cannabidiol and Substance-Withdrawal-Syndrome

Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Anxiety Agents; Antiemetics; Cannabidiol; Humans; Narcotics; Opioid-Related Disorders; Prospective Studies; Substance Withdrawal Syndrome

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders.

Topics: Amphetamine-Related Disorders; Animals; Cannabidiol; Cocaine-Related Disorders; Health Risk Behaviors; Humans; Methamphetamine; Mice; Observational Studies as Topic; Resilience, Psychological; Substance Withdrawal Syndrome

Cannabis is a common recreational drug that is generally considered to have low addictive potential. However, an increasing number of cannabis users are seeking treatment for dependence on the drug. There is interest in using agonist (substitution) pharmacotherapies to treat cannabis dependence and here we outline a novel approach involving a buccal spray (nabiximols) that contains tetrahydrocannabinol (THC) and cannabidiol (CBD). We review recent research with nabiximols and highlight findings relevant to clinical practice.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Marijuana Abuse; Substance Withdrawal Syndrome

Topics: Animals; Avoidance Learning; Behavior, Animal; Cannabidiol; Cannabinoids; Cannabinol; Conditioning, Operant; Dronabinol; Drug Administration Schedule; Drug Tolerance; Humans; Motor Activity; Reinforcement Schedule; Substance Withdrawal Syndrome

The rationale of this study was to assess occurrence of withdrawal symptoms induced by abrupt cessation of cannabidiol (CBD) after prolonged administration in healthy volunteers.. Thirty volunteers were randomized to receive 750 mg of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL; Epidiolex® in the United States and Epidyolex® in Europe) twice daily (b.i.d.) for 4 weeks (Part 1) followed by 2 weeks of 750 mg b.i.d. CBD (Part 2, Arm 1) or matched placebo (Part 2, Arm 2). All volunteers completed the Cannabis Withdrawal Scale (CWS) and the 20-item Penn Physician Withdrawal Checklist (PWC-20) on days -1, 21, 28, 31, 35, 42, and at follow-up.. Median CWS and PWC-20 scores slightly decreased from Part 1 to Part 2. Median CWS scores ranged from 0.0 to 4.0 (out of a possible 190) in Arm 1 and 0.0 to 0.5 in Arm 2. Median PWC-20 scores were 0.0 (out of a possible 60) in both arms. Twenty-nine (97%) volunteers in Part 1 reported all-causality treatment-emergent adverse events (AEs); the most commonly reported was diarrhea (63%). In Part 2, Arm 1, 6 (67%) volunteers reported all-causality AEs; the most commonly reported was diarrhea (44%). In Part 2, Arm 2, 9 (75%) volunteers reported all-causality AEs; the most commonly reported was headache (58%). Nine volunteers withdrew because of AEs in Part 1; 1 withdrew in Part 2, Arm 2, because of an AE that began in Part 1. Four severe AEs were reported in Part 1; the remainder were mild or moderate. No serious AEs were reported.. In healthy volunteers, no evidence of withdrawal syndrome was found with abrupt discontinuation of short-term treatment with CBD.

Topics: Adult; Anticonvulsants; Cannabidiol; Double-Blind Method; Europe; Healthy Volunteers; Humans; Middle Aged; Substance Withdrawal Syndrome; Young Adult

