shops and convenience stores under the disguise of innocuous products like herbal blends, incense, or air fresheners. Although package labels indicate “not for human consumption”, the number of intoxicated people presenting to emergency departments is dramatically increasing. The lack of validated and standardized human testing procedures and an endless supply of potential drugs of abuse are primary reasons why researchers find it difficult to fully characterize clinical consequences associated with Spice. While the exact chemical composition and toxicology of Spice remains to be determined, there is mounting evidence identifying several synthetic cannabinoids as causative agents responsible for psychoactive and adverse physical effects. This review provides updates of the legal status of common synthetic cannabinoids detected in Spice and analytical procedures used to test Spice products and human specimens collected under a variety of clinical circumstances. The pharmacological and toxicological consequences of synthetic cannabinoid abuse are also reviewed to provide a future perspective on potential short- and long-term implications. PMID:22561602

Effect of the synthetic cannabinoid HU-210 on quorum sensing and on the production of quorum sensing-mediated virulence factors by Vibrio harveyi.

PubMed

Soni, Divya; Smoum, Reem; Breuer, Aviva; Mechoulam, Raphael; Steinberg, Doron

2015-08-12

Bacterial populations communicate through the cell density-dependent mechanism of quorum sensing (QS). Vibrio harveyi, one of the best studied model organisms for QS, was used to explore effects of the synthetic cannabinoid HU-210 on QS and different QS-regulated physiological processes in bacteria. Analysis of QS-regulated bioluminescence in wild-type and mutant strains of V. harveyi revealed that HU-210 affects the autoinducer-2 (AI-2) pathway, one of three known QS cascades of V. harveyi. Furthermore, QS-mediated biofilm formation and swimming motility in the mutant strain BB152 (AI-1(-), AI-2(+)) were significantly reduced in the presence of HU-210. HU-210 inhibited QS-mediated virulence factor production without any inhibitory effect on bacterial growth. It also alters the expression of several genes, which are regulated by QS, specifically downregulating the genes of the AI-2 QS cascade. First evidence is being provided for interference of bacterial signal-transduction systems by a synthetic cannabinoid. The effect of HU-210 was specific to the AI-2 cascade in V. harveyi. AI-2 is known as a "universal autoinducer" and interference with its activity opens a broad spectrum of applications for synthetic cannabinoids in future research as a potential anti-QS agent.

Neurotoxicity of Synthetic Cannabinoids JWH-081 and JWH-210

PubMed Central

Cha, Hye Jin; Seong, Yeon-Hee; Song, Min-Ji; Jeong, Ho-Sang; Shin, Jisoon; Yun, Jaesuk; Han, Kyoungmoon; Kim, Young-Hoon; Kang, Hoil; Kim, Hyoung Soo

2015-01-01

Synthetic cannabinoids JWH-018 and JWH-250 in ‘herbal incense’ also called ‘spice’ were first introduced in many countries. Numerous synthetic cannabinoids with similar chemical structures emerged simultaneously and suddenly. Currently there are not sufficient data on their adverse effects including neurotoxicity. There are only anecdotal reports that suggest their toxicity. In the present study, we evaluated the neurotoxicity of two synthetic cannabinoids (JWH-081 and JWH-210) through observation of various behavioral changes and analysis of histopathological changes using experimental mice with various doses (0.1, 1, 5 mg/kg). In functional observation battery (FOB) test, animals treated with 5 mg/kg of JWH-081 or JWH-210 showed traction and tremor. Their locomotor activities and rotarod retention time were significantly (p<0.05) decreased. However, no significant change was observed in learning or memory function. In histopathological analysis, neural cells of the animals treated with the high dose (5 mg/kg) of JWH-081 or JWH-210 showed distorted nuclei and nucleus membranes in the core shell of nucleus accumbens, suggesting neurotoxicity. Our results suggest that JWH-081 and JWH-210 may be neurotoxic substances through changing neuronal cell damages, especially in the core shell part of nucleus accumbens. To confirm our findings, further studies are needed in the future. PMID:26535086

Enzyme-linked immunosorbent assay (ELISA) for the detection of use of the synthetic cannabinoid agonists UR-144 and XLR-11 in human urine.

PubMed

Mohr, Amanda L A; Ofsa, Bill; Keil, Alyssa Marie; Simon, John R; McMullin, Matthew; Logan, Barry K

2014-09-01

Ongoing changes in the synthetic cannabinoid drug market create the need for relevant targeted immunoassays for rapid screening of biological samples. We describe the validation and performance characteristics of an enzyme-linked immunosorbent assay designed to detect use of one of the most prevalent synthetic cannabinoids in urine, UR-144, by targeting its pentanoic acid metabolite. Fluorinated UR-144 (XLR-11) has been demonstrated to metabolize to this common product. The assay has significant cross-reactivity with UR-144-5-OH, UR-144-4-OH and XLR-11-4-OH metabolites, but <10% cross-reactivity with the parent compounds, and no measurable cross-reactivity with other synthetic cannabinoids and their metabolites at concentrations of <1,000 ng/mL. The assay's cutoff is 5 ng/mL relative to the pentanoic acid metabolite of UR-144, which is used as the calibrator. The method was validated with 90 positive and negative control urine samples for UR-144, XLR-11 and its metabolites tested versus liquid chromatography-tandem mass spectrometry. The accuracy, sensitivity and specificity were determined to be 100% for the assay at the specified cutoff. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis.

PubMed

Fattore, Liana

2016-04-01

Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Δ(9)-tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques - a review.

PubMed

Znaleziona, Joanna; Ginterová, Pavlína; Petr, Jan; Ondra, Peter; Válka, Ivo; Ševčík, Juraj; Chrastina, Jan; Maier, Vítězslav

2015-05-18

Synthetic cannabinoids have gained popularity due to their easy accessibility and psychoactive effects. Furthermore, they cannot be detected in urine by routine drug monitoring. The wide range of active ingredients in analyzed matrices hinders the development of a standard analytical method for their determination. Moreover, their possible side effects are not well known which increases the danger. This review is focused on the sample preparation and the determination of synthetic cannabinoids in different matrices (serum, urine, herbal blends, oral fluid, hair) published since 2004. The review includes separation and identification techniques, such as thin layer chromatography, gas and liquid chromatography and capillary electrophoresis, mostly coupled with mass spectrometry. The review also includes results by spectral methods like infrared spectroscopy, nuclear magnetic resonance or direct-injection mass spectrometry. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of a homogenous enzyme immunoassay for the detection of synthetic cannabinoids in urine

PubMed Central

Barnes, Allan J.; Young, Sheena; Spinelli, Eliani; Martin, Thomas M.; Klette, Kevin L.; Huestis, Marilyn A.

2014-01-01

Introduction The recent emergence and widespread availability of many new synthetic cannabinoids support the need for an accurate and high-throughput urine screen for these new designer drugs. We evaluated performance of the immunalysis homogeneous enzyme immunoassay (HEIA) to sensitively, selectively, and rapidly identify urinary synthetic cannabinoids. Methods 2443 authentic urine samples were analyzed with the HEIA that targets JWH-018 N-pentanoic acid, and a validated LC-MS/MS method for 29 synthetic cannabinoids and metabolites. Semiquantitative HEIA results were obtained, permitting performance evaluation at and around three cutoffs (5, 10 and 20 μg/L), and diagnostic sensitivity, specificity and efficiency determination. Performance challenges at ±25 and ±50% of each cutoff level, cross-reactivity and interferences also were evaluated. Results Sensitivity, specificity, and efficiency of the immunalysis HEIA K2 Spice kit with the manufacturer's recommended 10 μg/L cutoff were 75.6%, 99.6% and 96.8%, respectively, as compared to the reference LC-MS/MS method with limits of detection of 0.1 -10 μg/L. Performance at 5 μg/L was 92.2%, 98.1% and 97.4%, and for the 20 μg/L cutoff were 62.9%, 99.7% and 95.4%. Semi-quantitative results for in-house prepared standards were obtained from 2.5-30 μg/L, and documented acceptable linearity from 5-25 μg/L, with inter-day imprecision <30% (n = 17). Thirteen of 74 synthetic cannabinoids evaluated were classified as highly cross-reactive (≥50% at 10 μg/L); 4 showed moderate cross-reactivity (10–50% at 10 μg/L), 30 low cross-reactivity (<10% at 500 μg/L), and 27 <1% cross-reactivity at 500 μg/L. There was no interference from 102 investigated compounds. Only a mixture containing 1000 μg/L each of buprenorphine/norbuprenorphine produced a positive result above our proposed cutoff (5 μg/L) but below the manufacturer's recommended cutoff concentration (10 μg/L). Conclusion The Immunalysis HEIA K2 Spice kit required no sample preparation, had a high-throughput, and acceptable sensitivity, specificity and efficiency, offering a viable method for screening synthetic cannabinoids in urine that cross-react with JWH-018 N-pentanoic acid antibodies. PMID:24845968

Strokes are possible complications of cannabinoids use.

PubMed

Wolff, Valérie; Jouanjus, Emilie

2017-05-01

It is critically important to identify all factors that may play a role in the recent increase of the incidence of stroke among the young population. Considering the worldwide use of cannabinoids (cannabis and synthetic cannabinoids), the recent legalization of their consumption in some countries, and their supposed involvement in cardiovascular events, we evaluated their role in the occurrence of neurovascular complications among the young. Ninety-eight patients were described in the literature as having a cannabinoids-related stroke (85 after cannabis use and 13 after synthetic cannabinoids). The distribution by type of stroke was as follows: 4 patients with an undetermined type of stroke, 85 with an ischemic stroke and/or a transient ischemic attack, and 9 with a hemorrhagic stroke. The mean age of patients was 32.3±11.8years (range 15-63), and the majority of them were male with a sex ratio of 3.7:1. Cannabis was often smoked with tobacco in 66% of cases. Most of the patients with cannabinoids-related strokes were chronic cannabis users in 81% of cases, and for 18% of them, there was a recent increase of the amount of cannabis consumption during the days before the occurrence of stroke. Even if the prognosis of stroke was globally favorable in 46% of cases, with no or few sequelae, 5 patients died after the neurovascular event. One striking element reported in the majority of the reports was a temporal relationship between cannabinoids use, whether natural or synthetic, and the occurrence of stroke. However, a temporal correlation does not mean causation, and other factors may be involved. Cannabis may be considered as a risk factor of stroke until research shows evidence of an underlying mechanism that, alone or in association with others, contributes to the development of stroke. As of today, reversible cerebral vasoconstriction triggered by cannabinoids use may be a convincing mechanism of stroke in 27% of cases. Indeed, despite the widespread use of cannabinoids, the low frequency of neurovascular complications after their use may be due to a genetic predisposition to their neurovascular toxicity in some individuals. Further studies should focus on this point. More importantly however, this low frequency may be underestimated because the drug consumption may not be systematically researched, neither by questioning nor by laboratory screening. Besides this vascular role of cannabinoids in the occurrence of stroke, a cellular effect of cannabis on brain mitochondria was recently suggested in an experimental study. One of the mechanisms involved in young cannabis users with stroke may be the generation of reactive oxygen species leading to an oxidative stress, which is a known mechanism in stroke in humans. It is useful to inform the young population about the real potential risk of using cannabinoids. We suggest to systematically ask all young adults with stroke about their drug consumption including cannabinoids, to screen urine for cannabis or to include a specific diagnostic test to detect synthetic cannabinoids, and to obtain non-invasive intracranial arterial investigations (i.e. CT-angiography or cerebral MRA) in order to search for cerebral vasoconstriction. However, several questions remained unresolved and further research is still needed to assess the pathophysiological mechanisms involved in young cannabinoids users with stroke. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy". Copyright © 2017 Elsevier Inc. All rights reserved.

Synthetic cannabinoids: the multi-organ failure and metabolic derangements associated with getting high.

PubMed

Sherpa, Dolkar; Paudel, Bishow M; Subedi, Bishnu H; Chow, Robert Dobbin

2015-01-01

Synthetic cannabinoids (SC), though not detected with routine urine toxicology screening, can cause severe metabolic derangements and widespread deleterious effects in multiple organ systems. The diversity of effects is related to the wide distribution of cannabinoid receptors in multiple organ systems. Both cannabinoid-receptor-mediated and non-receptor-mediated effects can result in severe cardiovascular, renal, and neurologic manifestations. We report the case of a 45-year-old African American male with ST-elevation myocardial infarction, subarachnoid hemorrhage, reversible cardiomyopathy, acute rhabdomyolysis, and severe metabolic derangement associated with the use of K2, an SC. Though each of these complications has been independently associated with SCs, the combination of these effects in a single patient has not been heretofore reported. This case demonstrates the range and severity of complications associated with the recreational use of SCs. Though now banned in the United States, use of systemic cannabinoids is still prevalent, especially among adolescents. Clinicians should be aware of their continued use and the potential for harm. To prevent delay in diagnosis, tests to screen for these substances should be made more readily available.

Conjugation of the Dark Quencher QSY 7 to Various Synthetic Cannabinoids for Use in Fluorescence-Based Detection Platforms

DTIC Science & Technology

2015-02-01

much more potent than traditional cannabis. 12,17 Cannabis sativa contains tetrahydrocannabinol ( THC ) as the active psychotropic ingredient and...0.52 nM for CB1 and CB2, respectively, which is approximately 164 and 46 times, respectively, tighter than THC for the same receptors. 12,17 This...spectrometry QD quantum dot SC synthetic cannabinoid TEA triethylamine THC tetrahydrocannabinol TLC thin layer chromatography 18 1 DEFENSE

Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly.

PubMed

Pacher, Pal; Steffens, Sabine; Haskó, György; Schindler, Thomas H; Kunos, George

2018-03-01

Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB 1 R and CB 2 R) has been implicated in a variety of cardiovascular pathologies. Activation of CB 1 R facilitates the development of cardiometabolic disease, whereas activation of CB 2 R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ 9 -tetrahydrocannabinol (THC), is an agonist of both CB 1 R and CB 2 R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB 1 R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.

Quantitative measurement of XLR11 and UR-144 in oral fluid by LC-MS-MS.

PubMed

Amaratunga, Piyadarsha; Thomas, Christopher; Lemberg, Bridget Lorenz; Lemberg, Dave

2014-01-01

Availability and consumption of synthetic cannabinoids have risen recently in the USA and Europe. These drugs have adverse effects, including acute psychosis and bizarre behavior. In 2012, the United States Drug Enforcement Agency permanently banned five of the synthetic cannabinoids and in 2013, temporarily added XLR11, UR-144 and AKB48 to Schedule I of the Controlled Substances Act. As synthetic cannabinoid strains are added to the Schedule I list, new strains are being introduced into the market. XLR11 and UR-144 are two of the most recent additions to the synthetic cannabinoid drug class. To test collected oral fluid samples for XLR11 and UR-144, we developed a bioanalytical method that initially purifies the sample with solid-phase extraction and then quantitatively identifies the drugs with ultra-high-performance liquid chromatography-tandem mass spectrometry. The method was validated according to United States Food and Drug Administration guidelines and Scientific Working Group for Forensic Toxicology guidelines and the validation data showed that the method is an accurate, precise, robust and efficient method suited for high-throughput toxicological screening applications. We tested human subject samples with the developed method and found the presence of parent drugs (XLR11 and UR-144), their metabolites and their pyrolysis products in oral fluid. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Analysis and clinical findings of cases positive for the novel synthetic cannabinoid receptor agonist MDMB-CHMICA.

PubMed

Seywright, Alice; Torrance, Hazel J; Wylie, Fiona M; McKeown, Denise A; Lowe, David J; Stevenson, Richard

2016-09-01

MDMB-CHMICA is a synthetic cannabinoid receptor agonist which has caused concern due to its presence in cases of adverse reaction and death. 43 cases of suspected synthetic cannabinoid ingestion were identified from patients presenting at an Emergency Department and from post-mortem casework. These were subjected to liquid-liquid extraction using tertiary-butyl methyl ether and quantitatively analysed by Electrospray Ionisation Liquid Chromatography-tandem Mass Spectrometry. For positive samples, case and clinical details were sought and interrogated. 11 samples were found positive for MDMB-CHMICA. Concentrations found ranged from <1 to 22 ng/mL (mean: 6 ng/mL, median: 3 ng/mL). The age range was 15-44 years (mean: 26 years, median: 21 years), with the majority (82%) of positive results found in males. Clinical presentations included hypothermia, hypoglycaemia, syncope, recurrent vomiting, altered mental state and serotonin toxicity, with corresponding concentrations of MDMB-CHMICA as low as <1 ng/mL. Duration of hospitalisation ranged from 3 to 24 h (mean: 12 h, median: 8 h). The concentration range presented in this case series is indicative of MDMB-CHMICA having a high potency, as is known to be the case for other synthetic cannabinoid receptor agonists. The age range and gender representation were consistent with that reported for users of other drugs of this type. The clinical presentations observed were typical of synthetic cannabinoid receptor agonists and show the difficulties in identifying reactions potentially associated with drugs of this type. The range of MDMB-CHMICA concentrations in Emergency Department presentations (n = 9) and post-mortem cases (n = 2) was reported. No correlation between the concentration of this drug and clinical presentation or cause of death was reported in this sample. However, the potential for harm associated with low concentrations of MDMB-CHMICA and the symptoms of toxicity being non-specific were highlighted.

Isomeric discrimination of synthetic cannabinoids by GC-EI-MS: 1-adamantyl and 2-adamantyl isomers of N-adamantyl carboxamides.

PubMed

Asada, Akiko; Doi, Takahiro; Tagami, Takaomi; Takeda, Akihiro; Sawabe, Yoshiyuki

2017-03-01

N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA) and N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) are carboxamide-type synthetic cannabinoids comprising indazole/indole-3-carboxylic acid and adamantan-1-amine moieties. However, in the case of compounds like APINACA or APICA, adamantyl positional isomers exist, wherein either adamantan-1-amine or adamantan-2-amine is present. These adamantyl positional isomers have not been reported in previous studies, and no analytical data are available. To avoid misidentification of adamantyl carboxamide-type synthetic cannabinoids, it is important to develop methods to discriminate these adamantyl positional isomers. In this study, we report the analytical characterization by gas chromatography-electron ionization-mass spectrometry (GC-EI-MS). For providing analytical standards, we synthesized eight carboxamide-type synthetic cannabinoids (APINACA 2-adamantyl isomer, APICA 2-adamantyl isomer, 5 F-APINACA 2-adamantyl isomer, 5 F-APICA 2-adamantyl isomer, 5Cl-APINACA, 5Cl-APINACA 2-adamantyl isomer, adamantyl-THPINACA, 2-adamantyl-THPINACA) and purchased four 1-adamantyl derivatives (APINACA, APICA, 5 F-APINACA, 5 F-APICA). Although the retention times of the isomers are similar, 1-adamantyl carboxamides can be clearly discriminated from their 2-adamantyl isomers based on their different fragmentation patterns in the EI-MS spectra. Specifically, EI-MS spectra for adamantylindazole carboxamides showed remarkable differences between the 1-adamantyl and 2-adamantyl isomers. On the other hand, EI-MS spectra for adamantylindole carboxamides were similar, but the diagnostic ions of the 2-adamantyl isomers were observed. The method described herein was applicable to all compounds tested in this study and is expected to be of use for isomeric differentiation between other untested adamantyl carboxamide-type synthetic cannabinoids. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The behavioral profile of spice and synthetic cannabinoids in humans.

PubMed

Müller, Helge H; Kornhuber, Johannes; Sperling, Wolfgang

2016-09-01

The use of synthetic cannabinoids (spice) is increasing. The number of descriptions of (new) clinical side effects is also increasing. We screened relevant publications for articles about spice with a focus on the clinical manifestations of the use of this drug. Spice creates diffuse psychiatric and somatic effects that are only partially similar to those of natural cannabinoids. Most of the observed effects are related to sympathomimetic-cardiac effects and neuropsychiatric manifestations. Clinical treatment is primarily based on intensive apparative and laboratory monitoring and supportive therapy. Because the exact active ingredients of spice are often difficult to determine with standard specific toxicology testing, the assessment and analysis of consumed substances by specialized laboratories is recommended. Copyright © 2015 Elsevier Inc. All rights reserved.

Attitudes and Beliefs About New Psychoactive Substance Use Among Electronic Dance Music Party Attendees.

PubMed

Palamar, Joseph J; Acosta, Patricia; Cleland, Charles M

2018-02-23

Attitudes and beliefs about drug use have been shown to be robust correlates of use of drugs such as alcohol, marijuana, and cocaine; however, little is known regarding attitudes or beliefs about new psychoactive substances (NPS). We sought to examine attitudes and beliefs about NPS and how they relate to self-reported use in a high-risk population-electronic dance music (EDM) party attendees. 1,048 individuals (age 18-40) were surveyed entering EDM parties in New York City in 2016. We queried lifetime use and attitudes and beliefs specific to NBOMe, 2C series drugs, "bath salts" (synthetic cathinones), tryptamines, dissociative NPS, and synthetic cannabinoids. More than half the sample reported being unfamiliar with NPS other than "bath salts" and synthetic cannabinoids. "Bath salts" received the highest ratings of strong disapproval (34.3%), followed by synthetic cannabinoids (23.3%), compared to other NPS (10-14%). "Bath salts" were perceived to be a great risk by 43.1% of the sample, followed by synthetic cannabinoids (27.0%), and other NPS (12-16%). "Bath salts" were reportedly least likely to be used if offered (2.9%). In multivariable models, reporting no disapproval towards use was associated with increased odds of reporting use of 2C drugs, "bath salts", and tryptamines. Having friends who use and reporting intent to use or willingness to use if offered were also associated with use of various NPS classes. This study delineated attitudinal and belief-related correlates of use of various NPS classes. Results can inform prevention effects as NPS continue to emerge.

LACTIC ACIDOSIS: A RARE MANIFESTATION OF SYNTHETIC MARIJUANA INTOXICATION.

PubMed

Antill, T; Jakkoju, A; Dieguez, J; Laskhmiprasad, L

2015-01-01

Synthetic cannabinoids are designer drugs that mimic the effect of cannabis, which has become popular with young drug users. These drugs have a similar chemical structure and pharmacologic effects as marijuana, but seem to be more potent. These substances have been banned by the US Drug Enforcement Agency in 2010. Prior to 2010, these drugs were perceived as "safer" by the general population. Synthetic cannabinoids cause effects similar to marijuana making the subjects euphoric. However, they act as full, rather than partial, agonist at the receptor sites causing more severe side effects such as severe agitation, seizures, acute renal failure, and lactic acidosis.

Comorbidity

MedlinePlus

... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

Drug Facts: Anabolic Steroids

MedlinePlus

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Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons.

PubMed

Costain, Willard J; Tauskela, Joseph S; Rasquinha, Ingrid; Comas, Tanya; Hewitt, Melissa; Marleau, Vincent; Soo, Evelyn C

2016-09-05

There has been a worldwide proliferation of synthetic cannabinoids that have become marketed as legal alternatives to cannabis (marijuana). Unfortunately, there is a dearth of information about the pharmacological effects of many of these emerging synthetic cannabinoids (ESCs), which presents a challenge for regulatory authorities that need to take such scientific evidence into consideration in order to regulate ECSs as controlled substances. We aimed to characterize the pharmacological properties of ten ESCs using two cell based assays that enabled the determination of potency and efficacy relative to a panel of well-characterized cannabinoids. Agonist-mediated inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live HEK293T cells transfected with human cannabinoid receptor 1 gene (CNR1) and pGloSensor-22F. Pharmacological analysis of this data indicated that all of the ESCs tested were full agonists, with the following rank order of potency: Win 55212-2≈5F-PB-22≈AB-PINACA≈EAM-2201≈MAM-2201>JWH-250≈ PB-22>AKB48 N-(5FP)>AKB-48≈STS-135>XLR-11. Assessment of agonist-stimulated depression of Ca(2+) transients was also used to confirm the efficacy of five ESCs (XLR-11, JWH-250, AB-PINACA, 5F-PB-22, and MAM-2201) in cultured primary hippocampal neurons. This work aims to help inform decisions made by regulatory agencies concerned with the profusion of these poorly characterized recreational drugs. Copyright © 2016. Published by Elsevier B.V.

Health Consequences of Drug Misuse

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Gene Variants Reduce Opioid Risks

MedlinePlus

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Cigarettes and Other Tobacco Products

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Drugs + HIV, Learn the Link

MedlinePlus

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Metabolism of RCS-8, a synthetic cannabinoid with cyclohexyl structure, in human hepatocytes by high-resolution MS

PubMed Central

Wohlfarth, Ariane; Pang, Shaokun; Zhu, Mingshe; Gandhi, Adarsh S; Scheidweiler, Karl B; Huestis, Marilyn A

2015-01-01

Background Since 2008, synthetic cannabinoids are major new designer drugs of abuse. They are extensively metabolized and excreted in urine, but limited human metabolism data are available. As there are no reports on the metabolism of RCS-8, a scheduled phenylacetylindole synthetic cannabinoid with an N-cyclohexylethyl moiety, we investigated metabolism of this new designer drug by human hepatocytes and high resolution MS. Methods After human hepatocyte incubation with RCS-8, samples were analyzed on a TripleTOF 5600+ mass spectrometer with time-of-flight survey scan and information-dependent acquisition triggered product ion scans. Data mining of the accurate mass full scan and product ion spectra employed different data processing algorithms. Results and Conclusion More than 20 RCS-8 metabolites were identified, products of oxidation, demethylation, and glucuronidation. Major metabolites and targets for analytical methods were hydroxyphenyl RCS - 8 glucuronide, a variety of hydroxycyclohexyl-hydroxyphenyl RCS-8 glucuronides, hydroxyphenyl RCS-8, as well as the demethyl-hydroxycyclohexyl RCS-8 glucuronide. PMID:24946920

The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

PubMed

Kolla, Nathan J; Mishra, Achal

2018-01-01

Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

Cannabinoids as therapeutic agents in cancer: current status and future implications

PubMed Central

Ganju, Ramesh K.

2014-01-01

The pharmacological importance of cannabinoids has been in study for several years. Cannabinoids comprise of (a) the active compounds of the Cannabis sativa plant, (b) endogenous as well as (c) synthetic cannabinoids. Though cannabinoids are clinically used for anti-palliative effects, recent studies open a promising possibility as anti-cancer agents. They have been shown to possess anti-proliferative and anti-angiogenic effects in vitro as well as in vivo in different cancer models. Cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. There is more focus on CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities. PMID:25115386

THE SUBJECTIVE PSYCHOACTIVE EFFECTS OF ORAL DRONABINOL STUDIED IN A RANDOMIZED, CONTROLLED CROSSOVER CLINICAL TRIAL FOR PAIN

PubMed Central

Issa, Mohammed A.; Narang, Sanjeet; Jamison, Robert N.; Michna, Edward; Edwards, Robert R.; Penetar, David M.; Wasan, Ajay D.

2014-01-01

Background Many cannabinoid medications are approved in North America or in Phase III trials, such as Dronabinol, Nabilone, or Nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a dose response relationship, whose peak effects are comparable to smoking marijuana. Methods With IRB approval and written consent, this was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic non-cancer pain patients taking opioids and not using marijuana. Hourly, for 8 hours during 3 monitored sessions, subjects completed the Addiction Research Center Inventory (ARCI). Comparison sample was the ARCI ratings in a study population with no pain (N=20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette. Results The 10 and 20 mg dronabinol doses had significantly elevated scores on 4/5 subscales vs. placebo over time (p<.05). Average daily morphine use, total pain relief (TOTPAR), age, gender, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (p=.80, 10 mg=low, 20 mg=high strength). Conclusions In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain. PMID:24281276

The use of social networking sites: A risk factor for using alcohol, marijuana, and synthetic cannabinoids?

PubMed

Gutierrez, Kevin M; Cooper, Theodore V

2016-06-01

The use of social networking sites (SNS) has become a central aspect of youth culture allowing individuals to explore and assert their identities. A commonly portrayed online identity is an "alcohol identity," and past research suggests such identities may contribute to one's risk of using alcohol. The present study builds on past research by examining the relationship between alcohol, marijuana, and synthetic cannabinoid use (e.g., Spice, K2) and time spent on SNS in a sample of college students. Six hundred ninety nine undergraduates (62.4% female; Mage=21.0, SD=8.56) were recruited from a university on the U.S./Mexico border for an online study. Participants completed measures assessing demographics, substance use history, and amount of time spent on SNS. Participants reported spending 46h per month on SNS. Seventy-one percent, 14%, and 3% of the sample reported past month use of alcohol, marijuana, and synthetic cannabinoids, respectively. Regression analyses revealed that hours spent on SNS in the past month were significantly associated with frequency of alcohol (p<0.001) and synthetic cannabinoid use (p<0.001). In addition, being male was associated with frequency of alcohol and marijuana use in the past month (p<0.001 and p<0.001, respectively). These findings suggest that assessment of time spent on SNS is warranted in studies investigating drug use among college students. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dried haematic microsamples and LC-MS/MS for the analysis of natural and synthetic cannabinoids.

PubMed

Protti, Michele; Rudge, James; Sberna, Angelo Eliseo; Gerra, Gilberto; Mercolini, Laura

2017-02-15

Synthetic cannabinoids are new psychoactive substances (NPS) with similar effects when compared to natural ones found in Cannabis derivatives. They have rapidly integrated into the illicit market, often sold as alternatives under international control. The need to identify and quantify an unprecedented and growing number of new compounds represents a unique challenge for toxicological, forensic and anti-doping analysis. Dried blood spots have been used within the bioanalytical framework in place of plasma or serum, in order to reduce invasiveness, lower sample size, simplify handling, storage and shipping of samples and to facilitate home-based and on-field applications. However, DBS implementation has been limited mainly by concerns related to haematocrit effect on method accuracy. Volumetric absorptive microsampling (VAMS™), a second generation dried miniaturized sampling technology, has been developed just in order to eliminate haematocrit effect, thus providing accurate sampling but still granting feasible sample processing. An original LC-MS/MS method was herein developed and validated for the analysis of THC and its 2 main metabolites, together with 10 representative synthetic cannabinoids in both DBS and VAMS dried microsamples. The ultimate goal of this work is to provide highly innovative DBS and VAMS analytical protocols, whose performances were extensively optimized and compared, in order to provide effective and alternative tools that can be applied for natural and synthetic cannabinoid determination, in place of classical analytical strategies. Copyright © 2016 Elsevier B.V. All rights reserved.

Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry.

PubMed

Holm, Niels Bjerre; Pedersen, Anders Just; Dalsgaard, Petur Weihe; Linnet, Kristian

2015-03-01

New types of synthetic cannabinoid designer drugs are constantly introduced to the illicit drug market to circumvent legislation. Recently, N-​(1-Adamant​yl)-​1-​(5-​fluoropentyl)-​1H-​indazole-​3-​carboxamide (5F-AKB-48), also known as 5F-APINACA, was identified as an adulterant in herbal products. This compound deviates from earlier JHW-type synthetic cannabinoids by having an indazole ring connected to an adamantyl group via a carboxamide linkage. Synthetic cannabinoids are completely metabolized, and identification of the metabolites is thus crucial when using urine as the sample matrix. Using an authentic urine sample and high-resolution accurate-mass Fourier transform Orbitrap mass spectrometry, we identified 16 phase-I metabolites of 5F-AKB-48. The modifications included mono-, di-, and trihydroxylation on the adamantyl ring alone or in combination with hydroxylation on the N-fluoropentylindazole moiety, dealkylation of the N-fluoropentyl side chain, and oxidative loss of fluorine as well as combinations thereof. The results were compared to human liver microsomal (HLM) incubations, which predominantly showed time-dependent formation of mono-, di-, and trihydroxylated metabolites having the hydroxyl groups on the adamantyl ring. The results presented here may be used to select metabolites specific of 5F-AKB-48 for use in clinical and forensic screening. Copyright © 2014 John Wiley & Sons, Ltd.

Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure of the rabbit.

PubMed

ElSohly, M A; Harland, E C; Benigni, D A; Waller, C W

1984-06-01

Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.

The Science of Drug Use: Discussion Points

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Drug Use and Viral Infections (HIV, Hepatitis)

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Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair Novel Object Recognition in mice: Behavioral, electrophysiological and neurochemical evidence.

PubMed

Barbieri, M; Ossato, A; Canazza, I; Trapella, C; Borelli, A C; Beggiato, S; Rimondo, C; Serpelloni, G; Ferraro, L; Marti, M

2016-10-01

It is well known that an impairment of learning and memory function is one of the major physiological effects caused by natural or synthetic cannabinoid consumption in rodents, nonhuman primates and in humans. JWH-018 and its halogenated derivatives (JWH-018-Cl and JWH-018-Br) are synthetic CB1/CB2 cannabinoid agonists, illegally marketed as "Spice" and "herbal blend" for their Cannabis-like psychoactive effects. In the present study the effects of acute exposure to JWH-018, JWH-018-Cl, JWH-018-Br (JWH-018-R compounds) and Δ(9)-THC (for comparison) on Novel Object Recognition test (NOR) has been investigated in mice. Moreover, to better characterize the effects of JWH-018-R compounds on memory function, in vitro electrophysiological and neurochemical studies in hippocampal preparations have been performed. JWH-018, JWH-018-Cl and JWH-018-Br dose-dependently impaired both short- and long-memory retention in mice (respectively 2 and 24 h after training session). Their effects resulted more potent respect to that evoked by Δ(9)-THC. Moreover, in vitro studies showed as JWH-018-R compounds negatively affected electrically evoked synaptic transmission, LTP and aminoacid (glutamate and GABA) release in hippocampal slices. Behavioral, electrophysiological and neurochemical effects were fully prevented by CB1 receptor antagonist AM251 pretreatment, suggesting a CB1 receptor involvement. These data support the hypothesis that synthetic JWH-018-R compounds, as Δ(9)-THC, impair cognitive function in mice by interfering with hippocampal synaptic transmission and memory mechanisms. This data outline the danger that the use and/or abuse of these synthetic cannabinoids may represent for the cognitive process in human consumer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

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

Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N.

K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsicmore » activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018 and JWH-073 are synthetic cannabinoids present in abused K2 products. • JWH-018, JWH-073 and their human metabolites have high affinity for CB{sub 2} receptors. • JWH-018, JWH-073 and their human metabolites are potent agonists at CB{sub 2} receptors. • JWH-018, JWH-073 and their metabolites exhibit distinct CB{sub 2} signaling properties. • Studies of JWH-018 and JWH-073 should consider actions at CB{sub 1} and CB{sub 2} receptors.« less

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

PubMed Central

Bow, Eric W.; Rimoldi, John M.

2016-01-01

The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

HIV Infection Accelerates Hepatitis C-Related Liver Fibrosis

MedlinePlus

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

PubMed Central

Marusich, Julie A.; Lefever, Timothy W.; Antonazzo, Kateland R.; Wallgren, Michael T.; Cortes, Ricardo A.; Patel, Purvi R.; Grabenauer, Megan; Moore, Katherine N.

2015-01-01

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 Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC in Δ9-THC discrimination. Rank order of potency correlated with CB1 receptor-binding affinity, and all three compounds were full agonists in [35S]GTPγS binding, as compared with the partial agonist Δ9-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 receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids. PMID:26105953

Family Checkup: Positive Parenting Prevents Drug Abuse

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Hair analysis as a tool to evaluate the prevalence of synthetic cannabinoids in different populations of drug consumers.

PubMed

Salomone, A; Luciano, C; Di Corcia, D; Gerace, E; Vincenti, M

2014-01-01

Among the new psychoactive products, herbal mixtures containing synthetic cannabimimetics are likely the most abused worldwide. In this study, a specific ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the detection of 23 synthetic cannabinoids in hair samples was developed in order to (1) expand the number of screened compounds, coherent with new substances emerging in the European territory, (2) evaluate their consumption on a large period of examination, and (3) evaluate the diffusion of cannabimimetics among different populations of drug consumers. The method employs digestion of hair sample with NaOH followed by extraction with n-hexane/ethylacetate, and injection into the UHPLC-MS/MS system. After validation, the method was applied to the analysis of 344 hair samples previously tested in our laboratory for the most common drugs. Overall, 15 samples were found positive for at least one synthetic cannabinoid. Coherent with previously published results, the present data show that young males, former or still active Cannabis consumers, represent the population most often involved in synthetic cannabimimetics consumption. Several cases of poly-abuse were also determined. The drug most frequently detected was JWH-073 (11 samples) generally at low concentration (mean 7.69 ± 14.4 pg/mg, median 1.9 pg/mg, range 1.6-50.5 pg/mg), followed by JWH-122 (8 samples, mean concentration: 544 ± 968 pg/mg, median 28.4 pg/mg, range 7.4-2800 pg/mg). Other detected drugs included JWH-250, JWH-081, JWH-018, JWH-210, JWH-019, and AM-1220. For several positive samples, the synthetic cannabinoid concentration was lower than 50 pg/mg, underlining the need for established cut-off values for discrimination between chronic consumption and occasional use (or external contamination). Copyright © 2013 John Wiley & Sons, Ltd.

Smart drugs: green shuttle or real drug?

PubMed

Cornara, L; Borghesi, B; Canali, C; Andrenacci, M; Basso, M; Federici, S; Labra, M

2013-11-01

We have combined morphological, molecular, and chemical techniques in order to identify the plant and chemical composition of some last-generation smart drugs, present on the market under the following names: Jungle Mistic Incense, B-52, Blendz, and Kratom 10x. Micromorphological analyses of botanical fragments allowed identification of epidermal cells, stomata, trichomes, starch, crystals, and pollen. DNA barcoding was carried out by the plastidial gene rbcL and the spacer trnH-psbA as universal markers. The combination of morphological and molecular data revealed a mixture of plants from different families, including aromatic species, viz., Lamiaceae and Turneraceae. GC-MS and LC-MS analyses on ethanol or methanol extracts showed the presence of synthetic cannabinoids, including JWH-250 in Jungle, JWH-122 in B-52, and JWH-073 and JWH-018 in Blendz. In Kratom 10x, only the indole alkaloid mitragynine was detected. All the identified synthetic cannabinoids, apart from mitragynine, are under the restriction of law in Italy (TU 309/90). Synthetic cannabinoid crystals were also identified by scanning electron microscopy and energy dispersive X-ray spectroscopy, which also detected other foreign organic chemicals, probably preservatives or antimycotics. In Kratom only leaf fragments from Mitragyna speciosa, containing the alkaloid mitragynine, were found. In the remaining products, aromatic plant species have mainly the role of hiding synthetic cannabinoids, thus acting as a "green shuttle" rather than as real drugs. Such a multidisciplinary approach is proposed as a method for the identification of herbal blends of uncertain composition, which are widely marketed in "headshops" and on the Internet, and represent a serious hazard to public health.

Enantioseparation of the carboxamide-type synthetic cannabinoids N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide and methyl [1-(5-fluoropentyl)-1H-indazole-3-carbonyl]-valinate in illicit herbal products.

PubMed

Doi, Takahiro; Asada, Akiko; Takeda, Akihiro; Tagami, Takaomi; Katagi, Munehiro; Kamata, Hiroe; Sawabe, Yoshiyuki

2016-11-18

Synthetic cannabinoids, recently used as alternatives to Cannabis sativa, are among the most frequently abused drugs. Identified in 2014, the synthetic cannabinoids N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide (5F-AB-PINACA) and methyl [1-(5-fluoropentyl)-1H-indazole-3-carbonyl]-valinate (5F-AMB) are carboxamides composed of 1-(5-fluoropentyl)-1H-indazole-3-carboxylic acid and valine amide/methyl ester. Because of their composition, these molecules have pairs of enantiomers derived from the chiral center of their amino acid structures. Previous studies on the identification of 5F-AB-PINACA and 5F-AMB did not consider the existence of enantiomers, and there have been no reports on the enantiopurities of synthetic cannabinoids. We synthesized both enantiomers of these compounds and then separated the enantiomers by liquid chromatography-high-resolution mass spectrometry using a column with a chiral stationary phase consisted with amylose tris (3-chloro-4-methylphenylcarbamate). Under the optimized conditions, the enantiomer resolutions were 2.2 and 2.3 for 5F-AB-PINACA and 5F-AMB, respectively. Analysis of 10 herbal samples containing 5F-AB-PINACA and one herbal sample containing 5F-AMB showed that they all contained the (S)-enantiomer, but the (R)-enantiomer was only detected in two samples and at a ratio of less than 20%. Copyright © 2016 Elsevier B.V. All rights reserved.

Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans.

