Article

Cannabidiol for the treatment of cannabis withdrawal syndrome: A case report

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Abstract

What is known and objective: 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. Case summary: 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. What is new and conclusion: CBD can be effective for the treatment of cannabis withdrawal syndrome.

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... Comentaremos brevemente algunos de estos trabajos y de otras revisiones recientes. A este respecto, un reporte de caso en una mujer de 19 años con síndrome de abstinencia de cannabis tratada con cannabidiol (CBD) durante 10 días mostró ausencia de síntomas significativos de abstinencia, ansiedad y disociación durante el tratamiento (Crippa et al., 2012). Una revisión realizada en 2015 resume la evidencia en CUD sobre la terapia medicamentosa de reemplazo y la realizada con cannabinoides (CRT). ...
... La abstinencia del cannabis en los grandes consumidores suele ir seguida de un aumento de la ansiedad, insomnio, pérdida de apetito, migraña, irritabilidad, inquietud y otros signos físicos y psicológicos (Budney & Hughes, 2006 que muestran una mejoría tras el uso de CBD, en serie de casos se ha reportado junto a la abstinencia disminución de los puntajes en escalas específicas de craving (Crippa et al., 2012;Trigo et al., 2016a) y de disconfort causado por el síndrome de abstinencia del cannabis (Crippa et al., 2012;Trigo et al., 2016aTrigo et al., y 2016b, así como también, en puntajes de escalas de ansiedad y de los síntomas disociativos (Crippa et al., 2012). Los efectos en la reducción del craving y en puntajes totales de escalas de disconfort causado por el síndrome de abstinencia del cannabis también ha sido replicado en ensayos clínicos (Trigo et al., 2018). ...
... La abstinencia del cannabis en los grandes consumidores suele ir seguida de un aumento de la ansiedad, insomnio, pérdida de apetito, migraña, irritabilidad, inquietud y otros signos físicos y psicológicos (Budney & Hughes, 2006 que muestran una mejoría tras el uso de CBD, en serie de casos se ha reportado junto a la abstinencia disminución de los puntajes en escalas específicas de craving (Crippa et al., 2012;Trigo et al., 2016a) y de disconfort causado por el síndrome de abstinencia del cannabis (Crippa et al., 2012;Trigo et al., 2016aTrigo et al., y 2016b, así como también, en puntajes de escalas de ansiedad y de los síntomas disociativos (Crippa et al., 2012). Los efectos en la reducción del craving y en puntajes totales de escalas de disconfort causado por el síndrome de abstinencia del cannabis también ha sido replicado en ensayos clínicos (Trigo et al., 2018). ...
Article
Addictions are one of the most important health problems worldwide. Within these disorders, cannabis is one of the psychoactive substances with more burden of morbidity and mortality worldwide. The actual knowledge about the effectiveness of treatments for cannabis use disorders is unsatisfactory. This review aims to explore the evidence on cannabidiol for the treatment of cannabis use disorder. There are several clinical pharmacotherapy trials researching cannabis use disorders with limited evidence. A smaller number of trials in animal models and humans on the use of cannabinoids, especially Cannabidiol and Tetrahydrocannabinol to treat cannabis dependence show evidence of reduction in days of use, withdrawal symptoms and craving. New trials are under development, and there is an urgent need for trials with larger numbers of patients and longer treatment periods to support possible indications in the near future.
... Taking this all into consideration, new molecules should be discovered for treating drug abuse. Preliminary studies suggest that CBD may have therapeutic impacts helpful in treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). Several studies suggest that CBD, a phytocannabinoid devoid of the psychoactive effects associated with THC, may have therapeutic effects for treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). ...
... Preliminary studies suggest that CBD may have therapeutic impacts helpful in treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). Several studies suggest that CBD, a phytocannabinoid devoid of the psychoactive effects associated with THC, may have therapeutic effects for treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). CBD is not associated with adverse cognitive effects, presents good safety and tolerability profiles in humans, and has a broad pharmacological spectrum of action (Zhornitsky and Potvin, 2012;niesink & van laar, 2013). ...