Background A substantial and unmet clinical need exists for pharmacological treatment of cannabis use disorders. Cannabidiol could offer a novel treatment, but it is unclear which doses might be efficacious or safe. Therefore, we aimed to identify efficacious doses and eliminate inefficacious doses in a phase 2a trial using an adaptive Bayesian design.. We did a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial at the Clinical Psychopharmacology Unit (University College London, London, UK). We used an adaptive Bayesian dose-finding design to identify efficacious or inefficacious doses at a-priori interim and final analysis stages. Participants meeting cannabis use disorder criteria from DSM-5 were randomly assigned (1:1:1:1) in the first stage of the trial to 4-week treatment with three different doses of oral cannabidiol (200 mg, 400 mg, or 800 mg) or with matched placebo during a cessation attempt by use of a double-blinded block randomisation sequence. All participants received a brief psychological intervention of motivational interviewing. For the second stage of the trial, new participants were randomly assigned to placebo or doses deemed efficacious in the interim analysis. The primary objective was to identify the most efficacious dose of cannabidiol for reducing cannabis use. The primary endpoints were lower urinary 11-nor-9-carboxy-δ-9-tetrahydrocannabinol (THC-COOH):creatinine ratio, increased days per week with abstinence from cannabis during treatment, or both, evidenced by posterior probabilities that cannabidiol is better than placebo exceeding 0·9. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT02044809) and the EU Clinical Trials Register (2013-000361-36).. Between May 28, 2014, and Aug 12, 2015 (first stage), 48 participants were randomly assigned to placebo (n=12) and to cannabidiol 200 mg (n=12), 400 mg (n=12), and 800 mg (n=12). At interim analysis, cannabidiol 200 mg was eliminated from the trial as an inefficacious dose. Between May 24, 2016, and Jan 12, 2017 (second stage), randomisation continued and an additional 34 participants were allocated (1:1:1) to cannabidiol 400 mg (n=12), cannabidiol 800 mg (n=11), and placebo (n=11). At final analysis, cannabidiol 400 mg and 800 mg exceeded primary endpoint criteria (0·9) for both primary outcomes. For urinary THC-COOH:creatinine ratio, the probability of being the most efficacious dose compared with placebo given the observed data was 0·9995 for cannabidiol 400 mg and 0·9965 for cannabidiol 800 mg. For days with abstinence from cannabis, the probability of being the most efficacious dose compared with placebo given the observed data was 0·9966 for cannabidiol 400 mg and 0·9247 for cannabidiol 800 mg. Compared with placebo, cannabidiol 400 mg decreased THC-COOH:creatinine ratio by -94·21 ng/mL (95% interval estimate -161·83 to -35·56) and increased abstinence from cannabis by 0·48 days per week (0·15 to 0·82). Compared with placebo, cannabidiol 800 mg decreased THC-COOH:creatinine ratio by -72·02 ng/mL (-135·47 to -19·52) and increased abstinence from cannabis by 0·27 days per week (-0·09 to 0·64). Cannabidiol was well tolerated, with no severe adverse events recorded, and 77 (94%) of 82 participants completed treatment.. In the first randomised clinical trial of cannabidiol for cannabis use disorder, cannabidiol 400 mg and 800 mg were safe and more efficacious than placebo at reducing cannabis use.. Medical Research Council.

Topics: Adolescent; Adult; Bayes Theorem; Cannabidiol; Double-Blind Method; Dronabinol; Female; Hallucinogens; Humans; London; Male; Marijuana Abuse; Marijuana Smoking; Substance Withdrawal Syndrome; Treatment Outcome; Young Adult

The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Δ9-tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex®) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment-seeking cannabis-dependent participants.. Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time.. Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores.. Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence.

Topics: Adult; Cannabidiol; Cognitive Behavioral Therapy; Craving; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Marijuana Abuse; Middle Aged; Motivation; Pilot Projects; Placebos; Substance Withdrawal Syndrome; Young Adult

The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments. This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches.. A phase III multi-site outpatient, randomised, double-blinded, placebo controlled parallel design, comparing a 12-week course of nabiximols to placebo, with follow up at 24 weeks after enrolment. Four specialist drug and alcohol outpatient clinics in New South Wales, Australia. One hundred forty-two treatment seeking cannabis dependent adults, with no significant medical, psychiatric or other substance use disorders. Nabiximols is an oromucosal spray prescribed on a flexible dose regimen to a maximum daily dose of 32 sprays; 8 sprays (total 21.6 mg tetrahydrocannabinol (THC) and 20 mg cannabidiol (CBD)) four times a day, or matching placebo, dispensed weekly. All participants will receive six-sessions of individual cognitive behavioural therapy (CBT) and weekly clinical reviews. Primary endpoints are use of non-prescribed cannabis (self-reported cannabis use days, urine toxicology), safety measures (adverse events and abuse liability), and cost effectiveness (incremental cost effectiveness in achieving additional Quality Adjusted Life Years). Secondary outcomes include, improvement in physical and mental health parameters, substance use other than cannabis, cognitive functioning and patient satisfaction measures.. This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids).. Australian and New Zealand Clinical Trial Registry: ACTRN12616000103460 (Registered 1st February 2016).

Topics: Adult; Australia; Cannabidiol; Cannabinoids; Cognition; Cognitive Behavioral Therapy; Combined Modality Therapy; Craving; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Marijuana Abuse; New South Wales; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome; Treatment Outcome

There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects.. Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B-E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports.. High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower "high" following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions.. The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence.

Topics: Adult; Cannabidiol; Cannabis; Craving; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Marijuana Abuse; Marijuana Smoking; Middle Aged; Plant Extracts; Substance Withdrawal Syndrome; Substance-Related Disorders; Treatment Outcome; Young Adult

There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal.. To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal.. A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers.. A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission.. Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes.. Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22; P = .97). The number (F1,50 = 0.3; P = .59) and severity (F1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29; P = .75), cannabis-related problems (F1,49 = 2.33; P = .14), or cannabis dependence (F1,50 < 0.01; P = .89).. In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations.. anzctr.org.au Identifier: ACTRN12611000398909.