PubMed

Watanabe, Shimpei; Kuzhiumparambil, Unnikrishnan; Nguyen, My Ann; Cameron, Jane; Fu, Shanlin

2017-07-01

The knowledge of metabolic profile of synthetic cannabinoids is important for the detection of drugs in urinalysis due to the typical absence or low abundance of parent cannabinoids in human urine. The fungus Cunninghamella elegans has been reported to be a useful tool for metabolism study and thus applicability to synthetic cannabinoid metabolism was examined. In this study, 8-quinolinyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5F-PB-22), 8-quinolinyl 1-pentyl-1H-indole-3-carboxylate (PB-22), [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11) and (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144) were incubated with C. elegans and the metabolites were identified using liquid chromatography-quadrupole time-of-flight mass spectrometry. The obtained metabolites were compared with reported human metabolites to assess the suitability of the fungus to extrapolate human metabolism. 5F-PB-22 underwent dihydroxylation, dihydrodiol formation, oxidative defluorination, oxidative defluorination to carboxylic acid, ester hydrolysis and glucosidation, alone and/or in combination. The metabolites of PB-22 were generated by hydroxylation, dihydroxylation, trihydroxylation, dihydrodiol formation, ketone formation, carboxylation, ester hydrolysis and glucosidation, alone and/or in combination. XLR-11 was transformed through hydroxylation, dihydroxylation, aldehyde formation, carboxylation, oxidative defluorination, oxidative defluorination to carboxylic acid and glucosidation, alone and/or in combination. UR-144 was metabolised by hydroxylation, dihydroxylation, trihydroxylation, aldehyde formation, ketone formation, carboxylation, N-dealkylation and combinations. These findings were consistent with previously reported human metabolism except for the small extent of ester hydrolysis observed and the absence of glucuronidation. Despite the limitations, C. elegans demonstrated the capacity to produce a wide variety of metabolites including some major human metabolites of XLR-11 and UR-144 at high abundance, showing the potential for metabolism of newly emerging synthetic cannabinoids.

[Plants' materials and synthetic agonists of cannabinoid receptors use as a substitute of Marihuana, appearing in a current forensic toxicology practice of evidence materials].

PubMed

Geppert, Bogna; Tezyk, Artur; Florek, Ewa; Zaba, Czesław

2010-01-01

Cannabis sativa species Indica (Marihuana) is nowadays one of the most common plant drug, with psychoactive activity, presently appearing on the illegal market in Poland. It is reported that frequency of securing evidential materials so called substitute of Marihuana, is growing rapidly during the last few years. The substitutes of Marihuana occurring on the market are of natural or synthetic origins, for example different species of raw plants' materials having action similar to Cannabis or raw plants' materials with no psychoactive properities but with an addition of components so called synthetic cannabinoids. The review presents recent developments in drug market and current problems of forensic toxicology on the example of Marihuana.

Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.

PubMed

Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

2015-08-01

The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.

Prenatal Methamphetamine Exposure Linked with Problems

MedlinePlus

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Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists.

PubMed

Maslov, Leonid N; Khaliulin, Igor; Zhang, Yi; Krylatov, Andrey V; Naryzhnaya, Natalia V; Mechoulam, Raphael; De Petrocellis, Luciano; Downey, James M

2016-05-01

Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors. Cannabinoids are also involved in remote preconditioning of the heart. The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart. The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal-regulated kinase, and p38 kinase. The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3-kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression. The delayed cardioprotective effect of another cannabinoid, Δ9-tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory. The adenosine triphosphate-sensitive K(+)channel is involved in the synthetic cannabinoid HU-210-induced cardiac resistance to ischemia/reperfusion injury. Cannabinoids inhibit Na(+)/Ca(2+)exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids. The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia-reperfusion injury in the clinical setting. © The Author(s) 2015.

A Review of the Therapeutic Antitumor Potential of Cannabinoids.

PubMed

Bogdanović, Višnja; Mrdjanović, Jasminka; Borišev, Ivana

2017-11-01

The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment. A literature survey of medical and scientific databases was conducted with a focus on the biological and medical potential of cannabinoids in cancer treatment. Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of "cannabinoid sensitizers." Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness. A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with standard anticancer strategies. With such knowledge, cannabinoids could become a therapy of choice in contemporary oncology.

Although Relatively Few, "Doctor Shoppers" Skew Opioid Prescribing

MedlinePlus

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Intoxication from the novel synthetic cannabinoids AB-PINACA and ADB-PINACA: A case series and review of the literature.

PubMed

Armenian, Patil; Darracq, Michael; Gevorkyan, Jirair; Clark, Shane; Kaye, Bryan; Brandehoff, Nicklaus P

2018-05-15

Synthetic cannabinoids (SC), are a novel class of designer drugs which emerged as a drug of abuse in the late 2000's. We report a case series of 6 patients who may have smoked a synthetic cannabinoid product in a remote wilderness setting. They presented with varying degrees of altered mental status, agitation, and seizures. Two were confirmed to have AB-PINACA, ADB-PINACA and their respective pentanoic acid metabolites in biological specimens via liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS). Both compounds had DEA Schedule I classification at the time of case presentation, and 22 SCs are currently temporary or permanent DEA Schedule I. More than 150 SCs are known to date, and new compounds are appearing at a rapid rate on darknet and surface web e-commerce websites, marketed as "research chemicals" or "legal highs." The scale and rapidity of SC evolution make legal control and analytical detection difficult. Nontargeted testing with liquid chromatography high resolution mass spectrometry (LC-HRMS), examining both parent compounds and metabolites, is the ideal method for novel SC identification and confirmation. Due to full agonism at the cannabinoid receptors CB1 and CB2, clinical effects are more severe than marijuana, which is a partial cannabinoid receptor agonist. They include agitated delirium, lethargy and coma, seizures, tachycardia, hypertension, and hallucinations, among other findings. Treatment is primarily symptomatic and aimed at airway protection and control of agitation and seizures. SCs do not appear to be abating anytime soon and require the cooperation of law enforcement, analytical scientists, and clinicians to adequately control. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' Copyright © 2017 Elsevier Ltd. All rights reserved.

The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

PubMed

Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

2014-05-09

Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

PubMed Central

Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

2014-01-01

Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287

Cannabinoids and Pain: Sites and Mechanisms of Action.

PubMed

Starowicz, Katarzyna; Finn, David P

2017-01-01

The endocannabinoid system, consisting of the cannabinoid 1 receptor (CB 1 R) and cannabinoid 2 receptor (CB 2 R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB 1 R and CB 2 R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB 1 R agonists, CB 2 R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB 1 R/non-CB 2 R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders. © 2017 Elsevier Inc. All rights reserved.

Direct screening of herbal blends for new synthetic cannabinoids by MALDI-TOF MS.

PubMed

Gottardo, Rossella; Chiarini, Anna; Dal Prà, Ilaria; Seri, Catia; Rimondo, Claudia; Serpelloni, Giovanni; Armato, Ubaldo; Tagliaro, Franco

2012-01-01

Since 2004, a number of herbal blends containing different synthetic compounds mimicking the pharmacological activity of cannabinoids and displaying a high toxicological potential have appeared in the market. Their availability is mainly based on the so-called "e-commerce", being sold as legal alternatives to cannabis and cannabis derivatives. Although highly selective, sensitive, accurate, and quantitative methods based on GC-MS and LC-MS are available, they lack simplicity, rapidity, versatility and throughput, which are required for product monitoring. In this context, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) offers a simple and rapid operation with high throughput. Thus, the aim of the present work was to develop a MALDI-TOF MS method for the rapid qualitative direct analysis of herbal blend preparations for synthetic cannabinoids to be used as front screening of confiscated clandestine preparations. The sample preparation was limited to herbal blend leaves finely grinding in a mortar and loading onto the MALDI plate followed by addition of 2 µl of the matrix/surfactant mixture [α-cyano-4-hydroxy-cinnamic acid/cetyltrimethylammonium bromide (CTAB)]. After drying, the sample plate was introduced into the ion source for analysis. MALDI-TOF conditions were as follows: mass spectra were analyzed in the range m/z 150-550 by averaging the data from 50 laser shots and using an accelerating voltage of 20 kV. The described method was successfully applied to the screening of 31 commercial herbal blends, previously analyzed by GC-MS. Among the samples analyzed, 21 contained synthetic cannabinoids (namely JWH-018, JWH-073, JWH-081, JWH-250, JWH-210, JWH-019, and AM-694). All the results were in agreement with GC-MS, which was used as the reference technique. Copyright © 2012 John Wiley & Sons, Ltd.

Complementary and Alternative Medicine for Multiple Sclerosis

MedlinePlus

... Oral cannabis extract (OCE) – a cannabis pill • Synthetic tetrahydrocannabinol (THC) – a cannabis pill • Oromucosal cannabinoid spray – a spray ... Academy of Neurology AAN. com OCE and Synthetic THC OCE is taken orally (by mouth) in pill ...

The role of cannabinoids in adult neurogenesis

PubMed Central

Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

2015-01-01

The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. PMID:25951750

Simultaneous Analysis of Cannabinoid and Synthetic Cannabinoids in Dietary Supplements Using UPLC with UV and UPLC-MS-MS.

PubMed

Heo, Seok; Yoo, Geum Joo; Choi, Ji Yeon; Park, Hyoung Joon; Do, Jung-Ah; Cho, Sooyeul; Baek, Sun Young; Park, Sung-Kwan

2016-06-01

The primary purpose of this study was to develop and validate a method based on UPLC with UV and UPLC-MS-MS for the simultaneous analysis of different cannabinoids and synthetic cannabinoids in food as well as in herbal and dietary supplements. The limits of detection and quantitation of the method ranged from 0.1 to 0.3 and 0.3 to 0.9 μg/mL by UPLC with UV, respectively. The coefficient of determination was >0.999; the intra- and interday precision of the method were 0.1-3.7 and 0.9-4.1%, respectively. The intra- and interday accuracy were 94.8-103.1 and 98.3-100.9%, respectively. The mean recoveries of nine cannabinoids obtained from tablet samples ranged from 81.1 to 105.4%. The mean extraction recoveries of nine target cannabinoids obtained from various types of samples (tablets, capsules, powders, liquids, cookies and candies) ranged from 82.26 to 112.40%. The relative standard deviation (RSD) of the stability of the prepared sample solutions was <1.80%. Identification and quantification of the nine cannabinoids were accomplished by ion spray UPLC-MS-MS using multiple reaction monitoring. The UPLC-MS-MS method was validated for linearity (R(2) > 0.99); the precision was 0.1-4.0% (intraday) and 0.1-2.8% (interday), and the accuracy was 98.0-103.5% (intraday) and 97.1-103.2% (interday). The mean extraction recoveries of six types of samples were 82.2-114.5% and the RSD of stability was <6.54%, complying with the established international guidelines. The results indicated that the method can be used for rapid and accurate screening of cannabinoids present in food. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Myocardial infarction associated with use of the synthetic cannabinoid K2.

PubMed

Mir, Arshid; Obafemi, Adebisi; Young, Amy; Kane, Colin

2011-12-01

Designer drugs have been problematic over the years. Products such as K2 and Spice, which contain synthetic cannabinoids, are marketed as incense and are widely available on the Internet and at various specialty shops. The effects are reported as cannabis-like after smoking them. In addition, use of these synthetic cannabinoids will not appear on a routine urine toxicology screen. Recently, K2 became a popular alternative to marijuana among youths. Health implications of these designer drugs are not completely understood. Little has been reported about the harmful effects of K2. We report here the first (to our knowledge) cases of myocardial infarction (MI) after smoking K2. Three patients presented separately to the emergency department complaining of chest pain within days after the use of K2. Acute MI was diagnosed in each case on the basis of electrocardiogram changes and elevated troponin levels. Coronary angiography was performed, and the results were normal for the first 2 patients. The incidence of ST-elevation MI is low among teenagers, and association with drug use should be suspected. Public education and awareness need to be heightened about the possible health implications of K2.

The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies.

PubMed

Porcella, A; Maxia, C; Gessa, G L; Pani, L

2001-01-01

The search for new ocular hypotensive agents represents a frontier of current eye research because blindness due to optic neuropathy occurs insidiously in 10% of all patients affected by glaucoma. Cannabinoids have been proposed to lower intraocular pressure by either central or peripheral effects but a specific mechanism for this action has never been elucidated. We recently demonstrated the presence of the central cannabinoid receptor (CB(1)) mRNA and protein in the human ciliary body. In the present study we show that the synthetic CB(1) receptor agonist, WIN 55212--2, applied topically at doses of 25 or 50 microg (n = 8), decreases the intraocular pressure of human glaucoma resistant to conventional therapies within the first 30 min (15 +/- 0.5% and 23 +/- 0.9%, respectively). A maximal reduction of 20 +/- 0.7% and 31 +/- 0.6%, respectively, is reached in the first 60 min. These data confirm that CB(1) receptors have direct involvement in the regulation of human intraocular pressure, and suggest that, among various classes of promising antiglaucoma agents, synthetic CB(1) receptor agonists should deserve further research and clinical development.

Traditional marijuana, high‐potency cannabis and synthetic cannabinoids: increasing risk for psychosis

PubMed Central

Murray, Robin M.; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta

2016-01-01

Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose‐response relationship between the level of use and the risk of later psychosis. High‐potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co‐administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high‐potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high‐potency cannabis and synthetic cannabinoids. PMID:27717258

Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives

PubMed Central

Tambaro, Simone; Bortolato, Marco

2013-01-01

Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. PMID:22280339

Designing microorganisms for heterologous biosynthesis of cannabinoids

PubMed Central

Carvalho, Ângela; Hansen, Esben Halkjær; Kayser, Oliver; Stehle, Felix

2017-01-01

Abstract During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. PMID:28582498

Designing microorganisms for heterologous biosynthesis of cannabinoids.

PubMed

Carvalho, Ângela; Hansen, Esben Halkjær; Kayser, Oliver; Carlsen, Simon; Stehle, Felix

2017-06-01

During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. © FEMS 2017.

Phytocannabinoids and endocannabinoids.

PubMed

Fisar, Zdenek

2009-01-01

Progress in understanding the molecular mechanisms of cannabis action was made after discovery of cannabinoid receptors in the brain and the finding of endogenous metabolites with affinity to them. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by the cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some mental disorders and neurodegenerative illnesses. Cannabis contains a large amount of substances with affinity for the cannabinoid receptors. The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones. Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids in nerve signal transduction. Plant, endogenous and synthetic cannabinoids are using in these studies. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid, an important membrane constituent. The study of structure-activity relationships of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis.

Cannabis, cannabinoids, and health.

PubMed

Lafaye, Genevieve; Karila, Laurent; Blecha, Lisa; Benyamina, Amine

2017-09-01

Cannabis (also known as marijuana) is the most frequently used illicit psychoactive substance in the world. Though it was long considered to be a "soft" drug, studies have proven the harmful psychiatric and addictive effects associated with its use. A number of elements are responsible for the increased complications of cannabis use, including the increase in the potency of cannabis and an evolution in the ratio between the two primary components, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (toward a higher proportion of Δ 9 -THC), Synthetic cannabinoid (SC) use has rapidly progressed over the last few years, primarily among frequent cannabis users, because SCs provide similar psychoactive effects to cannabis. However, their composition and pharmacological properties make them dangerous substances. Cannabis does have therapeutic properties for certain indications. These therapeutic applications pertain only to certain cannabinoids and their synthetic derivatives. The objective of this article is to summarize current developments concerning cannabis and the spread of SCs. Future studies must further explore the benefit-risk profile of medical cannabis use.

Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events.

PubMed

Davidson, Colin; Opacka-Juffry, Jolanta; Arevalo-Martin, Angel; Garcia-Ovejero, Daniel; Molina-Holgado, Eduardo; Molina-Holgado, Francisco

2017-01-01

Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called "Spice." Spice, "K2" or "fake cannabis" is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB 1 cannabinoid receptor agonists falsely marketed and sold as safe and legal drugs. Here, we present an overview of the endocannabinoid system, CB, and SCB chemical structures and activity at CB receptors. Finally, we highlight the psychological effects of SCB, particularly on learning and memory, and adverse clinical effects including on the cardiovascular system, kidneys, and CNS, including psychosis. Taken together, it is clear that many SCB are extremely dangerous and a major public health problem. © 2017 Elsevier Inc. All rights reserved.

Synthetic Cannabinoids and Their Effects on the Cardiovascular System.

PubMed

Von Der Haar, Jonathan; Talebi, Soheila; Ghobadi, Farzaneh; Singh, Shailinder; Chirurgi, Roger; Rajeswari, Pingle; Kalantari, Hossein; Hassen, Getaw Worku

2016-02-01

In the past couple of years, there has been an outbreak of synthetic cannabinoid (SC) use in major cities in the United States. Patients can present with various symptoms affecting the central nervous and cardiovascular systems. The effects of endocannabinoid on contractility and Ca(2+) signaling have been shown through both cannabinoid receptors and a direct effect on ion channels. These effects result in abnormalities in ionotropy, chronotropy, and conduction. Here we report on two cases of SC abuse and abnormalities in the cardiovascular system. These cases raise concerns about the adverse effects of SCs and the possibility of QTc prolongation and subsequent complications when using antipsychotic medication in the presence of SC abuse. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Given the rise in SC use and the potential effect on the cardiovascular system, physicians need to be mindful of potential cardiac complications, such as QTc prolongation and torsade de pointe, especially when administering medications that have the potential to cause QTc prolongation. Copyright © 2016 Elsevier Inc. All rights reserved.

Cannabis, cannabinoids, and health

PubMed Central

Lafaye, Genevieve; Karila, Laurent; Blecha, Lisa; Benyamina, Amine

2017-01-01

Cannabis (also known as marijuana) is the most frequently used illicit psychoactive substance in the world. Though it was long considered to be a “soft” drug, studies have proven the harmful psychiatric and addictive effects associated with its use. A number of elements are responsible for the increased complications of cannabis use, including the increase in the potency of cannabis and an evolution in the ratio between the two primary components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (toward a higher proportion of Δ9-THC), Synthetic cannabinoid (SC) use has rapidly progressed over the last few years, primarily among frequent cannabis users, because SCs provide similar psychoactive effects to cannabis. However, their composition and pharmacological properties make them dangerous substances. Cannabis does have therapeutic properties for certain indications. These therapeutic applications pertain only to certain cannabinoids and their synthetic derivatives. The objective of this article is to summarize current developments concerning cannabis and the spread of SCs. Future studies must further explore the benefit-risk profile of medical cannabis use. PMID:29302228

Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a "CB3" receptor.

PubMed

Fride, Ester; Foox, Anat; Rosenberg, Elana; Faigenboim, Moran; Cohen, Vickey; Barda, Lena; Blau, Hannah; Mechoulam, Raphael

2003-02-07

Cannabinoids, whether plant-derived, synthetic or endogenous, have been shown to stimulate appetite in the adult organism. We have reported previously that cannabinoid receptors play a critical role during the early suckling period: The selective cannabinoid CB(1) receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141617A) permanently prevented milk ingestion in a dose-dependent manner, when administered to (Sabra, albino) mouse pups, within 1 day of birth. As a consequence, these pups died within the first week of life. We now generalize this finding to a different strain of mice (C57BL/6). Further, we show that cannabinoid CB(1) receptor blockade (20 mg/kg SR141716A) must occur within 24 h after birth as injection of SR141716A into 2- or 5-day-old pups had a much smaller effect or no effect at all, respectively. Cannabinoid CB(1) receptor knockout mice did not ingest milk on the first day of life, similarly to SR141716A-treated normal pups, as measured by the appearance of "milkbands". However, the knockout pups started to display milkbands from day 2 of life. Survival rates of cannabinoid CB(1) receptor knockout mice were affected significantly, but to a lesser extent than normal pups, by the administration of SR141716A. Daily administration of the endocannabinoid 2-arachidonoyl glycerol, or the synthetic agonists (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2, 5 mg/kg) or (-)-cis-3-[2-Hydroxy4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940, 5 or 20 mg/kg) did not promote survival or weight gain in CB(1)(-/-) pups. Our data support previous evidence for a critical role of cannabinoid CB(1) receptors for the initiation of suckling. Further, the present observations support the existence of an unknown cannabinoid receptor, with partial control over milk ingestion in newborns. Our data also suggest that the CB(1)(-/-) neonates possess a compensatory mechanism which helps them overcome the lack of cannabinoid CB(1) receptors.

Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

PubMed

Ovadia, H; Wohlman, A; Mechoulam, R; Weidenfeld, J

1995-02-01

In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.

Apparent Affinity Estimates and Reversal of the Effects of Synthetic Cannabinoids AM-2201, CP-47,497, JWH-122, and JWH-250 by Rimonabant in Rhesus Monkeys.

PubMed

Hruba, Lenka; McMahon, Lance R

2017-08-01

Synthetic cannabinoids have been prohibited due to abuse liability and toxicity. Four such synthetic cannabinoids, AM-2201 ([1-(5-fluoropentyl)indol-3-yl]-naphthalen-1-ylmethanone), CP-47,497 (2-[(1R,3S)-3-hydroxycyclohexyl]-5-(2-methyloctan-2-yl)phenol), JWH-122 [(4-methylnaphthalen-1-yl)-(1-pentylindol-3-yl)methanone], and JWH-250 [2-(2-methoxyphenyl)-1-(1-pentylindol-3-yl)ethanone], were tested for their capacity to produce CB 1 receptor-mediated discriminative stimulus effects in two groups of rhesus monkeys. One group ( n = 4) discriminated Δ 9 -tetrahydrocannabinol (∆ 9 -THC; 0.1 mg/kg i.v.), and a second group ( n = 4) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving 1 mg/kg/12 hours of ∆ 9 -THC. AM-2201, JWH-122, CP-47,497, JWH-250, and ∆ 9 -THC increased ∆ 9 -THC lever responding. Duration of action was 1-2 hours for AM-2201, JWH-122, and JWH-250 and 4-5 hours for CP-47,497 and ∆ 9 -THC. Rimonabant (1 mg/kg) surmountably antagonized the discriminative stimulus effects of all cannabinoid agonists; the magnitude of rightward shift was 10.6-fold for AM-2201, 10.7-fold for JWH-122, 11.0-fold for CP-47,497, and 15.7-fold for JWH-250. The respective pK B values were not significantly different: 6.61, 6.65, 6.66, and 6.83. In ∆ 9 -THC-treated monkeys discriminating rimonabant, AM-2201 (0.1 and 0.32 mg/kg), JWH-122 (0.32 and 1 mg/kg), JWH-250 (1 and 3.2 mg/kg), and CP-47,497 (0.32, 1, and 3.2 mg/kg) produced not only rate-decreasing effects that were reversed by rimonabant, but also dose-dependent, rightward shifts in the rimonabant discrimination dose-effect function. These results show striking similarity in the CB 1 receptor mechanism mediating the subjective effects of AM-2201, JWH-122, JWH-250, and CP-47,497. For products containing AM-2201 and JWH-122, a short duration of action could lead to more frequent use; moreover, inattention to differences in potency among synthetic cannabinoids could underlie unexpected toxicity. Rapid reversal of effects by intravenous rimonabant has potential value in emergency situations. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

A synthetic cannabinoid JWH-210 reduces lymphoid organ weights and T-cell activator levels in mice via CB2 receptors.

PubMed

Gu, Sun Mi; Lee, Hyun Jin; Lee, Tac-Hyung; Song, Yun Jeong; Kim, Young-Hoon; Han, Kyoung-Moon; Shin, Jisoon; Park, Hye-Kyung; Kim, Hyung Soo; Cha, Hye Jin; Yun, Jaesuk

2017-12-01

The problem of new psychoactive substances (NPS) is emerging globally. However, the immunotoxicity of synthetic cannabinoids is not evaluated extensively yet. The purpose of the present study was to investigate whether synthetic cannabinoids (JWH-210 and JWH-030) induce adverse effects on lymphoid organs, viability of splenocytes and thymocytes, and immune cell activator and cytokines in mice. JWH-210 (10 mg/kg, 3 days, i.p.) is more likely to have cytotoxicity and reduce lymphoid organ weight than JWH-030 of ICR mice in vivo. We also demonstrated that JWH-210 administration resulted in the decrease of expression levels of T-cell activator including Cd3e, Cd3g, Cd74p31, and Cd74p41, while JWH-030 increased Cd3g levels. In addition, JWH-210 reduced expression levels of cytokines, such as interleukin-3, interleukin-5, and interleukin-6. Furthermore, we demonstrated that a CB 2 receptor antagonist, AM630 inhibited JWH-210-induced cytotoxicity, whereas a CB 1 receptor antagonist, rimonabant did not in primary cultured splenocytes. These results suggest that JWH-210 has a cytotoxicity via CB 2 receptor action and results in decrement of lymphoid organ weights, T-cell activator, and cytokine mRNA expression levels.

CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48.

PubMed

Holm, Niels Bjerre; Nielsen, Line Marie; Linnet, Kristian

2015-09-01

Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents.

CHMICA and MDMB-FUBINACA) Into Schedule I. Notice of Intent.

PubMed

2016-12-21

The Administrator of the Drug Enforcement Administration is issuing this notice of intent to temporarily schedule six synthetic cannabinoids: methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate [5F-ADB; 5F-MDMB-PINACA]; methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate [5F-AMB]; N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide [5F-APINACA, 5F-AKB48]; N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide [ADB-FUBINACA]; methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate [MDMB-CHMICA, MMB-CHMINACA] and methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate [MDMB-FUBINACA], into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act (CSA). This action is based on a finding by the Administrator that the placement of these synthetic cannabinoids into schedule I of the Controlled Substances Act is necessary to avoid an imminent hazard to the public safety. Any final order will impose the administrative, civil, and criminal sanctions and regulatory controls applicable to schedule I substances under the Controlled Substances Act on the manufacture, distribution, possession, importation, exportation of, and research and conduct with, instructional activities of these synthetic cannabinoids.

Purity of synthetic cannabinoids sold online for recreational use.

PubMed

Ginsburg, Brett C; McMahon, Lance R; Sanchez, Jesus J; Javors, Martin A

2012-01-01

The recreational use of synthetic cannabinoids has recently increased. This increase is due, in part, to the recent availability of inexpensive compound sold legally online in bulk. In particular, JWH-018 (1-pentyl-3-(1-naphthoyl)indole) and JWH-073 (1-butyl-3-(1-naphthoyl)indole) have been found in herbal blends marketed as alternatives to cannabis. Although these particular compounds have recently been emergency scheduled in the United States, online suppliers have shifted sales to other, similar compounds that are not currently scheduled. However, the purity of the drugs obtained from online suppliers is not known. Relative purity of JWH-018 and JWH-073 from three different online suppliers was determined using high-performance liquid chromatography with ultraviolet detection and validated standards obtained from a traditional research chemical supplier. Our results show that JWH-018 and JWH-073 obtained from online vendors was of comparable purity to validated standards, even though the physical properties varied in color, texture, and odor. It is concluded that adverse events following consumption of synthetic cannabinoid preparations is unlikely to be due to impurities or residue from the manufacturing process, but rather to effects of the active drug or interactions with other psychoactive chemicals from herbs blended into products marketed as cannabis alternatives.

Traditional marijuana, high-potency cannabis and synthetic cannabinoids: increasing risk for psychosis.

PubMed

Murray, Robin M; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta

2016-10-01

Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose-response relationship between the level of use and the risk of later psychosis. High-potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co-administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high-potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high-potency cannabis and synthetic cannabinoids. © 2016 World Psychiatric Association.

Effects of acute and repeated dosing of the synthetic cannabinoid CP55,940 on intracranial self-stimulation in mice*

PubMed Central

Grim, Travis W.; Wiebelhaus, Jason M.; Negus, S. Stevens; Lichtman, Aron H.

2015-01-01

Background Synthetic cannabinoids have emerged as a significant public health concern. To increase the knowledge of how these molecules interact on brain reward processes, we investigated the effects of CP55,940, a high efficacy synthetic CB1 receptor agonist, in a frequency-rate intracranial self-stimulation (ICSS) procedure. Methods The impact of acute and repeated administration (seven days) of CP55,940 on operant responding for electrical brain stimulation of the medial forebrain bundle was investigated in C57BL/6J mice. Results CP55,940 attenuated ICSS in a dose-related fashion (ED50 (95% C.L.) = 0.15 (0.12–0.18) mg/kg). This effect was blocked by the CB1 receptor antagonist rimonabant. Tolerance developed quickly, though not completely, to the rate-decreasing effects of CP55,940 (0.3 mg/kg). Abrupt discontinuation of drug did not alter baseline responding for up to seven days. Moreover, rimonabant (10 mg/kg) challenge did not alter ICSS responding in mice treated repeatedly with CP55,940. Conclusions The finding that CP55,940 reduced ICSS in mice with no evidence of facilitation at any dose is consistent with synthetic cannabinoid effects on ICSS in rats. CP55,940-induced ICSS depression was mediated through a CB1 receptor mechanism. Additionally, tolerance and dependence following repeated CP55,940 administration were dissociable. Thus, CP55,940 does not produce reward-like effects in ICSS under these conditions. PMID:25772438

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

PubMed Central

Koay, Luan C.; Rigby, Rachael J.

2014-01-01

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered. PMID:24833710

Endocannabinoid system dysfunction in mood and related disorders.

PubMed

Ashton, C H; Moore, P B

2011-10-01

The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders. An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids. We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement. Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential. © 2011 John Wiley & Sons A/S.

The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications.

PubMed

Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

2016-01-01

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

Emerging Role of (Endo)Cannabinoids in Migraine.

PubMed

Leimuranta, Pinja; Khiroug, Leonard; Giniatullin, Rashid

2018-01-01

In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.

Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids

PubMed Central

Kuramoto, Kenta; Wang, Nan; Fan, Yuying; Zhang, Weiran; Schoenen, Frank J.; Frankowski, Kevin J.; Marugan, Juan; Zhou, Yifa; Huang, Sui; He, Congcong

2016-01-01

ABSTRACT Cannabinoids and related drugs generate profound behavioral effects (such as analgesic effects) through activating CNR1 (cannabinoid receptor 1 [brain]). However, repeated cannabinoid administration triggers lysosomal degradation of the receptor and rapid development of drug tolerance, limiting the medical use of marijuana in chronic diseases. The pathogenic mechanisms of cannabinoid tolerance are not fully understood, and little is known about its prevention. Here we show that a protein involved in macroautophagy/autophagy (a conserved lysosomal degradation pathway), BECN2 (beclin 2), mediates cannabinoid tolerance by preventing CNR1 recycling and resensitization after prolonged agonist exposure, and deletion of Becn2 rescues CNR1 activity in mouse brain and conveys resistance to analgesic tolerance to chronic cannabinoids. To target BECN2 therapeutically, we established a competitive recruitment model of BECN2 and identified novel synthetic, natural or physiological stimuli of autophagy that sequester BECN2 from its binding with GPRASP1, a receptor protein for CNR1 degradation. Co-administration of these autophagy inducers effectively restores the level and signaling of brain CNR1 and protects mice from developing tolerance to repeated cannabinoid usage. Overall, our findings demonstrate the functional link among autophagy, receptor signaling and animal behavior regulated by psychoactive drugs, and develop a new strategy to prevent tolerance and improve medical efficacy of cannabinoids by modulating the BECN2 interactome and autophagy activity. PMID:27305347

Cannabinoids as Anticancer Drugs.

PubMed

Ramer, Robert; Hinz, Burkhard

2017-01-01

The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics' effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression. © 2017 Elsevier Inc. All rights reserved.

Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands*

PubMed Central

Kapur, Ankur; Zhao, Pingwei; Sharir, Haleli; Bai, Yushi; Caron, Marc G.; Barak, Larry S.; Abood, Mary E.

2009-01-01

The cannabinoid receptor 1 (CB1) and CB2 cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a β-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing β-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CβII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of β-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CβII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy. PMID:19723626

Cannabidiol as potential anticancer drug

PubMed Central

Massi, Paola; Solinas, Marta; Cinquina, Valentina; Parolaro, Daniela

2013-01-01

Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ9-tetrahydrocannabinol (Δ9-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization. However, the clinical use of Δ9-THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive cannabinoid compounds with structural affinity for Δ9-THC, such as cannabidiol (CBD), has substantially increased in recent years. The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents. PMID:22506672

Synthetic cannabinoid JWH-018 and psychosis: an explorative study.

PubMed

Every-Palmer, Susanna

2011-09-01

Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms. This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service. All 15 subjects were familiar with a locally available JWH-018 containing product called "Aroma" and 86% reported having used it. They credited the product's potent psychoactivity, legality, ready availability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced cannabis as their drug of choice. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms. It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A high-sensitivity ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) method for screening synthetic cannabinoids and other drugs of abuse in urine.

PubMed

Sundström, Mira; Pelander, Anna; Angerer, Verena; Hutter, Melanie; Kneisel, Stefan; Ojanperä, Ilkka

2013-10-01

The continuing emergence of designer drugs imposes high demands on the scope and sensitivity of toxicological drug screening procedures. An ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) method was developed for screening and simultaneous confirmation of both designer drugs and other drugs of abuse in urine samples in a single run. The method covered selected synthetic cannabinoids and cathinones, amphetamines, natural cannabinoids, opioids, cocaine and other important drugs of abuse, together with their main urinary metabolites. The database consisted of 277 compounds with molecular formula and exact monoisotopic mass; retention time was included for 192 compounds, and primary and secondary qualifier ion exact mass for 191 and 95 compounds, respectively. Following a solid-phase extraction, separation was performed by UHPLC and mass analysis by HR-TOFMS. MS, and broad-band collision-induced dissociation data were acquired at m/z range 50-700. Compound identification was based on a reverse database search with acceptance criteria for retention time, precursor ion mass accuracy, isotopic pattern and abundance of qualifier ions. Mass resolving power in spiked urine samples was on average FWHM 23,500 and mass accuracy 0.3 mDa. The mean and median cut-off concentrations determined for 75 compounds were 4.2 and 1 ng/mL, respectively. The range of cut-off concentrations for synthetic cannabinoids was 0.2-60 ng/mL and for cathinones 0.7-15 ng/mL. The method proved to combine high sensitivity and a wide scope in a manner not previously reported in drugs of abuse screening. The method's feasibility was demonstrated with 50 authentic urine samples.

Synthetic Cannabis Overdose and Withdrawal in a Young Adult: A Case Report, Commentary on Regulation, and Review of the Literature.

PubMed

Samaan, John; Ferrer, Gerardo F; Akinyemi, Boye; Junquera, Patricia; Oms, Juan; Dumenigo, Rhaisa

2016-01-01

Introduction . Marijuana has been used for its psychotropic effects including enhanced relaxation and perceptual alterations. However, the use of synthetic marijuana (SM) leads to more frequent and drastic side effects than the typical use of regular marijuana, owing to the fact that SM has a shorter duration and an earlier peak of action. Despite all the potential adverse health effects associated with SM use, current health policies on SM are very limited. It is believed that the popularity of SM has increased, due to its easy accessibility in the US and lack of detection in typical urine drug screens for THC. Case Report . One case presented is of a young adult patient, with histories of recurrent synthetic cannabis and recreational cannabis use, who had developed drastic physiological and psychiatric symptoms, including the development of acute-onset psychosis. Conclusion/Discussion . This case, as many others nationwide, exemplifies the impact of synthetic cannabinoid use and abuse in adolescents. Side effects and adverse health consequences of synthetic cannabinoid use warrant stricter regulations and policies in order to decrease psychiatric hospital admissions and associated healthcare costs.

Clinical Effects of Synthetic Cannabinoid Receptor Agonists Compared with Marijuana in Emergency Department Patients with Acute Drug Overdose.

PubMed

Zaurova, Milana; Hoffman, Robert S; Vlahov, David; Manini, Alex F

2016-12-01

Synthetic cannabinoid receptor agonists (SCRAs) are heterogeneous compounds originally intended as probes of the endogenous cannabinoid system or as potential therapeutic agents. We assessed the clinical toxicity associated with recent SCRA use in a large cohort of drug overdose patients. This subgroup analysis of a large (n = 3739) drug overdose cohort study involved consecutive ED patients at two urban teaching hospitals collected between 2009 and 2013. Clinical characteristics of patients with the exposure to SCRAs (SRCA subgroup) were compared with those from patients who smoked traditional cannabinoids (marijuana subgroup). Data included demographics, exposure details, vital signs, mental status, and basic chemistries gathered as part of routine clinical care. Study outcomes included altered mental status and cardiotoxicity. Eighty-seven patients reported exposure to any cannabinoid, of whom 17 reported SCRAs (17 cases, 70 controls, mean age 38.9 years, 77 % males, 31 % Hispanic). There were no significant differences between SRCA and marijuana with respect to demographics (age, gender, and race/ethnicity), exposure history (suicidality, misuse, and intent), vital signs, or serum chemistries. Mental status varied between SRCA and marijuana, with agitation significantly more likely in SCRA subgroup (OR = 3.8, CI = 1.2-11.9). Cardiotoxicity was more pronounced in the SCRA subgroup with dysrhythmia significantly more likely (OR = 9.2, CI = 1.0-108). In the first clinical study comparing the adverse effects of SCRA overdose vs. marijuana controls in an ED population, we found that SCRA overdoses had significantly pronounced neurotoxicity and cardiotoxicity compared with marijuana.

Molecular analysis of genetic fidelity in Cannabis sativa L. plants grown from synthetic (encapsulated) seeds following in vitro storage.

PubMed

Lata, Hemant; Chandra, Suman; Techen, Natascha; Khan, Ikhlas A; ElSohly, Mahmoud A

2011-12-01

The increasing utilization of synthetic (encapsulated) seeds for germplasm conservation and propagation necessitates the assessment of genetic stability of conserved propagules following their plantlet conversion. We have assessed the genetic stability of synthetic seeds of Cannabis sativa L. during in vitro multiplication and storage for 6 months at different growth conditions using inter simple sequence repeat (ISSR) DNA fingerprinting. Molecular analysis of randomly selected plants from each batch was conducted using 14 ISSR markers. Of the 14 primers tested, nine produced 40 distinct and reproducible bands. All the ISSR profiles from in vitro stored plants were monomorphic and comparable to the mother plant which confirms the genetic stability among the clones. GC analysis of six major cannabinoids [Δ(9)-tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, cannabichromene, cannabigerol and cannabinol] showed homogeneity in the re-grown clones and the mother plant with insignificant differences in cannabinoids content, thereby confirming the stability of plants derived from synthetic seeds following 6 months storage. © Springer Science+Business Media B.V. 2011

The effects of the synthetic cannabinoid receptor agonists, WIN55,212-2 and CP55,940, on salicylate-induced tinnitus in rats.

PubMed

Zheng, Yiwen; Stiles, Lucy; Hamilton, Emma; Smith, Paul F; Darlington, Cynthia L

2010-09-01

Previous studies in animals and humans have shown that, in some cases at least, anti-epileptic drugs can reduce the severity of tinnitus. Given that cannabinoid receptor agonists have been shown to exert anti-epileptic effects in some circumstances, we investigated whether two synthetic CB(1)/CB(2) receptor agonists, WIN55,212-2, and CP55,940, could inhibit the behavioural manifestations of salicylate-induced tinnitus in rats in a conditioned suppression task. We found that neither WIN55,212-2 (3.0 mg/kg s.c) nor CP55,940 (0.1 or 0.3 mg/kg s.c), significantly reduced conditioned behaviour associated with tinnitus. However, both 3 mg/kg WIN55,212-2 and 0.3 mg/kg CP55,940 did significantly increase tinnitus-related behaviour compared to the vehicle control groups. These results suggest that cannabinoid receptor agonists may not be useful in the treatment of salicylate-induced tinnitus and that at certain doses, they could actually exacerbate the condition. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Elucidating Cannabinoid Biology in Zebrafish (Danio rerio)

PubMed Central

Krug, Randall G.; Clark, Karl J.

2015-01-01

The number of annual cannabinoid users exceeds 100,000,000 globally and an estimated 9 % of these individuals will suffer from dependency. Although exogenous cannabinoids, like those contained in marijuana, are known to exert their effects by disrupting the endocannabinoid system, a dearth of knowledge exists about the potential toxicological consequences on public health. Conversely, the endocannabinoid system represents a promising therapeutic target for a plethora of disorders because it functions to endogenously regulate a vast repertoire of physiological functions. Accordingly, the rapidly expanding field of cannabinoid biology has sought to leverage model organisms in order to provide both toxicological and therapeutic insights about altered endocannabinoid signaling. The primary goal of this manuscript is to review the existing field of cannabinoid research in the genetically tractable zebrafish model—focusing on the cannabinoid receptor genes, cnr1 and cnr2, and the genes that produce enzymes for synthesis and degradation of the cognate ligands anandamide and 2-arachidonylglycerol. Consideration is also given to research that has studied the effects of exposure to exogenous phytocannabinoids and synthetic cannabinoids that are known to interact with cannabinoid receptors. These results are considered in the context of either endocannabinoid gene expression or endocannabinoid gene function, and are integrated with findings from rodent studies. This provides the framework for a discussion of how zebrafish may be leveraged in the future to provide novel toxicological and therapeutic insights in the field of cannabinoid biology, which has become increasingly significant given recent trends in cannabis legislation. PMID:26192460

Cannabinoids and Psychosis.