... In a separate case study, a 19-year-old woman with a history of smoking 4-8 cannabis cigarettes per day since age 13 and exhibiting cannabis withdrawal syndrome was treated with CBD for ten days in the following regimen: 300 mg on Day 1 and 11; 600 mg on Days 2-10. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety, and dissociative symptoms during the treatment (Crippa et al., 2013) (Table 2). ...
Article
Background Cannabidiol (CBD) is one of the major constituents of Cannabis sativa L. that lacks psychotomimetic and rewarding properties and inhibits the rewarding and reinforcing effects of addictive drugs such as cocaine, methamphetamine (METH), and morphine. Additionally, CBD's safety profile and therapeutic potential are currently evaluated in several medical conditions, including pain, depression, movement disorders, epilepsy, multiple sclerosis, Alzheimer's disease, ischemia, and substance use disorder. There is no effective treatment for substance use disorders such as addiction, and this review aims to describe preclinical and clinical investigations into the effects of CBD in various models of opioid, psychostimulant, cannabis, alcohol, and nicotine abuse. Furthermore, the possible mechanisms underlying the therapeutic potential of CBD on drug abuse disorders are reviewed. Methods The current review considers and summarizes the preclinical and clinical investigations into CBD's effects in various models of drug abuse include opioids, psychostimulants, cannabis, alcohol, and nicotine. Results Several preclinical and clinical studies have proposed that CBD may be a reliable agent to inhibit the reinforcing and rewarding impact of drugs. Conclusions While the currently available evidence converges to suggest that CBD could effectively reduce the rewarding and reinforcing effects of addictive drugs, more preclinical and clinical studies are needed before CBD can be added to the therapeutic arsenal for treating addiction.
... Open-label case studies have reported that use of CBD products were associated with reduced cannabis withdrawal symptoms during cannabis abstinence. 22,23 A 10-week open-label trial found that CBD administration was associated with improvements in psychological wellbeing and cognition in regular cannabis users who were not engaged in a cessation attempt. 24 Nabiximols (a combination of THC and CBD at 1:1 ratio) has been found to reduce cannabis withdrawal symptoms and/or cannabis use in some randomised doubleblind placebo-controlled trials. ...
... 24 Nabiximols (a combination of THC and CBD at 1:1 ratio) has been found to reduce cannabis withdrawal symptoms and/or cannabis use in some randomised doubleblind placebo-controlled trials. [25][26][27] However, the causal role of CBD in these studies is unclear because they either used an open-label design [22][23][24] or co-administered THC with CBD. [25][26][27] Studies in human 28 and rat 29 models of anxiety have reported inverted-U shaped doseresponse effects of CBD. ...
... 17,20 However, sleep quality was lower in the 400mg CBD group compared to placebo, which may be interpreted in the context of greater reductions in cannabis use in this group. Compared to placebo, 800mg CBD reduced cannabis withdrawal symptoms, consistent with previous case reports 22,23 and reduced anxiety symptoms in line with experimental studies in humans 28 and rats. 29 Key strengths of this study include its novel indication for which there is substantial clinical need, and its adaptive Bayesian dose-finding design. ...
Article
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. Methods 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). Findings 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. Interpretation 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. Funding Medical Research Council.
... The present review included three RCTs (107 patients), two open-label trials (28 patients), one case series of four patients, and two case reports for cannabis-related disorders as summarized in Table 2 (Solowij et al., 2018;Crippa et al., 2013;Trigo et al., 2016a;Trigo et al., 2018;Trigo et al., 2016b;Allsop et al., 2014;Pokorski et al., 2017;Shannon & Opila-Lehman, 2015). Of the eight studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in two case reports and one case series (OCEBM, 2019). ...
... The remaining studies were either case series or case reports; all found positive outcomes in withdrawal and cannabis-dependence symptoms (Crippa et al., 2013;Trigo et al., 2016b;Shannon & Opila-Lehman, 2015). Mean age in the case series was 35 years, although the first participant was 19 years old and the second was 27 years old. ...