Topics: Adult; Australia; Cannabidiol; Cannabinoid Receptor Agonists; Combined Modality Therapy; Double-Blind Method; Dronabinol; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Marijuana Abuse; Middle Aged; Placebo Effect; Placebos; Psychotherapy; Severity of Illness Index; Substance Withdrawal Syndrome; Treatment Outcome

Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical.. To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal.. An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects' previous effective and tolerated dose was continued.. A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome of time to treatment failure was significantly in favour of Sativex (p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject's Global Impression of Change scales in favour of Sativex.. Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.

Topics: Aged; Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Muscle Spasticity; Placebos; Plant Extracts; Substance Withdrawal Syndrome

Cannabidiol (CBD), one of the major products of the marijuana plant, is devoid of marijuana's typical psychological effects. In contrast, potential antipsychotic efficacy has been suggested based on preclinical and clinical data (Zuardi et al., 2002). In this report, we further investigated the efficacy and safety of CBD monotherapy in three patients with treatment-resistant schizophrenia (TRS). This was an in-patient study. All patients were given placebo for the initial 5 days, and from the 6th to 35th day (inclusive) they received CBD (initial oral dose of 40 mg reaching 1280 mg/day). On the 36th day, CBD treatment was discontinued and replaced by placebo for 5 days, which was subsequently switched to olanzapine for over 15 days. Efficacy, tolerability and side effects were assessed. One patient showed mild improvement, but two patients didn't show any improvement during CBD monotherapy. All patients tolerated CBD very well and no side effects were reported. These preliminary data suggest that CBD monotherapy may not be effective for TRS.

Topics: Adult; Aggression; Antipsychotic Agents; Behavior; Cannabidiol; Drug Resistance; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses.. As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms.. Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling.. Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD

Topics: Alcoholism; Animals; Cannabidiol; Dopamine; Ethanol; Humans; Nucleus Accumbens; Rats; Substance Withdrawal Syndrome

The main goal of this study was to evaluate if the administration of cannabidiol (CBD) regulates behavioral and gene expression alterations induced by spontaneous alcohol withdrawal (SAW) in mice. Increasing doses of ethanol were administered to C57BL/6J male mice for 15 days (2.5, 3 and 3.5 g/kg/12 h, p. o.), and SAW was studied at 6, 12, 24, and 72 h after the last ethanol administration. The efficacy of acute CBD (10, 20, and 40 mg/kg, i. p.) to regulate behavioral changes induced by SAW was explored at 6 h. Gene expression analyses of cannabinoid receptors 1 (Cnr1) and 2 (Cnr2), mu-opioid receptor (Opmr1), and proopiomelanocortin (Pomc) in the nucleus accumbens (NAcc), and Pomc and tyrosine hydroxylase (Th) in the ventral tegmental area (VTA), were carried out by real time-PCR. Pearson correlation was used to identify potential associations between the gene expression data and the anxiety-like behaviors. Biostatistical studies suggest associations between gene expression data and the anxiogenic behaviors in mice exposed to the SAW model and treated with VEH and 40 mg/kg of CBD. Mice exposed to the SAW model showed significant somatic withdrawal signs, anxiety-like behaviors, and remarkable changes in the gene expression of all brain targets at 6 h. CBD dose-dependently normalized the behavioral, somatic withdrawal signs and anxiety-like behaviors and modulated gene expression changes in the NAcc, but not in the VTA. The results of this study suggest that CBD may regulate specific alcohol withdrawal-associated alterations. However, further studies are required to explore the possible mechanisms involved.

Topics: Alcoholism; Animals; Brain; Cannabidiol; Ethanol; Male; Mice; Mice, Inbred C57BL; Pro-Opiomelanocortin; Substance Withdrawal Syndrome; Ventral Tegmental Area