PubMed

D'Souza, Deepak Cyril; Radhakrishnan, Rajiv; Sherif, Mohamed; Cortes-Briones, Jose; Cahill, John; Gupta, Swapnil; Skosnik, Patrick D; Ranganathan, Mohini

2016-01-01

There is growing interest in the relationship between cannabis and psychosis. The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication and persisting as long as a month. Exposure to cannabis in adolescence is associated with an increased risk for later psychotic disorder in adulthood; this association is consistent, somewhat specific, shows a dose-response, and is biologically plausible. The link between cannabinoids and psychosis is greater with earlier age of exposure to cannabinoids, childhood abuse and genetic vulnerability. However, cannabinoids are neither necessary nor sufficient to cause a persistent psychotic disorder. More likely cannabinoids are a 'component cause' interacting with other known (family history) and unknown factors to result in psychosis outcomes. While more research is needed to better understand the relationship between cannabinoid use and psychosis, and the neural underpinnings of this link, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Human Laboratory Studies on Cannabinoids and Psychosis.

PubMed

Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Ranganathan, Mohini

2016-04-01

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. Copyright © 2016. Published by Elsevier Inc.

The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

PubMed Central

Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

2016-01-01

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing. PMID:26881099

Study on the phase I metabolism of novel synthetic cannabinoids, APICA and its fluorinated analogue.

PubMed

Sobolevsky, Tim; Prasolov, Ilya; Rodchenkov, Grigory

2015-02-01

The data are reported for an in vitro metabolism study of two novel synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and its fluorinated analog N-(1-adamantyl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (5F-APICA, STS-135), which are active ingredients of smoking mixtures sold in Russia since 2012. The cannabinoids were isolated from herbal mixtures using preparative liquid chromatography and then incubated with human liver microsomes (HLMs). The formed metabolites were characterized by liquid chromatography - triple quadrupole mass spectrometry and high-resolution mass spectrometry with electrospray ionization in positive ion mode. It was found that HLMs produce mono-, di-, and trihydroxylated metabolites, as well as N-desalkyl metabolites, which can be further hydroxylated; the amide bond resisted the metabolic cleavage. For 5F-APICA, a series of oxidative defluorination products formed as well. For in vivo confirmation of the formed in vitro metabolites, spot urine samples from drug users were analyzed with the created method. It was shown that for the detection of APICA abuse, the preferred metabolites are the di- and tri-hydroxylated species, while in case of 5F-APICA, a monohydroxy metabolite is a better target. The N-despentyl (desfluoropentyl) hydroxyadamantyl metabolite also provides good retrospectivity to confirm the administration of any of these cannabinoids. Copyright © 2014 John Wiley & Sons, Ltd.

[Prevalence of new designer drugs and their legal status in Japan].

PubMed

Kikura-Hanajiri, Ruri; Uchiyama, Nahoko; Kawamura, Maiko; Ogata, Jun; Goda, Yukihiro

2013-01-01

In recent years, many analogs of narcotics have been widely distributed as easily available psychotropic substances and have become a serious problem in Japan. To counter the spread of these non-controlled substances, the Pharmaceutical Affairs Law in Japan was amended in 2006 to establish a new category; Designated Substances in order to more strictly control these substances. In April 2007, 31 compounds and 1 plant were first controlled as Designated Substances. Before 2007, the major compounds distributed in the Japanese illegal drug market were tryptamines, phenethylamines and piperazines. Alkyl nitrites, such as isobutyl nitrite and isopentyl nitrite, were also widely distributed. After they were listed as Narcotics or Designated Substances in 2007, these compounds, especially the tryptamines, quickly disappeared from the market. In their place, cathinone derivatives have been widely distributed, as well as different phenethylamines and piperazines. Additionally, in recent years, new herbal products containing synthetic cannabinoids have appeared globally. As at July 2012, 78 substances (including 1 plant; Salvia divinorum) were listed in the category of Designated Substances. They were 13 tryptamines, 17 phenethylamines, 11 cathinones, 4 piperazines, 23 synthetic cannabinoids, 6 alkyl nitrites, 3 other compounds and 1 plant. In this review, we show our survey of the spread of new designer drugs in Japan, focusing especially on synthetic cannabinoids and cathinone derivatives. Also, the prevalence and legal status of these substances in other countries will be presented.

Straightforward single-calibrant quantification of seized designer drugs by liquid chromatography-chemiluminescence nitrogen detection.

PubMed

Rasanen, Ilpo; Kyber, Marianne; Szilvay, Ilmari; Rintatalo, Janne; Ojanperä, Ilkka

2014-04-01

Sixty-one different psychoactive substances were quantified by liquid chromatography-chemiluminescence nitrogen detection (LC-CLND) in 177 samples, using a single secondary standard (caffeine), in a trial concerning the quantitative purity assessment of drug-related material seized by the police in 2011-2012 and customs in 2011-2013 in Finland. The substances found were predominantly substituted phenethylamines, cathinones, tryptamines and synthetic cannabinoids, which were identified by appropriate methods prior to submitting the samples for quantification by LC-CLND. The equimolarity and expanded uncertainty of measurement by LC-CLND were on average 95% and 13%, respectively, based on 16 different substances. The median (mean) purity of stimulant/hallucinogenic drug samples seized at the border was 92.9% (87.6%) and in the street 82.0% (64.5%). The corresponding figures for powdery synthetic cannabinoid samples seized at the border and in the street were 99.0% (96.8%) and 90.0% (92.2%), respectively. There was generally only one active drug to be quantified in each sample. Seized herbal samples contained 0.15-9.2% of between one and three components. LC-CLND was found to be suitable for quantification of the nitrogen-containing drugs encountered in the study, showing sufficient N-equimolarity for both stimulant/hallucinogenic drugs and synthetic cannabinoids. The technique possesses great potential as a standard technique in forensic laboratories. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[The role of endocannabinoid system in physiological and pathological processes in the eye].

PubMed

Nadolska, Krystyna; Goś, Roman

2008-01-01

Plant of Cannabis sativa/ marihuana except for its psychotropic effects possesses a range of pharmacological properties, that has been utilized for medical purposes over a period of millenia. Investigations concerning biochemical mechanism of action of the main and most active pharmacological compound of Cannabis sativa, cannabinoid 9-THC, contributed to the discovery of cannabinoid receptors both in the central nervous system (CNS) and peripheral tissues, that mediated actions of this substance. The discovery made possible identification of a new, endogenous signaling system reffered to as the endocannabinoid system. Besides cannabinoid receptors CB1 and CB2, the system includes it's endogenic ligands (endocannabinoids) and compounds that participate in their biosynthesis and inactivation. Structure and functioning of the endocannabinoid system is conservative in all vertebrates. It's activation with plant, synthetic and endogenous cannabinoids has an influence on multiple physiological and pathological processes within the eye.

Electroconvulsive therapy (ECT) for catatonia in a patient with schizophrenia and synthetic cannabinoid abuse: a case report.

PubMed

Leibu, Evan; Garakani, Amir; McGonigle, Daniel P; Liebman, Lauren S; Loh, Daniella; Bryson, Ethan O; Kellner, Charles H

2013-12-01

We present the case of a young man with a long-standing history of schizophrenia who presented with severe and life-threatening catatonia in the setting of synthetic cannabis use who was successfully treated with electroconvulsive therapy. To our knowledge, this is the first reported case of severe and persistent catatonia in the setting of synthetic cannabis use and the first documented successful treatment.

Novel psychoactive substances of interest for psychiatry

PubMed Central

Schifano, Fabrizio; Orsolini, Laura; Duccio Papanti, G; Corkery, John M

2015-01-01

Novel psychoactive substances include synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, phencyclidine-like dissociatives, piperazines, GABA-A/B receptor agonists, a range of prescribed medications, psychoactive plants/herbs, and a large series of performance and image enhancing drugs. Users are typically attracted by these substances due to their intense psychoactive effects and likely lack of detection in routine drug screenings. This paper aims at providing psychiatrists with updated knowledge of the clinical pharmacology and psychopathological consequences of the use of these substances. Indeed, these drugs act on a range of neurotransmitter pathways/receptors whose imbalance has been associated with psychopathological conditions, including dopamine, cannabinoid CB1, GABA-A/B, 5-HT2A, glutamate, and k opioid receptors. An overall approach in terms of clinical management is briefly discussed. PMID:25655145

Novel natural and synthetic ligands of the endocannabinoid system.

PubMed

Hanus, Lumír O; Mechoulam, Raphael

2010-01-01

In this review we describe recent advances in the chemistry of novel CB(1)/CB(2) agonists, CB(1) antagonists, selective CB(2) agonists, fatty acid amide hydrolase inibitors, monoglyceride (MGL) and diglyceride (DAGL) inhibitors and cannabinoid-type agonists and antagonists of non CB(1)/CB(2) receptors. In view of recent interest in the activities of fatty acid amides of amino acids (N-acyl amino acids) a list of this type of compounds was compiled and is presented as a Table. We conclude that further synthetic work based on both the plant cannabinoids and on the endocannabinoids may lead to novel therapeutics and that the identification and the elucidation of the biological profile of the myriad of endogenous N-acyl amino acids and related compounds may enhance the already wide spectrum of lipidomics.

Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

PubMed

Lee, Dayong; Karschner, Erin L; Milman, Garry; Barnes, Allan J; Goodwin, Robert S; Huestis, Marilyn A

2013-06-01

We characterize cannabinoid disposition in oral fluid (OF) after dronabinol, synthetic oral Δ(9)-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5 h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25-1 h. Median CBD/THC and CBN/THC ratios were 0.82-1.34 and 0.04-0.06, respectively, reflecting cannabinoids' composition in Sativex. THCCOOH/THC ratios within 4.5 h post Sativex were ≤ 1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. Published by Elsevier Ireland Ltd.

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-tetrahydrocannabinol (Δ9-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

Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?

PubMed Central

Malinowska, Barbara; Baranowska-Kuczko, Marta; Schlicker, Eberhard

2012-01-01

The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ9-tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ9-tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB1 and CB2 receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB1 receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined. PMID:22022923

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

PubMed Central

Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E.; Redhi, Godfrey H.; Panlilio, Leigh V.; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D.; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R.

2013-01-01

In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

PubMed

Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E; Redhi, Godfrey H; Panlilio, Leigh V; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R

2013-11-01

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

The Psychiatric Consequences of Cannabinoids.

PubMed

De Aquino, Joao P; Sherif, Mohamed; Radhakrishnan, Rajiv; Cahill, John D; Ranganathan, Mohini; D'Souza, Deepak C

2018-04-17

With rising rates of cannabis use in the general population and an increasing number of US states legalizing both recreational and medical cannabis use, it is important to be informed about the adverse consequences of cannabinoids. This Commentary provides an overview of the psychiatric effects of plant-based and synthetic cannabinoids, differentiating acute effects from effects associated with persistent use. Cannabinoids produce multiphasic and dose-dependent effects on anxiety, mood, and perception, in addition to impairing cognition and psychomotor function. Generally, in healthy individuals, the acute negative psychiatric effects of cannabinoids are rated as milder in severity compared with those in individuals with pre-existing psychiatric disorders. With chronic exposure to cannabinoids, the probability of developing tolerance and dependence can increase. A problematic pattern of cannabis use can lead to clinically significant impairment and distress. Cessation of cannabis use in individuals who are tolerant and dependent can lead to a withdrawal syndrome. Studies report long-term cannabis exposure has been linked to psychiatric disorders, such as anxiety, psychotic and mood disorders. Limitations to the existing evidence notwithstanding, the plausibility of a causal relationship between cannabinoid exposure and persistent negative psychiatric outcomes, and the potential for long-term brain changes by regular exposure, especially for adolescents, are sufficient to warrant discussions with clinicians and the public. Implications for clinicians who certify, prescribe, or care for patients receiving cannabinoids are discussed, and a case is made for further research to better understand the impact of legalization on public mental health. Copyright © 2018. Published by Elsevier Inc.

Synthetic cannabis and respiratory depression.

PubMed

Jinwala, Felecia N; Gupta, Mayank

2012-12-01

In recent years, synthetic cannabis use has been increasing in appeal among adolescents, and its use is now at a 30 year peak among high school seniors. The constituents of synthetic cannabis are difficult to monitor, given the drug's easy accessibility. Currently, 40 U.S. states have banned the distribution and use of some known synthetic cannabinoids, and have included these drugs in the Schedule I category. The depressive respiratory effect in humans caused by synthetic cannabis inhalation has not been thoroughly investigated in the medical literature. We are the first to report, to our knowledge, two cases of self-reported synthetic cannabis use leading to respiratory depression and necessary intubation.

Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems.

PubMed

Fantegrossi, William E; Wilson, Catheryn D; Berquist, Michael D

2018-02-01

An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin, and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users.

Effects of Cannabinoids on T-cell Function and Resistance to Infection

PubMed Central

Eisenstein, Toby K.

2015-01-01

This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of Δ9-THC extracted from the marijuana plant, and synthetic cannabinoids. Of particular interest are synthetic compounds that are CB2 receptor (CB2R) selective agonists. As the CB2R is principally expressed on cells of the immune system, agonists that target this receptor, and not CB1 (which is mainly expressed on neurons), have the possibility of altering immune function without psychoactive effects. The overall conclusion of the studies discussed in this review is that cannabinoids that bind to the CB2 receptor, including Δ9-THC and CB2 selective agonists are immunosuppressive. The studies provide objective evidence for potentially beneficial effects of marijuana and Δ9-THC on the immune system in conditions where it is desirable to dampen immune responses. Evidence is also reviewed supporting the conclusion that these same compounds can sensitize to some infections through their immunosuppressive activities, but not to others. An emerging area of investigation that is reviewed is evidence to support the conclusion that CB2 selective agonists are a new class of immunosuppressive and anti-inflammatory compounds that may have exceptional beneficial effects in a variety of conditions, such as autoimmune diseases and graft rejection, where it is desirable to dampen the immune response without psychoactive effects. PMID:25876735

Synthetic Pot: Not Your Grandfather’s Marijuana

PubMed Central

Ford, Benjamin M.; Tai, Sherrica; Fantegrossi, William E.

2017-01-01

In the early 2000’s in Europe and shortly thereafter in the USA, it was reported that “legal” forms of marijuana were being sold under the name K2 and/or Spice. Active ingredients in K2/Spice products were determined to be synthetic cannabinoids (SCBs), producing psychotropic actions via CB1 cannabinoid receptors, similar to those of Δ9-THC, the primary active constituent in marijuana. Often abused by adolescents and military personnel to elude detection in drug tests due to their lack of structural similarity to Δ9-THC, SCBs are falsely marketed as safe marijuana substitutes. Instead, SCBs are a highly structural diverse group of compounds, easily synthesized, which produce very dangerous adverse effects occurring by, as of yet, unknown mechanisms. Therefore, available evidence indicates that K2/Spice products are clearly not safe marijuana alternatives. PMID:28162792

Suicidal ideation and self-harm following K2 use.

PubMed

Thomas, Shannon; Bliss, Sarah; Malik, Mohammed

2012-11-01

There is emerging evidence of adverse effects associated with K2 and similar synthetic cannabinoid compounds marketed as herbal alternatives to marijuana. Few studies were identified regarding the psychiatric effects of K2, including suicidal ideation, and to our knowledge none have been written related to self-harm following use of K2. A healthy 20-year-old single Caucasian male with no previous psychiatric diagnoses or treatment was brought by police to the ED with acute agitation, confusion, suicidal ideation, and self-inflicted trauma after smoking K2. Evaluation in the ED was notable for agitation, significant abrasions, respiratory rate of 30, negative UDS, and sinus tachycardia on EKG. Once medically stabilized, he was transferred to the inpatient psychiatric unit for continued monitoring. Upon evaluation on the psychiatric unit the following day, his symptoms had completely resolved, he continued to deny any previous psychiatric history, and was discharged home. K2 and other synthetic cannabinoids have been shown to have significant medical and psychiatric adverse effects and they are still readily available for purchase. Evidence is limited regarding the psychiatric effects; however, synthetic cannabinoid products may potentially lead to suicidal ideation and self-harm behaviors amongst many other psychiatric symptoms.The long-term risks are still unclear, but some studies suggest the possibility of inducing chronic psychotic symptoms and worsening underlying psychiatric illness. Continued research is needed regarding the effects of these substances as well as an increase in public awareness of the risks.

Psychometric Properties of the Turkish Versions of the Cannabis Use Problems Identification Test (CUPIT) and the Adult Cannabis Problems Questionnaire (CPQ).

PubMed

Evren, Cuneyt; Yilmaz Cengel, Hanife; Bozkurt, Muge; Evren, Bilge; Umut, Gokhan; Agachanli, Ruken

2017-01-01

Cannabis and synthetic cannabinoids are widely used illicit substances in Turkey. The Cannabis Use Problems Identification Test (CUPIT) is a brief self-report screening instrument for detection of problematic cannabis use, whereas the Cannabis Problems Questionnaire (CPQ) is a measure for cannabis treatment outcome. The aim of this study was to evaluate the psychometric properties of the CUPIT and CPQ among Turkish male outpatients with cannabis (n = 52) and synthetic cannabinoid (n = 45) use disorder. Participants were evaluated with the CUPIT, the CPQ, and the Cannabis Withdrawal Scale (CWS). Principal Component Analysis (PCA) supported two-factor construct validity for CUPIT. Cronbach's alpha was 0.84 for CUPIT-A factor, 0.83 for CUPIT-B factor, and 0.89 for CUPIT, when considered as a unidimensional scale. Cronbach's alpha was 0.82 for CPQ-A factor, 0.73 for CPQ-B factor, 0.30 for CPQ-C, and 0.87 for CPQ, when considered as a unidimensional scale. The CUPIT and the CPQ were moderately correlated with the CWS (r = 0.63 and r = 0.74, respectively), whereas the CUPIT and the CPQ were strongly correlated with each other (r = 0.76). The Turkish version of the CUPIT and the CPQ can effectively identify substance use problems and treatment outcome, respectively, among outpatients with cannabis or synthetic cannabinoid use disorder.

Toxicokinetics of new psychoactive substances: plasma protein binding, metabolic stability, and human phase I metabolism of the synthetic cannabinoid WIN 55,212-2 studied using in vitro tools and LC-HR-MS/MS.

PubMed

Mardal, Marie; Gracia-Lor, Emma; Leibnitz, Svenja; Castiglioni, Sara; Meyer, Markus R

2016-10-01

The new psychoactive substance WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone) is a potent synthetic cannabinoid receptor agonist. The metabolism of WIN 55,212-2 in man has never been reported. Therefore, the aim of this study was to identify the human in vitro metabolites of WIN 55,212-2 using pooled human liver microsomes and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) to provide targets for toxicological, doping, and environmental screening procedures. Moreover, a metabolic stability study in pooled human liver microsomes (pHLM) was carried out. In total, 19 metabolites were identified and the following partly overlapping metabolic steps were deduced: degradation of the morpholine ring via hydroxylation, N- and O-dealkylation, and oxidative deamination, hydroxylations on either the naphthalene or morpholine ring or the alkyl spacer with subsequent oxidation, epoxide formation with subsequent hydrolysis, or combinations. In conclusion, WIN 55,212-2 was extensively metabolized in human liver microsomes incubations and the calculated hepatic clearance was comparably high, indicating a fast and nearly complete metabolism in vivo. This is in line with previous findings on other synthetic cannabinoids. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

First characterization of AKB-48 metabolism, a novel synthetic cannabinoid, using human hepatocytes and high-resolution mass spectrometry.

PubMed

Gandhi, Adarsh S; Zhu, Mingshe; Pang, Shaokun; Wohlfarth, Ariane; Scheidweiler, Karl B; Liu, Hua-Fen; Huestis, Marilyn A

2013-10-01

Since the federal authorities scheduled the first synthetic cannabinoids, JWH-018 and JWH-073, new synthetic cannabinoids were robustly marketed. N-(1-Adamantyl)-1-pentylindazole-3-carboxamide (AKB-48), also known as APINACA, was recently observed in Japanese herbal smoking blends. The National Forensic Laboratory Information System registered 443 reports of AKB-48 cases in the USA from March 2010 to January 2013. In May 2013, the Drug Enforcement Administration listed AKB-48 as a Schedule I drug. Recently, AKB-48 was shown to have twice the CB1 receptor binding affinity than CB2. These pharmacological effects and the difficulty in detecting the parent compound in urine highlight the importance of metabolite identification for developing analytical methods for clinical and forensic investigations. Using human hepatocytes and TripleTOF mass spectrometry, we identified 17 novel phase I and II AKB-48 metabolites, products of monohydroxylation, dihydroxylation, or trihydroxylation on the aliphatic adamantane ring or N-pentyl side chain. Glucuronide conjugation of some mono- and dihydroxylated metabolites also occurred. Oxidation and dihydroxylation on the adamantane ring and N-pentyl side chain formed a ketone. More metabolites were identified after 3 h of incubation than at 1 h. For the first time, we present a AKB-48 metabolic scheme obtained from human hepatocytes and high-resolution mass spectrometry. These data are needed to develop analytical methods to identify AKB-48 consumption in clinical and forensic testing.

Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18.

PubMed

Kevin, Richard C; Lefever, Timothy W; Snyder, Rodney W; Patel, Purvi R; Gamage, Thomas F; Fennell, Timothy R; Wiley, Jenny L; McGregor, Iain S; Thomas, Brian F

2018-01-01

In 2014 and 2015, synthetic cannabinoid receptor agonists NNEI (N-1-naphthalenyl-1-pentyl-1H-indole-3-carboxamide) and MN-18 (N-1-naphthalenyl-1-pentyl-1H-indazole-3-carboxamide) were detected in recreationally used and abused products in multiple countries, and were implicated in episodes of poisoning and toxicity. Despite this, the pharmacokinetic profiles of NNEI and MN-18 have not been characterized. In the present study NNEI and MN-18 were incubated in rat and human liver microsomes and hepatocytes, to estimate kinetic parameters and to identify potential metabolic pathways, respectively. These parameters and pathways were then examined in vivo, via analysis of blood and urine samples from catheterized male rats following intraperitoneal (3 mg/kg) administration of NNEI and MN-18. Both NNEI and MN-18 were rapidly cleared by rat and human liver microsomes, and underwent a range of oxidative transformations during incubation with rat and human hepatocytes. Several unique metabolites were identified for the forensic identification of NNEI and MN-18 intake. Interestingly, NNEI underwent a greater number of biotransformations (20 NNEI metabolites versus 10 MN-18 metabolites), yet parent MN-18 was eliminated at a faster rate than NNEI in vivo. Additionally, in vivo elimination was more rapid than in vitro estimates. These data highlight that even closely related synthetic cannabinoids can possess markedly distinct pharmacokinetic profiles, which can vary substantially between in vitro and in vivo models. Copyright © 2017 John Wiley & Sons, Ltd.

Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.

PubMed

Vikingsson, Svante; Gréen, Henrik; Brinkhagen, Linda; Mukhtar, Shahzabe; Josefsson, Martin

2016-09-01

Synthetic cannabinoids are a group of psychoactive drugs presently widespread among drug users in Europe. Analytical methods to measure these compounds in urine are in demand as urine is a preferred matrix for drug testing. For most synthetic cannabinoids, the parent compounds are rarely detected in urine. Therefore urinary metabolites are needed as markers of drug intake. AB-FUBINACA was one of the top three synthetic cannabinoids most frequently found in seizures and toxicological drug screening in Sweden (2013-2014). Drug abuse is also reported from several other countries such as the USA and Japan. In this study, 28 authentic case samples were used to identify urinary markers of AB-FUBINACA intake using liquid chromatography quadrupole tandem time of flight mass spectrometry and human liver microsomes. Three metabolites suitable as markers of drug intake were identified and at least two of them were detected in all but one case. In total, 15 urinary metabolites of AB-FUBINACA were reported, including hydrolxylations on the indazole ring and the amino-oxobutane moiety, dealkylations and hydrolysis of the primary amide. No modifications on the fluorobenzyl side-chain were observed. The parent compound was detected in 54% of the case samples. Also, after three hours of incubation with human liver microsomes, 77% of the signal from the parent compound remained. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

CB2 Receptor Agonists Protect Human Dopaminergic Neurons against Damage from HIV-1 gp120

PubMed Central

Hu, Shuxian; Sheng, Wen S.; Rock, R. Bryan

2013-01-01

Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia. PMID:24147028

An Update on Non-CB1, Non-CB2 Cannabinoid Related G-Protein-Coupled Receptors

PubMed Central

Morales, Paula; Reggio, Patricia H.

2017-01-01

Abstract The endocannabinoid system (ECS) has been shown to be of great importance in the regulation of numerous physiological and pathological processes. To date, two Class A G-protein-coupled receptors (GPCRs) have been discovered and validated as the main therapeutic targets of this system: the cannabinoid receptor type 1 (CB1), which is the most abundant neuromodulatory receptor in the brain, and the cannabinoid receptor type 2 (CB2), predominantly found in the immune system among other organs and tissues. Endogenous cannabinoid receptor ligands (endocannabinoids) and the enzymes involved in their synthesis, cell uptake, and degradation have also been identified as part of the ECS. However, its complex pharmacology suggests that other GPCRs may also play physiologically relevant roles in this therapeutically promising system. In the last years, GPCRs such as GPR18 and GPR55 have emerged as possible missing members of the cannabinoid family. This categorization still stimulates strong debate due to the lack of pharmacological tools to validate it. Because of their close phylogenetic relationship, the Class A orphan GPCRs, GPR3, GPR6, and GPR12, have also been associated with the cannabinoids. Moreover, certain endo-, phyto-, and synthetic cannabinoid ligands have displayed activity at other well-established GPCRs, including the opioid, adenosine, serotonin, and dopamine receptor families. In addition, the cannabinoid receptors have also been shown to form dimers with other GPCRs triggering cross-talk signaling under specific conditions. In this mini review, we aim to provide insight into the non-CB1, non-CB2 cannabinoid-related GPCRs that have been reported thus far. We consider the physiological relevance of these molecular targets in modulating the ECS. PMID:29098189

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2

PubMed Central

Howlett, A. C.; Abood, M. E.; Alexander, S. P. H.; Di Marzo, V.; Elphick, M. R.; Greasley, P. J.; Hansen, H. S.; Kunos, G.; Mackie, K.; Mechoulam, R.; Ross, R. A.

2010-01-01

There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature. PMID:21079038

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂.

PubMed

Pertwee, R G; Howlett, A C; Abood, M E; Alexander, S P H; Di Marzo, V; Elphick, M R; Greasley, P J; Hansen, H S; Kunos, G; Mackie, K; Mechoulam, R; Ross, R A

2010-12-01

There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes.

PubMed

Manzanares, J; Julian, Md; Carrascosa, A

2006-07-01

Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB(1)mediated suppression of mast cell activation responses, CB(2)-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.

Polypharmacology Shakes Hands with Complex Aetiopathology.

PubMed

Brodie, James S; Di Marzo, Vincenzo; Guy, Geoffrey W

2015-12-01

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex(®)), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the 'therapeutic handshake', to predict efficacy/safety of compound combinations of either natural or synthetic origin. Copyright © 2015 Elsevier Ltd. All rights reserved.

2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor

PubMed Central

Hanuš, Lumír; Abu-Lafi, Saleh; Fride, Ester; Breuer, Aviva; Vogel, Zvi; Shalev, Deborah E.; Kustanovich, Irina; Mechoulam, Raphael

2001-01-01

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids—arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series—and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB1 cannabinoid receptor (Ki = 21.2 ± 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor (Ki > 3 μM). PMID:11259648

Tripping with Synthetic Cannabinoids ("Spice"): Anecdotal and Experimental Observations in Animals and Man.

PubMed

Järbe, Torbjörn U C; Raghav, Jimit Girish

2017-01-01

The phenomenon of consuming synthetic cannabinoids ("Spice") for recreational purposes is a fairly recent trend. However, consumption of cannabis dates back millennia, with numerous accounts written on the experience of its consumption, and thousands of scientific reports published on the effects of its constituents in laboratory animals and humans. Here, we focus on consolidating the scientific literature on the effects of "Spice" compounds in various behavioral assays, including assessing abuse liability, tolerance, dependence, withdrawal, and potential toxicity. In most cases, the behavioral effects of "Spice" compounds are compared with those of Δ 9 -tetrahydrocannabinol. Methodological aspects, such as modes of administration and other logistical issues, are also discussed. As the original "Spice" molecules never were intended for human consumption, scientifically based information about potential toxicity and short- and long-term behavioral effects are very limited. Consequently, preclinical behavioral studies with "Spice" compounds are still in a nascent stage. Research is needed to address the addiction potential and other effects, including propensity for producing tissue/organ toxicity, of these synthetic cannabimimetic "Spice" compounds.

Teens and Spice: A Review of Adolescent Fatalities Associated with Synthetic Cannabinoid Use.

PubMed

Paul, Anthea B Mahesan; Simms, Lary; Amini, Saeideh; Paul, Abraham Ebenezer

2017-12-01

Synthetic cannabinoids (SCs) are commonly abused by adolescents with reported past year (2013) use in high school students between 3 and 10%. Standard adolescent postmortem toxicology does not include routine SC analysis, and thus, the true burden of fatalities related to SCs is unknown. A retrospective case review of two cases included scene investigation, interviews, autopsy, and toxicology. SCs were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Review of the eight adolescent SC-associated fatalities in the literature revealed five of eight cases had no other discernible cause of death on autopsy. Compounds detected included PB-22 (1.1 ng/mL), JWH-210 (12 ng/mL), XLR-11 (1.3 ng/mL), JWH-122, AB-CHMINACA (8.2 ng/mL), UR-144 (12.3 ng/mL), and JWH-022 (3 ng/mL). With synthetic drug use on the rise, forensic experts should have a high index of suspicion for the possibility of SC intoxication in adolescent fatalities with no other discernible cause of death. © 2017 American Academy of Forensic Sciences.

Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants

PubMed Central

Hampson, A. J.; Grimaldi, M.; Axelrod, J.; Wink, D.

1998-01-01

The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (−)Δ9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-d-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-d-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or α-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia. PMID:9653176

Cannabinoids - a new weapon against cancer?

PubMed

Pokrywka, Małgorzata; Góralska, Joanna; Solnica, Bogdan

2016-12-29

Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis - Δ9 - tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.

Synthetic Pot: Not Your Grandfather's Marijuana.

PubMed

Ford, Benjamin M; Tai, Sherrica; Fantegrossi, William E; Prather, Paul L

2017-03-01

In the early 2000s in Europe and shortly thereafter in the USA, it was reported that 'legal' forms of marijuana were being sold under the name K2 and/or Spice. Active ingredients in K2/Spice products were determined to be synthetic cannabinoids (SCBs), producing psychotropic actions via CB 1 cannabinoid receptors, similar to those of Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the primary active constituent in marijuana. Often abused by adolescents and military personnel to elude detection in drug tests due to their lack of structural similarity to Δ 9 -THC, SCBs are falsely marketed as safe marijuana substitutes. Instead, SCBs are a highly structural diverse group of compounds, easily synthesized, which produce very dangerous adverse effects occurring by, as of yet, unknown mechanisms. Therefore, available evidence indicates that K2/Spice products are clearly not safe marijuana alternatives. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pre-hospital identification and post-recovery challenges of intoxication with synthetic cannabinoid containing legal high products such as 'Exodus Damnation'.

PubMed

Fitzpatrick, David; O'Meara, Patrick; Cunningham, Andrew

2016-11-01

This short report describes the case of a young adult male who had smoked a synthetic cannabinoid legal high product called 'Exodus Damnation'. The patient's presentation was atypical from that described in the literature, with hypotension and hypoxaemia. Of note was the rapid recovery after pre-hospital intervention with high-flow oxygen therapy and intravenous fluids. The patient refused on-going care, despite repeated advice to attend the Emergency Department. The distinct lack of specialist support and referral to drug treatment for this patient population, with whom ambulance services are coming into contact with increasing frequency, is reported. For those patients with the capacity to refuse on-going care, ambulance services may be in an opportune position to actively promote referral to support services for these vulnerable individuals. © The Author(s) 2016.

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease.

PubMed

Carroll, C B; Zeissler, M-L; Hanemann, C O; Zajicek, J P

2012-10-01

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC. Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ⁹-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ⁹-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation. We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

A survey of synthetic cannabinoid consumption by current cannabis users.

PubMed

Gunderson, Erik W; Haughey, Heather M; Ait-Daoud, Nassima; Joshi, Amruta S; Hart, Carl L

2014-01-01

Despite growing concern about the increased rates of synthetic cannabinoid (SC) use and their effects, only limited data are available that addresses these issues. This study assessed the extent of SC product use and reported effects among a cohort of adult marijuana and tobacco users. A brief telephone interview was conducted with individuals who had given permission to be contacted for future research while screening for a cannabis/nicotine dependence medication development study (NCT01204723). Respondents (N = 42; 88% participation rate) were primarily young adults, male, racially diverse, and high school graduates. Nearly all currently smoked tobacco and cannabis, with 86% smoking cannabis on 5 or more days per week. Nearly all (91%) were familiar with SC products, half (50%) reported smoking SC products previously, and a substantial minority (24%) reported current use (i.e., past month). Despite a federal ban on 5 common SCs, which went into effect on March 1, 2011, a number of respondents reported continued SC product use. Common reasons reported for use included, but were not limited to, seeking a new "high" similar to that produced by marijuana and avoiding drug use detection via a positive urine screen. The primary side effects were trouble thinking clearly, headache, dry mouth, and anxiety. No significant differences were found between synthetic cannabinoid product users (ever or current) and nonusers by demographics or other characteristics. Among current marijuana and tobacco users, SC product consumption was common and persisted despite a federal ban. The primary reasons for the use of SC-containing products seem to be to evade drug detection and to experience a marijuana-like high.

Engineering yeasts as platform organisms for cannabinoid biosynthesis.

PubMed

Zirpel, Bastian; Degenhardt, Friederike; Martin, Chantale; Kayser, Oliver; Stehle, Felix

2017-10-10

Δ 9 -tetrahydrocannabinolic acid (THCA) is a plant derived secondary natural product from the plant Cannabis satival. The discovery of the human endocannabinoid system in the late 1980s resulted in a growing number of known physiological functions of both synthetic and plant derived cannabinoids. Thus, manifold therapeutic indications of cannabinoids currently comprise a significant area of research. Here we reconstituted the final biosynthetic cannabinoid pathway in yeasts. The use of the soluble prenyltransferase NphB from Streptomyces sp. strain CL190 enables the replacement of the native transmembrane prenyltransferase cannabigerolic acid synthase from C. sativa. In addition to the desired product cannabigerolic acid, NphB catalyzes an O-prenylation leading to 2-O-geranyl olivetolic acid. We show for the first time that the bacterial prenyltransferase and the final enzyme of the cannabinoid pathway tetrahydrocannabinolic acid synthase can both be actively expressed in the yeasts Saccharomyces cerevisiae and Komagataella phaffii simultaneously. While enzyme activities in S. cerevisiae were insufficient to produce THCA from olivetolic acid and geranyl diphosphate, genomic multi-copy integrations of the enzyme's coding sequences in K. phaffii resulted in successful synthesis of THCA from olivetolic acid and geranyl diphosphate. This study is an important step toward total biosynthesis of valuable cannabinoids and derivatives and demonstrates the potential for developing a sustainable and secure yeast bio-manufacturing platform. Copyright © 2017 Elsevier B.V. All rights reserved.

Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex.

PubMed

Oropeza, V C; Page, M E; Van Bockstaele, E J

2005-06-07

Cannabinoid agonists modulate a variety of behavioral functions by activating cannabinoid receptors that are widely distributed throughout the central nervous system. In the present study, norepinephrine efflux was assessed in the frontal cortex of rats that received a systemic administration of the cannabinoid agonist, WIN 55,212-2. The synthetic cannabinoid agonist dose-dependently increased the release of norepinephrine in this brain region. Pretreatment with the cannabinoid receptor antagonist, SR 141716A, blocked the increase in norepinephrine release. To identify sites of cellular activation, immunocytochemical detection of c-Fos was combined with detection of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in the brainstem nucleus locus coeruleus (LC), a region that is the sole source of norepinephrine to the frontal cortex. Systemic administration of WIN 55,212-2 significantly increased the number of c-Fos immunoreactive cells within TH-containing neurons in the LC compared to vehicle-treated rats. Pretreatment with SR 141716A inhibited the WIN 55,212-2 induced c-Fos expression, while the antagonist alone did not affect c-Fos expression. Taken together, these data indicate that systemically administered cannabinoid agonists stimulate norepinephrine release in the frontal cortex by activating noradrenergic neurons in the coeruleo-frontal cortex pathway. These effects may partially underlie changes in attention, arousal and anxiety observed following exposure to cannabis-based drugs.

The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease

PubMed Central

Hasenoehrl, Carina; Taschler, Ulrike; Storr, Martin; Schicho, Rudolf

2016-01-01

Background and Purpose In ancient medicine, extracts of the marijuana plant Cannabis sativa were used against diseases of the gastrointestinal (GI) tract. Today, our knowledge of the ingredients of the Cannabis plant has remarkably advanced enabling us to use a variety of herbal and synthetic cannabinoid compounds to study the endocannabinoid system (ECS), a physiologic entity that controls tissue homeostasis with the help of endogenously produced cannabinoids and their receptors. After many anecdotal reports suggested beneficial effects of Cannabis in GI disorders, it was not surprising to discover that the GI tract accommodates and expresses all the components of the ECS. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, participate in the regulation of GI motility, secretion, and the maintenance of the epithelial barrier integrity. In addition, other receptors, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPARα) and the G-protein coupled receptor 55 (GPR55), are important participants in the actions of cannabinoids in the gut and critically determine the course of bowel inflammation and colon cancer. The following review summarizes important and recent findings on the role of cannabinoid receptors and their ligands in the GI tract with emphasis on GI disorders, such as irritable bowel syndrome, inflammatory bowel disease and colon cancer. PMID:27561826

The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects.

PubMed

van Amsterdam, Jan; Brunt, Tibor; van den Brink, Wim

2015-03-01

Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk. The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed. © The Author(s) 2015.

International trends in spice use: Prevalence, motivation for use, relationship to other substances, and perception of use and safety for synthetic cannabinoids.

PubMed

Loeffler, George; Delaney, Eileen; Hann, Michael

2016-09-01

Synthetic cannabinoids (SC), commonly known as Spice, are a class of compounds that share affinity for the cannabinoid receptors. Recreational use of SCs has grown in recent years. A literature search was conducted of national and international organizations as well as peer-reviewed publications describing SC use in non-clinical populations. Our primary goal was summarizing SC use prevalence within the general population from representative surveys. Our secondary goals included describing SC use frequency, motivation for use, the relationship between SC use and use of other substances, and perception of SC use including beliefs about safety and use by peers. Nationally and regionally representative surveys describe lifetime prevalence of SC use in the general population as between 0.2% and 4%. Longitudinal data, though limited, shows decline in SC use with peak use occurring in the late teens and early twenties. Users tend to be males. The majority of SC users report using only a small number of times and use tends to not be sustained. The most common motive for SC use is curiosity. SC users generally report a history of extensive use of other substances. Perception of SC use by others tends to be significantly greater than actual SC use. Published by Elsevier Inc.

Simultaneous Quantification of 20 Synthetic Cannabinoids and 21 Metabolites, and Semi-quantification of 12 Alkyl Hydroxy Metabolites in Human Urine by Liquid Chromatography-Tandem Mass Spectrometry

PubMed Central

Scheidweiler, Karl B.; Huestis, Marilyn A.