... mg CBD (Trigo et al., 2016b). Moreover, all participants reported a significant reduction in craving (Crippa et al., 2013;Trigo et al., 2016b;Shannon & Opila-Lehman, 2015), quicker relief (Crippa et al., 2013), lower anxiety, and an improved sleep schedule (Shannon & Opila-Lehman, 2015). However, the case series reported increased craving scores during the first 2 weeks with a subsequent reduction in craving at week 9. CBD was well-tolerated in this patient population, except for decreased appetite reported in one study (Trigo et al., 2016b). ...
Article
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Background: The therapeutic application of cannabidiol (CBD) is gaining interest due to expanding evidence for its use. Objective: To summarize the clinical outcomes, study designs and limitations for the use of CBD and nabiximols (whole plant extract from Cannabis sativa L. that has been purified into 1:1 ratio of CBD and delta-9- tetrahydrocannabinol) in the treatment of psychiatric disorders. Materials and method: A systematic review was conducted including case reports, case series, open-label trials, non-randomized and randomized controlled trials (RCTs). The search resulted in 23 relevant studies on CBD and nabiximols in the treatment of a wide range of psychiatric disorders. The quality of evidence was judged by using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence that ranges from Level 1 to Level 5 based on the quality and study design. These levels of evidence help in grading the recommendations, including Grade A (strong), Grade B (moderate), Grade C (weak), and Grade D (weakest). Results: CBD and CBD-containing compounds such as nabiximols were helpful in alleviating psychotic symptoms and cognitive impairment in patients with a variety of conditions, and several studies provided evidence of effectiveness in the treatment of cannabis withdrawal and moderate to severe cannabis use disorder with Grade B recommendation. There is Grade B recommendation supporting the use of CBD for the treatment of schizophrenia, social anxiety disorder and autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). Grade C recommendation exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies. Conclusion: CBD and CBD-containing compounds such as nabiximols were helpful in alleviating symptoms of cannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD with moderate recommendation. However, there is weaker evidence for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. The evidence for the use of CBD and CBD-containing compounds for psychiatric disorders needs to be explored in future studies, especially large-scale and well- designed RCTs.
... While the previous studies used CBD/THC mixtures, the following three studies described treatments of cannabis dependence with pure CBD. The first study by Crippa et al. (2013), reported a 19-year-old female with cannabis dependence who was treated with oral CBD over 11 days [61]. The dose was 300 mg on day 1, 600 mg on days 2-10 and 300 mg on day 11. ...
... While the previous studies used CBD/THC mixtures, the following three studies described treatments of cannabis dependence with pure CBD. The first study by Crippa et al. (2013), reported a 19-year-old female with cannabis dependence who was treated with oral CBD over 11 days [61]. The dose was 300 mg on day 1, 600 mg on days 2-10 and 300 mg on day 11. ...
... During treatment, cannabis withdrawal, anxiety, and dissociative symptoms progressively decreased. A six-month follow-up period revealed a relapse of cannabis use, however at a lower frequency than on admission [61]. In a second case report, Shannon and Opila-Lehman (2015) described the treatment with 24-18 mg CBD oil adjunctive to citalopram and lamotrigine for a 27-year-old male with cannabis disorder and bipolar disorder. ...
Article
Full-text available
The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.
... 36 Moreover, CBD is an allosteric modulator at mu-and delta-receptors in the opioid system. 37 Recent articles suggested that CBD may be useful to treat addiction to several substances 17,38 including cannabis, 39,40 tobacco, 41,42 alcohol, 43,44 heroin, 45 and cocaine. [46][47][48][49] Furthermore, CBD has demonstrated anxiolytic, 38,50-54 antidepressant, 55 and neuroprotective properties. ...
... The 300 mg/day dose was chosen on the basis of previous studies in human models of anxiety that show that this dose is within the therapeutic window of the inverted U-shaped doseresponse curve of CBD, 80,81 as well as on a previous case study of an inpatient with heavy cannabis use and withdrawal symptoms who was successfully treated with this dose regimen. 39 Preparation for the study ...