The misuse of and addiction to opioids are serious public health problems in some countries, such as the USA. Drug addiction is a chronic and relapsing medical condition that involves motivational and memory-related processes due to the strong associations between drugs and consuming-related stimuli. These stimuli usually trigger continuous and compulsive use and are associated with relapses after periods of withdrawal. Several factors contribute to relapse, including withdrawal-induced mood changes. Therefore, drugs attenuating withdrawal-induced affective alterations could be useful alternative treatments for relapse prevention. Cannabidiol (CBD), a non-psychotomimetic component from the Cannabis sativa plant, has anti-anxiety and anti-stress properties and has been investigated as an alternative for the treatment of several mental disorders, including drug addiction. Here, we evaluated if CBD administered 30 min prior to test for a conditioned place aversion (CPA) would attenuate the aversion induced by morphine withdrawal precipitated by the opioid receptor antagonist naloxone in male C57BL/6 mice. We also investigated if this effect involves the activation of 5-HT1A receptors, a mechanism previously associated with CBD anti-aversive effects. As expected, morphine-treated mice spent less time exploring the compartment paired with the naloxone-induced withdrawal, indicating a CPA induced by naloxone-precipitated morphine withdrawal. This effect was not observed in animals treated with CBD, at 30 and 60 mg/kg, prior to the CPA test, indicating that CBD attenuated the expression of CPA induced by naloxone-precipitated morphine withdrawal. Pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) blocked CBD effects. Our findings suggest that CBD may reduce the expression of a previously established conditioned aversion induced by morphine withdrawal by a mechanism involving the activation of 5-HT1A receptors. Thus, CBD may be a therapeutic alternative for preventing relapse to opioid addiction by decreasing withdrawal-induced negative affective changes.

Topics: Animals; Avoidance Learning; Cannabidiol; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptor, Serotonin, 5-HT1A; Substance Withdrawal Syndrome

The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12 days (15 to 60 mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6 h after the last cocaine administration. The effects of CBD (10, 20, and 40 mg/kg, i.p.) were evaluated on cocaine withdrawal-induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal.

Topics: Animals; Anxiety; Cannabidiol; Cocaine; Dopamine Plasma Membrane Transport Proteins; Gene Expression; Male; Mice; Motor Activity; Nucleus Accumbens; Real-Time Polymerase Chain Reaction; Substance Withdrawal Syndrome; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking.. The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence.. Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded.. CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results.. This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial.

Topics: Animals; Anticonvulsants; Cannabidiol; Female; Infusion Pumps; Male; Nicotine; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Tobacco Use Disorder

Cocaine dependence is a highly prevalent disease in modern society and lacks an effective treatment. Cannabidiol (CBD), a major non-psychoactive constituent of Cannabis sativa, has been shown to be a promising tool in the management of some neuropsychiatric disorders, including cocaine abuse. However, its therapeutic effects on the behavioral outcomes related to cocaine addiction remain unclear. The present research evaluates the effects of CBD (30, 60 and 120 mg/kg; injected intraperitoneally) on the acquisition, expression, extinction and reinstatement of cocaine (10 mg/kg)-induced conditioned place preference (CPP; Study 1); cocaine (25 mg/kg)-induced locomotor stimulation (Study 2); and cocaine withdrawal symptoms (Study 3) in male C57BL/6 J mice. The results show that CBD does not possess motivational properties in itself and does not modify the acquisition, expression or extinction of cocaine-induced CPP. Interestingly, when administered during the extinction phase of the cocaine-induced CPP, CBD (30 and 60 mg/kg) prevented priming-induced reinstatement of CPP. Moreover, CBD abolished cocaine-induced hyperactivity without altering the spontaneous locomotion of the animals. Furthermore, CBD (120 mg/kg) reduced the memory deficits induced by cocaine withdrawal in the object recognition test, though it did not reverse depressive-like symptoms measured in the tail suspension test. Overall, our data suggest that CBD can prevent the development of cocaine addiction, and, when administered during cocaine abstinence, may be of help in avoiding relapse to drug-seeking and in ameliorating the memory disturbances provoked by chronic consumption of cocaine.

Topics: Animals; Cannabidiol; Cocaine; Cocaine-Related Disorders; Conditioning, Classical; Dose-Response Relationship, Drug; Extinction, Psychological; Hyperkinesis; Injections, Intraperitoneal; Locomotion; Male; Mice; Mice, Inbred C57BL; Substance Withdrawal Syndrome

Cannabis addiction is worldwide one of the most prevalent addictions, without any effective pharmacotherapeutic options. Nabiximols spray, consisting of 2.7 mg tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD), could serve as an effective substitution therapy for cannabis addiction. Researchers reported that patients who were treated for 12 weeks with nabiximols significantly reduced the number of days on which they used cannabis (18.6 days less compared to placebo users; 95% CI: 3.5-33.7). There was no difference between groups regarding general health, the use of other substances, cannabis craving, withdrawal symptoms or achieving abstinence.

Topics: Analgesics; Cannabidiol; Cannabis; Clinical Trials as Topic; Dronabinol; Drug Combinations; Female; Humans; Male; Marijuana Abuse; Nasal Sprays; Substance Withdrawal Syndrome

  Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC..   This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment..   CBD can be effective for the treatment of cannabis withdrawal syndrome.