2014-01-01

Clandestine laboratories constantly produce new synthetic cannabinoids to circumvent legislative efforts, complicating toxicological analysis. No extensive synthetic cannabinoid quantitative urinary methods are reported in the literature. We developed and validated a liquid chromatography tandem mass spectrometric (LC-MS/MS) method for simultaneously quantifying JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, JWH-398, RCS-4, AM-2201, MAM-2201, UR-144, CP 47,497-C7, CP 47,497-C8 and their metabolites, and JWH-203, AM-694, RCS-8, XLR-11 and HU-210 parent compounds in urine. Non-chromatographically resolved alkyl hydroxy metabolite isomers were considered semi-quantitative. β-glucuronidase hydrolyzed urine was extracted with 1 ml Biotage SLE+ columns. Specimens were reconstituted in 150 µL mobile phase consisting of 50% A (0.01% formic acid in water) and 50% B (0.01% formic acid in 50:50 methanol:acetonitrile). 4 and 25 µL injections were performed to acquire data in positive and negative ionization modes, respectively. The LC-MS/MS instrument consisted of a Shimadzu UFLCxr system and an ABSciex 5500 Qtrap mass spectrometer with an electrospray source. Gradient chromatographic separation was achieved utilizing a Restek Ultra Biphenyl column with a 0.5 ml/min flow rate and an overall run time of 19.5 and 11.4 min for positive and negative mode methods, respectively. Quantification was by multiple reaction monitoring with CP 47,497 compounds and HU-210 ionized via negative polarity; all other analytes were acquired in positive mode. Lower and upper limits of linearity were 0.1–1.0 and 50–100 µg/l (r2 > 0.994). Validation parameters were evaluated at three concentrations spanning linear dynamic ranges. Inter-day analytical recovery (bias) and imprecision (N=20) were 88.3–112.2% and 4.3–13.5% coefficient of variation, respectively. Extraction efficiencies and matrix effect (N=10) were 44–110 and −73 to 52%, respectively. We present a novel LC-MS/MS method for simultaneously quantifying 20 synthetic cannabinoids and 21 metabolites, and semi-quantifying 12 alkyl hydroxy metabolites in urine. PMID:24418231

When and How to Treat Possible Cannabis Use Disorder.

PubMed

Lévesque, Annie; Le Foll, Bernard

2018-07-01

Cannabis (marijuana) is a drug product derived from the plant Cannabis sativa. Cannabinoid is a general term for all chemical constituents of the cannabis plant. Legalization of marijuana in numerous US states, the availability of cannabis of higher potency, and the emergence of synthetic cannabinoids may have contributed to increased demand for related medical services. The most effective available treatments for cannabis use disorder are psychosocial approaches. There is no pharmacotherapy approved treatment. This article reviews the current state of knowledge regarding effective treatments for cannabis use disorder. Copyright © 2018 Elsevier Inc. All rights reserved.

The Endocannabinoid System as a Target for Treatment of Breast Cancer

DTIC Science & Technology

2009-08-01

psychoactive constituent of marijuana , as well as other naturally occurring and synthetically derived cannabinoids possess potential therapeutic effects...receptor agonists for therapeutic uses because of their marijuana -like and psychomimetic effects. An alternative promising approach is the indirect

Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction

PubMed Central

Olière, Stéphanie; Jolette-Riopel, Antoine; Potvin, Stéphane; Jutras-Aswad, Didier

2013-01-01

Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamines. Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants. PMID:24069004

Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons*

PubMed Central

Laprairie, Robert B.; Bagher, Amina M.; Kelly, Melanie E. M.; Dupré, Denis J.; Denovan-Wright, Eileen M.

2014-01-01

Modulation of type 1 cannabinoid receptor (CB1) activity has been touted as a potential means of treating addiction, anxiety, depression, and neurodegeneration. Different agonists of CB1 are known to evoke varied responses in vivo. Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor that can signal through multiple pathways. To understand cannabinoid-specific functional selectivity, different groups have examined the effect of individual cannabinoids on various signaling pathways in heterologous expression systems. In the current study, we compared the functional selectivity of six cannabinoids, including two endocannabinoids (2-arachidonyl glycerol (2-AG) and anandamide (AEA)), two synthetic cannabinoids (WIN55,212-2 and CP55,940), and two phytocannabinoids (cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC)) on arrestin2-, Gαi/o-, Gβγ-, Gαs-, and Gαq-mediated intracellular signaling in the mouse STHdhQ7/Q7 cell culture model of striatal medium spiny projection neurons that endogenously express CB1. In this system, 2-AG, THC, and CP55,940 were more potent mediators of arrestin2 recruitment than other cannabinoids tested. 2-AG, AEA, and WIN55,212-2, enhanced Gαi/o and Gβγ signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gαq-dependent pathways. CP55,940 and CBD both signaled through Gαs. CP55,940, but not CBD, activated downstream Gαs pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias. PMID:25037227

[Synthetic cannabinoids: spread, addiction biology & current perspective of personal health hazard].

PubMed

Bonnet, U; Mahler, H

2015-04-01

Among the new psychoactive substances (NPS), most frequently synthetic cannabinoids (SCBs) have been found in Europe. These are sold as active compounds in e. g. so-called "herbal blends". When inhaled or ingested, besides intoxication symptoms, as they occur with heavy cannabis use (e. g., tachycardia, myocardial infarction, confusion, hallucinations, panic attacks, and paranoia), harmful effects (severe agitation, coma, catatonic stupor, hypertension, cardiac arrhythmia, dyspnoea, seizures, myoclonus, rhabdomyolysis, hyperthermia, diaphoresis, acute kidney injury, vomiting, headache, and hypokalemia) arise, which are mostly unusual about cannabis use. In addition, the first cases of addiction and death related to SCBs have been reported. Taking into account the newest literature and using an algorithm with two main criteria (addiction potential, toxicity), the authors made a first attempt to rank the personal health hazard of SCBs in comparison to that of other psychoactive drugs. Accordingly, the relative health hazard of SCBs is found to be somewhat higher than that of cannabis and lower than that of synthetic cathinones ("bath salts"). However, the toxicity of SCBs, is significantly greater than the toxicity of cannabis, thus being similar to that of synthetic cathinones and benzodiazepines. The addiction potential appears to be lower than that of synthetic cathinones, benzodiazepines, or cannabis. Due to the fluctuation of substances and the availability in internet resources, legislation is facing a serious "hare-hedgehog" problem to control the manufacture, trade and possession of SCBs. © Georg Thieme Verlag KG Stuttgart · New York.

78 FR 28735 - Schedules of Controlled Substances: Temporary Placement of Three Synthetic Cannabinoids Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-16

... the U.S. in December 2008, when a shipment of ``Spice'' was seized and analyzed by U.S. Customs and..., when U.S. Customs and Border Protection analyzed ``Spice'' products. NFLIS has reported 14,831 exhibits...

Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

PubMed Central

Lee, Dayong; Karschner, Erin L.; Milman, Garry; Barnes, Allan J.; Goodwin, Robert S.; Huestis, Marilyn A.

2012-01-01

OBJECTIVES We characterize cannabinoid disposition in oral fluid (OF) after Dronabinol, synthetic oral Δ9-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. METHODS 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25–1h. Median CBD/THC and CBN/THC ratios were 0.82–1.34 and 0.04–0.06, respectively, reflecting cannabinoids’ composition in Sativex. THCCOOH/THC ratios within 4.5h post Sativex were ≤1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. CONCLUSIONS Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. PMID:23146820

Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease.

PubMed

Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

2016-01-01

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.

Cannabinoid-induced conditioned place preference in the spontaneously hypertensive rat-an animal model of attention deficit hyperactivity disorder.

PubMed

Pandolfo, Pablo; Vendruscolo, Leandro F; Sordi, Regina; Takahashi, Reinaldo N

2009-08-01

Cannabis preparations are the most widely consumed illicit drugs, and their use typically begins in adolescence. The prevalence of cannabis abuse is higher in patients with attention deficit/hyperactivity disorder (ADHD) than in the general population, yet, knowledge about the motivational properties of cannabinoids in animal models of ADHD are lacking. To compare the motivational effects of the synthetic cannabinoid agonist WIN55,212-2 (WIN) in adolescent and adult spontaneously hypertensive rats (SHR), a validated animal model of ADHD, and Wistar rats, representing a "normal" genetically heterogeneous population. We also asked whether the effects of WIN depended (1) on the activation of the cerebral subtype of cannabinoid receptors, namely, the CB(1) cannabinoid receptor and (2) on putative changes by WIN in blood pressure. WIN was tested under an unbiased conditioned place preference (CPP) paradigm. Blood pressure after WIN administration was also monitored in additional groups of rats. In the Wistar rats, WIN produced place aversion only in the adult but not adolescent rats. In contrast, WIN produced CPP in both adolescent and adult SHR rats. The behavioral effects of WIN were CB(1)-mediated and not related to blood pressure. The contrasting effects of WIN in Wistar and SHR, and the higher resistance of adolescent rats to the aversive and rewarding effects of WIN in these two strains suggests that both adolescence and the ADHD-like profile exhibited by the SHR strain constitute factors that influence the motivational properties of cannabinoids.

Cannabinoids in health and disease.

PubMed

Kogan, Natalya M; Mechoulam, Raphael

2007-01-01

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.

Cannabinoids in health and disease

PubMed Central

Kogan, Natalya M.; Mechoulam, Raphael

2007-01-01

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable - instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and - in cases where it is impossible to separate the desired clinical action and the psychoactivity - just to monitor these side effects carefully. PMID:18286801

Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA ("Ecstasy") in rats.

PubMed

Morley, Kirsten C; Li, Kong M; Hunt, Glenn E; Mallet, Paul E; McGregor, Iain S

2004-06-01

Cannabinoid-MDMA interactions were examined in male Wistar rats. MDMA (4 x 5 mg/kg or 2 x 10 mg/kg over 4 h on each of 2 days) was administered with or without Delta 9-tetrahydrocannabinol (THC) (4 x 2.5 mg/kg), the synthetic cannabinoid receptor agonist CP 55,940 (2 x 0.1 or 0.2 mg/kg) or the cannabinoid receptor antagonist SR 141716 (2 x 5 mg/kg). Co-administered Delta 9-THC and CP 55,940 but not SR 141716 prevented MDMA-induced hyperthermia, causing a powerful hypothermia. Co-administered Delta 9-THC, CP 55,940 and SR 141716 all tended to decrease MDMA-induced hyperactivity. Co-administered Delta 9-THC provided protection against the long-term increases in anxiety seen in the emergence test, but not the social interaction test, 6 weeks after MDMA treatment. Co-administered Delta 9-THC and CP 55,940, but not SR 141716, partly prevented the long-term 5-HT and 5-HIAA depletion caused by MDMA in various brain regions. SR 141716 administered with CP 55,940 and MDMA prevented the hypothermic response to the CP 55,940/MDMA combination but did not alter the CP 55,940 attenuation of MDMA-induced 5-HT depletion. These results suggest a partial protective effect of co-administered cannabinoid receptor agonists on MDMA-induced 5-HT depletion and long-term anxiety. This action appears to operate independently of cannabinoid CB1 receptors.

Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls.

PubMed

Möller, Ines; Wintermeyer, Annette; Bender, Katja; Jübner, Martin; Thomas, Andreas; Krug, Oliver; Schänzer, Wilhelm; Thevis, Mario

2011-09-01

Referred to as 'spice', several new drugs, advertised as herbal blends, have appeared on the market in the last few years, in which the synthetic cannabinoids JWH-018 and a C(8) homologue of CP 47,497 were identified as major active ingredients. Due to their reported cannabis-like effects, many European countries have banned these substances. The World Anti-Doping Agency has also explicitly prohibited synthetic cannabinoids in elite sport in-competition. Since urine specimens have been the preferred doping control samples, the elucidation of the metabolic pathways of these substances is of particular importance to implement them in sports drug testing programmes. In a recent report, an in vitro phase-I metabolism study of JWH-018 was presented yielding mainly hydroxylated and N-dealkylated metabolites. Due to these findings, a urine sample of a healthy man declaring to have smoked a 'spice' product was screened for potential phase-I and -II metabolites by high-resolution/high-accuracy mass spectrometry in the present report. The majority of the phase-I metabolites observed in earlier in vitro studies of JWH-018 were detected in this urine specimen and furthermore most of their respective monoglucuronides. As no intact JWH-018 was detectable, the monohydroxylated metabolite being the most abundant one was chosen as a target analyte for sports drug testing purposes; a detection method was subsequently developed and validated in accordance to conventional screening protocols based on enzymatic hydrolysis, liquid-liquid extraction, and liquid chromatography/electrospray tandem mass spectrometry analysis. The method was applied to approximately 7500 urine doping control samples yielding two JWH-018 findings and demonstrated its capability for a sensitive and selective identification of JWH-018 and its metabolites in human urine. Copyright © 2010 John Wiley & Sons, Ltd.

Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies.

PubMed

Canazza, Isabella; Ossato, Andrea; Vincenzi, Fabrizio; Gregori, Adolfo; Di Rosa, Fabiana; Nigro, Federica; Rimessi, Alessandro; Pinton, Paolo; Varani, Katia; Borea, Pier Andrea; Marti, Matteo

2017-05-01

5F-ADBINACA, AB-FUBINACA, and STS-135 are 3 novel third-generation fluorinate synthetic cannabinoids that are illegally marketed as incense, herbal preparations, or research chemicals for their psychoactive cannabis-like effects. The present study aims at investigating the in vitro and in vivo pharmacological activity of 5F-ADBINACA, AB-FUBINACA, and STS-135 in male CD-1 mice, comparing their in vivo effects with those caused by the administration of Δ 9 -THC and JWH-018. In vitro competition binding experiments revealed a nanomolar affinity and potency of the 5F-ADBINACA, AB-FUBINACA, and STS-135 on mouse and human CB 1 and CB 2 receptors. Moreover, these synthetic cannabinoids induced neurotoxicity in murine neuro-2a cells. In vivo studies showed that 5F-ADBINACA, AB-FUBINACA, and STS-135 induced hypothermia; increased pain threshold to both noxious mechanical and thermal stimuli; caused catalepsy; reduced motor activity; impaired sensorimotor responses (visual, acoustic, and tactile); caused seizures, myoclonia, and hyperreflexia; and promoted aggressiveness in mice. Behavioral and neurological effects were fully prevented by the selective CB 1 receptor antagonist/inverse agonist AM 251. Differently, the visual sensory response induced by STS-135 was only partly prevented by the AM 251, suggesting a CB 1 -independent mechanism. For the first time, the present study demonstrates the pharmaco-toxicological effects induced by the administration of 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice and suggests their possible detrimental effects on human health. Copyright © 2017 John Wiley & Sons, Ltd.

Transdermal permeation of WIN 55,212-2 and CP 55,940 in human skin in vitro.

PubMed

Valiveti, Satyanarayana; Kiptoo, Paul K; Hammell, Dana C; Stinchcomb, Audra L

2004-06-18

Synthetic cannabinoids have a promising future as treatments for nausea, appetite modulation, pain, and many neurological disorders. Transdermal delivery is a convenient and desirable dosage form for these drugs and health conditions. The aim of the present study was to investigate the in vitro transdermal permeation of two synthetic cannabinoids, WIN 55,212-2 and CP 55,940. Transdermal flux, drug content in the skin, and lag times were measured in split-thickness human abdominal skin in flow-through diffusion cells with receiver solutions of 4% bovine serum albumin (BSA) or 0.5% Brij 98. Differential thermal analysis (DSC) was performed in order to determine heats of fusion, melting points, and relative thermodynamic activities. The in vitro diffusion studies in 0.5% Brij 98 indicated that WIN 55,212-2 diffuses across human skin faster than CP 55,940. The WIN 55,212-2 skin disposition concentration levels were also significantly higher than that of CP 55,940. Correspondingly, CP 55,940 was significantly metabolized in the skin. WIN 55,212-2 flux and skin disposition were significantly lower into 4% BSA than into 0.5% Brij 98 receiver solutions. There was no significant difference in the flux, lag time, and drug content in the skin of CP 55,940 in 4% BSA versus 0.5% Brij 98 receiver solutions. The DSC studies showed that CP 55,940 had a significantly lower melting point, smaller heat of fusion, and corresponding higher calculated thermodynamic activity than the more crystalline WIN 55,212-2 mesylate salt. The permeation results indicated that WIN 55,212-2 mesylate, CP 55,940, and other potent synthetic cannabinoids with these physicochemical properties could be ideal candidates for the development of a transdermal therapeutic system. Copyright 2004 Elsevier B.V.

Schedules of Controlled Substances: Temporary Placement of Six Synthetic Cannabinoids (5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA) into Schedule I. Temporary Scheduling Order.

PubMed

2017-04-10

The Administrator of the Drug Enforcement Administration is issuing this temporary scheduling order to schedule six synthetic cannabinoids: methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate [5F-ADB; 5F-MDMB-PINACA]; methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate [5F-AMB]; N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide [5F-APINACA, 5F-AKB48]; N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide [ADB-FUBINACA]; methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate [MDMB-CHMICA, MMB-CHMINACA] and methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate [MDMB-FUBINACA], and their optical, positional, and geometric isomers, salts, and salts of isomers into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act. This action is based on a finding by the Administrator that the placement of these synthetic cannabinoids into schedule I of the Controlled Substances Act is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA or MDMB-FUBINACA.

A new challenge in forensic toxicology exemplified by a case of murder under the influence of a synthetic cannabinoid - AM-2201.

PubMed

Rojek, Sebastian; Kłys, Małgorzata; Maciów-Głąb, Martyna; Kula, Karol

2017-07-01

Among new psychoactive substances (NPS) available on the narcotic market, a significant number consists of synthetic cannabinoids commonly known as smokable herbal "spice" and "K2", and which are legally treated as a legal alternative to marijuana. The dearth of information on the pharmacology of these intoxicants as they are introduced into the market has created the urgent need among healthcare providers for case studies on the substances belonging to this group, both in terms of the consequences of using such intoxicants, and in methods of detection. The subject of the present report is a multi-parameter analysis of a criminal case of an 18-year-old male who was charged with murder of his female relative and attempted murder of two other victims by stabbing. The defendant pleaded guilty, but he claimed that he had been acting without volition, because he was under the influence of the synthetic cannabinoid AM-2201, which had been purchased from a dealer as a 10g package labelled "Mr Green - No bad trip". Analytical methods including gas chromatography - electron ionization - quadrupole ion trap mass spectrometry (GC-EI-QIT/MS) and liquid chromatography, electrospray ionization, tandem mass spectrometry (LC-ESI-MS-MS) were developed to determine the presence of AM-2201 in the Mr Green - No Bad Trip, and in the blood of the perpetrator, respectively. Toxicological findings are discussed in the context of psychoactive and adverse physical effects resulting from the presence of AM-2201 in the human body; the observations were also analyzed in conjunction with data from the literature. Copyright © 2017. Published by Elsevier B.V.

Qualitative analysis of seized synthetic cannabinoids and synthetic cathinones by gas chromatography triple quadrupole tandem mass spectrometry.

PubMed

Gwak, Seongshin; Arroyo-Mora, Luis E; Almirall, José R

2015-02-01

Designer drugs are analogues or derivatives of illicit drugs with a modification of their chemical structure in order to circumvent current legislation for controlled substances. Designer drugs of abuse have increased dramatically in popularity all over the world for the past couple of years. Currently, the qualitative seized-drug analysis is mainly performed by gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) in which most of these emerging designer drug derivatives are extensively fragmented not presenting a molecular ion in their mass spectra. The absence of molecular ion and/or similar fragmentation pattern among these derivatives may cause the equivocal identification of unknown seized-substances. In this study, the qualitative identification of 34 designer drugs, mainly synthetic cannabinoids and synthetic cathinones, were performed by gas chromatography-triple quadrupole-tandem mass spectrometry with two different ionization techniques, including electron ionization (EI) and chemical ionization (CI) only focusing on qualitative seized-drug analysis, not from the toxicological point of view. The implementation of CI source facilitates the determination of molecular mass and the identification of seized designer drugs. Developed multiple reaction monitoring (MRM) mode may increase sensitivity and selectivity in the analysis of seized designer drugs. In addition, CI mass spectra and MRM mass spectra of these designer drug derivatives can be used as a potential supplemental database along with EI mass spectral database. Copyright © 2014 John Wiley & Sons, Ltd.

Analysis of new classes of recreational drugs in sewage: synthetic cannabinoids and amphetamine-like substances.

PubMed

Reid, Malcolm J; Derry, Lisa; Thomas, Kevin V

2014-01-01

The analysis of sewage for the residues of commonly used illicit drugs has successfully been applied as a suitable approach for estimating community illicit drug use. The drug market is increasingly dynamic with new substances continually being marketed for recreational purposes. In this study, ultra-high pressure liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was used to simultaneously and quantitatively detect the exogenous biomarkers of new classes of recreational drugs in sewage collected from three different Norwegian cities (Oslo, Bergen, Hamar). The samples were screened for the presence of khat (d-norpseudoephedrine and cathinone), mephedrone, pseudoephedrine, 7-aminoflunitrazepam, para-methoxyamphetamine (PMA), para-methoxy-N-methylamphetamine (PMMA) and a selection of urinary metabolites of synthetic cannabinoids collectively termed ´Spice´ (5-3-1-naphthoyl-1H-indol-1-yl-pentanoic acid (JWH 018 N-pentanoic acid), 1-5-hydroxypentyl-1H-indol-3-ylnaphthalen-1-yl-methanone (JWH 018 N-5-hydroxypentyl), 4-3-1-naphthoyl-1H-indol-1-yl-butanoic acid (JWH 073 N-butanoic acid), 1-4-hydroxybutyl-1H-indol-3-ylnaphthalen-1-yl-methanone (JWH 073 N-4-hydroxybutyl), 1-5-hydroxypentyl-1H-indol-3-yl4-methylnaphthalen-1-yl-methanone (JWH 122 N-5-hydroxypentyl), 1-5-fluoro-4-hydroxypentyl-1H-indol-3-ylnaphthalen-1-ylmethanone (AM2201 N-4-hydroxypentyl), and 1-5-hydroxypentyl-1H-indol-3-yl4-methoxyphenyl-methanone (RCS-4 N-5-hydroxypentyl)). Limits of detection were 1 ng/L for amphetamine like compounds and 5 ng/L for the metabolites of synthetic cannabinoids while the limits of quantification were 3 and 15 ng/L, respectively. Three of the fourteen selected biomarkers (cathine, pseudoephedrine and the synthetic cannabinoid metabolite JWH-018 N-5-hydroxypentyl) were detected in sewage, alongside the illicit drugs (and/or metabolites) typically found in sewage (cocaine, benzoylecognine, methamphetamine, MDMA, and THC-COOH). The khat biomarker d-norpseudoephedrine was detected in Oslo sewage at a mean concentration of 93 ng/L that represents a daily load of 54 mg/day/1000 inhabitants. Pseudoephedrine was present at mean concentrations of between 27 and 67 ng/L representing normalized daily loads of between 10 (Hamar) and 24 mg/day/1000 inhabitants (Bergen). The daily normalized loads of JWH-018 N-5-hydroxypentyl were between 49 (Oslo) and 62 mg/day/1000 inhabitants (Hamar). This study demonstrates for the first time that sewage biomarker analysis can be applied to evaluate not only the use the traditional illicit drugs (cocaine, cannabis and amphetamines), but also the use of certain new synthetic drugs. Copyright © 2013 John Wiley & Sons, Ltd.

[Synthetic cannabinoids: A new addiction matrix].

PubMed

Scocard, Amandine; Benyamina, Amine; Coscas, Sarah; Karila, Laurent

2017-01-01

Synthetic cannabinoids (SC) belong to the emergent market of new psychoactive substances, sold on the Internet or specialized shops. Since the 1970s, more than 160 new SC have invaded the drug market. These substances imitate the psychoactive effects of cannabis. Underestimated for too long, SC's market growth and consequences are no longer to be ignored, first of all in terms of public health. SC were first synthesized during researches on the endocannabinoid system. Though they are agonists of the cannabinoid receptors 1 and 2, as Δ9-tetrahydrocannabinol in cannabis, they can also have a really high affinity with these receptors, rising up their potency. Each country in the world has chosen various ways how to deal with SC: scheduling, blanket ban, regulation… In order to contour the legal system, producers regularly modify the chemical formulas of those substances and hand out an attracting packaging looking harmless. However, the content of those small packets is extremely unstable and unreliable, including harmful compounds to health. Reports show an increasing number of non-fatal intoxications but also fatalities. Consequences on the body are numerous but there have been also reports of mental health imbalance and appearances of addiction-linked clinical signs. This review of literature aims at establishing a picture on SC in order to raise awareness among professionals in the health field on this new addiction matrix. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Motor vehicle collisions caused by the 'super-strength' synthetic cannabinoids, MAM-2201, 5F-PB-22, 5F-AB-PINACA, 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014.

PubMed

Kaneko, Shuji

2017-01-01

From 2012 to 2014 in Japan, 214 cases of motor vehicle collisions were attributed to the use of illegal drugs. In 93 out of 96 investigated cases, the causative agents were a variety of synthetic cannabinoids (SCs). These SCs can be classified into three groups according to the lineage of the chemical structures: (1) naphthoyl indoles, such as MAM-2201, (2) quinolinyl ester indoles, such as 5F-PB-22, and (3) indazole carboxamides, such as 5F-AB-PINACA, 5F-AMB, and 5F-ADB. These SCs became available sequentially with increasing cannabinoid CB 1 agonist potencies and reached a nationwide outbreak in the summer of 2014. They caused acute intoxication with impaired consciousness, anterograde amnesia (impaired memory), catalepsy with muscle rigidity, tachycardia, and vomiting or drooling soon after smoking. Drivers who had abused one of these SCs might unexpectedly experience the acute intoxication that caused uncontrolled driving. These SCs were generally difficult to detect from body fluid samples. It is thought that the highly lipophilic SCs disappear from the blood via rapid degradation by liver enzymes and selective accumulation into adipose tissues. Thus, much effort should be directed to the development of fast and sensitive chemical detection of the drug usage.

Variation in commercial smoking mixtures containing third-generation synthetic cannabinoids.

PubMed

Frinculescu, Anca; Lyall, Catherine L; Ramsey, John; Miserez, Bram

2017-02-01

Variation in ingredients (qualitative variation) and in quantity of active compounds (quantitative variation) in herbal smoking mixtures containing synthetic cannabinoids has been shown for older products. This can be dangerous to the user, as accurate and reproducible dosing is impossible. In this study, 69 packages containing third-generation cannabinoids of seven brands on the UK market in 2014 were analyzed both qualitatively and quantitatively for variation. When comparing the labels to actual active ingredients identified in the sample, only one brand was shown to be correctly labelled. The other six brands contained less, more, or ingredients other than those listed on the label. Only two brands were inconsistent, containing different active ingredients in different samples. Quantitative variation was assessed both within one package and between several packages. Within-package variation was within a 10% range for five of the seven brands, but two brands showed larger variation, up to 25% (Relative Standard Deviation). Variation between packages was significantly higher, with variation up to 38% and maximum concentration up to 2.7 times higher than the minimum concentration. Both qualitative and quantitative variation are common in smoking mixtures and endanger the user, as it is impossible to estimate the dose or to know the compound consumed when smoking commercial mixtures. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain

PubMed Central

Bridges, Daniel; Ahmad, Kamran; Rice, Andrew S C

2001-01-01

The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed.The effect of WIN55,212-2 (0.1 – 5.0 mg kg−1, i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co-administration of the CB1 receptor antagonist SR141716a, but not by co-administration of the CB2 receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB1 receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone.These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB1 receptor. PMID:11399676

A new cause of ischaemic priapism: Synthetic cannabinoids.

PubMed

Ortac, M; Pazır, Y; Kadıoğlu, A

2018-04-01

Priapism is a urological emergency that needs early intervention and may lead to irreversible cavernosal damage. Ischaemic priapism is the most common type, which is frequently idiopathic and commonly associated with haematological diseases, medications or recreational drugs. Synthetic cannabinoids (SCs) have been increasingly used all over the world, particularly among young-adult population. SCs can cause severe adverse effects on several organ systems. However, there are no studies in the literature which have stated the possible relationship between using of SCs and priapism. We present a case of 28-year-old man who was diagnosed with a 58-hr lasting priapism after regular administrations of SCs. The priapism did not resolve neither after applying aspiration with irrigation nor shunt surgery. Finally, penile prosthesis implantation was performed as last treatment option. The SCs have been increasingly used among young population in recent years; therefore, new SC-related ischaemic priapism cases might be encountered in the emergency departments. © 2018 Blackwell Verlag GmbH.

Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity.

PubMed

Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

2013-06-01

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic-pituitary-adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory.

Novelty-Induced Emotional Arousal Modulates Cannabinoid Effects on Recognition Memory and Adrenocortical Activity

PubMed Central

Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

2013-01-01

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings—describing both enhancing and impairing effects—have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic–pituitary–adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory. PMID:23340520

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

PubMed Central

Kwilasz, Andrew J.

2012-01-01

Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist Δ9-tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1–10 mg/kg) and CP55940 (0.0032–0.32 mg/kg) dose-dependently blocked acid- stimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiation-related depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans. PMID:22892341

Repeated stimulation of D1 dopamine receptors enhances (-)-11-hydroxy-delta 8-tetrahydrocannabinol-dimethyl-heptyl-induced catalepsy in male rats.

PubMed

Rodríguez de Fonseca, F; Martín Calderón, J L; Mechoulam, R; Navarro, M

1994-03-21

Dopaminergic and cannabinoid receptors are localized in the outflow nuclei of the basal ganglia. We have investigated the possible interrelation of these receptors in the regulation of motor activity in male rats. To this end we have first studied the behavioural effects of the highly potent cannabinoid receptor agonist (-)11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (HU-210, 20 micrograms mg) after chronic stimulation of dopamine D1 and D2 receptors. The catalepsy induced by the synthetic cannabinoid, measured as the descent latency in the bar test, was enhanced in male rats chronically treated with the dopamine D1 receptor agonist SKF38393 (8 mg kg-1, twice a day during 21 days). However, animals exposed to the dopamine D2 agonist quinpirole (1 mg kg-1 daily during 21 days) displayed the same degree of catalepsy as those exposed to HU-210 alone. Although a possible involvement of D2 receptors cannot be excluded, this finding suggests a predominant role for dopamine D1 receptors in the regulation of the cataleptic response to cannabinoids. The possible cross-talk between dopamine D1 and cannabinoid receptors is further supported by the decreased responsiveness to the acute behavioural effects of SKF38393 (8 mg kg-1) observed in animals chronically exposed to HU-210 (20 micrograms kg-1 daily during 14 days).

Effects and risks associated with novel psychoactive substances: mislabeling and sale as bath salts, spice, and research chemicals.

PubMed

Hohmann, Nicolas; Mikus, Gerd; Czock, David

2014-02-28

The number of newly reported psychoactive substances in Europe is now higher than ever. In order to evade legal restrictions, old and novel psychoactive substances from medical research and their derivatives are commonly mislabeled as "not for human consumption" and offered for sale on the Internet and elsewhere. Such substances are widely taken by young people as "club drugs." Their consumption must be considered in the differential diagnosis of psychiatric, neurological, cardiovascular, or metabolic disturbances of unclear origin in a young patient. Selective review of pertinent literature retrieved by a PubMed search, including publications by government-sponsored organizations. From 2010 to 2012, 163 substances were reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), mostly either synthetic cannabinoids (39.3%) or synthetic cathinones (16.6%). Synthetic cannabinoids alter mood and perception; intoxications cause agitation, tachy cardia, and arterial hypertension. Synthetic cathinones are hallucinogenic stimulants with predominantly cardiovascular and psychiatric side effects. Severe intoxications cause serotonin syndrome and potentially fatal rhabdomyolysis. Substances in either of these classes often escape detection in screening tests. Young persons who present with agitation and cardiovascular and/or psychiatric manifestations of unclear origin and whose drug screening tests are negative may be suffering from an intoxication with a novel psychoactive substance. Physicians should know the classes of such substances and their effects. Targeted toxicological analysis can be carried out in a toxicology laboratory or a facility for forensic medicine.

Cannabinoid Type 1 Receptor (CB1) Ligands with Therapeutic Potential for Withdrawal Syndrome in Chemical Dependents of Cannabis sativa.

PubMed

Ferreira, Jaderson V; Chaves, Gisele A; Marino, Bianca L B; Sousa, Kessia P A; Souza, Lucilene R; Brito, Maiara F B; Teixeira, Hueldem R C; da Silva, Carlos H T P; Santos, Cleydson B R; Hage-Melim, Lorane I S

2017-08-22

Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease

PubMed Central

Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

2016-01-01

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease. PMID:26881135

76 FR 81979 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-29

... (2010) I Tetrahydrocannabinols (7370) I Methamphetamine (1105) II Pentobarbital (2270) II Nabilone (7379) II With regard to Gamma Hydroxybutyric Acid (2010), Tetrahydrocannabinols (7370), and Methamphetamine...

Nabilone

MedlinePlus

... one else can take it accidentally or on purpose. Keep track of how many capsules are left ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R.; Liberzon, Israel; Phan, K. Luan

2013-01-01

Pre-extinction administration of ∆9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 hours after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595

ACPA and JWH-133 modulate the vascular tone of superior mesenteric arteries through cannabinoid receptors, BKCa channels, and nitric oxide dependent mechanisms.

PubMed

López-Dyck, Evelyn; Andrade-Urzúa, Felipa; Elizalde, Alejandro; Ferrer-Villada, Tania; Dagnino-Acosta, Adan; Huerta, Miguel; Osuna-Calleros, Zyanya; Rangel-Sandoval, Cinthia; Sánchez-Pastor, Enrique

2017-12-01

Some cannabinoids, a family of compounds derived from Cannabis sativa (marijuana), have previously shown vasodilator effects in several studies, a feature that makes them suitable for the generation of a potential treatment for hypertension. The mechanism underlying this vasodilator effect in arteries is still controversial. In this report, we explored how the synthetic cannabinoids ACPA (CB 1 -selective agonist) and JWH-133 (CB 2 -selective agonist) regulate the vascular tone of rat superior mesenteric arteries. To screen the expression of CB 1 (Cannabinoid receptor 1) and CB 2 (Cannabinoid receptor 2) receptors in arterial rings or isolated smooth muscle cells obtained from the artery, immunocytochemistry, immunohistochemistry, and confocal microscopy were performed. In addition, the effects on vascular tone induced by the two cannabinoids were tested in isometric tension experiments in rings obtained from superior mesenteric arteries. The participation of voltage and calcium-activated potassium channel of big conductance (BK Ca ) and the role of nitric oxide (NO) release on the vascular effects induced by ACPA and JWH-133 were tested. CB 1 and CB 2 receptors were highly expressed in the rat superior mesenteric artery, in both smooth muscle and endothelium. The vasodilation effect shown by ACPA was endothelium-dependent through a mechanism involving CB 1 receptors, BK Ca channel activation, and NO release; meanwhile, the vasodilator effect of JWH-133 was induced by the activation of CB 2 receptors located in smooth muscle and by a CB 2 receptor-independent mechanism inducing NO release. CB 1 and CB 2 receptor activation in superior mesenteric artery causes vasorelaxation by mechanisms involving BK Ca channels and NO release. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Cannabinoids increase conditioned ultrasonic vocalisations and cat odour avoidance in rats: strain differences in drug-induced anxiety.

PubMed

Arnold, Jonathon C; Dielenberg, Robert A; McGregor, Iain S

2010-10-23

Genetic disposition modulates the psychoactive effects of cannabis. Cannabinoids have a greater impact on brain regions that subserve anxiety in Wistar compared to Lewis strain rats. Here we aim to show that this correlates with strain differences in cannabinoid-induced anxiety-related behaviour. Lewis and Wistar rats were administered vehicle or the synthetic cannabinoid receptor agonist, CP 55,940 (10, 25 and 50μg/kg) before testing in the conditioned ultrasonic vocalization (USV), cat odour avoidance or open area avoidance models. Animals were placed in a chamber in which they had previously received footshock. Wistar but not Lewis rats re-exposed under the influence of all CP 55,940 doses emitted significantly more USVs than vehicle-treated rats. In the cat odour avoidance model, rats were exposed to cat odour and given the opportunity to hide in a small box. In Wistar but not Lewis rats, 50μg/kg of CP 55,940 magnified hiding behaviour promoted by cat odour exposure. Animals were also tested in the open area avoidance model which occurred in the same arena as the predatory avoidance model but without cat odour. In Wistar, but not Lewis rats, 25 and 50μg/kg of CP 55,940 increased the avoidance of the open space. CP 55,940 increased anxiety-related behaviour in Wistar rats but not Lewis rats providing a model to dissect the genetic basis of cannabinoid-induced anxiety. We show for the first time that cannabinoids magnify conditioned USVs and cat odour avoidance behaviour dependent on the strain being tested. Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.

[Severe rhabdomyolysis and intracranial hemorrhage associated with synthetic cannabinoid: a case report].

PubMed

Tanei, Takafumi; Morita, Yoshiki; Yashima, Akihito; Wakita, Hiroyuki; Takebayashi, Shigenori; Nakahara, Norimoto; Wakabayashi, Toshihiko

2014-09-01

A 28-year-old male presented with language and behavior disorders a few days prior to examination. Magnetic resonance images and cerebral angiography revealed an arteriovenous malformation (AVM) in the right frontal lobe. The size of the nidus was 2.0 cm, and it was fed by the middle cerebral arteries and drained by the superior sagittal and transverse sinuses. The AVM was completely surgically resected without any complications. Ten months after the surgery, the patient presented with behavior disorders again and general convulsion. Computed tomography showed a small intracranial hemorrhage at the right frontal lobe, where the AVM was located. Blood examination revealed severe rhabdomyolysis (CK:536,620U/L)and acute kidney injury (Cr:5.20mg/dL). After admission, it became clear that the patient had used synthetic cannabinoid (SC). SC refers to a variety of herbal/chemical mixtures, which mimic the effects of marijuana. Little data is available on the psychopathological and physical effects of SC. This is the first report of severe rhabdomyolysis and intracranial hemorrhage associated with SC use in Japan.

N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties.

PubMed

Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh; Horowitz, Michal; Gallily, Ruth; Batkai, Sandor; Mo, Fong-Ming; Offertaler, Laszlo; Pacher, Pal; Kunos, George; Mechoulam, Raphael

2006-02-14

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.

75 FR 76756 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-09

... Tetrahydrocannabinols (7370) I Methamphetamine (1105) II Nabilone (7379) II With regard to Gamma Hydroxybutyric Acid (2010), Tetrahydrocannabinols (7370), and Methamphetamine (1105) only, the company manufactures these...

77 FR 19718 - Manufacturer of Controlled Substances; Notice of Registration, Norac Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-02

... (2010) I Tetrahydrocannabinols (7370) I Methamphetamine (1105) II Pentobarbital (2270) II Nabilone (7379) II With regard to Gamma Hydroxybutyric Acid (2010), Tetrahydrocannabinols (7370), and Methamphetamine...

Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants.

PubMed

Patton, Amy L; Seely, Kathryn A; Yarbrough, Azure L; Fantegrossi, William; James, Laura P; McCain, Keith R; Fujiwara, Ryoichi; Prather, Paul L; Moran, Jeffery H; Radominska-Pandya, Anna

2018-04-06

Synthetic cannabinoids (SCBs), synonymous with 'K2', 'Spice' or 'synthetic marijuana', are psychoactive drugs of abuse that frequently result in clinical effects and toxicity more severe than those classically associated with Δ 9 -tetrahydrocannabinol such as extreme agitation, hallucinations, supraventricular tachycardia, syncope, and seizures. JWH-018 is one of the earliest compounds identified in various SCB products, and our laboratory previously demonstrated that JWH-018 undergoes extensive metabolism by cytochromes P450 (P450), binds to, and activates cannabinoid receptors (CBRs). The major enzyme involved in the metabolism of JWH-018 is CYP2C9, a highly polymorphic enzyme found largely in the intestines and liver, with *1 being designated as the wild type, and *2 and *3 as the two most common variants. Three different major products have been identified in human urine and plasma: JWH-018 (ω)-OH, JWH-018 (ω-1)-OH(R), and JWH-018 (ω-1)-OH(S). The (ω-1)-OH metabolite of JWH-018 is a chiral molecule, and is thus designated as either (ω-1)-OH(R) or (ω-1)-OH(S). Here, in vitro enzyme kinetic assays performed with human recombinant CYP2C9 variants (*1, *2, and *3) revealed that oxidative metabolism by CYP2C9*3 resulted in significantly less formation of (ω)-OH and (ω-1)-OH metabolites. Surprisingly, CYP2C9*2 was roughly 3.6-fold more efficient as the CYP2C9*1 enzyme based on V max /K m , increasing the rate of JWH-018 metabolism and allowed for a much more rapid elimination. These results suggest that genetic polymorphisms of P450 enzymes result in the production of varying levels of biologically active JWH-018 metabolites in some individuals, offering a mechanistic explanation for the diverse clinical toxicity often observed following JWH-018 abuse. Copyright © 2018 Elsevier Inc. All rights reserved.