Article
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Objective: To assess the efficacy of cannabidiol (CBD) in the management of crack-cocaine craving and the treatment of frequent withdrawal symptoms. Methods: Thirty-one men with a diagnosis of crack-cocaine dependence were enrolled in a randomized, double-blind, placebo-controlled trial. We applied neuropsychological tests and assessed craving intensity, anxiety and depression symptoms, and substance use patterns at baseline and at the end of the trial. The participants were treated with CBD 300 mg/day or placebo for 10 days. During this period, we used a technique to induce craving and assessed the intensity of symptoms before and after the induction procedure. Results: Craving levels reduced significantly over the 10 days of the trial, although no differences were found between the CBD and placebo groups. Craving induction was successful in both groups, with no significant differences between them. Indicators of anxiety, depression, and sleep alterations before and after treatment also did not differ across groups. Conclusion: Under the conditions of this trial, CBD was unable to interfere with symptoms of crack-cocaine withdrawal. Further studies with larger outpatient samples involving different doses and treatment periods would be desirable and timely to elucidate the potential of CBD to induce reductions in crack-cocaine self-administration.
... 72 This approach led to a quick and progressive reduction in withdrawal, depression, anxiety, and dissociative symptoms. 73 ...
... For example, an open-label trial and a case report assessed depressive symptoms in cannabis use disorder through BDI. 62,73 Only one of the open-label studies testing purified cannabidiol assessed symptoms with the POMS. 64 A cross-sectional study that assessed the concentration of cannabidiol in cannabis used by evaluating hair samples included BDI as an outcome. ...
Article
Objective: To review the current evidence for efficacy of cannabidiol in the treatment of mood disorders. Methods: We systematically searched PubMed, Embase, Web of Science, PsychInfo, Scielo, ClinicalTrials.gov , and The Cochrane Central Register of Controlled Trials for studies published up to July 31, 2019. The inclusion criteria were clinical trials, observational studies, or case reports evaluating the effect of pure cannabidiol or cannabidiol mixed with other cannabinoids on mood symptoms related to either mood disorders or other health conditions. The review was reported in accordance with guidelines from Preferred Reporting Items for Systematic reviews and Meta-Analyses protocol. Results: Of the 924 records initially yielded by the search, 16 were included in the final sample. Among them, six were clinical studies that used cannabidiol to treat other health conditions but assessed mood symptoms as an additional outcome. Similarly, four tested cannabidiol blended with Δ-9-tetrahydrocannabinol in the treatment of general health conditions and assessed affective symptoms as secondary outcomes. Two were case reports testing cannabidiol. Four studies were observational studies that evaluated the cannabidiol use and its clinical correlates. However, there were no clinical trials investigating the efficacy of cannabidiol, specifically in mood disorders or assessing affective symptoms as the primary outcome. Although some articles point in the direction of benefits of cannabidiol to treat depressive symptoms, the methodology varied in several aspects and the level of evidence is not enough to support its indication as a treatment for mood disorders. Conclusions: There is a lack of evidence to recommend cannabidiol as a treatment for mood disorders. However, considering the preclinical and clinical evidence related to other diseases, cannabidiol might have a role as a treatment for mood disorders. Therefore, there is an urgent need for well-designed clinical trials investigating the efficacy of cannabidiol in mood disorders.
... Conversely, the use of nabiximols (i.e. a combination of THC and CBD; trade name Sativex®) in a population of recreational cannabis users showed comparable abuse potential with dronabinol (i.e. the enantiomer (−)-trans-Δ9-tetrahydrocannabinol; trade names Marinol® and Syndros®) (Schoedel et al., 2011). No studies concerning the effect of the use of CBD alone in cannabis dependence were identified, although a case report of a 19-year-old woman successfully treated with CBD for the treatment of cannabis withdrawal syndrome has been described (Crippa et al., 2013). Furthermore, Turna et al. (2019) carried out a systematic review to assess the potential of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). ...
... The use of CBD in dissociative disorders (DDs) has not yet been explored. However, a case report described the effectiveness of CBD use in a subject with cannabis dependence and a history of cannabis withdrawal syndrome (Crippa et al., 2013). After ten days of daily CBD treatment, all significant withdrawal, anxiety and dissociative symptoms improved. ...