Topics: Adult; Cannabidiol; Cannabis; Female; Humans; Substance Withdrawal Syndrome; Young Adult

Delta-9-tetrahydrocannabinol (THC), the main psychoactive principle of cannabis, has been shown to attenuate the exhibition of signs of the quasi-morphine withdrawal syndrome in rats. Cannabinol (CBN) showed the same activity but required a dosage of approximately eight times that of THC to produce an equivalent effect. Cannabidiol was without effect at the dosage levels used. The efficacy of these cannabinoids and the potency differences recorded in this study are in accord with their effects on other behaviours, both in experimental animals and in man. The activity of THC and CBN was not affected by the narcotic antagonist, naloxone.

Topics: Animals; Cannabidiol; Cannabinoids; Cannabinol; Dronabinol; Humans; Morphine; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

1 The effects of subacute treatment with cannabidiol, delta 9-tetrahydrocannabinol (delta 9-THC), phenytoin and phenobarbitone on anticonvulsant activity and on withdrawal excitability in mice were compared in three electrically induced seizure-threshold tests. 2 In the maximal electroshock-threshold test, subacute treatment did not alter the anticonvulsant activity of cannabidiol, phenytoin or phenobarbitone, but tolerance developed to delta 9-THC. 3 In the 60 Hz electroshock-threshold test, the activity of delta 9-THC and cannabidiol did not change, but tolerance developed to phenobarbitone, and there was an increase in sensitivity to phenytoin. 4 In the 6 Hz electroshock-threshold test, there was an increase in sensitivity to both delta 9-THC and cannabidiol, there was tolerance to phenobarbitone, while the activity of phenytoin did not change. 5 Although tolerance developed in some of the seizure-threshold tests to delta 9-THC and phenobarbitone, tolerance to cannabidiol and phenytoin did not develop in any of the tests. 6 Hyperexcitability followed withdrawal from only delta 9-THC (6 Hz and 60 Hz electroshock-threshold tests) and phenobarbitone (maximal electroshock-threshold and 60 Hz electroshock-threshold tests). 7 The delta 9-THC withdrawal hyperexcitability suggests that the use of marihuana may jeopardize the control of seizures in epileptics.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Dronabinol; Drug Tolerance; Electroshock; Humans; Male; Mice; Mice, Inbred ICR; Substance Withdrawal Syndrome

Mice were rendered morphine-dependent by the subcutaneous implantation of a pellet containing 75 mg of morphine base; 72 h after the implantation, the animals were injected intraperitoneally either with vehicle or with various doses of delta9-tetrahydrocannabinol, delta8-tetrahydrocannabinol, cannabidiol, cannabinol, or 11-hydroxy-delta8-tetrahydrocannabinol. Thirty minutes after injection of the cannabinoids, the antagonist, naloxone HC1, was administered to induce the stereotyped withdrawal jumping syndrome. The dose of naloxone needed to induce withdrawal jumping in 50% of the animals (ED50) was determined for each dose of the cannabinoids. All of the cannabinoids inhibited the naloxone-precipitated morphine abstinence as evidenced by an increase in the naloxone ED50. Two additional signs of morphine abstinence, defecation and rearing behavior, were also suppressed by the cannabinoids. The relative effectiveness of the cannabinoids in inhibiting morphine abstinence appeared to be in the following order: delta9-tetrahydrocannabinol greater than delta8-tetrahydrocannabinol greater than 11-hydroxy-delta8-tetrahydrocannabinol greater than cannabidiol greater than cannabinol. These data suggest that cannabinoids may be useful in facilitating narcotic detoxification.

Topics: Animals; Cannabidiol; Cannabinoids; Cannabinol; Dronabinol; Heroin Dependence; Humans; Male; Mice; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome

The same dose of cannabinol (CBN) or cannabidiol (CBD) further increased the attenuation of precipitated abstinence signs observed in morphine-dependent rats that also received an acute dose of delta 9-THC. By contrast, rotational behavior (turning), which is observed concomitantly in THC-treated rats during morphine abstinence, was not increased by CBN, but was potentiated by CBD. These data illustrate differences between psychoinactive cannabinoids in their interaction with delta 9-THC that might be relevant to possible clinical use of Cannabis in narcotic detoxification.

Topics: Animals; Cannabidiol; Cannabis; Depression, Chemical; Dronabinol; Drug Synergism; Humans; Male; Morphine Dependence; Rats; Stereotyped Behavior; Substance Withdrawal Syndrome

Topics: Animals; Cannabidiol; Cannabis; Dronabinol; Drug Synergism; Herb-Drug Interactions; Humans; Male; Morphine; Phytotherapy; Rats; Substance Withdrawal Syndrome