Substance use is a risk factor for violent behavior in male patients with bipolar disorder.

PubMed

Alnıak, İzgi; Erkıran, Murat; Mutlu, Elif

2016-03-15

To determine the factors involved in violent behavior in patients with bipolar disorder (BD) and to investigate the relationship between violence and substance use disorder (SUD). A sample of 100 male inpatients diagnosed with BD type I who were experiencing a current mood episode participated in the study. Violent behavior was defined as physical aggression against others. All patients were evaluated using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Positive and Negative Syndrome Scale-positive subscale (PANSS-p), Barratt Impulsivity Scale-11 (BIS-11), Buss-Perry Aggression Questionnaire (BPAQ) and Overt Aggression Scale (OAS). Lifetime SUD and current use of substances were evaluated. Logistic regression analysis was conducted to predict violent behavior. Current substance use (CSU) rather than lifetime SUD was found to be related to violent behavior in patients with BD, and CSU was associated with a threefold increase in the risk of violence. The rate of lifetime SUD in our sample was 59%, and the rate of CSU was 39%. The most commonly abused substances were cannabis and alcohol, followed by synthetic cannabinoids, in both groups of patients with lifetime SUD and CSU. Individuals abusing any substance were more likely to have a criminal record and history of incarceration than other patients. One of the most significant risk factors for violence was a previous history of violent behavior. The sample was limited to male patients. Data on some participants' recent substance use from standard urine analysis was not obtained. The data on the use of synthetic cannabinoids was obtained from patients and their families owing to the lack of equipment for detecting synthetic cannabinoids using laboratory analysis. CSU appears to be a significant predictive factor in violent behavior in male patients. Further investigation of co-occurrence of violence with CSU and improvement in treatment strategies might reduce or prevent violence in patients with BD. Copyright © 2015 Elsevier B.V. All rights reserved.

Metabolism of the synthetic cannabinoids AMB-CHMICA and 5C-AKB48 in pooled human hepatocytes and rat hepatocytes analyzed by UHPLC-(IMS)-HR-MSE.

PubMed

Mardal, Marie; Dalsgaard, Petur Weihe; Qi, Bing; Mollerup, Christian Brinch; Annaert, Pieter; Linnet, Kristian

2018-04-15

The main analytical targets of synthetic cannabinoids are often metabolites. With the high number of new psychoactive substances entering the market, suitable workflows are needed for analytical target identification in biological samples. The aims of this study were to identify the main metabolites of the synthetic cannabinoids, AMB-CHMICA and 5C-AKB48, using an in silico-assisted workflow with analytical data acquired using ultra-high-performance liquid chromatography-(ion mobility spectroscopy)-high resolution-mass spectrometry in data-independent acquisition mode (UHPLC-(IMS)-HR-MS E ). The metabolites were identified after incubation with rat and pooled human hepatocytes using UHPLC-HR-MS E , followed by UHPLC-IMS-HR-MS E . Metabolites of AMB-CHMICA and 5C-AKB48 were predicted with Meteor (Lhasa Ltd) and imported to the UNIFI software (Waters). The predicted metabolites were assigned to analytical components supported by the UNIFI in silico fragmentation tool. The main metabolic pathway of AMB-CHMICA was O-demethylation and hydroxylation of the methylhexyl moiety. For 5C-AKB48, the main metabolic pathways were hydroxylation(s) of the adamantyl moiety and oxidative dechlorination with subsequent oxidation to the ω-COOH. The matrix components in the metabolite spectra were reduced with IMS, which improved the accuracy of the spectral interpretation; however, this left fewer fragment ions for assigning sites of metabolism. Meteor was able to predict the majority of the metabolites, with the most notable exception being the oxidative dechlorination and, consequently, all metabolites that underwent that transformation pathway. Oxidative dechlorination of ω-chloroalkanes in humans has not been previously reported in the literature. The postulated metabolites can be used for screening of biological samples, with four-dimensional identification based on retention time, collision cross section, precursor ion, and fragment ions. Copyright © 2018 Elsevier B.V. All rights reserved.

Smoking, alcohol, and substance use and rates of quitting during pregnancy: is it hard to quit?

PubMed Central

Yazici, Ahmet Bulent; Uslu Yuvaci, Hilal; Yazici, Esra; Halimoglu Caliskan, Ebru; Cevrioglu, Arif Serhan; Erol, Atila

2016-01-01

Background Alcohol and substance use is a major health challenge in Turkey, as it is worldwide. Recently, there has been a rapid increase in the number of females using substances and although usage tends to reduce during pregnancy, it is of critical importance to determine its exact level as substance use negatively impacts on the health of both the mother and infant. Aim The aim of the present study was to investigate the frequency of smoking, alcohol, and substance use, and quitting rates during pregnancy. Method This study was conducted on pregnant females in Sakarya, Turkey. A total of 1,082 consecutively presenting females who agreed to participate in the study were evaluated. The study team prepared a sociodemographic data form and adapted the “Introduction” section, derived from the Addiction Profile Index, to cover substance use during pregnancy. Results The substances most frequently used by pregnant females in their previous pregnancies and current pregnancies were cigarettes/tobacco products (11% and 11.8%, respectively), alcohol (0.6% and 0.4%, respectively), and rarely, synthetic cannabinoids (0.3% and 0.2%, respectively). Daily tobacco smokers continued to smoke during pregnancy, with a rate of 42.5%. Based on research into predictors of smoking (cigarettes) in pregnancy, a correlation was found between lifetime smoking and smoking during a previous pregnancy. A similar link was found with respect to alcohol. Conclusion Cigarettes are the most frequently used substance in pregnancy, and to a lesser extent, alcohol and synthetic cannabinoids, also considered to be risky substances. A high incidence of smoking regularly during pregnancy was found in daily smokers. It is recommended that physicians should sensitively ask pregnant females presenting at clinics about all forms of substance use, including alcohol and synthetic cannabinoids, and to include such questions in their routine enquiries. PMID:27785104

Local administration of a cannabinoid agonist alters norepinephrine efflux in the rat frontal cortex.

PubMed

Page, M E; Oropeza, V C; Van Bockstaele, E J

2008-01-24

Delta(9)-tetrahydrocannabinol, the main psychoactive ingredient in marijuana, activates specific cannabinoid (CB) receptors to exert complex actions on modulatory neurotransmitters involved in attention and cognition. Previous research has demonstrated that systemic administration of the synthetic cannabinoid agonist, WIN 55,212-2, increases norepinephrine efflux in the frontal cortex. The distribution of CB1 receptors on noradrenergic fibers in the frontal cortex suggests this may be one potential site for the regulation of norepinephrine release. In the present study, we first examined the ability of a CB1 antagonist, applied locally in the frontal cortex of adult male Sprague-Dawley rats, to block the actions of systemic WIN 55,212-2. Pretreatment with SR 141716A (300 microM) significantly attenuated the excitatory effects of WIN 55,212-2 (15 mg/kg, i.p.). Next, the impact of direct perfusion of WIN 55,212-2 into the frontal cortex on extracellular norepinephrine efflux was measured. Direct application of WIN 55,212-2 (100 microM) into the frontal cortex elicited a significant increase in extracellular norepinephrine efflux suggesting that activation of cortical cannabinoid receptors contributes to alterations in norepinephrine levels in this brain region. Finally, local administration of SR 141716A followed by local administration of WIN 55,212-2 revealed a paradoxical inhibition of norepinephrine efflux.

Health aspects of cannabis.

PubMed

Hollister, L E

1986-03-01

Marijuana seems firmly established as another social drug in Western countries, regardless of its current legal status. Patterns of use vary widely. As with other social drugs, the pattern of use is critical in determining adverse effects on health. Perhaps the major area of concern about marijuana use is among the very young. Using any drug on a regular basis that alters reality may be detrimental to the psychosocial maturation of young persons. Chronic use of marijuana may stunt the emotional growth of youngsters. Evidence for an amotivational syndrome is largely based on clinical reports; whether marijuana use is a cause or effect is uncertain. A marijuana psychosis, long rumored, has been difficult to prove. No one doubts that marijuana use may aggravate existing psychoses or other severe emotional disorders. Brain damage has not been proved. Physical dependence is rarely encountered in the usual patterns of social use, despite some degree of tolerance that may develop. The endocrine effects of the drug might be expected to delay puberty in prepubertal boys, but actual instances have been rare. As with any material that is smoked, chronic smoking of marijuana will produce bronchitis; emphysema or lung cancer have not yet been documented. Cardiovascular effects of the drug are harmful to those with preexisting heart disease; fortunately the number of users with such conditions is minimal. Fears that the drug might accumulate in the body to the point of toxicity have been groundless. The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult. The drug is probably harmful when taken during pregnancy, but the risk is uncertain. One would be prudent to avoid marijuana during pregnancy, just as one would do with most other drugs not essential to life or well-being. No clinical consequences have been noted from the effects of the drug on immune response, chromosomes, or cell metabolites. Contamination of marijuana by spraying with defoliants has created the clearest danger to health; such attempts to control production should be abandoned. Therapeutic uses for marijuana, THC, or cannabinoid homologs are being actively explored. Only the synthetic homolog, nabilone, has been approved for use to control nausea and vomiting associated with cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of illicit, licit, and designer drugs in the traffic in Hungary.

PubMed

Institóris, László; Hidvégi, Előd; Dobos, Adrienn; Sija, Éva; Kereszty, Éva M; Tajti, László Balázs; Somogyi, Gábor Pál; Varga, Tibor

2017-06-01

The aim of this study was to investigate the prevalence and pattern of psychoactive substances among suspected DUID (Driving Under the Influence of Drugs) drivers in Hungary in 2014 and 2015. Blood and/or urine samples of 1252 suspected drivers (600 in 2014 and 652 in 2015) were analyzed for classical illicit and licit drugs, stimulant designer drugs (SDDs), and for synthetic cannabinoids, with 78.3% and 79.6% positive cases for at least one substance in 2014, and 2015, respectively. Impairment was proven in 39.2% (2014) and 35.7% (2015) of all drivers tested, based on the legal criteria of Hungary. Classical illicit drugs were found to be present in blood or urine of 89-61%, drivers tested. Drivers also tested positive for legal medications in 20-22%, SDDs in 21-28%, and synthetic cannabinoids in 15-19% of all cases. This indicates a drop in prevalence for classical illicit drugs and a slight but statistically non-significant increase for the other three substance groups. The distribution of drug types in each category were: [1] classical illicit drugs: cannabis (432), amphetamine (321), and cocaine (79); [2] medicines: alprazolam (94) and clonazepam (36); [3] SDDs: pentedrone (137) and α-PVP (33); [4] synthetic cannabinoids: AB-CHMINACA (46) and MDMB-CHMICA (30). The average age of illicit drug and SDD users was 30 years, while legal medications users were 36 years old on average, and the mean age of synthetic cannabinoid users was 26.5 years. The presence of both alcohol and at least one drug in samples was found in about 10% of the cases, both years. The ratio of multi-drug use was 33.0% in 2014 and 41.3% in 2015. Compared to former years the number of drivers who tested positive for drugs doubled in Hungary, but it is still low compared to alcohol positive cases. The relatively low detected rate of DUID can be explained by (1) combined alcohol consumption masking drug symptoms, (2) the absence of road-side tests for illicit and designer drugs and, (3) police officers not adequately trained to recognize milder symptoms of impairment. Targeted education of police officers, prompt medical examination and the use of a symptom-focused on-site survey, could improve the efficacy of DUID investigations. Our findings are not comparable with drug consumption habits of the general driving population. The last roadside survey (DRUID EU-6 Project) was performed in Hungary in 2008-2009, prior to the mass spreading of designer drugs. As their appearance has drastically changed the pattern of drug consumption of the population, a new roadside survey, targeting general drivers, would be necessary. Copyright © 2017 Elsevier B.V. All rights reserved.

75 FR 53720 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-01

... Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I Alphamethadol (9605) I Nabilone (7379) II... controlled substances in bulk for distribution to its customers. In reference to drug code 7360 (Marihuana...

The Changing Drug Culture: Emerging Drugs of Abuse and Legal Highs.

PubMed

Albertson, Timothy E; Chenoweth, James A; Colby, Daniel K; Sutter, Mark E

2016-02-01

In recent years, there has been a large increase in the number of synthetic drugs used recreationally. One class of drugs is synthetic cannabinoids, which are sprayed onto herbal preparations and marketed under names such as K2 and spice. Others include amphetaminelike compounds, such as cathinones (eg, bath salts) and methylenedioxymethamphetamine (MDMA) (eg, ecstasy, Molly). New hallucinogens, such as Bromo-Dragonfly, and hallucinogens that have been used for centuries, such as Salvia divinorum, also are gaining popularity. Because these substances are sold labeled as not for human consumption and because the chemicals in them frequently change, they often are unregulated, and many users consider them legal, although they are not. Their use often goes undetected because testing for them is not included in routine drug screening. Nonetheless, these substances can be associated with significant toxicities, often because their concentrations are unpredictable. Adverse effects of synthetic cannabinoids include psychosis and other effects. Amphetaminelike drugs have stimulant effects and can cause hyponatremia and seizures. The new hallucinogens can cause serious vasoconstriction with ischemia. Clinicians, especially those working with adolescents and young adults (ie, the main users of these drugs), should be aware of these new substances and counsel patients about their adverse effects. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Screening new psychoactive substances in urban wastewater using high resolution mass spectrometry.

PubMed

González-Mariño, Iria; Gracia-Lor, Emma; Bagnati, Renzo; Martins, Claudia P B; Zuccato, Ettore; Castiglioni, Sara

2016-06-01

Analysis of drug residues in urban wastewater could complement epidemiological studies in detecting the use of new psychoactive substances (NPS), a continuously changing group of drugs hard to monitor by classical methods. We initially selected 52 NPS potentially used in Italy based on seizure data and consumption alerts provided by the Antidrug Police Department and the National Early Warning System. Using a linear ion trap-Orbitrap high resolution mass spectrometer, we designed a suspect screening and a target method approach and compared them for the analysis of 24 h wastewater samples collected at the treatment plant influents of four Italian cities. This highlighted the main limitations of these two approaches, so we could propose requirements for future research. A library of MS/MS spectra of 16 synthetic cathinones and 19 synthetic cannabinoids, for which analytical standards were acquired, was built at different collision energies and is available on request. The stability of synthetic cannabinoids was studied in analytical standards and wastewater, identifying the best analytical conditions for future studies. To the best of our knowledge, these are the first stability data on NPS. Few suspects were identified in Italian wastewater samples, in accordance with recent epidemiological data reporting a very low prevalence of use of NPS in Italy. This study outlines an analytical approach for NPS identification and measurement in urban wastewater and for estimating their use in the population.

The undead in culture and science.

PubMed

Nugent, Connie; Berdine, Gilbert; Nugent, Kenneth

2018-04-01

The undead have a significant role in mythology, religion, folklore, and literature. In the 1800s, the word zombie was used to describe reanimated corpses in the Caribbean who often worked on plantations doing long, arduous field work. The movie White Zombie was released in 1932 and exploited this folklore, but it ignored the fact that zombies represent one outcome in Vodou religious beliefs regarding death and the migration of spirits following death. The interest in zombies eventually led to sociological and medical investigations into zombification. Wade Davis reported that powders used by malevolent priests (bokors) contained tetrodotoxin, which could cause the neurologic changes underlying the zombie phenotype. Recent clinical studies have indicated that synthetic cannabinoids and synthetic cathinones can cause bizarre zombie-like behavior. According to Haitian folklore, zombies can develop when bokors reanimate someone who suddenly died from an acute illness or who was purposely poisoned. Recent studies in molecular biology suggest that the sequence of programmed cell death can be reversed when the stressor is removed and that cells, tissues, and bodies (at least in Drosophila flies) can recover. These scientific studies would support the remote possibility that the near dead might recover under certain circumstances but have residual neuropsychological dysfunction. Alternatively, the bokors could maintain control of their victims using drugs with properties similar to those of synthetic cannabinoids. The concept of zombification needs to be considered in the context of culture, religion, and science.

[Cannabinoid and cathinone designer drugs - the workings and selected methods of analysis].

PubMed

Nędza, Jadwiga; Polaniak, Renata; Bułdak, Rafał J; Majchrzak, Milena; Margasiń-Ska, Joanna; Rojkiewicz, Marcin; Celiński, Rafał; Grochowska-Niedworok, Elżbieta

2016-07-29

Recently, there has been an increase in the consumption of designer drugs, substances aimed at producing psychoactive, energizing, euphoric or anesthetic effects. Designer drugs are substitutes of actual narcotics, whose possession is banned under Polish law according to the Act of 29 July 2005. The latest reports suggest that the number of synthetic psychoactive substances is increasing. In the span of 2012, a total of 28 new synthetic cannabinoids were discovered in member states of the European Union. Synthetic psychoactive substances appear in different forms on the market: tablets (often very colourful and interestingly-shaped), seeds, dried product (sprayed with synthetic substance and redried), crystals or powder. The way of application is greatly diverse, and depends on the form in which a drug is produced and dispensed. The methods of intoxication include smoke inhalation (oftentimes blends are smoked), intranasal or oral application, placing crystals on the eye, or injection. Said methods correspond, with varying degrees, to invoking different psychotic effects, such as agitation, panic attacks, paranoia, hallucinations, overall irritation, and aggression. Various cardiovascular effects, such as tachycardia or increase in blood pressure, may follow as well. However, the primary influence is on the nervous system, inhibiting the reuptake of neurotransmitters such as serotonin, noradrenalin and dopamine, and leading to their increased concentration at the presynaptic cleft, which in turn causes feelings of agitation and pleasure. The knowledge regarding the strength, toxicity, and metabolism of designer drugs is yet sparse. The same pertains to the knowledge regarding the handling of overdose cases. © 2016 MEDPRESS.

Suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones: Case report of non-fatal intoxication with AB-CHMINACA, AB-FUBINACA, alpha-PHP, alpha-PVP and 4-CMC.

PubMed

Klavž, Janez; Gorenjak, Maksimiljan; Marinšek, Martin

2016-08-01

We report on a case of intoxication with a mix of new psychoactive substances. A 38-year-old male was brought to the emergency department (ED) following the ingestion of an unknown drug in a suicide attempt. During the transport, he became progressively more somnolent and unresponsive to painful stimuli. Urine and stomach content were collected on admission to be screened for drugs of abuse and medicinal drugs. After admission, the patient's next of kin presented five small grip seal plastic bags containing different powders/crystals, and they were sent for analysis along with urine and stomach content to the toxicology laboratory. An easy and rapid sample preparation technique was applied for the extraction of urine and stomach content. Samples were extracted with liquid-liquid extraction (LLE) technique and analysed using gas chromatography-mass spectrometry (GC-MS). A small amount of powder material from the bags was diluted in methanol and injected directly into the GC-MS instrument. Obtained spectra (EI) were evaluated against SWGDRUG library. Five different designer drugs were identified in the powder material, including synthetic cannabinoids (AB-CHMINACA, AB-FUBINACA) and synthetic cathinones (alpha-PHP, alpha-PVP and 4-CMC). With the exception of 4-CMC, all of these substances were also detected in the stomach content along with the prescription drugs. This is the first time that a positive identification of these five drugs has been made by a clinical laboratory in Slovenia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Nephrotoxic effects of designer drugs: synthetic is not better!

PubMed

Luciano, Randy L; Perazella, Mark A

2014-06-01

Designer drugs are synthetic, psychoactive substances with similar structures and activity to existing scheduled drugs or controlled chemical compounds. The use of these drugs is not generally considered illegal and they cannot be detected using standard toxicology tests--essentially they are considered to be 'legal highs'. Over the past several years, increasing numbers of designer drugs have become available. These drugs are classified as amphetamine derivatives, phenylpiperazine derivatives, synthetic cathinones, synthetic cannabinoids, phencyclidine derivatives and synthetic opioids. Although euphoria is the desired effect, neuropsychiatric and cardiac manifestations are frequently observed in individuals using these drugs at high doses or using drugs that are contaminated with other substances. Some designer drugs are also associated with adverse renal effects, including acute kidney injury from pigment nephropathy, acute tubular necrosis, obstructive nephropathy and hyponatraemia. The misuse of these drugs should be recognized and clinicians made aware of the potential for acute nephrotoxicity as the health burden of these compounds increases.

Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology.

PubMed

Schaefer, Nadine; Wojtyniak, Jan-Georg; Kettner, Mattias; Schlote, Julia; Laschke, Matthias W; Ewald, Andreas H; Lehr, Thorsten; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

2016-06-24

Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence.

PubMed

Abboussi, Oualid; Said, Nadia; Fifel, Karim; Lakehayli, Sara; Tazi, Abdelouahhab; El Ganouni, Soumaya

2016-04-01

Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.

The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

PubMed

Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel

2017-01-01

Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Single oral dose of cannabinoid derivate loaded PLGA nanocarriers relieves neuropathic pain for eleven days.

PubMed

Berrocoso, Esther; Rey-Brea, Raquel; Fernández-Arévalo, Mercedes; Micó, Juan Antonio; Martín-Banderas, Lucía

2017-11-01

Neuropathic pain, resistant to opiates and other drugs, is a chronic/persistent state with a complex treatment and often poor efficacy. In this scenario, cannabinoids are increasingly regarded as a genuine alternative. In this paper, and in an experimental animal model of neuropathic pain, we studied the efficacy of three kinds of PLGA nanoparticles containing synthetic cannabinoid CB13: (i) plain nanoparticles (PLGA); (ii) particles coated with PEG chains (PLGA+PEG) and (iii) particles possessing hydrophilic surfaces obtained by covalently binding PEG chains (PLGA-PEG). The optimized formulation, CB13-PLGA-PEG, showed high drug loading (13%) and small size (<300nm) with a narrow distribution and controlled surface properties (near-neutral zeta potential and stable PEG corona). Animal nociceptive behavioral studies were conducted by paw pressure and acetone tests. Versus the free CB13, CB13-PLGA-PEG nanoparticles showed a very noticeable analgesic efficacy with the longest sustained pain-relieving effect, lasting up to eleven days after one oral dose. Copyright © 2017 Elsevier Inc. All rights reserved.

CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release*

PubMed Central

Malenczyk, Katarzyna; Jazurek, Magdalena; Keimpema, Erik; Silvestri, Cristoforo; Janikiewicz, Justyna; Mackie, Ken; Di Marzo, Vincenzo; Redowicz, Maria J.; Harkany, Tibor; Dobrzyn, Agnieszka

2013-01-01

Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes. PMID:24089517

75 FR 36693 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-28

... Nabilone (7379) II Phencyclidine (7471) II Cocaine (9041) II Codeine (9050) II Diprenorphine (9058) II..., conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated Sigma Aldrich...

76 FR 23626 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-27

...) II Nabilone (7379) II Phencyclidine (7471) II Cocaine (9041) II Codeine (9050) II Diprenorphine (9058..., conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated Sigma Aldrich...

Teenage cardiac arrest following abuse of synthetic cannabis.

PubMed

Davis, C; Boddington, D

2015-10-01

The cardiac effects of many illegal substances (cocaine, methadone) have previously been well described [1,2]. However the association between synthetic cannabis and cardiac arrest is less well documented. Here we describe an out-of-hospital cardiac arrest in a previously healthy 16-year-old female associated with the use of inhaled synthetic cannabis. An electronic systematic search of online databases PubMed and Embase was performed using keywords, "synthetic cannabis death" and "cardiac arrest". In this case study a previously healthy 16-year-old had a cardiac arrest after synthetic cannabis use. Despite extensive investigations no other cause for her arrest was found. To the best of our knowledge there has been one previous case report of cardiac arrest following synthetic cannabis use in a 56-year-old man [3]. This case report augments the relationship between synthetic cannabis and cardiac arrest in the medical community. More awareness surrounding the risk of synthetic cannabinoids is warranted. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

The evolving high: new designer drugs of abuse.

PubMed

Pourmand, A; Armstrong, P; Mazer-Amirshahi, M; Shokoohi, H

2014-10-01

Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients. © The Author(s) 2014.

Profiling of new psychoactive substances (NPS) by using stable isotope ratio mass spectrometry (IRMS): study on the synthetic cannabinoid 5F-PB-22.

PubMed

Münster-Müller, S; Scheid, N; Holdermann, T; Schneiders, S; Pütz, M

2018-05-21

In this paper results of a pilot study on the profiling of the synthetic cannabinoid receptor agonist 5F-PB-22 (5F-QUPIC, pentylfluoro-1H-indole-3-carboxylic acid-8-quinolinyl ester) via isotope ratio mass spectrometry are presented. It is focused on δ 13 C, δ 15 N and δ 2 H isotope ratios, which are determined using elemental analyser (EA) and high temperature elemental analyser (TC/EA) coupled to an isotope ratio mass spectrometer (IRMS). By means of a sample of pure material of 5F-PB-22 it is shown that the extraction of 5F-PB-22 from herbal material, a rapid clean-up procedure, or preparative column chromatography had no influences on the isotope ratios. Furthermore, 5F-PB-22 was extracted from fourteen different herbal blend samples ("Spice products" from police seizures) and analysed via IRMS, yielding three clusters containing seven, five and two samples, distinguishable through their isotopic composition, respectively. It is assumed that herbal blends in each cluster have been manufactured from individual batches of 5F-PB-22. This article is protected by copyright. All rights reserved.

Psyclones: a roller coaster of life? Hidden synthetic cannabinoids and stimulants in apparently harmless products.

PubMed

Santacroce, Rita; Corazza, Ornella; Martinotti, Giovanni; Bersani, Francesco Saverio; Valeriani, Giuseppe; Di Giannantonio, Massimo

2015-07-01

The urge to gain information on a new drug marketed online as 'Psyclone' has emerged after the death of a 38-year-old man in Bolton (UK). The fatality appeared to be a consequence of smoking this psychoactive product. From October to December 2013, qualitative searches of the Web have been carried out in English and Italian, using the keywords 'Psyclone', 'Psyclone legal high', 'Psyclone incense' and 'Psyclone research chemical' on the Google search engine and on the database provided by the Global Public Health Intelligence Network. Our research highlighted the existence of two psychoactive products labelled as Psyclone but with different contents and packaging: a herbal blend containing two synthetic cannabinoids (AKB-48 and 5f-PB-22) and a research chemical containing 50% ethylphenidate, 30% caffeine and 20% lidocaine. Desired and side effects of both compounds are explored in the paper. Being sold as a legal product, Psyclone may appeal to recreational users, who remain unaware of its real content. This is a serious public health threat, which may lead to acute intoxications and fatalities. Further studies in the field, including Internet monitoring, are therefore required. Copyright © 2015 John Wiley & Sons, Ltd.

N-arachidonoyl l-serine, an endocannabinoid-like brain constituent with vasodilatory properties

PubMed Central

Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh; Horowitz, Michal; Gallily, Ruth; Batkai, Sandor; Mo, Fong-Ming; Offertaler, Laszlo; Pacher, Pal; Kunos, George; Mechoulam, Raphael

2006-01-01

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-l-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-α in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor. PMID:16467152

Phase I metabolism of the recently emerged synthetic cannabinoid CUMYL-PEGACLONE and detection in human urine samples.

PubMed

Mogler, Lukas; Wilde, Maurice; Huppertz, Laura M; Weinfurtner, Georg; Franz, Florian; Auwärter, Volker

2018-05-01

Indole-, indazole-, or azaindole-based synthetic cannabinoids (SCs), bearing a cumyl substituent are a widespread, recreationally used subgroup of new psychoactive substances (NPS). The latest cumyl-derivative, CUMYL-PEGACLONE, emerged in December 2016 on the German drug market. The substance features a novel γ-carboline core structure, which is most likely synthesized to bypass generic legislative approaches to control SCs by prohibiting distinct core structures. Using liquid chromatography-tandem mass spectrometry and liquid chromatography-high resolution mass spectrometry techniques, the main in vivo phase I metabolites of this new substance were detected. A pooled human liver microsome assay was applied to generate in vitro reference spectra of CUMYL-PEGACLONE phase I metabolites. Additionally, 30 urine samples were investigated leading to 22 in vivo metabolites. A metabolite mono-hydroxylated at the γ-carbolinone core system and a metabolite with an additional carbonyl group at the pentyl side chain were evaluated as highly specific and sensitive markers to proof CUMYL-PEGACLONE uptake. Moreover, 3 immunochemical assays commonly used for SC screening in urine were tested for their capability of detecting the new drug but failed due to insufficient cross-reactivity. Copyright © 2018 John Wiley & Sons, Ltd.

75 FR 6061 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-05

... to import the listed controlled substance for distribution to its customers. One comment was received... national quota for Nabilone established by DEA will be affected by Kenco VPI's application. DEA's response... application. The [[Page 6062

Effects of Pubertal Cannabinoid Administration on Attentional Set-Shifting and Dopaminergic Hyper-Responsivity in a Developmental Disruption Model of Schizophrenia

PubMed Central

Guimarães, Francisco S.; Grace, Anthony A.

2015-01-01

Background: Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing, or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. Methods: This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2mg/kg) was extended over 25 days throughout puberty (postnatal days 40–65) in control and MAM rats. The rats received 20 injections, which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. Results: MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration, and an increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats (Sal). Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. Conclusions: Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted. PMID:25522381

The undead in culture and science

PubMed Central

Nugent, Connie; Berdine, Gilbert; Nugent, Kenneth

2018-01-01

ABSTRACT The undead have a significant role in mythology, religion, folklore, and literature. In the 1800s, the word zombie was used to describe reanimated corpses in the Caribbean who often worked on plantations doing long, arduous field work. The movie White Zombie was released in 1932 and exploited this folklore, but it ignored the fact that zombies represent one outcome in Vodou religious beliefs regarding death and the migration of spirits following death. The interest in zombies eventually led to sociological and medical investigations into zombification. Wade Davis reported that powders used by malevolent priests (bokors) contained tetrodotoxin, which could cause the neurologic changes underlying the zombie phenotype. Recent clinical studies have indicated that synthetic cannabinoids and synthetic cathinones can cause bizarre zombie-like behavior. According to Haitian folklore, zombies can develop when bokors reanimate someone who suddenly died from an acute illness or who was purposely poisoned. Recent studies in molecular biology suggest that the sequence of programmed cell death can be reversed when the stressor is removed and that cells, tissues, and bodies (at least in Drosophila flies) can recover. These scientific studies would support the remote possibility that the near dead might recover under certain circumstances but have residual neuropsychological dysfunction. Alternatively, the bokors could maintain control of their victims using drugs with properties similar to those of synthetic cannabinoids. The concept of zombification needs to be considered in the context of culture, religion, and science. PMID:29706835

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-tetrahydrocannabinol (Δ9-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

The K2/Spice Phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products

PubMed Central

Brents, Lisa K.; Prather, Paul L.

2014-01-01

In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH-073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the ″K2/Spice Phenomenon″. Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review. PMID:24063277

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. © 2013.

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. Copyright © 2014 Elsevier Inc. All rights reserved.

The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats.

PubMed

Robinson, L; Goonawardena, A V; Pertwee, R G; Hampson, R E; Riedel, G

2007-07-01

Previous work implied that the hippocampal cannabinoid system was particularly important in some forms of learning, but direct evidence for this hypothesis is scarce. We therefore assessed the effects of the synthetic cannabinoid HU210 on memory and hippocampal activity. HU210 (100 microg kg(-1)) was administered intraperitoneally to rats under three experimental conditions. One group of animals were pre-trained in spatial working memory using a delayed-matching-to-position task and effects of HU210 were assessed in a within-subject design. In another, rats were injected before acquisition learning of a spatial reference memory task with constant platform location. Finally, a separate group of animals was implanted with electrode bundles in CA1 and CA3 and single unit responses were isolated, before and after HU210 treatment. HU210 treatment had no effect on working or short-term memory. Relative to its control Tween 80, deficits in acquisition of a reference memory version of the water maze were obtained, along with drug-related effects on anxiety, motor activity and spatial learning. Deficits were not reversed by the CB(1) receptor antagonists SR141716A (3 mg kg(-1)) or AM281 (1.5 mg kg(-1)). Single unit recordings from principal neurons in hippocampal CA3 and CA1 confirmed HU210-induced attenuation of the overall firing activity lowering both the number of complex spikes fired and the occurrence of bursts. These data provide the first direct evidence that the underlying mechanism for the spatial memory deficits induced by HU210 in rats is the accompanying abnormality in hippocampal cell firing.

In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB(1) receptor antagonist for the management of obesity.

PubMed

Hadcock, John R; Griffith, David A; Iredale, Phillip A; Carpino, Phillip A; Dow, Robert L; Black, Shawn C; O'Connor, Rebecca; Gautreau, Denise; Lizano, Jeffrey S; Ward, Karen; Hargrove, Diane M; Kelly-Sullivan, Dawn; Scott, Dennis O

2010-04-02

Cannabinoid CB(1) receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB(1) receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB(1) receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB(1) receptors in both binding (K(i)=0.7 nM) and functional assays (K(i)=0.2 nM). The compound has low affinity (K(i)=7600 nM) for human CB(2) receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB(1) receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB(1) receptor competitive antagonist that may further our understanding of the endocannabinoid system. 2010 Elsevier Inc. All rights reserved.

Cannabinoid WIN 55,212-2 inhibits TRPV1 in trigeminal ganglion neurons via PKA and PKC pathways.

PubMed

Wang, Wei; Cao, Xuehong; Liu, Changjin; Liu, Lieju

2012-02-01

Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid-induced inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A "bell"-shaped concentration-dependent curve was obtained from the effects of WIN on TRPV1 channel. The maximal inhibition on capsaicin-induced current (I (cap)) by WIN was at a concentration of 10(-9) M, and at this concentration I (cap) was reduced by 95 ± 1.6%. When the concentration of WIN was at 10(-6) M, it displayed a stimulatory effect on I (cap). In this study, several intracellular signaling transduction pathways were tested to study whether they were involved in the inhibitory effects of WIN on I (cap). We found that the inhibitory effect of WIN on I (cap) was completely reversed by PKA antagonists H-89 and KT5720 as well as by PKC antagonists BIM and staurosporine. It was also found that the inhibitory effect was partly reversed by PKG antagonist PKGi, while G-protein antagonist GDP-βs/pertussis toxin (PTX) and PLC antagonist U-73122 had no effect on the inhibitory effect of WIN on I(cap). These results suggest that several intracellular signaling transduction pathways including PKA and PKC systems underlie the inhibitory effects of WIN on I (cap); however, G protein-coupled receptors CB1 or CB2 were not involved.

Impact of Oral Fluid Collection Device on Cannabinoid Stability Following Smoked Cannabis

PubMed Central

Anizan, Sébastien; Bergamaschi, Mateus M.; Barnes, Allan J.; Milman, Garry; Desrosiers, Nathalie; Lee, Dayong; Gorelick, David A.; Huestis, Marilyn A.

2014-01-01

Evaluation of cannabinoid stability in authentic oral fluid (OF) is critical, as most OF stability studies employed fortified or synthetic OF. Participants (n=16) smoked a 6.8% delta-9-tetrahydrocannabinol (THC) cigarette, and baseline concentrations of THC, 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), and cannabinol (CBN) were determined within 24h in 16 separate pooled samples (collected 1h before to 10.5 or 13h after smoking). OF was collected with the StatSure Saliva Sampler™ and Oral-Eze® devices. Oral-Eze samples were re-analyzed after room temperature (RT) storage for 1 week, and for both devices after 4°C for 1 and 4 weeks, and –20°C for 4 and 24 weeks. Concentrations ±20% from initial concentrations were considered stable. With the StatSure device, all cannabinoids were within 80-120% median %baseline for all storage conditions. Individual THC, CBD, CBN and THCCOOH pool concentrations were stable in 100%, 100%, 80-94% and >85%, respectively, across storage conditions. With the Oral-Eze device, at RT or refrigerated storage (for 1 and 4 weeks), THC, CBD and THCCOOH were stable in 94-100%, 78-89% and 93-100% of samples, respectively, while CBN concentrations were 53–79% stable. However, after 24 weeks at -20°C, stability decreased, especially for CBD, with a median of 56% stability. Overall, the collection devices’ elution/stabilizing buffers provided good stability for OF cannabinoids, with the exception of the more labile CBN. To ensure OF cannabinoid concentration accuracy, these data suggest analysis within 4 weeks at 4°C storage for Oral-Eze collection and within 4 weeks at 4°C or 24 weeks at -20°C for StatSure collection. PMID:24995604

Gone to Pot – A Review of the Association between Cannabis and Psychosis

PubMed Central

Radhakrishnan, Rajiv; Wilkinson, Samuel T.; D’Souza, Deepak Cyril

2014-01-01

Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy. PMID:24904437

Endothelial atypical cannabinoid receptor: do we have enough evidence?

PubMed Central

Bondarenko, Alexander I

2014-01-01

Cannabinoids and their synthetic analogues affect a broad range of physiological functions, including cardiovascular variables. Although direct evidence is still missing, the relaxation of a vast range of vascular beds induced by cannabinoids is believed to involve a still unidentified non-CB1, non-CB2 Gi/o protein-coupled receptor located on endothelial cells, the so called endothelial cannabinoid receptor (eCB receptor). Evidence for the presence of an eCB receptor comes mainly from vascular relaxation studies, which commonly employ pertussis toxin as an indicator for GPCR-mediated signalling. In addition, a pharmacological approach is widely used to attribute the relaxation to eCB receptors. Recent findings have indicated a number of GPCR-independent targets for both agonists and antagonists of the presumed eCB receptor, warranting further investigations and cautious interpretation of the vascular relaxation studies. This review will provide a brief historical overview on the proposed novel eCB receptor, drawing attention to the discrepancies between the studies on the pharmacological profile of the eCB receptor and highlighting the Gi/o protein-independent actions of the eCB receptor inhibitors widely used as selective compounds. As the eCB receptor represents an attractive pharmacological target for a number of cardiovascular abnormalities, defining its molecular identity and the extent of its regulation of vascular function will have important implications for drug discovery. This review highlights the need to re-evaluate this subject in a thoughtful and rigorous fashion. More studies are needed to differentiate Gi/o protein-dependent endothelial cannabinoid signalling from that involving the classical CB1 and CB2 receptors as well as its relevance for pathophysiological conditions. PMID:25073723

The Endocannabinoid System as a Target for Treatment of Breast Cancer

DTIC Science & Technology

2009-08-01

4 Introduction ∆9-tetradyrocannabinol (THC), the chief psychoactive constituent of marijuana , as well as other naturally occurring and... synthetically derived cannabinoids possess potential therapeutic effects related to cancer treatment, including reduction in nausea and vomiting...However, there is little enthusiasm for the development of mixed CB1/CB2 receptor agonists for therapeutic uses because of their marijuana -like and

Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8

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

Koller, Verena J., E-mail: verena.koller@meduniwien.ac.at; Auwärter, Volker, E-mail: volker.auwaerter@uniklinik-freiburg.de; Grummt, Tamara, E-mail: tamara.grummt@uba.de

Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) andmore » a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥ 7.5 μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥ 10 μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material. - Highlights: • We tested the toxic properties of a synthetic cannabinoid. • Acute cytotoxic effects were detected with doses ≥ 7 μM. • No hormonal effects were found. • DNA damage was detected at levels ≥ 10 μM in comet assay and micronucleus tests. • Effects in directly exposed tissues may occur in humans.« less

Synthetic marijuana and acute kidney injury: an unforeseen association.

PubMed

Kazory, Amir; Aiyer, Ravi

2013-06-01

Synthetic cannabinoids (SCs) have emerged as drugs of abuse with increasing popularity among young adults. The potential renal complication related to the abuse of SC was not recognized until recently. Here, we present a case of severe acute kidney injury (AKI) that developed after inhalation of SC in an otherwise healthy young patient. A kidney biopsy revealed severe acute tubular necrosis, and supportive management resulted in the recovery of the kidney function. Herein, we briefly summarize the only two previous reports (a total of 21 cases) on the association between SC abuse and renal dysfunction and identify the common aspects in all observations.

Impact of Cannabis Use on the Development of Psychotic Disorders

PubMed Central

Wilkinson, Samuel T.; Radhakrishnan, Rajiv; D’Souza, Deepak Cyril

2014-01-01

The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication but resolves within a month. Exposure to cannabis in adolescence is associated with a risk for later psychotic disorder in adulthood; this association is consistent, temporally related, shows a dose-response, and is biologically plausible. However, cannabis is neither necessary nor sufficient to cause a persistent psychotic disorder. More likely it is a component cause that interacts with other factors to result in psychosis. The link between cannabis and psychosis is moderated by age at onset of cannabis use, childhood abuse and genetic vulnerability. While more research is needed to better characterize the relationship between cannabinoid use and the onset and persistence of psychosis, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis. PMID:25767748

Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol.

PubMed

Smeriglio, Antonella; Giofrè, Salvatore V; Galati, Enza M; Monforte, Maria T; Cicero, Nicola; D'Angelo, Valeria; Grassi, Gianpaolo; Circosta, Clara

2018-02-07

Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro. A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors. Copyright © 2018 Elsevier B.V. All rights reserved.

Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools.

PubMed

Macedonio, Giorgia; Stefanucci, Azzurra; Maccallini, Cristina; Mirzaie, Sako; Novellino, Ettore; Mollica, Adriano

2016-01-01

The endocannabinoid system (ECS) is activated when natural arachidonic acid derivatives (endogenous cannabinoids or endocannabinoids) bind as lipophilic messengers to cannabinoid receptors CB1 and CB2. The ECS comprises many hydrolytic enzymes responsible for the endocannabinoids cleavage. These hydrolases, such as fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MAGL), are possible therapeutic targets for the development of new drugs as indirect cannabinoid agonists. Recently, a new family of endocannabinoid modulators was discovered; the lead structure of this family is the nonapeptide hemopressin produced from enzymatic cleavage of the α-chain of hemoglobin and acting as negative allosteric modulator of CB1. Hemopressin shows several physiological effects, e.g., antinociception, hypophagy, and hypotension. However, it is still a matter of debate whether this peptide, isolated from the brain of rats, is a real neuromodulator of the ECS. Recent evidence indicates that hemopressin could be a by-product formed by chemical degradation of a longer peptide RVD-hemopressin during the extraction from the brain homolysate. Indeed, RVD-hemopressin is more active than hemopressin in certain biological tests and may bind to the same subsite as Rimonabant, which is an inverse agonist of CB1 and a μ-opioid receptor antagonist. These findings have stimulated several studies to verify this hypothesis and to evaluate possible therapeutic applications of hemopressin, its peptidic derivatives, and synthetic analogues, opening new perspectives to the development of novel cannabinoid drugs.

Therapeutic potential of cannabinoids in schizophrenia.

PubMed

Kucerova, Jana; Tabiova, Katarina; Drago, Filippo; Micale, Vincenzo

2014-04-01

Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

77 FR 67675 - Importer of Controlled Substances, Notice of Registration, SA INTL GMBH C/O., Sigma Aldrich Co...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-13

... (2315) II Glutethimide (2550) II Nabilone (7379) II Phencyclidine (7471) II Cocaine (9041) II Codeine... international treaties, conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated...

Spice-y Kidney Failure: A Case Report and Systematic Review of Acute Kidney Injury Attributable to the Use of Synthetic Cannabis.

PubMed

Zarifi, Ceyda; Vyas, Shuchi

2017-01-01

Spice is a synthetic cannabinoid that is readily available for purchase in smoke shops at relatively low cost. Spice is not detectable upon routine drug screening, making it an increasingly popular new street drug. A 21-year-old man presented with new-onset seizures. During the next 2 days, he developed uncontrollable hypertension, agitation, respiratory failure requiring intubation, pulmonary hypertension, and acute kidney injury (AKI) with a maximum blood urea nitrogen/creatinine level of 54/7.90 mg/dL. A complete renal workup was negative, but his urine sediment revealed granular casts. A discussion with family and friends revealed that this patient had smoked Spice during the last month. His renal function started to improve with supportive therapy, and his AKI resolved by the time of discharge without renal replacement therapy. Spice differs from marijuana because it is a cannabinoid receptor type 1 and 2 agonist. The pathologic mechanism of AKI remains unclear, but the condition likely is attributable to acute tubular necrosis or acute interstitial nephritis, as proven by biopsies performed in previous case series. It is important to raise awareness that a new Spice strain that may be circulating in the Southern California Inland Empire can endanger young users who may develop seizures, respiratory failure, and AKI.

Fatal intoxication with synthetic cannabinoid MDMB-CHMICA.

PubMed

Adamowicz, Piotr

2016-04-01

MDMB-CHMICA is a synthetic cannabinoid that appeared on the European drug market in September 2014. This substance was found in Poland in the herbal mixture "Mocarz" ("Strongman"), which caused a large outbreak of intoxications at the beginning of July 2015. This paper describes the circumstances of death and toxicological findings in a fatal intoxication with MDMB-CHMICA (in combination with alcohol). Loss of consciousness and asystole occurred a few minutes after smoking the 'legal high'. The man died after 4 days of hospitalisation. The cause of death accepted by the medical examiner was multiple organ failure. MDMB-CHMICA was detected and quantified in blood (ante- and postmortem) and internal organs tissues. The samples were analysed using liquid chromatography with mass spectrometry (LC-MS/MS). The concentration of MDMB-CHMICA in antemortem blood was 5.6 ng/mL. Although the death occurred after 4 days from administration a relatively high concentration (2.6 ng/g) was estimated in the brain. Traces of this compound were also found in other postmortem materials (blood, stomach, liver, bile, and kidney). The presented case shows the health risks associated with MDMB-CHMICA use. The administration of this substance can lead to the number of organ failures, cardiac arrest and consequently death. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Synthetic cannabis and acute ischemic stroke.

PubMed

Bernson-Leung, Miya E; Leung, Lester Y; Kumar, Sandeep

2014-01-01

An association between marijuana use and stroke has been previously reported. However, the health risks of newer synthetic cannabinoid compounds are less well known. We describe 2 cases that introduce a previously unreported association between synthetic cannabis use and ischemic stroke in young adults. A 22-year-old woman presented with dysarthria, left hemiplegia, and left hemianesthesia within hours of first use of synthetic cannabis. She was healthy and without identified stroke risk factors other than oral contraceptive use and a patent foramen ovale without venous thromboses. A 26-year-old woman presented with nonfluent aphasia, left facial droop, and left hemianesthesia approximately 12 hours after first use of synthetic cannabis. Her other stroke risk factors included migraine with aura, oral contraceptive use, smoking, and a family history of superficial thrombophlebitis. Both women were found to have acute, large-territory infarctions of the right middle cerebral artery. Our 2 cases had risk factors for ischemic stroke but were otherwise young and healthy and the onset of their deficits occurred within hours after first-time exposure to synthetic cannabis. Synthetic cannabis use is an important consideration in the investigation of stroke in young adults. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Spice/K2 drugs--more than innocent substitutes for marijuana.

PubMed

Zawilska, Jolanta B; Wojcieszak, Jakub

2014-03-01

Smokeable herbal mixtures containing synthetic agonists of cannabinoid receptors, known under brand names such as Spice, K2 and Kronic, represent a relatively new type of designer psychoactive drugs that has recently emerged on the recreational drug market. Although the Spice packages are labelled 'not for human consumption' or 'for aromatherapy only' and declared to be purely herbal, these herbal mixtures produce cannabis-like effects after smoking. This review surveys the current state of knowledge regarding the pharmacological properties of synthetic cannabimimetics and the prevalence and pattern of their use. Special emphasis is given to the negative consequences of using these products, including, among others, hallucinations, psychoses with delusions, seizures, cardiovascular symptoms and acute kidney injury.

Evidence for the Risks and Consequences of Adolescent Cannabis Exposure.

PubMed

Levine, Amir; Clemenza, Kelly; Rynn, Moira; Lieberman, Jeffrey

2017-03-01

This review of the scientific literature examines the potential adult sequelae of exposure to cannabis and related synthetic cannabinoids in adolescence. We examine the four neuropsychiatric outcomes that are likely most vulnerable to alteration by early cannabinoid use, as identified within both the clinical and preclinical research: cognition, emotional functioning, risk for psychosis, and addiction. A literature search was conducted through PubMed, PsychInfo, and Google Scholar with no publication date restrictions. The search terms used were "adolescent" and "adult," and either "cannabis," "marijuana," "delta-9-tetra-hydrocannabinol," or "cannabinoid," which was then crossed with one or more of the following terms: "deficit," "impairment," "alteration," "long-term," "persistent," "development," "maturation," and "pubescent." The majority of the clinical and preclinical data point to a strong correlation between adolescent cannabinoid exposure and persistent, adverse neuropsychiatric outcomes in adulthood. Although the literature supports the hypothesis that adolescent cannabis use is connected to impaired cognition and mental health in adults, it does not conclusively demonstrate that cannabis consumption alone is sufficient to cause these deficits in humans. The animal literature, however, clearly indicates that adolescent-onset exposure to cannabinoids can catalyze molecular processes that lead to persistent functional deficits in adulthood, deficits that are not found to follow adult-onset exposure and that model some of the adverse outcomes reported in humans among adult populations of early-onset cannabis users. Based on the data in the current literature, a strong association is found between early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood, yet definite conclusions cannot yet be made as to whether cannabis use alone has a negative impact on the human adolescent brain. Future research will require animal models and longitudinal studies to be carefully designed with a focus on integrating assessments of molecular, structural, and behavioral outcomes in order to elucidate the full range of potential adverse and long-term consequences of cannabinoid exposure in adolescence. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring.

PubMed

Alpár, Alán; Di Marzo, Vincenzo; Harkany, Tibor

2016-04-01

Endocannabinoids regulate brain development via modulating neural proliferation, migration, and the differentiation of lineage-committed cells. In the fetal nervous system, (endo)cannabinoid-sensing receptors and the enzymatic machinery of endocannabinoid metabolism exhibit a cellular distribution map different from that in the adult, implying distinct functions. Notably, cannabinoid receptors serve as molecular targets for the psychotropic plant-derived cannabis constituent Δ(9)-tetrahydrocannainol, as well as synthetic derivatives (designer drugs). Over 180 million people use cannabis for recreational or medical purposes globally. Recreational cannabis is recognized as a niche drug for adolescents and young adults. This review combines data from human and experimental studies to show that long-term and heavy cannabis use during pregnancy can impair brain maturation and predispose the offspring to neurodevelopmental disorders. By discussing the mechanisms of cannabinoid receptor-mediated signaling events at critical stages of fetal brain development, we organize histopathologic, biochemical, molecular, and behavioral findings into a logical hypothesis predicting neuronal vulnerability to and attenuated adaptation toward environmental challenges (stress, drug exposure, medication) in children affected by in utero cannabinoid exposure. Conversely, we suggest that endocannabinoid signaling can be an appealing druggable target to dampen neuronal activity if pre-existing pathologies associate with circuit hyperexcitability. Yet, we warn that the lack of critical data from longitudinal follow-up studies precludes valid conclusions on possible delayed and adverse side effects. Overall, our conclusion weighs in on the ongoing public debate on cannabis legalization, particularly in medical contexts. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action

PubMed Central

Maione, Sabatino; Piscitelli, Fabiana; Gatta, Luisa; Vita, Daniela; De Petrocellis, Luciano; Palazzo, Enza; de Novellis, Vito; Di Marzo, Vincenzo

2011-01-01

BACKGROUND AND PURPOSE Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception. EXPERIMENTAL APPROACH Electrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey. KEY RESULTS Cannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB1 adenosine A1 and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD. CONCLUSIONS AND IMPLICATIONS CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action. PMID:20942863

Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation

PubMed Central

Gyires, Klára; Zádori, Zoltán S.

2016-01-01

Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies. PMID:26935536

CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency.

PubMed

Smoum, Reem; Baraghithy, Saja; Chourasia, Mukesh; Breuer, Aviva; Mussai, Naama; Attar-Namdar, Malka; Kogan, Natalya M; Raphael, Bitya; Bolognini, Daniele; Cascio, Maria G; Marini, Pietro; Pertwee, Roger G; Shurki, Avital; Mechoulam, Raphael; Bab, Itai

2015-07-14

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ(9)-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3-4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [(3)H]CP55,940 displacement and its effect on [(35)S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [(35)S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.

CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency

PubMed Central

Smoum, Reem; Baraghithy, Saja; Chourasia, Mukesh; Breuer, Aviva; Mussai, Naama; Attar-Namdar, Malka; Kogan, Natalya M.; Raphael, Bitya; Bolognini, Daniele; Cascio, Maria G.; Marini, Pietro; Pertwee, Roger G.; Shurki, Avital; Mechoulam, Raphael; Bab, Itai

2015-01-01

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ9-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3–4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [3H]CP55,940 displacement and its effect on [35S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [35S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes. PMID:26124120

Adolescent cannabinoid exposure effects on natural reward seeking and learning in rats.

PubMed

Schoch, H; Huerta, M Y; Ruiz, C M; Farrell, M R; Jung, K M; Huang, J J; Campbell, R R; Piomelli, D; Mahler, S V

2018-01-01

Adolescence is characterized by endocannabinoid (ECB)-dependent refinement of neural circuits underlying emotion, learning, and motivation. As a result, adolescent cannabinoid receptor stimulation (ACRS) with phytocannabinoids or synthetic agonists like "Spice" cause robust and persistent changes in both behavior and circuit architecture in rodents, including in reward-related regions like medial prefrontal cortex and nucleus accumbens (NAc). Here, we examine persistent effects of ACRS with the cannabinoid receptor 1/2 specific agonist WIN55-212,2 (WIN; 1.2 mg/kg/day, postnatal day (PD) 30-43), on natural reward-seeking behaviors and ECB system function in adult male Long Evans rats (PD 60+). WIN ACRS increased palatable food intake, and altered attribution of incentive salience to food cues in a sign-/goal-tracking paradigm. ACRS also blunted hunger-induced sucrose intake, and resulted in increased anandamide and oleoylethanolamide levels in NAc after acute food restriction not seen in controls. ACRS did not affect food neophobia or locomotor response to a novel environment, but did increase preference for exploring a novel environment. These results demonstrate that ACRS causes long-term increases in natural reward-seeking behaviors and ECB system function that persist into adulthood, potentially increasing liability to excessive natural reward seeking later in life.

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

PubMed Central

Grant, Igor; Cahn, B. Rael

2008-01-01

The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886

Non-psychotropic analgesic drugs from the endocannabinoid system: "magic bullet" or "multiple-target" strategies?

PubMed

Starowicz, Katarzyna; Di Marzo, Vincenzo

2013-09-15

The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics. © 2013 Elsevier B.V. All rights reserved.

Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

PubMed Central

Merrick, John; Lane, Brian; Sebree, Terri; Yaksh, Tony; O'Neill, Carol; Banks, Stan L.

2016-01-01

Abstract Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF). Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concentration range used in this study. CBD was spiked into media containing 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatography with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid. Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degradation followed first-order kinetics at a rate constant of −0.031 min−1 (R2=0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiological buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral analysis, mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic reference standards. Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored. PMID:28861485

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

PubMed

Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

2016-08-01

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

76 FR 38209 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-29

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of... renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of Nabilone (7379), a... controlled substance as a finished drug product in dosage form only for distribution to its customers. The...

Determination of a selection of synthetic cannabinoids and metabolites in urine by UHPSFC-MS/MS and by UHPLC-MS/MS.

PubMed

Berg, Thomas; Kaur, Lakhwinder; Risnes, Anna; Havig, Stine Marie; Karinen, Ritva

2016-07-01

Two different analytical techniques, ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) and reversed phase ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), were used for the determination of two synthetic cannabinoids and eleven metabolites in urine; AM-2201 N-4-OH-pentyl, AM-2233, JWH-018 N-5-OH-pentyl, JWH-018 N-pentanoic acid, JWH-073 N-4-OH-butyl, JWH-073 N-butanoic acid, JWH-122 N-5-OH-pentyl, MAM-2201, MAM-2201 N-4-OH-pentyl, RCS-4 N-5-OH-pentyl, UR-144 degradant N-pentanoic acid, UR-144 N-4-OH-pentyl, and UR-144 N-pentanoic acid. Sample preparation included a liquid-liquid extraction after deconjugation with ß-glucuronidase. The UHPSFC-MS/MS method used an Acquity UPC(2 TM) BEH column with a mobile phase consisting of CO2 and 0.3% ammonia in methanol, while the UHPLC-MS/MS method used an Acquity UPLC® BEH C18 column with a mobile phase consisting of 5 mM ammonium formate (pH 10.2) and methanol. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions. Deuterated internal standards were used for six of the compounds. Limits of quantification (LOQs) were between 0.04 and 0.4 µg/L. Between-day relative standard deviations at concentrations ≥ LOQ were ≤20%, with biases within ±19%. Recoveries ranged from 40 to 90%. Corrected matrix effects were within 100 ± 10%, except for MAM-2201 with UHPSFC-MS/MS, and for UR-144 N-pentanoic acid and MAM-2201 N-4-OH-pentyl with UHPLC-MS/MS. Elution order obtained by UHPSFC-MS/MS was almost opposite to that obtained by UHPLC-MS/MS, making this instrument setup an interesting combination for screening and confirmation analyses in forensic cases. The UHPLC-MS/MS method has, since August 2014, been successfully used for confirmation of synthetic cannabinoids in urine samples revealing a positive immunoassay screening result. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Medical use of cannabis products: Lessons to be learned from Israel and Canada.

PubMed

Ablin, J; Ste-Marie, P A; Schäfer, M; Häuser, W; Fitzcharles, M-A

2016-02-01

The German government intends to reduce the barriers for the medical use of cannabis products. A discussion on the indications and contraindications of the medical use of cannabis and on the changes of the regulatory framework has already begun in Germany. It is useful to draw from the experiences of other countries with a more liberal medical use of cannabis. The Israeli and Canadian experience is outlined by physicians who have been charged with expertise on the medical use of cannabis by their jurisdiction. In Israel, only the plant-based cannabinoid nabiximol (mixture of tetrahydrocannabinol/cannabidiol) can be prescribed for spasticity/chronic pain in multiple sclerosis and for cancer pain. The costs of nabiximole are reimbursed by some, but not by all health maintenance organizations. The medical use of marijuana is permitted; however, it is strictly regulated by the government. Selected companies are allowed to produce marijuana for medical use, and only certain physicians are licensed to prescribe marijuana as a therapeutic drug for specific indications such as chronic neuropathic, and cancer pain, inflammatory bowel diseases, or posttraumatic stress disorder if conventional treatments have failed. The costs of marijuana are not reimbursed by health insurance companies. In Canada, synthetic cannabinoids and the plant-based (nabiximol) are licensed for neuropathic and cancer pain, HIV-related anorexia and chemotherapy-associate nausea. The costs of these synthetic cannabinoids are covered by health insurance companies. The medical use of marijuana as a treatment option is allowed for individual patients suffering from any medical condition when authorized by a medical practitioner or nurse. Licensed producers are the only source for patients to newly access medical cannabis, although those with previous permission to grow may continue cultivation at the present time. The costs of marijuana are not reimbursed by health insurance companies. There are multiple contraindications for the medical use of cannabis products in both countries. The use of standardized, synthetic, and plant-based cannabis products should be allowed in Germany for defined medical conditions when high-level evidence of efficacy and safety exists. The costs should be reimbursed by the health insurance companies. Contraindications for the medical use of cannabis should be defined. Growing marijuana by patients for their medical use should not be allowed.

Cannabis constituents modulate δ9-tetrahydrocannabinol-induced hyperphagia in rats.

PubMed

Farrimond, Jonathan A; Hill, Andrew J; Whalley, Benjamin J; Williams, Claire M

2010-05-01

The hyperphagic effect of Delta9-tetrahydrocannabinol (Delta9THC) in humans and rodents is well known. However, no studies have investigated the importance of Delta9THC composition and any influence other non-Delta9THC cannabinoids present in Cannabis sativa may have. We therefore compared the effects of purified Delta9THC, synthetic Delta9THC (dronabinol), and Delta9THC botanical drug substance (Delta9THC-BDS), a Delta9THC-rich standardized extract comparable in composition to recreationally used cannabis. Adult male rats were orally dosed with purified Delta9THC, synthetic Delta9THC, or Delta9THC-BDS, matched for Delta9THC content (0.34-2.68 mg/kg). Prior to dosing, subjects were satiated, and food intake was recorded following Delta9THC administration. Data were then analyzed in terms of hourly intake and meal patterns. All three Delta9THC substances tested induced significant hyperphagic effects at doses >or=0.67 mg/kg. These effects included increased intake during hour one, a shorter latency to onset of feeding and a greater duration and consumption in the first meal. However, while some differences in vehicle control intakes were observed, there were significant, albeit subtle, differences in pattern of effects between the purified Delta9THC and Delta9THC-BDS. All Delta9THC compounds displayed classical Delta9THC effects on feeding, significantly increasing shortterm intake whilst decreasing latency to the first meal. We propose that the subtle adjustment to the meal patterns seen between the purified Delta9THC and Delta9THC-BDS are due to non-Delta9THC cannabinoids present in Delta9THC-BDS. These compounds and other non-cannabinoids have an emerging and diverse pharmacology and can modulate Delta9THC-induced hyperphagia, making them worth further investigation for their therapeutic potential.

Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.

PubMed

Fox, Susan H; Lang, Anthony E; Brotchie, Jonathan M

2006-10-01

Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.

Inhalation exposure to smoke from synthetic "marijuana" produces potent cannabimimetic effects in mice.

PubMed

Wiebelhaus, Jason M; Poklis, Justin L; Poklis, Alphonse; Vann, Robert E; Lichtman, Aron H; Wise, Laura E

2012-12-01

Use of synthetic "marijuana" has increased in recent years, produced adverse effects and prompted the temporary DEA ban of five specific cannabinoid analogs, including JWH-018. The objectives of the current study include determining the chemical content of the herbal product, Buzz, assessing its behavioral effects upon inhalation exposure to mice, determining whether CB(1) receptors mediate its pharmacological activity, and ascertaining its biodisposition in blood and various organs. Using a nose-only exposure system, mice were exposed to smoke produced from combustion of an herbal incense product, Buzz, which contained 5.4% JWH-018. Cannabimimetic effects following smoke exposure were evaluated using the tetrad procedure, consisting of the following indices: hypomotility, antinociception, catalepsy, and hypothermia. Additionally, blood and tissues were collected for JWH-018 quantification. Inhalation exposure to Buzz produced dose-related tetrad effects similar to marijuana as well as dose-related increased levels of JWH-018 in the blood, brain, heart, kidney, liver, lung, and spleen. The behavioral effects were blocked by rimonabant, a CB(1) receptor antagonist. Effects produced by Buzz were similar in magnitude and time-course to those produced by marijuana, though equipotent doses of Buzz and marijuana yielded considerably lower brain levels of JWH-018 than THC for the respective materials. Inhalation exposure to a product containing JWH-018 penetrates into the brain and other organs and produces CB(1) receptor-mediated behavioral pharmacological effects in mice. The increased potency of JWH-018 compared to THC, the variable amount of drug added to various herbal products, and unknown toxicity, undoubtedly contribute to public health risks of synthetic cannabinoids. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Self-reported use of novel psychoactive substances in a US nationally representative survey: Prevalence, correlates, and a call for new survey methods to prevent underreporting.

PubMed

Palamar, Joseph J; Martins, Silvia S; Su, Mark K; Ompad, Danielle C

2015-11-01

In recent years, there has been an increase in emergence and use of novel psychoactive substances (NPS) in the US and worldwide. However, there is little published epidemiological survey data estimating the prevalence of use in the US. Data on self-reported NPS use came from the National Survey of Drug Use and Health (2009-2013), a national representative sample of non-institutionalized individuals in the US. Subjects were asked to provide names of (non-traditional) drugs they used that they were not specifically asked about. We examined lifetime prevalence and sociodemographic correlates of self-reported use of new and uncommon synthetic drugs (NPS) among subjects ages 12-34-years-old. 1.2% of subjects self-reported any use of the 57 NPS we examined. Use of psychedelic tryptamines (primarily DMT) was most common, followed by psychedelic phenethylamines (e.g., 2C series) and synthetic cannabinoids. Prevalence of self-reported use of NPS increased from 2009 to 2013 and use was most common among males, whites, older subjects, those of lower income, and among those residing in cities. Lifetime use of various other illicit drugs (e.g., LSD, cocaine, ecstasy/MDMA) was highly prevalent among NPS users. This the first study reporting on use of a variety of NPS in a nationally representative US sample; however, use appears to be underreported as other national data suggest higher rates of NPS (e.g., synthetic cannabinoid) use. Developing more adaptable survey tools and systematically assessing NPS use would allow researchers to ask about hundreds of NPS and improve reporting as new drugs continue to rapidly emerge. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

DTIC Science & Technology

2014-04-01

tetrahydrocannabinol ( THC ) treatment-induced autophagy in U87-MG glioblastoma cells based on GFP-LC3 puncta formation and electron microscopic autophagosome imaging...Shrivastava et al. (2011) and Salazar et al. (2009) showed that CBD and THC , respectively, induced autophagic effects that were linked to the induction of...animals treated with THC and the synthetic cannabinoid JWH-133 express higher levels of cleaved caspase-3 when compared to vehicle (Caffarel et al

Risk of emergency medical treatment following consumption of cannabis or synthetic cannabinoids in a large global sample.

PubMed

Winstock, Adam; Lynskey, Michael; Borschmann, Rohan; Waldron, Jon

2015-06-01

Synthetic cannabinoids (SCs) have become increasingly popular in recent years. Diverse in chemical structure, many have been subjected to legislative regulation, but their availability and use persists. Often marketed to reflect their similar effects to cannabis, their use has been associated with a range of negative health effects. We sought to determine the relative risk of seeking emergency medical treatment (EMT) following use of SCs and natural cannabis. We utilized an anonymous online survey of drug use, obtaining data from 22,289 respondents. We calculated the relative risk of seeking EMT between the two substances using an estimate for days used in the past year. Thirty-seven cannabis users (0.2%) and 21 SC users (1.0%) had sought EMT during the past year following use. The relative risk associated with the use of SCs was 30 (95% CI 17.5-51.2) times higher than that associated with cannabis. Significantly more symptoms (p=0.03) were reported by respondents seeking treatment for SCs than for cannabis. Whilst these findings must be treated with caution, SCs potentially pose a greater risk to users' health than natural forms of cannabis. Regulation is unlikely to remove SCs from the market, so well-informed user-focused health promotion messages need to be crafted to discourage their use. © The Author(s) 2015.

From niche to stigma-Headshops to prison: Exploring the rise and fall of synthetic cannabinoid use among young adults.

PubMed

Blackman, Shane; Bradley, Rick

2017-02-01

The aim of this paper will be to consider the rise and subsequent fall in NPS use at national and local level with a focus on synthetic cannabinoid products in Kent. We will examine the local practice and policy responses by Kent's Young Persons' Drug and Alcohol Service towards a possible change in patterns of NPS drug consumption. The county has seen an expansion in the number of Headshops and we present local media coverage on NPS, and the Trading Standards and Kent Police intervention Operation Lantern to regulate Headshops. Through quantitative and qualitative data sets on socially vulnerable young people and prison populations we explore young adults' perception of pleasure and harm in the use of NPS. Emergent data suggests young adults are now assessing the differences between NPS and more traditional illicit drugs, with this impacting on decision-making about the substances being used. When 'legal highs' first appeared they were associated with a more niche middle class demographic, 'psychonauts' and experimental users interested in pursuing recreational drug diversity. We examine macro and micro data to suggest that populations most likely to become involved in NPS use are those with degrees of stigma linked to socially vulnerable young adults suggesting that Spice is no longer a feature of middle class recreational drug use. Copyright © 2016 Elsevier B.V. All rights reserved.

Psychiatric comorbidity associated with synthetic cannabinoid use compared to cannabis.

PubMed

Bassir Nia, Anahita; Medrano, Benjamin; Perkel, Charles; Galynker, Igor; Hurd, Yasmin L

2016-12-01

Synthetic cannabinoids (SC) use has had a dramatic increase in recent years, but data regarding their adverse effects on mental health is limited. In this study, we compared clinical presentations of SC users with cannabis users in a psychiatric inpatient setting. Digital charts of all patients who were admitted to a dual diagnosis psychiatric unit in one year were reviewed. Patients who had any current substance use disorder were categorized in four groups: (1) SC use and cannabis use (SC+MJ+), (2) SC use without cannabis use (SC+MJ-), (3) cannabis use without SC use (SC-MJ+), and (4) No SC or cannabis use (SC-MJ-). A total of 594 charts were included. SC+MJ- patients had significantly more psychotic symptoms (OR: 4.44, 95% CI: 1.98-9.94), followed by SC+MJ+ (OR: 3.61, 95% CI: 1.87-6.97) and SC-MJ+ (OR: 1.87, 95%CI: 1.33-2.64) patients. The SC+MJ- group also had more agitation and aggression was most prominent in SC+MJ+ subjects. Multivariate analyses showed that the psychiatric associations of SC and cannabis use remained significant even after controlling for potential confounds such as other substance use. The prominent psychiatric features of SC users as compared to cannabis users in an inpatient setting are psychotic presentations and agitation, which have important treatment implications. © The Author(s) 2016.

Examination of YouTube videos related to synthetic cannabinoids.

PubMed

Fullwood, M Dottington; Kecojevic, Aleksandar; Basch, Corey H

2016-08-17

The popularity of synthetic cannabinoids (SCBs) is increasing the chance for adverse health issues in the United States. Moreover, social media platforms such as YouTube that provided a platform for user-generated content can convey misinformation or glorify use of SCBs. The aim of this study was to fill this gap by describing the content of the most popular YouTube videos containing content related to the SCBs. Videos with at least 1000 or more views found under the search terms "K2" and "spice" included in the analysis. The collective number of views was over 7.5 million. Nearly half of videos were consumer produced (n=42). The most common content in the videos was description of K2 (n=69), followed by mentioning dangers of using K2 (n=47), mentioning side effects (n=38) and showing a person using K2 (n=37). One-third of videos (n=34) promoted use of K2, while 22 videos mentioned risk of dying as a consequence of using K2. YouTube could be used as a surveillance tool to combat this epidemic, but instead, the most widely videos related to SCBs are uploaded by consumers. The content of these consumer videos on YouTube often provide the viewer with access to view a wide array of uploaders describing, encouraging, participating and promoting use.

Examination of YouTube videos related to synthetic cannabinoids

PubMed Central

Kecojevic, Aleksandar; Basch, Corey H.

2016-01-01

The popularity of synthetic cannabinoids (SCBs) is increasing the chance for adverse health issues in the United States. Moreover, social media platforms such as YouTube that provided a platform for user-generated content can convey misinformation or glorify use of SCBs. The aim of this study was to fill this gap by describing the content of the most popular YouTube videos containing content related to the SCBs. Videos with at least 1000 or more views found under the search terms “K2” and “spice” included in the analysis. The collective number of views was over 7.5 million. Nearly half of videos were consumer produced (n = 42). The most common content in the videos was description of K2 (n = 69), followed by mentioning dangers of using K2 (n = 47), mentioning side effects (n = 38) and showing a person using K2 (n = 37). One-third of videos (n = 34) promoted use of K2, while 22 videos mentioned risk of dying as a consequence of using K2. YouTube could be used as a surveillance tool to combat this epidemic, but instead, the most widely videos related to SCBs are uploaded by consumers. The content of these consumer videos on YouTube often provide the viewer with access to view a wide array of uploaders describing, encouraging, participating and promoting use. PMID:27639268

Synthetic marijuana "K2" induced ITP.

PubMed

Öztürk, Erman; Oral, Alihan; Özdemir, Melek; Bambul, Nail

2015-01-01

Immune thrombocytopenia (ITP) is a heterogeneous disease which can be primary or secondary due to other conditions such as drugs. CB2 receptors (CB2R) also have a role in the ITP pathogenesis as CB2 receptor gene (CNR2) polymorphisms are associated with chronic immune thrombocytopenia and autoimmune diseases. K2 is synthetic marijuana which acts on cannabinoid receptors that are found on immune cells and thrombocytes. Here, we present a case who presented with ITP secondary to K2 usage and was successfully treated with 1 mg/kg prednisolone. This is the first ITP case in the literature due to K2. It is important in the era of the new drugs development of the CB2R mimetics.

"When 'Bad' is 'Good'": Identifying Personal Communication and Sentiment in Drug-Related Tweets.

PubMed

Daniulaityte, Raminta; Chen, Lu; Lamy, Francois R; Carlson, Robert G; Thirunarayan, Krishnaprasad; Sheth, Amit

2016-10-24

To harness the full potential of social media for epidemiological surveillance of drug abuse trends, the field needs a greater level of automation in processing and analyzing social media content. The objective of the study is to describe the development of supervised machine-learning techniques for the eDrugTrends platform to automatically classify tweets by type/source of communication (personal, official/media, retail) and sentiment (positive, negative, neutral) expressed in cannabis- and synthetic cannabinoid-related tweets. Tweets were collected using Twitter streaming Application Programming Interface and filtered through the eDrugTrends platform using keywords related to cannabis, marijuana edibles, marijuana concentrates, and synthetic cannabinoids. After creating coding rules and assessing intercoder reliability, a manually labeled data set (N=4000) was developed by coding several batches of randomly selected subsets of tweets extracted from the pool of 15,623,869 collected by eDrugTrends (May-November 2015). Out of 4000 tweets, 25% (1000/4000) were used to build source classifiers and 75% (3000/4000) were used for sentiment classifiers. Logistic Regression (LR), Naive Bayes (NB), and Support Vector Machines (SVM) were used to train the classifiers. Source classification (n=1000) tested Approach 1 that used short URLs, and Approach 2 where URLs were expanded and included into the bag-of-words analysis. For sentiment classification, Approach 1 used all tweets, regardless of their source/type (n=3000), while Approach 2 applied sentiment classification to personal communication tweets only (2633/3000, 88%). Multiclass and binary classification tasks were examined, and machine-learning sentiment classifier performance was compared with Valence Aware Dictionary for sEntiment Reasoning (VADER), a lexicon and rule-based method. The performance of each classifier was assessed using 5-fold cross validation that calculated average F-scores. One-tailed t test was used to determine if differences in F-scores were statistically significant. In multiclass source classification, the use of expanded URLs did not contribute to significant improvement in classifier performance (0.7972 vs 0.8102 for SVM, P=.19). In binary classification, the identification of all source categories improved significantly when unshortened URLs were used, with personal communication tweets benefiting the most (0.8736 vs 0.8200, P<.001). In multiclass sentiment classification Approach 1, SVM (0.6723) performed similarly to NB (0.6683) and LR (0.6703). In Approach 2, SVM (0.7062) did not differ from NB (0.6980, P=.13) or LR (F=0.6931, P=.05), but it was over 40% more accurate than VADER (F=0.5030, P<.001). In multiclass task, improvements in sentiment classification (Approach 2 vs Approach 1) did not reach statistical significance (eg, SVM: 0.7062 vs 0.6723, P=.052). In binary sentiment classification (positive vs negative), Approach 2 (focus on personal communication tweets only) improved classification results, compared with Approach 1, for LR (0.8752 vs 0.8516, P=.04) and SVM (0.8800 vs 0.8557, P=.045). The study provides an example of the use of supervised machine learning methods to categorize cannabis- and synthetic cannabinoid-related tweets with fairly high accuracy. Use of these content analysis tools along with geographic identification capabilities developed by the eDrugTrends platform will provide powerful methods for tracking regional changes in user opinions related to cannabis and synthetic cannabinoids use over time and across different regions.

Effects of Adolescent Cannabinoid Self-Administration in Rats on Addiction-Related Behaviors and Working Memory

PubMed Central

Kirschmann, Erin K; Pollock, Michael W; Nagarajan, Vidhya; Torregrossa, Mary M

2017-01-01

Use of marijuana (Cannabis sativa) often begins in adolescence, and heavy adolescent marijuana use is often associated with impaired cognitive function in adulthood. However, clinical reports of long-lasting cognitive deficits, particularly in subjects who discontinue use in adulthood, are mixed. Moreover, dissociating innate differences in cognitive function from cannabis-induced deficits is challenging. Therefore, the current study sought to develop a rodent model of adolescent cannabinoid self-administration (SA), using the synthetic cannabinoid receptor agonist WIN55,212-2 (WIN), in order to assess measures of relapse/reinstatement of drug seeking and long-term effects on cognitive function assessed in a delay-match-to-sample working memory task and a spatial recognition task. Adolescent male rats readily self-administered WIN in 2-h or 6-h sessions/day, but did not demonstrate an escalation of intake with 6-h access. Rats exhibited significant cue-induced reinstatement of WIN seeking that increased with 21 days of abstinence (ie, ‘incubation of craving’). Cognitive testing occurred in adulthood under drug-free conditions. Both 2-h and 6-h adolescent WIN SA groups exhibited significantly better working memory performance in adulthood relative to sucrose SA controls, and performance was associated with altered expression of proteins regulating GABAergic and glutamatergic signaling in the prefrontal cortex. Self-administered WIN did not produce either acute or chronic effects on short-term memory, but experimenter administration of WIN in adolescence, at doses previously reported in the literature, produced acute deficits in short-term memory that recovered with abstinence. Thus, SA of a rewarding cannabinoid in adolescence does not produce long-term cognitive dysfunction. PMID:27582345

Cardiovascular Complications of Marijuana and Related Substances: A Review.

PubMed

Singh, Amitoj; Saluja, Sajeev; Kumar, Akshat; Agrawal, Sahil; Thind, Munveer; Nanda, Sudip; Shirani, Jamshid

2018-06-01

The recreational use of cannabis has sharply increased in recent years in parallel with its legalization and decriminalization in several countries. Commonly, the traditional cannabis has been replaced by potent synthetic cannabinoids and cannabimimetics in various forms. Despite overwhelming public perception of the safety of these substances, an increasing number of serious cardiovascular adverse events have been reported in temporal relation to recreational cannabis use. These have included sudden cardiac death, vascular (coronary, cerebral and peripheral) events, arrhythmias and stress cardiomyopathy among others. Many of the victims of these events are relatively young men with few if any cardiovascular risk factors. However, there are reasons to believe that older individuals and those with risk factors for or established cardiovascular disease are at even higher danger of such events following exposure to cannabis. The pathophysiological basis of these events is not fully understood and likely encompasses a complex interaction between the active ingredients (particularly the major cannabinoid, Δ 9 -tetrahydrocannabinol), and the endo-cannabinoid system, autonomic nervous system, as well as other receptor and non-receptor mediated pathways. Other complicating factors include opposing physiologic effects of other cannabinoids (predominantly cannabidiol), presence of regulatory proteins that act as metabolizing enzymes, binding molecules, or ligands, as well as functional polymorphisms of target receptors. Tolerance to the effects of cannabis may also develop on repeated exposures at least in part due to receptor downregulation or desensitization. Moreover, effects of cannabis may be enhanced or altered by concomitant use of other illicit drugs or medications used for treatment of established cardiovascular diseases. Regardless of these considerations, it is expected that the current cannabis epidemic would add significantly to the universal burden of cardiovascular diseases.

Human studies of cannabinoids and medicinal cannabis.

PubMed

Robson, P

2005-01-01

Cannabis has been known as a medicine for several thousand years across many cultures. It reached a position of prominence within Western medicine in the nineteenth century but became mired in disrepute and legal controls early in the twentieth century. Despite unremitting world-wide suppression, recreational cannabis exploded into popular culture in the 1960s and has remained easily obtainable on the black market in most countries ever since. This ready availability has allowed many thousands of patients to rediscover the apparent power of the drug to alleviate symptoms of some of the most cruel and refractory diseases known to humankind. Pioneering clinical research in the last quarter of the twentieth century has given some support to these anecdotal reports, but the methodological challenges to human research involving a pariah drug are formidable. Studies have tended to be small, imperfectly controlled, and have often incorporated unsatisfactory synthetic cannabinoid analogues or smoked herbal material of uncertain composition and irregular bioavailability. As a result, the scientific evaluation of medicinal cannabis in humans is still in its infancy. New possibilities in human research have been opened up by the discovery of the endocannabinoid system, a rapidly expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries. More and more scientists and clinicians are becoming interested in exploring the potential of cannabis-based medicines. Future targets will extend beyond symptom relief into disease modification, and already cannabinoids seem to offer particular promise in the treatment of certain inflammatory and neurodegenerative conditions. This chapter will begin with an outline of the development and current status of legal controls pertaining to cannabis, following which the existing human research will be reviewed. Some key safety issues will then be considered, and the chapter will conclude with some suggestions as to future directions for human research.

Adolescent cannabinoid exposure attenuates adult female sexual motivation but does not alter adulthood CB1R expression or estrous cyclicity

PubMed Central

Chadwick, Benjamin; Saylor, Alicia J.; López, Hassan H.

2013-01-01

Adolescence is a developmental period characterized by neuronal remodeling and the maturation of adult emotionality, reproductive behavior and social behavior. We examined whether chronic cannabinoid exposure in adolescent rats alters female sexual motivation, estrous cyclicity, sucrose preference, and CB1R expression in adulthood. Female rats were administered with the synthetic cannabinoid agonist, CP-55,940 (0.4 mg/kg, intraperitoneal), daily during adolescent development (PND 35–45). In a subset of subjects, socio-sexual motivation was investigated in adulthood (PND 75–86) using a runway apparatus. Estrous cyclicity was tracked in adulthood via vaginal cytology and a single-mount test. A two-bottle sucrose preference test was also conducted to determine whether predicted changes in socio-sexual motivation might be linked to alterations in hedonic processing. CB1R expression was examined in two separate subsets of subjects, one sacrificed following drug treatment (PND 46) and one before behavioral testing (PND 74). Drug treatment significantly decreased adult preference for a male conspecific (sexual motivation), as assessed by both Run Time and Proximity Time, but did not affect estrous cyclicity or sucrose preference. CP-55,940 treatment also induced immediate, but transient, decreases in CB1R expression in the ventromedial nucleus of the hypothalamus and amygdala. Drug treatment did not affect CB1R expression in the nucleus accumbens (core or shell) or globus pallidus at either time point. We suggest that the endocannabinoid system may play a role in the maturation of neuroendocrine axes and adult female reproductive behavior, and that chronic exposure to cannabinoids during adolescence disrupts these neurodevelopmental processes. PMID:21777606

Effects of Adolescent Cannabinoid Self-Administration in Rats on Addiction-Related Behaviors and Working Memory.

PubMed

Kirschmann, Erin K; Pollock, Michael W; Nagarajan, Vidhya; Torregrossa, Mary M

2017-04-01

Use of marijuana (Cannabis sativa) often begins in adolescence, and heavy adolescent marijuana use is often associated with impaired cognitive function in adulthood. However, clinical reports of long-lasting cognitive deficits, particularly in subjects who discontinue use in adulthood, are mixed. Moreover, dissociating innate differences in cognitive function from cannabis-induced deficits is challenging. Therefore, the current study sought to develop a rodent model of adolescent cannabinoid self-administration (SA), using the synthetic cannabinoid receptor agonist WIN55,212-2 (WIN), in order to assess measures of relapse/reinstatement of drug seeking and long-term effects on cognitive function assessed in a delay-match-to-sample working memory task and a spatial recognition task. Adolescent male rats readily self-administered WIN in 2-h or 6-h sessions/day, but did not demonstrate an escalation of intake with 6-h access. Rats exhibited significant cue-induced reinstatement of WIN seeking that increased with 21 days of abstinence (ie, 'incubation of craving'). Cognitive testing occurred in adulthood under drug-free conditions. Both 2-h and 6-h adolescent WIN SA groups exhibited significantly better working memory performance in adulthood relative to sucrose SA controls, and performance was associated with altered expression of proteins regulating GABAergic and glutamatergic signaling in the prefrontal cortex. Self-administered WIN did not produce either acute or chronic effects on short-term memory, but experimenter administration of WIN in adolescence, at doses previously reported in the literature, produced acute deficits in short-term memory that recovered with abstinence. Thus, SA of a rewarding cannabinoid in adolescence does not produce long-term cognitive dysfunction.

Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors.

PubMed

Martínez-Pinilla, Eva; Varani, Katia; Reyes-Resina, Irene; Angelats, Edgar; Vincenzi, Fabrizio; Ferreiro-Vera, Carlos; Oyarzabal, Julen; Canela, Enric I; Lanciego, José L; Nadal, Xavier; Navarro, Gemma; Borea, Pier Andrea; Franco, Rafael

2017-01-01

The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB 2 receptors (CB 2 Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB 2 R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB 2 R. Using membrane preparations from CB 2 R-expressing HEK-293T (human embryonic kidney 293T) cells, we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB 2 R where the synthetic cannabinoid, [ 3 H]-WIN 55,212-2, binds. CBD was, however, able to produce minor but consistent reduction in the homogeneous binding assays in living cells using the fluorophore-conjugated CB 2 R-selective compound, CM-157. The effect on binding to CB 2 R-expressing living cells was different to that exerted by the orthosteric antagonist, SR144528, which decreased the maximum binding without changing the K D . CBD at nanomolar concentrations was also able to significantly reduce the effect of the selective CB 2 R agonist, JWH133, on forskolin-induced intracellular cAMP levels and on activation of the MAP kinase pathway. These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities.

Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors

PubMed Central

Martínez-Pinilla, Eva; Varani, Katia; Reyes-Resina, Irene; Angelats, Edgar; Vincenzi, Fabrizio; Ferreiro-Vera, Carlos; Oyarzabal, Julen; Canela, Enric I.; Lanciego, José L.; Nadal, Xavier; Navarro, Gemma; Borea, Pier Andrea; Franco, Rafael

2017-01-01

The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB2 receptors (CB2Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB2R. Using membrane preparations from CB2R-expressing HEK-293T (human embryonic kidney 293T) cells, we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB2R where the synthetic cannabinoid, [3H]-WIN 55,212-2, binds. CBD was, however, able to produce minor but consistent reduction in the homogeneous binding assays in living cells using the fluorophore-conjugated CB2R-selective compound, CM-157. The effect on binding to CB2R-expressing living cells was different to that exerted by the orthosteric antagonist, SR144528, which decreased the maximum binding without changing the KD. CBD at nanomolar concentrations was also able to significantly reduce the effect of the selective CB2R agonist, JWH133, on forskolin-induced intracellular cAMP levels and on activation of the MAP kinase pathway. These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities. PMID:29109685

Notes from the field: severe illness associated with reported use of synthetic marijuana - Colorado, August-September 2013.

PubMed

2013-12-13

On August 30, 2013, the Colorado Department of Public Health and Environment (CDPHE) was notified by several hospitals of an increase in the number of patients visiting their emergency departments (EDs) with altered mental status after using synthetic marijuana. Synthetic marijuana is dried plant material sprayed with various synthetic cannabinoids and smoked as an alternative to smoking marijuana. In response to the increase in ED visits associated with the use of synthetic marijuana, CDPHE asked all Colorado EDs to report through EMResource (a web-based reporting system) any patients examined on or after August 21 with altered mental status after use of a synthetic marijuana product. Serum and urine specimens from patients also were requested. On September 8, CDPHE, with the assistance of CDC, began an epidemiologic investigation to characterize the outbreak, determine the active substance and source of the synthetic marijuana product, and prevent further morbidity and mortality. Investigators reviewed ED visit reports submitted through EMResource and medical charts. A probable case was defined as any illness resulting in a visit to a Colorado ED during August 21-September 18, 2013, by a patient with suspected synthetic marijuana use in the 24 hours preceding illness onset. Of 263 patient visits reported to CDPHE through EMResource (214) and other means, such as e-mail and fax (49), a total of 221 (84%) represented probable cases (Figure).

Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs.

PubMed

Parmar, Jayesh R; Forrest, Benjamin D; Freeman, Robert A

2016-01-01

The purpose of this report is to present a review of the medical uses, efficacy, and adverse effects of the three approved cannabis-based medications and ingested marijuana. A literature review was conducted utilizing key search terms: dronabinol, nabilone, nabiximols, cannabis, marijuana, smoke, efficacy, toxicity, cancer, multiple sclerosis, nausea, vomiting, appetite, pain, glaucoma, and side effects. Abstracts of the included literature were reviewed, analyzed, and organized to identify the strength of evidence in medical use, efficacy, and adverse effects of the approved cannabis-based medications and medical marijuana. A total of 68 abstracts were included for review. Dronabinol's (Marinol) most common medical uses include weight gain, chemotherapy-induced nausea and vomiting (CINV), and neuropathic pain. Nabiximol's (Sativex) most common medical uses include spasticity in multiple sclerosis (MS) and neuropathic pain. Nabilone's (Cesamet) most common medical uses include CINV and neuropathic pain. Smoked marijuana's most common medical uses include neuropathic pain and glaucoma. Orally ingested marijuana's most common medical uses include improving sleep, reducing neuropathic pain, and seizure control in MS. In general, all of these agents share similar medical uses. The reported adverse effects of the three cannabis-based medications and marijuana show a major trend in central nervous system (CNS)-related adverse effects along with cardiovascular and respiratory related adverse effects. Marijuana shares similar medical uses with the approved cannabis-based medications dronabinol (Marinol), nabiximols (Sativex), and nabilone (Cesamet), but the efficacy of marijuana for these medical uses has not been fully determined due to limited and conflicting literature. Medical marijuana also has similar adverse effects as the FDA-approved cannabis-based medications mainly consisting of CNS related adverse effects but also including cardiovascular and respiratory related adverse effects. Finally, insufficient higher-order evidence to support the widespread use of medical marijuana was found, but a limited amount of moderate-level evidence supports its use in pain and seizure management. Published by Elsevier Inc.

Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.

PubMed

Formukong, E A; Evans, A T; Evans, F J

1988-02-01

Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.

GC-MS and GC-IR Analyses of the Methoxy-1-n-pentyl-3-(1-naphthoyl)-indoles: Regioisomeric Designer Cannabinoids.

PubMed

Thaxton-Weissenfluh, Amber; Belal, Tarek S; DeRuiter, Jack; Smith, Forrest; Abiedalla, Younis; Neel, Logan; Abdel-Hay, Karim M; Clark, C Randall

2018-06-16

The indole ring regioisomeric methoxy-1-n-pentyl-3-(1-naphthoyl)-indoles represent indole ring-substituted analogs of the synthetic cannabinoid JWH-018. The electron ionization mass spectra show equivalent regioisomeric major fragments resulting from cleavage of the groups attached to the central indole nucleus. The characteristic (M-17)+ fragment ion at m/z 354 resulting from the loss of OH group is significant in the mass spectra of all four compounds. Fragmentation of the naphthoyl and/or pentyl groups yields the cations at m/z 314, 300, 244 and 216. The vapor-phase infrared spectra provide a number of characteristic absorption bands to identify the individual isomers. Gas chromatographic separations on a capillary column containing a film of trifluoropropylmethyl polysiloxane (Rtx-200) provided excellent resolution of these compounds, their precursor indoles and intermediate pentylindoles. The elution order appears related to the degree of crowding of indole ring substituents.

Effects of alprazolam and cannabinoid-related compounds in an animal model of panic attack.

PubMed

Batista, Luara A; Haibara, Andrea S; Schenberg, Luiz C; Moreira, Fabricio A

2017-01-15

Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80μg) in rats. Alprazolam (1, 2, 4mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder. Copyright © 2016 Elsevier B.V. All rights reserved.

Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment.

PubMed

Richards, John R; Lapoint, Jeff M; Burillo-Putze, Guillermo

2018-01-01

Cannabinoid hyperemesis syndrome is a clinical disorder that has become more prevalent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symptoms with hot showers and baths, and topical capsaicin. In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and explore possible mechanisms for its beneficial effect, including activation of transient receptor potential vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hydrotherapy are also investigated. An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017 was performed to identify known and theoretical thermoregulatory mechanisms associated with the endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for relevant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References from the selected articles were also hand-searched. A total of 137 articles were considered relevant and included. Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of benefit is longer. Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a novel type of desensitization analgesia. Transient receptor potential vanilloid 1 receptors also respond to noxious stimuli, such as heat (>43 °C), acids (pH <6), pain, change in osmolarity, and endovanilloids. The action of topical capsaicin may mimic the effect of heat-activation of transient receptor potential vanilloid 1. Endocannabinoid system and transient receptor potential vanilloid 1: Cannabinoid hyperemesis syndrome may result from a derangement in the endocannabinoid system secondary to chronic exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endocannabinoid system and transient receptor potential vanilloid 1. Temperature regulation: Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential vanilloid 1 activation. "Sensocrine" antiemetic effects: Transient receptor potential vanilloid 1 activation by heat or capsaicin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypeptide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic transmission. These downstream effects represent further possible explanations for transient receptor potential vanilloid 1-associated antiemesis. These complex interactions between the endocannabinoid systems and transient receptor potential vanilloid 1, in the setting of cannabinoid receptor desensitization, may yield important clues into the pathophysiology and treatment of cannabinoid hyperemesis syndrome. This knowledge can provide clinicians caring for these patients with additional treatment options that may reduce length of stay, avoid unnecessary imaging and laboratory testing, and decrease the use of potentially harmful medications such as opioids.

Acute psychosis associated with recreational use of benzofuran 6-(2-aminopropyl)benzofuran (6-APB) and cannabis.

PubMed

Chan, Wui Ling; Wood, David M; Hudson, Simon; Dargan, Paul I

2013-09-01

There is evidence from around Europe of the availability and use of 6-(2-aminopropyl)benzofuran (6-APB) as a recreational drug. However, there is currently limited information on the acute toxicity of this compound. We describe here a case of acute toxicity associated with recreational use of legal high (6-APB) and cannabis, in which the comprehensive toxicological analysis confirmed the presence of a significant amount of 6-APB together with metabolites of both tetrahydrocannabinol and the synthetic cannabinoid receptor agonist (JWH-122). A 21-year-old gentleman with no previous medical and psychiatric history was brought to the emergency department (ED) after he had developed agitation and paranoid behaviour following the use of 6-APB purchased over the Internet. There was no obvious medical cause for his acute psychosis. He required diazepam to control his agitation and was subsequently transferred to a psychiatric hospital for ongoing management of his psychosis. Toxicological screening of a urine sample collected after presentation to the ED detected 6-APB, with an estimated urinary concentration of 2,000 ng/ml; other drugs were also detected, but at lower concentrations including metabolites of the synthetic cannabinoid receptor agonist JWH-122 and tetrahydrocannabinol. This is the first case of analytically confirmed acute toxicity associated with the detection of 6-APB which will provide some information on acute toxicity of this drug to help clinicians with the management of such patients and legislative authorities in their consideration for the need of its control.

Acute Toxicity Associated with Use of 5F-Derivations of Synthetic Cannabinoid Receptor Agonists with Analytical Confirmation.

PubMed

Abouchedid, Rachelle; Ho, James H; Hudson, Simon; Dines, Alison; Archer, John R H; Wood, David M; Dargan, Paul I

2016-12-01

Synthetic Cannabinoid Receptor Agonists (SCRAs) are the largest group of new psychoactive substances reported to the European Warning System and the United Nations Office on Drugs and Crime to date. The heterogeneous nature and speed of diversification of these compounds make it challenging to accurately characterise and predict harms of these compounds in pre-clinical studies, ahead of their appearance. We report the case of a 19-year-old female who purchased three products from a headshop: two new psychoactive substances (sachets of "cannabis tea" and "mushroom tea") as well as two LSD blotters. After the "cannabis tea" was smoked and the two LSD blotters and "mushroom tea" were ingested, the patient became tachycardic (HR 128), developed seizures, agitation, visual hallucinations as well as suspected serotonergic toxicity (sustained ankle clonus 20-30 beats) 1-2 hours after use. She was treated with 1 mg of intravenous midazolam. Symptoms/signs resolved within 13 hours. No further supportive care was required. Plasma, blood, and urine samples confirmed the presence of two SCRAs: 5FAKB-48 and 5F-PB-22. The patient also reported therapeutic use of both fluoxetine and citalopram for depression. To the best of our knowledge, this is the first case report of non-fatal intoxication with 5F-AKB-48 with analytical confirmation and exposure times. It also highlights the difficulties in understanding the pattern of toxicity of certain SCRAs in the context of psychotropic medications/co-morbid mental illness.

Acute intoxication of four individuals following use of the synthetic cannabinoid MAB-CHMINACA.

PubMed

Adamowicz, Piotr; Gieroń, Joanna

2016-09-01

The largest group of new psychoactive substances (NPS) are synthetic cannabinoids (SC). Those that become controlled are immediately replaced by new uncontrolled substances. The recent resurgence of the NPS market in Poland resulted in a further amendment to the Drug Addiction Counteraction Act. This resulted in significant changes in the composition of "legal high" preparations, and consequently a large outbreak of intoxications with SC was reported in Poland at the beginning of July 2015. This paper describes the circumstances of intoxication and toxicological findings in an acute intoxication of four individuals with MAB-CHMINACA. They each smoked tobacco mixed with powder from the package with the description "AM-2201". The adverse effects observed in the individuals included vomiting, seizures, limb twisting, muscle tremors, aggression, agitation, slurred speech, blood pressure spikes, wheezing, respiratory failure and losses of consciousness. Blood samples were analysed using liquid chromatography with mass spectrometry. Results from analysis performed on the blood samples showed the presence of MAB-CHMINACA, while AM-2201 was not found (LOD 0.09 ng/mL). The determined concentrations were 5.2, 1.3, 1.7 and 14.6 ng/mL, respectively. The analyses of the blood did not reveal any other substances (excluding medicines given in hospital). The presented cases show the health risks associated with MAB-CHMINACA use and confirm that "legal high" preparations do not always contain a substance represented on the package.

The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α*

PubMed Central

Downer, Eric J.; Clifford, Eileen; Amu, Sylvie; Fallon, Padraic G.; Moynagh, Paul N.

2012-01-01

We have demonstrated that R(+)WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN-β expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor-α (PPARα) in mediating the effects of R(+)WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN-β expression and R(+)WIN55,212-2 enhances TLR3-induced IFN-β expression in a stereoselective manner via PPARα. R(+)WIN55,212-2 promotes increased transactivation and expression of PPARα. Using the PPARα antagonist GW6471, we demonstrate that R(+)WIN55,212-2 acts via PPARα to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN-β promoter. Furthermore, GW6471 ameliorated the protective effects of R(+)WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPARα as an important mediator in manifesting the effects of R(+)WIN55,212-2 on the signaling cascade regulating IFN-β expression. The study adds to our molecular appreciation of potential therapeutic effects of R(+)WIN55,212-2 in multiple sclerosis. PMID:22654113

Chemical characterization of synthetic cannabinoids by electrospray ionization FT-ICR mass spectrometry.

PubMed

Kill, Jade B; Oliveira, Izabela F; Tose, Lilian V; Costa, Helber B; Kuster, Ricardo M; Machado, Leandro F; Correia, Radigya M; Rodrigues, Rayza R T; Vasconcellos, Géssica A; Vaz, Boniek G; Romão, Wanderson

2016-09-01

The synthetic cannabinoids (SCs) represent the most recent advent of the new psychotropic substances (NPS) and has become popularly known to mitigate the effects of the Δ(9)-THC. The SCs are dissolved in organic solvents and sprayed in a dry herbal blend. However, little information is reported on active ingredients of SCs as well as the excipients or diluents added to the herbal blend. In this work, the direct infusion electrospray ionization Fourier transform ion cyclotron mass spectrometry technique (ESI-FT-ICR MS) was applied to explore the chemical composition of nine samples of herbal extract blends, where a total of 11 SCs (UR-144, JWH-073, XLR-11, JWH-250, JWH-122, AM-2201, AKB48, JWH-210, JWH-081, MAM-2201 and 5F-AKB48) were identified in the positive ionization mode, ESI(+), and other 44 chemical species (saturated and unsaturated fatty acids, sugars, flavonoids, etc.) were detected in the negative ionization mode, ESI(-). Additionally, CID experiments were performed, and fragmentation pathways were proposed to identify the connectivity of SCs. Thus, the direct infusion ESI-FT-ICR MS technique is a powerful tool in forensic chemistry that enables the rapid and unequivocal way for the determination of molecular formula, the degree of unsaturation (DBE-double bond equivalent) and exact mass (<1ppm) of a total of 55 chemical species without the prior separation step. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In vitro metabolism of a novel synthetic cannabinoid, EAM-2201, in human liver microsomes and human recombinant cytochrome P450s.

PubMed

Kim, Ju Hyun; Kim, Hee Seung; Kong, Tae Yeon; Lee, Joo Young; Kim, Jin Young; In, Moon Kyo; Lee, Hye Suk

2016-02-05

In vitro metabolism of a new synthetic cannabinoid, EAM-2201, has been investigated with human liver microsomes and major cDNA-expressed cytochrome P450 (CYP) isozymes using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Incubation of EAM-2201 with human liver microsomes in the presence of NADPH resulted in the formation of 37 metabolites, including nine hydroxy-EAM-2201 (M1-M9), five dihydroxy-EAM-2201 (M10-M14), dihydrodiol-EAM-2201 (M15), oxidative defluorinated EAM-2201 (M16), two hydroxy-M16 (M17 and M18), three dihydroxy-M16 (M19-M21), N-dealkyl-EAM-2201 (M22), two hydroxy-M22 (M23 and M24), dihydroxy-M22 (M25), EAM-2201 N-pentanoic acid (M26), hydroxy-M26 (M27), dehydro-EAM-2201 (M28), hydroxy-M28 (M29), seven dihydroxy-M28 (M30-M36), and oxidative defluorinated hydroxy-M28 (M37). Multiple CYPs, including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2, 3A4, and 3A5, were involved in the metabolism of EAM-2201. In conclusion, EAM-2201 is extensively metabolized by CYPs and its metabolites can be used as an indicator of EAM-2201 abuse. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites

PubMed Central

Tai, Sherrica

2017-01-01

Commercial preparations containing synthetic cannabinoids (SCBs) are rapidly emerging as drugs of abuse. Although often assumed to be “safe” and “legal” alternatives to cannabis, reports indicate that SCBs induce toxicity not often associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This chapter will summarize the evidence that use of SCBs poses greater health risks relative to marijuana and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to this increased toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs act as full CB1 and CB2 receptor agonists both in 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 CB2 receptors. Finally, the potential for SCBs to cause adverse drug–drug interactions with other drugs of abuse, as well as with common therapeutic agents, will be discussed. Collectively, the evidence provided in this chapter indicates that SCBs should not be considered safe and legal alternatives to marijuana. Instead, the enhanced toxicity of SCBs 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 CB2 receptors, highlights the inherent danger that may accompany use of these substances. PMID:28012093

Role of cannabis in cardiovascular disorders

PubMed Central

Awad, Hamza H.; Ghali, Jalal K.

2017-01-01

The growing popularity of medical and recreational consumption of cannabis, especially among the youth, raises immediate concerns regarding its safety and long-terms effects. The cardiovascular effects of cannabis are not well known. Cannabis consumption has been shown to cause arrhythmia including ventricular tachycardia, and potentially sudden death, and to increase the risk of myocardial infarction (MI). These effects appear to be compounded by cigarette smoking and precipitated by excessive physical activity, especially during the first few hours of consumption. Cannabinoids, or the active compounds of cannabis, have been shown to have heterogeneous effects on central and peripheral circulation. Acute cannabis consumption has been shown to cause an increase in blood pressure, specifically systolic blood pressure (SBP), and orthostatic hypotension. Cannabis use has been reported to increase risk of ischemic stroke, particularly in the healthy young patients. The endocannabinoid system (ECS) is currently considered as a promising therapeutic target in the management of several disease conditions. Synthetic cannabinoids (SCs) are being increasingly investigated for their therapeutic effects; however, the value of their benefits over possible complications remains controversial. Despite the considerable research in this field, the benefits of cannabis and its synthetic derivatives remains questionable even in the face of an increasingly tolerating attitude towards recreational consumption and promotion of the therapeutic complications. More efforts are needed to increase awareness among the public, especially youth, about the cardiovascular risks associated with cannabis use and to disseminate the accumulated knowledge regarding its ill effects. PMID:28840009

Examination of Synthetic Cannabinoid and Cathinone Use among a Drug-Using Offender Sample, 2013-2015.

PubMed

Smith, Kirsten Elin; Bunting, Amanda M; Staton, Michele; Walker, Robert; Shalash, Sara; Winston, Erin; Pangburn, Kevin

2017-01-01

Use of novel psychoactive substances (NPS) such as synthetic cannabinoids (e.g., "Spice," "Serenity") and cathinones (e.g., "bath salts") has proliferated in recent years; however, there is a gap in research examining prevalence among offender samples. This study examined demographics, drug use, mental health characteristics, and criminal histories of NPS users compared to non-NPS users within an offender sample entering drug treatment. Using logistic regression analysis, combined 2013-2015 assessment data were examined (N = 8,791). NPS users offended more often (x̄ = 10.3), were more likely to have experienced homelessness (12.2%), and to have lived in a metro area (59.0%). NPS users reported significantly more past-year drug use, including substances not readily detected by standard urine analysis (e.g., hallucinogens, alcohol, and inhalants). Individuals with higher anxiety symptom counts (OR = 1.07; p < .001) and those who reported drinking to intoxication (OR = 1.30; p < .001) had an increased likelihood of NPS use. Older individuals (OR = 0.95; p < .001) and those who began using drugs at an older age (OR = 0.95; p < .001) were less likely to report NPS use. NPS use may be a marker of more severe using patterns in an offender sample. Future investigation should focus on NPS use as a possible method for bypassing drug testing measures.

Role of cannabis in cardiovascular disorders.

PubMed

Goyal, Hemant; Awad, Hamza H; Ghali, Jalal K

2017-07-01

The growing popularity of medical and recreational consumption of cannabis, especially among the youth, raises immediate concerns regarding its safety and long-terms effects. The cardiovascular effects of cannabis are not well known. Cannabis consumption has been shown to cause arrhythmia including ventricular tachycardia, and potentially sudden death, and to increase the risk of myocardial infarction (MI). These effects appear to be compounded by cigarette smoking and precipitated by excessive physical activity, especially during the first few hours of consumption. Cannabinoids, or the active compounds of cannabis, have been shown to have heterogeneous effects on central and peripheral circulation. Acute cannabis consumption has been shown to cause an increase in blood pressure, specifically systolic blood pressure (SBP), and orthostatic hypotension. Cannabis use has been reported to increase risk of ischemic stroke, particularly in the healthy young patients. The endocannabinoid system (ECS) is currently considered as a promising therapeutic target in the management of several disease conditions. Synthetic cannabinoids (SCs) are being increasingly investigated for their therapeutic effects; however, the value of their benefits over possible complications remains controversial. Despite the considerable research in this field, the benefits of cannabis and its synthetic derivatives remains questionable even in the face of an increasingly tolerating attitude towards recreational consumption and promotion of the therapeutic complications. More efforts are needed to increase awareness among the public, especially youth, about the cardiovascular risks associated with cannabis use and to disseminate the accumulated knowledge regarding its ill effects.

Optimization of recombinant β-glucuronidase hydrolysis and quantification of eight urinary cannabinoids and metabolites by liquid chromatography tandem mass spectrometry.

PubMed

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

2018-03-01

Prolonged urinary cannabinoid excretion in chronic frequent cannabis users confounds identification of recent cannabis intake that may be important in treatment, workplace, clinical, and forensic testing programs. In addition, differentiation of synthetic Δ9-tetrahydrocannabinol (THC) intake from cannabis plant products might be an important interpretive issue. THC, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) urine concentrations were evaluated during previous controlled cannabis administration studies following tandem alkaline/E. coli β-glucuronidase hydrolysis. We optimized recombinant β-glucuronidase enzymatic urinary hydrolysis before simultaneous liquid chromatography tandem mass spectrometry (LC-MS/MS) quantification of THC, 11-OH-THC, THCCOOH, cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin (THCV) and 11-nor-9-carboxy-THCV (THCVCOOH) in urine. Enzyme amount, incubation time and temperature, buffer molarity and pH were optimized using pooled urine samples collected during a National Institute on Drug Abuse, Institutional Review Board-approved clinical study. Optimized cannabinoid hydrolysis with recombinant β-glucuronidase was achieved with 2000 IU enzyme, 2 M pH 6.8 sodium phosphate buffer, and 0.2 mL urine at 37°C for 16 h. The LC-MS/MS quantification method for hydrolyzed urinary cannabinoids was validated per the Scientific Working Group on Toxicology guidelines. Linear ranges were 1-250 μg/L for THC and CBG, 2-250 μg/L for 11-OH-THC, CBD, CBN, THCV and THCVCOOH, and 1-500 μg/L for THCCOOH. Inter-batch analytical bias was 92.4-112.4%, imprecision 4.4-9.3% CV (n = 25), extraction efficiency 44.3-97.1% and matrix effect -29.6 to 1.8% (n = 10). The method was utilized to analyze urine specimens collected during our controlled smoked, vaporized, and edible cannabis administration study to improve interpretation of urine cannabinoid test results. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Impact of oral fluid collection device on cannabinoid stability following smoked cannabis.

PubMed

Anizan, Sébastien; Bergamaschi, Mateus M; Barnes, Allan J; Milman, Garry; Desrosiers, Nathalie; Lee, Dayong; Gorelick, David A; Huestis, Marilyn A

2015-02-01

Evaluation of cannabinoid stability in authentic oral fluid (OF) is critical, as most OF stability studies employed fortified or synthetic OF. Participants (n = 16) smoked a 6.8% delta-9-tetrahydrocannabinol (THC) cigarette, and baseline concentrations of THC, 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), and cannabinol (CBN) were determined within 24 h in 16 separate pooled samples (collected 1 h before to 10.5 or 13 h after smoking). OF was collected with the StatSure Saliva Sampler™ and Oral-Eze® devices. Oral-Eze samples were re-analyzed after room temperature (RT) storage for 1 week, and for both devices after 4 °C for 1 and 4 weeks, and -20 °C for 4 and 24 weeks. Concentrations ±20% from initial concentrations were considered stable. With the StatSure device, all cannabinoids were within 80-120% median %baseline for all storage conditions. Individual THC, CBD, CBN and THCCOOH pool concentrations were stable in 100%, 100%, 80-94% and >85%, respectively, across storage conditions. With the Oral-Eze device, at RT or refrigerated storage (for 1 and 4 weeks), THC, CBD and THCCOOH were stable in 94-100%, 78-89%, and 93-100% of samples, respectively, while CBN concentrations were 53-79% stable. However, after 24 weeks at -20 °C, stability decreased, especially for CBD, with a median of 56% stability. Overall, the collection devices' elution/stabilizing buffers provided good stability for OF cannabinoids, with the exception of the more labile CBN. To ensure OF cannabinoid concentration accuracy, these data suggest analysis within 4 weeks at 4 °C storage for Oral-Eze collection and within 4 weeks at 4 °C or 24 weeks at -20 °C for StatSure collection. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

PubMed Central

PACHER, PÁL; BÁTKAI, SÁNDOR; KUNOS, GEORGE

2008-01-01

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients’ need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy. PMID:16968947

Ischemic stroke after use of the synthetic marijuana "spice".

PubMed

Freeman, Melissa J; Rose, David Z; Myers, Martin A; Gooch, Clifton L; Bozeman, Andrea C; Burgin, W Scott

2013-12-10

To report and associate acute cerebral infarctions in 2 young, previously healthy siblings with use of the street drug known as "spice" (a synthetic marijuana product, also known as "K2"), which they independently smoked before experiencing acute embolic-appearing ischemic strokes. We present history, physical examination, laboratory data, cerebrovascular imaging, echocardiogram, ECG, and hospital course of these patients. We found that in both siblings spice was obtained from the same source. The drug was found to contain the schedule I synthetic cannabinoid JWH-018. Full stroke workup was unrevealing of a stroke etiology; urine drug screen was positive for marijuana. We found that our 2 patients who smoked the street drug spice had a temporal association with symptoms of acute cerebral infarction. This association may be confounded by contaminants in the product consumed (i.e., marijuana or an unidentified toxin) or by an unknown genetic mechanism. The imaging of both patients suggests an embolic etiology, which is consistent with reports of serious adverse cardiac events with spice use, including tachyarrhythmias and myocardial infarctions.

Cannabinoid facilitation of fear extinction memory recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Sripada, Chandra S.; Abelson, James L.; Liberzon, Israel; Milad, Mohammed R.; Phan, K. Luan

2012-01-01

A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. PMID:22796109

HU-446 and HU-465, Derivatives of the Non-psychoactive Cannabinoid Cannabidiol, Decrease the Activation of Encephalitogenic T Cells.

PubMed

Kozela, Ewa; Haj, Christeene; Hanuš, Lumir; Chourasia, Mukesh; Shurki, Avital; Juknat, Ana; Kaushansky, Nathali; Mechoulam, Raphael; Vogel, Zvi

2016-01-01

Cannabidiol (CBD), the non-psychoactive cannabinoid, has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8,9-dihydro-7-hydroxy-CBD; HU-446) and of synthetic (+)-CBD ((+)-8,9-dihydro-7-hydroxy-CBD; HU-465) on activated myelin oligodendrocyte glycoprotein (MOG)35-55-specific mouse encephalitogenic T cells (T(MOG) ) driving EAE/MS-like pathologies. Binding assays followed by molecular modeling revealed that HU-446 has negligible affinity toward the cannabinoid CB1 and CB2 receptors while HU-465 binds to both CB1 and CB2 receptors at the high nanomolar concentrations (Ki = 76.7 ± 5.8 nm and 12.1 ± 2.3 nm, respectively). Both, HU-446 and HU-465, at 5 and 10 μm (but not at 0.1 and 1 μm), inhibited the MOG35-55-induced proliferation of autoreactive T(MOG) cells via CB1/CB2 receptor independent mechanisms. Moreover, both HU-446 and HU-465, at 5 and 10 μm, inhibited the release of IL-17, a key autoimmune cytokine, from MOG35-55-stimulated T(MOG) cells. These results suggest that HU-446 and HU-465 have anti-inflammatory potential in inflammatory and autoimmune diseases. © 2015 John Wiley & Sons A/S.

Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease.

PubMed

Badal, S; Smith, K N; Rajnarayanan, R

2017-12-01

The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB 1 than CB 2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB 2 selective affinity; the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB 1 antagonist, Rimonabant was pulled from commercial markets for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules. Copyright © 2017 Elsevier Inc. All rights reserved.

High-resolution mass spectrometric metabolite profiling of a novel synthetic designer drug, N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (STS-135) using cryopreserved human hepatocytes and assessment of metabolic stability with human liver microsomes

PubMed Central

Gandhi, Adarsh S.; Wohlfarth, Ariane; Zhu, Mingshe; Pang, Shaokun; Castaneto, Marisol; Scheidweiler, Karl B.; Huestis, Marilyn A.

2014-01-01

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (STS-135) is a new synthetic cannabinoid in herbal incense products discussed on internet drug user forums and identified in police seizures. To date, there are no STS-135 clinical or in vitro studies identifying STS-135 metabolic profiles. However, characterizing STS-135 metabolism is critical because synthetic cannabinoid metabolites can possess pharmacological activity and parent compounds are rarely detectable in urine. To characterize the metabolite profile, human hepatocytes were incubated with 10 μmol/L STS-135 for up to 3 h. High-resolution mass spectrometry with software-assisted data mining identified 29 STS-135 metabolites. Less than 25% of STS-135 parent compound remained after 3 h incubation. Primary metabolites were generated by mono-, di- or trihydroxylation with and without ketone formation, dealkylation and oxidative defluorination of N-fluoropentyl side chain or possible oxidation to carboxylic acid, some of them further glucuronidated. Hydroxylations occurred mainly on the aliphatic adamantane ring and less commonly on the N-pentyl side chain. At 1 h phase I metabolites predominated, while at 3 h phase II metabolites were present in higher amounts. The major metabolites were monohydroxy STS-135 (M25) and dihydroxy STS-135 (M21), both hydroxylated on the adamantane system. Moreover, metabolic stability of STS-135 (1 μmol/L) was assessed in human liver microsomes experiments. The in vitro half-life of STS-135 was 7.2±0.6 min and intrinsic clearance (CLint) was 93.6 mL·min−1·kg−1. This is the first report characterizing STS-135 hepatic metabolic pathways. These data provide potential urinary targets to document STS-135 intake in clinical and forensic settings and potential candidates for pharmacological testing. PMID:24827428

CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations.

PubMed

Basavarajappa, Balapal S; Subbanna, Shivakumar

2014-02-01

Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as "Spice" or "K2" to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of "Spice/K2", including JWH-081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH-081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of JWH-081 on pCaMKIV, pCREB, and pERK1/2 signaling events followed by long-term potentiation (LTP), hippocampal-dependent learning and memory tasks using CB1 receptor wild-type (WT) and knockout (KO) mice. Acute administration of JWH-081 impaired CaMKIV phosphorylation in a dose-dependent manner, whereas inhibition of CREB phosphorylation in CB1 receptor WT mice was observed only at higher dose of JWH-081 (1.25 mg/kg). JWH-081 at higher dose impaired CaMKIV and CREB phosphorylation in a time-dependent manner in CB1 receptor WT mice but not in KO mice and failed to alter ERK1/2 phosphorylation. In addition, SR treated or CB1 receptor KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio compared with vehicle or WT littermates. In hippocampal slices, JWH-081 impaired LTP in CB1 receptor WT but not in KO littermates. Furthermore, JWH-081 at higher dose impaired object recognition, spontaneous alternation and spatial memory on the Y-maze in CB1 receptor WT mice but not in KO mice. Collectively our findings suggest that deleterious effects of JWH-081 on hippocampal function involves CB1 receptor mediated impairments in CaMKIV and CREB phosphorylation, LTP, learning and memory in mice. © 2013 Wiley Periodicals, Inc.

Cannabis in the Treatment of Dystonia, Dyskinesias, and Tics.

PubMed

Koppel, Barbara S

2015-10-01

Cannabis has been used for many medicinal purposes, including management of spasms, dystonia, and dyskinesias, with variable success. Its use for tetanus was described in the second century BCE, but the literature continues to include more case reports and surveys of its beneficial effects in managing symptoms of hyperkinetic movement disorders than randomized controlled trials, making evidence-based recommendations difficult. This paper reviews clinical research using various formulations of cannabis (botanical products, oral preparations containing ∆(9)-tetrahydrocannabinol and/or cannabidiol) and currently available preparations in the USA (nabilone and dronabinol). This has been expanded from a recent systematic review of cannabis use in several neurologic conditions to include case reports and case series and results of anonymous surveys of patients using cannabis outside of medical settings, with the original evidence classifications marked for those papers that followed research protocols. Despite overlap in some patients, dyskinesias will be treated separately from dystonia and chorea; benefit was not established beyond individual patients for these conditions. Tics, usually due to Tourettes, did respond to cannabis preparations. Side effects reported in the trials will be reviewed but those due to recreational use, including the dystonia that can be secondary to synthetic marijuana preparations, are outside the scope of this paper.

Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2.

PubMed

Lisboa, Sabrina Francesca; Niraula, Anzela; Resstel, Leonardo Barbosa; Guimaraes, Francisco Silveira; Godbout, Jonathan P; Sheridan, John F

2018-04-17

Psychosocial stress contributes to the development of psychiatric disorders. Repeated social defeat (RSD) is a murine stressor that causes a release of inflammatory monocytes into circulation. Moreover, RSD-induced anxiety-like behavior is dependent on the recruitment of these monocytes to the brain. Activation of the endocannabinoid (ECB) system may modulate both neuroendocrine and inflammatory responses mediated by stress. Therefore, we hypothesized that a cannabinoid receptor agonist would attenuate RSD-induced inflammation, anxiety, and stress sensitization. To test this hypothesis, mice received an injection of the synthetic cannabinoid 1/2 receptor agonist, WIN55,212-2 (WIN; 1 mg/kg, intraperitoneally) daily for six consecutive days, 30 min before each exposure to RSD. Anxiety-like behavior, immune activation, neuroinflammation, and microglial reactivity were determined 14 h after RSD. RSD-induced anxiety-like behavior in the open field and in the EPM was reversed by WIN55,212-2. Moreover, WIN55,212-2 reduced the accumulation of inflammatory monocytes in circulation and brain after RSD and attenuated RSD-induced interleukin-1β (IL-1β) messenger RNA (mRNA) expression in microglia/macrophages. Increased ex vivo reactivity of microglia/monocytes to lipopolysaccharides (LPS) after RSD was also attenuated by WIN55,212-2. Next, fear expression, extinction, and recall were evaluated 24 and 48 h, respectively, after contextual fear conditioning, which took place 7 days after RSD. Here, RSD caused prolonged fear expression and impaired fear extinction recall, which was associated with increased IL-1β mRNA in the brain. Moreover, these stress-induced effects were reversed by WIN55,212-2. In conclusion, activation of cannabinoid receptors limited the immune and neuroinflammatory responses to RSD and reversed the short-term and long-term behavioral deficits associated with RSD.

The impact of Australian legislative changes on synthetic cannabinoid exposures reported to the New South Wales Poisons Information Centre.

PubMed

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

2017-05-01

The emergence of new psychoactive substances (NPS), including synthetic cannabinoid receptor agonists (SCRAs) poses novel challenges for drug regulation and public health. Misconceptions of safety and legality, coupled with the fact that NPS are undetectable on routine drugs screens contributes to their popularity. Concerns over the unpredictable toxicity and abuse potential of NPS has led to a variety of legislative responses worldwide. We wish to describe Australian trends in SCRA use, examining the effects of legislative changes on calls to Australia's largest poisons centre. A retrospective review of calls to the New South Wales Poisons Information Centre (NSWPIC). Cases occurring between 1 January 2010 and 30 June 2015 with documented use of SCRAs were included. There were 146 exposures to SCRAs recorded in the NSWPIC database. Federal bans of specific SCRA compounds in 2011/2012 had little impact on call volumes. State-based legislation introduced in 2013 banning specific brand names of SCRA products was followed by a dramatic, sustained decrease in exposures. The most common symptoms reported with SCRA use were tachycardia, vomiting, drowsiness, anxiety/panic, decreased level of consciousness, chest pain, agitation, hallucinations, confusion, seizures and hypertension. Banning of specific brand names of SCRA (timed with raids and social media campaigns) appears effective at reducing SCRA exposures. We postulate that this raised awareness within the community of the illegality of these substances while also reducing supply through bricks-and-mortar shops. These results could help inform future legislative responses. Copyright © 2017 Elsevier B.V. All rights reserved.

Immunoassay screening in urine for synthetic cannabinoids - an evaluation of the diagnostic efficiency.

PubMed

Franz, Florian; Angerer, Verena; Jechle, Hanna; Pegoro, Melanie; Ertl, Harald; Weinfurtner, Georg; Janele, David; Schlögl, Christian; Friedl, Matthias; Gerl, Stefan; Mielke, Reinhard; Zehnle, Ralf; Wagner, Matthias; Moosmann, Bjoern; Auwärter, Volker

2017-08-28

The abuse of synthetic cannabinoids (SCs) as presumed legal alternative to cannabis poses a great risk to public health. For economic reasons many laboratories use immunoassays (IAs) to screen for these substances in urine. However, the structural diversity and high potency of these designer drugs places high demands on IAs regarding cross-reactivity of the antibodies used and detection limits. Two retrospective studies were carried out in order to evaluate the capability of two homogenous enzyme IAs for the detection of currently prevalent SCs in authentic urine samples. Urine samples were analyzed utilizing a 'JWH-018' kit and a 'UR-144' kit. The IA results were confirmed by an up-to-date liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) screening method covering metabolites of 45 SCs. The first study (n=549) showed an 8% prevalence of SCs use (LC-MS/MS analysis) among inpatients of forensic-psychiatric clinics, whereas all samples were tested negative by the IAs. In a second study (n=200) the combined application of both IAs led to a sensitivity of 2% and a diagnostic accuracy of 51% when applying the recommended IA cut-offs. Overall, 10 different currently prevalent SCs were detected in this population. The results can be explained by an insufficient cross-reactivity of the antibodies towards current SCs in combination with relatively high detection limits of the IAs. In light of the presented study data it is strongly recommended not to rely on the evaluated IA tests for SCs in clinical or forensic settings. For IA kits of other providers similar results can be expected.

Advancing the Use of Emergency Department Syndromic Surveillance Data, New York City, 2012-2016.

PubMed

Lall, Ramona; Abdelnabi, Jasmine; Ngai, Stephanie; Parton, Hilary B; Saunders, Kelly; Sell, Jessica; Wahnich, Amanda; Weiss, Don; Mathes, Robert W

The use of syndromic surveillance has expanded from its initial purpose of bioterrorism detection. We present 6 use cases from New York City that demonstrate the value of syndromic surveillance for public health response and decision making across a broad range of health outcomes: synthetic cannabinoid drug use, heat-related illness, suspected meningococcal disease, medical needs after severe weather, asthma exacerbation after a building collapse, and Ebola-like illness in travelers returning from West Africa. The New York City syndromic surveillance system receives data on patient visits from all emergency departments (EDs) in the city. The data are used to assign syndrome categories based on the chief complaint and discharge diagnosis, and analytic methods are used to monitor geographic and temporal trends and detect clusters. For all 6 use cases, syndromic surveillance using ED data provided actionable information. Syndromic surveillance helped detect a rise in synthetic cannabinoid-related ED visits, prompting a public health investigation and action. Surveillance of heat-related illness indicated increasing health effects of severe weather and led to more urgent public health messaging. Surveillance of meningitis-related ED visits helped identify unreported cases of culture-negative meningococcal disease. Syndromic surveillance also proved useful for assessing a surge of methadone-related ED visits after Superstorm Sandy, provided reassurance of no localized increases in asthma after a building collapse, and augmented traditional disease reporting during the West African Ebola outbreak. Sharing syndromic surveillance use cases can foster new ideas and build capacity for public health preparedness and response.

Study of magnetization switching for MRAM based memory technologies

NASA Astrophysics Data System (ADS)

Pham, Huy

Amphibian alkaloids are attractive targets for synthesis due to their biological activity. An important class of amphibian alkaloids is the 2,5-disubstituted pyrrolidine-based family of compounds. There are many synthetic approaches for the preparation of the trans-2,5-disubstituted pyrrolidines, but methods for the construction of the cis-2,5-pyrrolidines are limited. Therefore, it was desired to develop an enantioselective approach for the preparation of cis-2,5-disubsituted pyrrolidines. (+)-Tropin-2-one derived from cocaine was used as starting material to exploit the inherent stereochemistry for construction of the cis-pyrrolidine ring. This permitted the unequivocal assignment of the absolute configuration of the target pyrrolidine. The structurally simple pyrrolidine alkaloid, 225H, was selected as a target to develop a general synthetic approach. The enantioselective synthesis of 225H was achieved in nine steps and good overall yield. The search for potent cannabinoid receptor partial agonist ligands as potential marijuana addiction therapeutic agents has led to an investigation of the synthesis of diaryl ether hybrid analogues of BAY 59-3074. A series of 2-(3-alkyl-5-hydroxyphenoxy)-6-(trifluoromethyl)benzonitriles, 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenylalkanoates, and (3-(benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitriles were synthesized and evaluated in vitro for CB1 affinity. The olivetol diaryl ether analogue was the most potent ligand of the alkyl series, but the diaryl ester analogues exhibited modest affinity for CB1 receptors. The most potent compound of the series was the 2-(3-(benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitrile. Keywords. amphibian alkaloids, enantioselective synthesis, pyrrolidine, cannabinoid receptor, marijuana.

Synthetic cannabis: a comparison of patterns of use and effect profile with natural cannabis in a large global sample.

PubMed

Winstock, Adam R; Barratt, Monica J

2013-07-01

The last decade has seen the appearance of myriad novel psychoactive substances with diverse effect profiles. Synthetic cannabinoids are among the most recently identified but least researched of these substances. An anonymous online survey was conducted in 2011 using a quantitative structured research tool. Missing data (median 2%) were treated by available-case analysis. Of 14,966 participants, 2513 (17%) reported use of synthetic cannabis. Of these, 980 (41% of 2417) reported its use in the last 12 months. Almost all recent synthetic cannabis users (99% of 975) reported ever use of natural cannabis. Synthetic cannabis reportedly had both a shorter duration of action (z=17.82, p<.001) and quicker time to peak onset of effect (z=-9.44, p<.001) than natural cannabis. Natural cannabis was preferred to synthetic cannabis by 93% of users, with natural cannabis rated as having greater pleasurable effects when high (t(930)=-37.1, p<.001, d=-1.22) and being more able to function after use (t(884)=-13.3, p<.001, d=-0.45). Synthetic cannabis was associated with more negative effects (t(859)=18.7, p<.001, d=0.64), hangover effects (t(854)=6.45, p<.001, d=0.22) and greater paranoia (t(889)=7.91, p<.001, d=0.27). Users report a strong preference for natural over synthetic cannabis. The latter has a less desirable effect profile. Further research is required to determine longer term consequences of use and comparative dependence potential. Copyright © 2013. Published by Elsevier Ireland Ltd.

Ischemic stroke after use of the synthetic marijuana “spice”

PubMed Central

Freeman, Melissa J.; Rose, David Z.; Myers, Martin A.; Gooch, Clifton L.; Bozeman, Andrea C.

2013-01-01

Objectives: To report and associate acute cerebral infarctions in 2 young, previously healthy siblings with use of the street drug known as “spice” (a synthetic marijuana product, also known as “K2”), which they independently smoked before experiencing acute embolic-appearing ischemic strokes. Methods: We present history, physical examination, laboratory data, cerebrovascular imaging, echocardiogram, ECG, and hospital course of these patients. Results: We found that in both siblings spice was obtained from the same source. The drug was found to contain the schedule I synthetic cannabinoid JWH-018. Full stroke workup was unrevealing of a stroke etiology; urine drug screen was positive for marijuana. Conclusions: We found that our 2 patients who smoked the street drug spice had a temporal association with symptoms of acute cerebral infarction. This association may be confounded by contaminants in the product consumed (i.e., marijuana or an unidentified toxin) or by an unknown genetic mechanism. The imaging of both patients suggests an embolic etiology, which is consistent with reports of serious adverse cardiac events with spice use, including tachyarrhythmias and myocardial infarctions. PMID:24212384

An Expanding World of Novel Psychoactive Substances: Opioids

PubMed Central

Zawilska, Jolanta B.

2017-01-01

The abuse of novel psychoactive substances (NPS) has been increasing dramatically worldwide since late 2000s. By the end of 2015, more than 560 NPS had been reported to the European Monitoring Centre for Drugs and Drug Addiction. Although the most popular compounds are synthetic cannabinoids and psychostimulatory derivatives of cathinone (so-called β-keto-amphetamines), novel synthetic opioids have recently emerged on the recreational drug market. They include fentanyl (a potent narcotic analgesic) and its analogs (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, α-methylfentanyl, 3-methylfentanyl, furanylfentanyl, 4-fluorobutyrylfentanyl, 4-methoxybutyrylfentanyl, 4-chloroisobutyrylfentanyl, 4-fluoroisobutyrylfentanyl, tetrahydrofuranylfentanyl, cyclopentylfentanyl, and ocfentanil) and compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. This survey provides an overview of the pharmacological properties, pattern of use, and desired and unwanted effects of the above-listed novel opioids. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds. PMID:28713291

Pharmacology, signaling and physiological relevance of the G protein-coupled receptor 55.

PubMed

Balenga, Nariman A B; Henstridge, Christopher M; Kargl, Julia; Waldhoer, Maria

2011-01-01

According to The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), ∼70 million European adults have consumed cannabis on at least one occasion. Cannabis consumption leads to a variety of psychoactive effects due to the presence of the constituent Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Δ(9)-THC interacts with the endocannabinoid system (ECS), which consists of the seven transmembrane spanning (7TM)/G protein-coupled receptors (GPCRs) CB(1) and CB(2), their respective ligands (endocannabinoids), and enzymes involved in their biosynthesis and degradation. This system plays a critical role in many physiological processes such as learning and memory, appetite control, pain sensation, motor coordination, lipogenesis, modulation of immune response, and the regulation of bone mass. Therefore, a huge effort has been spent trying to fully elucidate the composition and function of the ECS. The G protein-coupled receptor 55 (GPR55) was recently proposed as a novel component of this system; however, its classification as a cannabinoid receptor has been significantly hampered by its complex pharmacology, signaling, and cellular function. GPR55 is phylogenetically distinct from the traditional cannabinoid receptors, but in some experimental paradigms, it is activated by endocannabinoids, phytocannabinoids, and synthetic cannabinoid ligands. However, the most potent compound appears to be a lysophospholipid known as lysophosphatidylinositol (LPI). Here, we provide a comprehensive evaluation of the current pharmacology and signaling of GPR55 and review the proposed role of this receptor in a number of physiological and pathophysiological processes. Copyright © 2011 Elsevier Inc. All rights reserved.

Kronic hysteria: exploring the intersection between Australian synthetic cannabis legislation, the media, and drug-related harm.

PubMed

Bright, Stephen J; Bishop, Brian; Kane, Robert; Marsh, Ali; Barratt, Monica J

2013-05-01

Having first appeared in Europe, synthetic cannabis emerged as a drug of concern in Australia during 2011. Kronic is the most well-known brand of synthetic cannabis in Australia and received significant media attention. Policy responses were reactive and piecemeal between state and federal governments. In this paper we explore the relationship between media reports, policy responses, and drug-related harm. Google search engine applications were used to produce time-trend graphs detailing the volume of media stories being published online about synthetic cannabis and Kronic, and also the amount of traffic searching for these terms. A discursive analysis was then conducted on those media reports that were identified by Google as 'key stories'. The timing of related media stories was also compared with self-reported awareness and month of first use, using previously unpublished data from a purposive sample of Australian synthetic cannabis users. Between April and June 2011, mentions of Kronic in the media increased. The number of media stories published online connected strongly with Google searches for the term Kronic. These stories were necessarily framed within dominant discourses that served to construct synthetic cannabis as pathogenic and created a 'moral panic'. Australian state and federal governments reacted to this moral panic by banning individual synthetic cannabinoid agonists. Manufacturers subsequently released new synthetic blends that they claimed contained new unscheduled chemicals. Policies implemented within in the context of 'moral panic', while well-intended, can result in increased awareness of the banned product and the use of new yet-to-be-scheduled drugs with unknown potential for harm. Consideration of regulatory models should be based on careful examination of the likely intended and unintended consequences. Such deliberation might be limited by the discursive landscape. Copyright © 2012 Elsevier B.V. All rights reserved.

Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants

PubMed Central

Miliano, Cristina; Serpelloni, Giovanni; Rimondo, Claudia; Mereu, Maddalena; Marti, Matteo; De Luca, Maria Antonietta

2016-01-01

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds. PMID:27147945

Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes.

PubMed

Diao, Xingxing; Scheidweiler, Karl B; Wohlfarth, Ariane; Zhu, Mingshe; Pang, Shaokun; Huestis, Marilyn A

Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. It is much more challenging to confirm a specific isomer's intake and distinguish it from its structural analog because the isomers and their major metabolites usually have identical molecular weights and display the same product ions. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to distinguish their consumption. THJ-2201 was scheduled in the US, Japan, and Europe; however, FUBIMINA is easily available on the Internet. We previously investigated THJ-2201 metabolism in human hepatocytes, but human FUBIMINA metabolism is unknown. We aim to characterize FUBIMINA metabolism in human hepatocytes, recommend optimal metabolites to confirm its consumption, and propose strategies to distinguish between intakes of FUBIMINA and THJ-2201. FUBIMINA (10 μM) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS). We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. We recommend 5'-OH-BIM-018 (M34), BIM-018 pentanoic acid (M33), and BIM-018 pentanoic acid dihydrodiol (M7) as FUBIMINA specific metabolites. THJ-2201 produced specific metabolite markers 5'-OH-THJ-018 (F26), THJ-018 pentanoic acid (F25), and hydroxylated THJ-2201 (F13). Optimized chromatographic conditions to achieve different retention times and careful selection of specific product ion spectra enabled differentiation of isomeric metabolites, in this case FUBIMINA from THJ-2201. Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.

[Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

PubMed

Goullé, Jean-Perre; Guerbet, Michel

2014-03-01

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

A preliminary evaluation of synthetic cannabinoid use among adolescent cannabis users: Characteristics and treatment outcomes.

PubMed

Blevins, Claire E; Banes, Kelsey E; Stephens, Robert S; Walker, Denise D; Roffman, Roger A

2016-12-01

Little is known regarding the use of synthetic cannabinoids (SC), particularly use among adolescent substance users who may be at higher risk. The present exploratory study seeks to describe SC use and subjective effects among cannabis-using adolescents as well as compare the characteristics of cannabis users who do and do not use SC. Exploratory analyses evaluated cannabis treatment outcomes among SC users and non-users. Participants enrolled in a randomized, controlled intervention for cannabis-using high school students aged 14-19 (N=252) completed questionnaires regarding their use of SC and other substances. Those who used SC in the past 60days reported subjective effects of SC, consequences, and SC use disorder symptoms. Baseline characteristics, alcohol and other drug use, and treatment outcomes of SC users were compared to participants who never tried SC. Within this sample 29% had tried SC, and 6% used SC recently. Although most reported use at a relatively low rate, 43% of recent SC users reported SC use-disorder symptoms. Positive and negative subjective effects of SC were endorsed, with positive subjective effects reported more often. SC use was associated with more cannabis use, but not more alcohol or other (non-SC and non-cannabis) drug use. SC users did not differ from non-users on cannabis treatment outcomes. This exploratory study described SC use, and compared characteristics and treatment outcomes among SC users and non-users. Negative subjective effects of SC were reported as occurring less often, but SC use was associated with use disorder psychopathology. SC use was associated with more problematic cannabis use at baseline, but was not associated with use of other substances or differences in treatment outcome. Copyright © 2016 Elsevier Ltd. All rights reserved.

Suspected synthetic cannabinoid toxicosis in a dog.

PubMed

Williams, Keysa; Wells, Raegan J; McLean, Mary Kay

2015-01-01

To describe the effects of suspected synthetic cannabinoid (SC) toxicosis and the response to intravenous lipid emulsion (ILE) therapy in a dog. A 2-year-8-month-old male Boxer dog was evaluated at an emergency hospital for progressive ataxia and inappropriate mentation. The initial physical examination identified marked hypothermia (32.7°C [90.9°F]), intermittent sinus bradycardia (60/min), stuporous mentation with intermittent aggression, and severe ataxia. Neurologic status deteriorated to comatose mentation within 2 hours of presentation. The initial diagnostic evaluation (eg, CBC, serum biochemistry profile, venous blood gas, and electrolyte determination) revealed a respiratory acidosis and thrombocytopenia. The owner reported that the dog was exposed to an SC containing Damiana leaf, Marshmallow leaf, and Athaea leaves. Initial treatment included IV fluids and supplemental oxygen. Mechanical ventilation was provided due to hypoventilation and periods of apnea. Intravenous lipid emulsion therapy was administered as a bolus (1.5 mL/kg) and continued as a continuous rate infusion (0.5 mL/kg/h) for a total of 6 hours. The dog became rousable and was weaned from mechanical ventilation approximately 15 hours following presentation. The dog was eating and walking with no ataxia, had a normal mentation at approximately 33 hours following presentation, and was discharged home at that time. Communication with the owners 5 days following discharge revealed that the dog was apparently normal. Based on this case and other reports in the literature regarding human exposures, SC ingestion may result in more severe clinical signs than marijuana ingestion in dogs. Significant clinical intervention may be necessary. Intravenous lipid emulsion treatment may be beneficial due to the lipophilicity of SC. © Veterinary Emergency and Critical Care Society 2015.

Scheduled multiple reaction monitoring algorithm as a way to analyse new designer drugs combined with synthetic cannabinoids in human serum with liquid chromatography-tandem mass spectrometry.

PubMed

Dziadosz, Marek; Weller, Jens-Peter; Klintschar, Michael; Teske, Jörg

2013-06-15

Here, we describe the development and application of a liquid chromatography-tandem mass spectrometry method with positive electrospray ionisation and scheduled multiple reaction monitoring algorithm (s-MRM) to analyse synthetic cannabinoids (SC) combined with new designer drugs (NDD) in human serum. A Luna 5μm C18 (2) 100A, 150mm×2mm analytical column and a mobile phase consisted of A (H2O/methanol=95/5, v/v) and B (H2O/methanol=3/97, v/v) - both with 10mM ammonium acetate and 0.1% acetic acid (pH=3.2), were used for the separation. A binary flow pumping mode with a total flow rate of 0.400mL/min was used. A single sample extraction with 1-chlorobutane for both substance groups was performed. Acceptable linearity in the validated calibration ranges of 0.05-1ng/mL for SC and 1-50ng/mL for NDD was achieved. The limit of detection was not greater than 0.02/0.40ng/mL and the limit of quantification not greater than 0.05/0.50ng/mL for SC/NDD respectively. The presented study revealed that this method is a very effective way for sensitive SC and NDD identification in human serum and has useful application in hospitals, therapy centres and forensic psychiatric centres. S-MRM ensures a method upgrade with a smaller loss of sensitivity, precision and accuracy in comparison to traditional MRM methods. Also addition of new SC and NDD can be performed in the future. Copyright © 2013 Elsevier B.V. All rights reserved.

Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans.

PubMed

Reis Rodrigues, Pedro; Kaul, Tiffany K; Ho, Jo-Hao; Lucanic, Mark; Burkewitz, Kristopher; Mair, William B; Held, Jason M; Bohn, Laura M; Gill, Matthew S

2016-06-01

Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB) receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans. Copyright © 2016 Rodrigues et al.

Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans

PubMed Central

Reis Rodrigues, Pedro; Kaul, Tiffany K.; Ho, Jo-Hao; Lucanic, Mark; Burkewitz, Kristopher; Mair, William B.; Held, Jason M.; Bohn, Laura M.; Gill, Matthew S.

2016-01-01

Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB) receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans. PMID:27172180

Multi-class analysis of new psychoactive substances and metabolites in hair by pressurized liquid extraction coupled to HPLC-HRMS.

PubMed

Montesano, Camilla; Vannutelli, Gabriele; Massa, Maristella; Simeoni, Maria Chiara; Gregori, Adolfo; Ripani, Luigi; Compagnone, Dario; Curini, Roberta; Sergi, Manuel

2017-05-01

In this paper, an analytical method has been developed and validated for the analysis of new psychoactive substances (NPS) and metabolites in hair samples. The method was based on pressurized liquid extraction (PLE) followed by solid-phase extraction (SPE) clean-up and high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) analysis. To evaluate extraction efficiency and the applicability of the method, hair samples were fortified by soaking in order to obtain a good surrogate for drug users' hair; the amount of incorporated drugs related to their lipophilicity, similarly to in vivo drug incorporation. To the best of our knowledge, this is the first method that allowed for the analysis of both cathinones (5) and synthetic cannabinoids (7) in hair with a single extraction procedure and chromatographic run. A phenethylamine (2C-T-4), 4- fluorophenylpiperazine and methoxetamine were also included showing that PLE coupled to SPE clean-up was suitable for a multi-class analysis of NPS in hair. In addition, the use of PLE significantly reduced hair analysis time: decontamination, incubation, clean-up, and liquid chromatography-mass spectrometry (LC-MS) analysis were carried out in approximately 45 min. The method was fully validated according to Scientific Working Group for Forensic Toxicology (SWGTOX) and Society of Hair Testing (SoHT) guidelines. Limit of quantification (LOQ) values ranged from 8 to 50 pg mg -1 for cathinones, phenetylamines and piperazines, and from 9 to 40 pg mg -1 for synthetic cannabinoids (10 pg mg -1 for methoxetamine). Matrix effects were below 15% for all the analytes, demonstrating the effectiveness of the clean-up step. Inaccuracy was lower than 9% in terms of bias. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22.

PubMed

Diao, Xingxing; Scheidweiler, Karl B; Wohlfarth, Ariane; Pang, Shaokun; Kronstrand, Robert; Huestis, Marilyn A

2016-03-01

In 2014, FDU-PB-22 and FUB-PB-22, two novel synthetic cannabinoids, were detected in herbal blends in Japan, Russia, and Germany and were quickly added to their scheduled drugs list. Unfortunately, no human metabolism data are currently available, making it challenging to confirm their intake. The present study aims to identify appropriate analytical markers by investigating FDU-PB-22 and FUB-PB-22 metabolism in human hepatocytes and confirm the results in authentic urine specimens. For metabolic stability, 1 μM FDU-PB-22 and FUB-PB-22 was incubated with human liver microsomes for up to 1 h; for metabolite profiling, 10 μM was incubated with human hepatocytes for 3 h. Two authentic urine specimens from FDU-PB-22 and FUB-PB-22 positive cases were analyzed after β-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Both FDU-PB-22 and FUB-PB-22 were rapidly metabolized in HLM with half-lives of 12.4 and 11.5 min, respectively. In human hepatocyte samples, we identified seven metabolites for both compounds, generated by ester hydrolysis and further hydroxylation and/or glucuronidation. After ester hydrolysis, FDU-PB-22 and FUB-PB-22 yielded the same metabolite M7, fluorobenzylindole-3-carboxylic acid (FBI-COOH). M7 and M6 (hydroxylated FBI-COOH) were the major metabolites. In authentic urine specimens after β-glucuronidase hydrolysis, M6 and M7 also were the predominant metabolites. Based on our study, we recommend M6 (hydroxylated FBI-COOH) and M7 (FBI-COOH) as suitable urinary markers for documenting FDU-PB-22 and/or FUB-PB-22 intake.

Issues with monitoring the safety of psychoactive products under a legal regulated market for new psychoactive substances ('legal highs') in New Zealand.

PubMed

Rychert, Marta; Wilkins, Chris; Witten, Karen

2017-09-01

New Zealand's Psychoactive Substances Act (2013) established the world's first regulated market for 'low risk' psychoactive products ('legal highs'). Under an interim PSA regime, 47 existing products were permitted to be continued to be sold. To explore issues with the implementation of regulatory systems to monitor the safety of products on the legal market under the interim Psychoactive Substances Act regime. Semi-structured interviews with 30 key stakeholders, including industry, government agency, health and drug service professionals were conducted, transcribed and analysed thematically. In retrospect stakeholders questioned the decision to approve strong synthetic cannabinoid smoking products, noting their health risks because of product formulation, inconsistent manufacturing practices and smoking as the means of administration. Industry actors claimed the decision to approve synthetic cannabinoid smokeable products prevented potentially safer products from gaining market share. The system for withdrawing approved products which were subsequently found to be harmful was criticised for the poor quality of data available, limited engagement with health professionals and the slowness of product withdrawal. Many of the problems with the regime were attributed to the urgency under which the legal market under the interim Psychoactive Substances Act was established and implemented. The selection of 'safer' products, implementation of the product monitoring system, and engagement with health professionals may have benefited from more time and resources. An incremental approach to establishing the new market may have made the regulatory management of the new regime more workable. [Rychert M, Wilkins C, Witten K. Issues with monitoring the safety of psychoactive products under a legal regulated market for new psychoactive substances ('legal highs') in New Zealand. Drug Alcohol Rev 2017;00:000-000]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

Distribution of Synthetic Cannabinoids JWH-210, RCS-4 and ∆ 9-Tetrahydrocannabinol After Intravenous Administration to Pigs

PubMed Central

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

2017-01-01

Background: Synthetic cannabinoids (SCs) have become an increasing issue in forensic toxicology. Controlled human studies evaluating pharmacokinetic data of SCs are lacking and only few animal studies have been published. Thus, an interpretation of analytical results found in intoxicated or poisoned individuals is difficult. Therefore, the distribution of two selected SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) as well as ∆9-tetrahydrocannabinol (THC) as reference were examined in pigs. Methods: Pigs (n = 6 per drug) received a single intravenous 200 µg/kg BW dose of JWH-210, RCS-4, or THC. Six hours after administration, the animals were exsanguinated and relevant organs, important body fluids such as bile, and tissues such as muscle and adipose tissue, as well as the bradytrophic specimens dura and vitreous humor were collected. After hydrolysis and solid phase extraction, analysis was performed by LC-MS/MS. To overcome matrix effects of the LC-MS/MS analysis, a standard addition method was applied for quantification. Results: The parent compounds could be detected in every analyzed specimen with the exception of THC that was not present in dura and vitreous humor. Moderate concentrations were present in brain, the site of biological effect. Metabolite concentrations were highest in tissues involved in metabolism and/or elimination. Conclusions: Besides kidneys and lungs routinely analyzed in postmortem toxicology, brain, adipose, and muscle tissue could serve as alternative sources, particularly if other specimens are not available. Bile fluid is the most appropriate specimen for SCs and THC metabolites detection. PMID:27834143

Distribution of Synthetic Cannabinoids JWH-210, RCS-4 and Δ 9-Tetrahydrocannabinol After Intravenous Administration to Pigs.

PubMed

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

2017-01-01

Synthetic cannabinoids (SCs) have become an increasing issue in forensic toxicology. Controlled human studies evaluating pharmacokinetic data of SCs are lacking and only few animal studies have been published. Thus, an interpretation of analytical results found in intoxicated or poisoned individuals is difficult. Therefore, the distribution of two selected SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1- pentyl-indol-3-yl)methanone (RCS-4) as well as Δ9-tetrahydrocannabinol (THC) as reference were examined in pigs. Pigs (n = 6 per drug) received a single intravenous 200 μg/kg BW dose of JWH-210, RCS- 4, or THC. Six hours after administration, the animals were exsanguinated and relevant organs, important body fluids such as bile, and tissues such as muscle and adipose tissue, as well as the bradytrophic specimens dura and vitreous humor were collected. After hydrolysis and solid phase extraction, analysis was performed by LC-MS/MS. To overcome matrix effects of the LC-MS/MS analysis, a standard addition method was applied for quantification. The parent compounds could be detected in every analyzed specimen with the exception of THC that was not present in dura and vitreous humor. Moderate concentrations were present in brain, the site of biological effect. Metabolite concentrations were highest in tissues involved in metabolism and/or elimination Conclusions: Besides kidneys and lungs routinely analyzed in postmortem toxicology, brain, adipose, and muscle tissue could serve as alternative sources, particularly if other specimens are not available. Bile fluid is the most appropriate specimen for SCs and THC metabolites detection. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Detection of metabolites of the new synthetic cannabinoid CUMYL-4CN-BINACA in authentic urine samples and human liver microsomes using high-resolution mass spectrometry.

PubMed

Öztürk, Yeter Erol; Yeter, Oya; Öztürk, Serkan; Karakus, Goksun; Ates, Ismail; Buyuk, Yalçın; Yurdun, Turkan

2018-03-01

CUMYL-4CN-BINACA(1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide) is a recently introduced indazole-3-carboxamide-type synthetic cannabinoid (SC) that was detected in herbal incense seized by of the Council of Forensic Medicine, Istanbul Narcotics Department, in May 2016 in Turkey. Recently introduced SCs are not detected in routine toxicological analysis; therefore, analytical methods to measure these compounds are in demand. The present study aims to identify urinary marker metabolites of CUMYL-4CN-BINACA by investigating its metabolism in human liver microsomes and to confirm the results in authentic urine samples (n = 80). In this study, 5 μM CUMYL-4CN-BINACA was incubated with human liver microsomes (HLMs) for up to 3 hours, and metabolites were identified using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Less than 21% of the CUMYL-4CN-BINACA parent compound remained after 3 hours of incubation. We identified 18 metabolites that were formed via monohydroxylation, dealkylation, oxidative decyanation to aldehyde, alcohol, and carboxylic acid formation, glucuronidation or reaction combinations. CUMYL-4CN-BINACA N-butanoic acid (M16) was found to be major metabolite in HLMs. In urine samples CUMYL-4CN-BINACA was not detected; CUMYL-4CN-BINACA N-butanoic acid (M16) was major metabolite after β-glucuronidase hydrolysis. Based on these findings, we recommend using M16 (CUMYL-4CN-BINACA N-butanoic acid), M8 and M11 (hydroxylcumyl CUMYL-4CN-BINACA) as urinary marker metabolites to confirm CUMYL-4CN-BINACA intake. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.

PubMed

Canazza, Isabella; Ossato, Andrea; Trapella, Claudio; Fantinati, Anna; De Luca, Maria Antonietta; Margiani, Giulia; Vincenzi, Fabrizio; Rimondo, Claudia; Di Rosa, Fabiana; Gregori, Adolfo; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; Marti, Matteo

2016-10-01

AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ 9 -THC and JWH-018. In vitro competition binding experiments performed on mouse and human CB 1 and CB 2 receptors revealed a nanomolar affinity and potency of the AKB48 and 5F-AKB48. In vivo studies showed that AKB48 and 5F-AKB48, induced hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promoted aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of AKB48 and 5F-AKB48 stimulated dopamine release in the nucleus accumbens. Behavioural, neurological and neurochemical effects were fully prevented by the selective CB 1 receptor antagonist/inverse agonist AM 251. For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.

Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole Quinuclidine analogues

PubMed Central

Franks, Lirit N.; Ford, Benjamin M.; Madadi, Nikhil R.; Penthala, Narsimha R.; Crooks, Peter A.; Prather, Paul L.

2014-01-01

Our laboratory recently reported that a group of novel indole quinuclidine analogues bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analogue exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogues acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogues demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. PMID:24858620

The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory.

PubMed

Khan, Mohammed I; Sobocińska, Anna A; Czarnecka, Anna M; Król, Magdalena; Botta, Bruno; Szczylik, Cezary

2016-01-01

The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.

Psychiatric comorbidities in a young man with subacute myelopathy induced by abusive nitrous oxide consumption: a case report

PubMed Central

Mancke, Falk; Kaklauskaitė, Gintarė; Kollmer, Jennifer; Weiler, Markus

2016-01-01

Nitrous oxide (N2O), a long-standing anesthetic, is known for its recreational use, and its consumption is on the rise. Several case studies have reported neurological and psychiatric complications of N2O use. To date, however, there has not been a study using standardized diagnostic procedures to assess psychiatric comorbidities in a patient consuming N2O. Here, we report about a 35-year-old male with magnetic resonance imaging confirmed subacute myelopathy induced by N2O consumption, who suffered from comorbid cannabinoid and nicotine dependence as well as abuse of amphetamines, cocaine, lysergic acid diethylamide, and ketamine. Additionally, there was evidence of a preceding transient psychotic and depressive episode induced by synthetic cannabinoid abuse. In summary, this case raises awareness of an important mechanism of neural toxicity, with which physicians working in the field of substance-related disorders should be familiar. In fact, excluding N2O toxicity in patients with recognized substance-related disorders and new neurological deficits is compulsory, as untreated for months the damage to the nervous system is at risk of becoming irreversible. PMID:27729826

The consequences of chronic cannabis smoking in vulnerable adolescents.

PubMed

Iede, Montaha Al; Nunn, Kenneth; Milne, Bronwyn; Fitzgerald, Dominic A

2017-09-01

Cannabis, like the mythic shape-shifter, presents in various guises, morphing with the perspective and context of the observer. Arguments about cannabis are confused by a myriad of debates-medical, social, ethical and political-as if a single conceptual umbrella can capture the variety and granularity of marijuana-related issues. This paper responds to marijuana use as it is commonly practised by youth in Australia. It has little to say about synthetic cannabinoids, specific medicinal cannabinoids, or medicinal properties of marijuana. We address those adolescents genetically and environmentally vulnerable to mental illness, with specific emphasis on indigenous and neurodevelopmentally impaired young people who show patterns of usage and response very different to adults and more resilient members of the population. Specifically, the practice of mixing tobacco with marijuana by aboriginal youth, and the resultant coalition of dependencies, will likely presage a rise in pulmonary and central nervous system pathology over the coming decades. Aboriginal youth begin using earlier, persist longer, and take greater quantities of cannabis than non-indigenous youth. This paper recommends practical interventions to reduce the multiple health consequences of chronic cannabis use in young people, especially indigenous young people. Copyright © 2016. Published by Elsevier Ltd.

Psychiatric comorbidities in a young man with subacute myelopathy induced by abusive nitrous oxide consumption: a case report.

PubMed

Mancke, Falk; Kaklauskaitė, Gintarė; Kollmer, Jennifer; Weiler, Markus

2016-01-01

Nitrous oxide (N 2 O), a long-standing anesthetic, is known for its recreational use, and its consumption is on the rise. Several case studies have reported neurological and psychiatric complications of N 2 O use. To date, however, there has not been a study using standardized diagnostic procedures to assess psychiatric comorbidities in a patient consuming N 2 O. Here, we report about a 35-year-old male with magnetic resonance imaging confirmed subacute myelopathy induced by N 2 O consumption, who suffered from comorbid cannabinoid and nicotine dependence as well as abuse of amphetamines, cocaine, lysergic acid diethylamide, and ketamine. Additionally, there was evidence of a preceding transient psychotic and depressive episode induced by synthetic cannabinoid abuse. In summary, this case raises awareness of an important mechanism of neural toxicity, with which physicians working in the field of substance-related disorders should be familiar. In fact, excluding N 2 O toxicity in patients with recognized substance-related disorders and new neurological deficits is compulsory, as untreated for months the damage to the nervous system is at risk of becoming irreversible.

Effect of CB1 Ligands on Neurogenic and Myogenic Contractile Responses in the Guinea-Pig Ileum.

PubMed

Donnerer, Josef; Liebmann, Ingrid

2018-01-01

This study aimed at investigating whether the synthetic cannabinoid receptor agonist (+)-WIN 55212-2 has neurogenic and myogenic relaxant effects on the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. (+)-WIN 55212-2, 1-1,000 nmol/L, concentration-dependently inhibited both the electrical stimulation-induced cholinergic twitch responses as well as the myogenic smooth muscle contractions in the LMMP preparation. SR-141716A (rimonabant) 1-1,000 nmol/L, the cannabinoid CB1 receptor antagonist, being without effect on its own, antagonized the (+)-WIN 55212-2-induced effects. The allyl isothiocyanate (mustard oil, 100 µmol/L) induced a relaxant effect in the guinea-pig ileum, which can be regarded as neurogenic and myogenic, was augmented by (+)-WIN 55212-2, and inhibited by SR-141716A. (+)-WIN 55212-2 only moderately modified the 60 mmol/L KCl-evoked contractions. These results provide functional evidence that the CB1 agonist (+)-WIN 55212-2-induced inhibitory effects in the guinea-pig ileum are exerted both at the neuronal as well as at the intestinal smooth muscle cell level. © 2018 S. Karger AG, Basel.

21 CFR 862.3870 - Cannabinoid test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... measure any of the cannabinoids, hallucinogenic compounds endogenous to marihuana, in serum, plasma... cannabinoid use or abuse and in monitoring levels of cannabinoids during clinical investigational use. (b...

The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.

PubMed

Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

2007-11-01

Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (-)-11-nor-9-carboxy-delta 9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates.

New insights into antimetastatic and antiangiogenic effects of cannabinoids.

PubMed

Ramer, Robert; Hinz, Burkhard

2015-01-01

Cannabinoids exert antitumorigenic effects via multiple mechanisms. Of these, antimetastatic and antiangiogenic actions have attracted considerable interest in the past years. Regarding the underlying antimetastatic mechanism, several studies revealed cannabinoids to alter the gene expression of cancer cells toward a less-aggressive phenotype and to modulate their secretomic profile. Cannabinoids likewise modulate the release of factors from tumor cells that subsequently suppress the chemoattraction of vessel cells thereby conferring antiangiogenesis. Among the diverse mediators of cannabinoids' antitumorigenic action, the tissue inhibitor of matrix metalloproteinases-1, which is released from cancer cells upon cannabinoid treatment, has been implicated as a pivotal factor conferring both anti-invasive properties of cancer cells as well as antiangiogenic capacities of endothelial cells. In addition, cannabinoids have been shown to inhibit angiogenic capacities of endothelial cells directly via suppressing their proliferation, tube formation, and migration. This chapter reviews the cell- and substance-specific antitumorigenic mechanisms of cannabinoids with particular consideration of their antimetastatic/anti-invasive and antiangiogenic actions. In addition, beneficial interactions of cannabinoids with currently used chemotherapeutics as well as the influence of cannabinoids on tumor-immune surveillance are addressed. Collectively, the currently available data suggest cannabinoids as a potential tool in modern cancer pharmacotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Cannabinoid signaling in health and disease.

PubMed

Lu, Yan; Anderson, Hope D

2017-04-01

Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.

State of the evidence: Cannabinoids and cancer pain-A systematic review.

PubMed

Tateo, Sydney

2017-02-01

Cannabinoids are widely used to alleviate intractable symptoms such as pain, nausea, and muscle spasticity. The purpose of this review was to ascertain the current state of the science regarding use of cannabinoids for cancer pain. Four electronic databases were searched for randomized control trials of cannabinoids and cancer pain. Studies included examined the analgesic effects of cannabinoids for cancer pain. Methodological quality was assessed using the Jadad scale. Eight randomized control trials met the inclusion criteria for review. Most trials found analgesic effects from cannabinoids when compared to placebo, although not all associations reached statistical significance. The analgesic effects of cannabinoids were also limited by dose-dependent side effects. Side effects most commonly reported were changes in cognition, sedation, and dizziness. There is evidence that cannabinoids are effective adjuvants for cancer pain not completely relieved by opioid therapy, but there is a dearth of high-quality studies to support a stronger conclusion. Cannabinoids appear to be safe in low and medium doses. Methodological limitations of the trials limited the ability to make sound conclusions. Further research is warranted before efficacy, safety, and utility of cannabinoids for cancer pain can be determined. ©2016 American Association of Nurse Practitioners.

The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids

PubMed Central

Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

2007-01-01

Background and purpose: Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Experimental approach: Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. Key results: CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (−)-11-nor-9-carboxy-Δ9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Conclusions and implications: Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates. PMID:17906686