Article
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most represented phytocannabinoids in Cannabis sativa plants. However, CBD may present with a different activity compared with the psychotomimetic THC. Most typically, CBD is reported to be used in some medical conditions, including chronic pain. Conversely, the main aim of this systematic review is to assess and summarise the available body of evidence relating to both efficacy and safety of CBD as a treatment for psychiatric disorders, alone and/or in combination with other treatments. Eligible studies included randomized controlled trials (RCT) assessing the effect of CBD in a range of psychopathological conditions, such as substance use; psychosis, anxiety, mood disturbances, and other psychiatric (e.g., cognitive impairment; sleep; personality; eating; obsessive-compulsive; post-traumatic stress/PTSD; dissociative; and somatic) disorders. For data gathering purposes, the PRISMA guidelines were followed. The initial search strategy identified some n = 1301 papers; n = 190 studies were included after the abstract's screening and n = 27 articles met the inclusion criteria. There is currently limited evidence regarding the safety and efficacy of CBD for the treatment of psychiatric disorders. However, available trials reported potential therapeutic effects for specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Further large-scale RCTs are required to better evaluate the efficacy of CBD in both acute and chronic illnesses, special categories, as well as to exclude any possible abuse liability.
... CBD itself has been trialed in rats, and found to be effective in ameliorating conditioned place aversion (CPA) produced by THC injection, but did not alter CPP (142). In human case studies, CBD has also been found to reduce selfreported cannabis use to non-use in a dependent male (128), and to reduced cannabis withdrawal in another (135), although the latter case study did find the subject to have relapsed after a 6months follow up (135). CBD may have potential in reducing euphoria associated with cannabis use, despite not directly reducing cannabis use (124). ...
... CBD itself has been trialed in rats, and found to be effective in ameliorating conditioned place aversion (CPA) produced by THC injection, but did not alter CPP (142). In human case studies, CBD has also been found to reduce selfreported cannabis use to non-use in a dependent male (128), and to reduced cannabis withdrawal in another (135), although the latter case study did find the subject to have relapsed after a 6months follow up (135). CBD may have potential in reducing euphoria associated with cannabis use, despite not directly reducing cannabis use (124). ...
Article
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Substance use disorder is characterized by repeated use of a substance, leading to clinically significant distress, making it a serious public health concern. The endocannabinoid system plays an important role in common neurobiological processes underlying substance use disorder, in particular by mediating the rewarding and motivational effects of substances and substance-related cues. In turn, a number of cannabinoid drugs (e.g., rimonabant, nabiximols) have been suggested for potential pharmacological treatment for substance dependence. Recently, cannabidiol (CBD), a non-psychoactive phytocannabinoid found in the cannabis plant, has also been proposed as a potentially effective treatment for the management of substance use disorder. Animal and human studies suggest that these cannabinoids have the potential to reduce craving and relapse in abstinent substance users, by impairing reconsolidation of drug-reward memory, salience of drug cues, and inhibiting the reward-facilitating effect of drugs. Such functions likely arise through the targeting of the endocannabinoid and serotonergic systems, although the exact mechanism is yet to be elucidated. This article seeks to review the role of the endocannabinoid system in substance use disorder and the proposed pharmacological action supporting cannabinoid drugs' therapeutic potential in addictions, with a focus on CBD. Subsequently, this article will evaluate the underlying evidence for CBD as a potential treatment for substance use disorder, across a range of substances including nicotine, alcohol, psychostimulants, opioids, and cannabis. While early research supports CBD's promise, further investigation and validation of CBD's efficacy, across preclinical and clinical trials will be necessary.
... Thus, recent interest has turned to clinically evaluating CBD alone for managing CUD-related problems. Crippa et al. (2013) found that CBD monotherapy led to a rapid decrease in cannabis withdrawal symptoms. Another clinical study, comparing p.o. CBD alone versus placebo, found no difference between groups for cannabis-induced subjective effects (Haney et al., 2016). ...
... To our knowledge, this is the first study that has evaluated the effect of CBD on spontaneous cannabinoid withdrawal in an animal model and explored some of the underlying neurobiological mechanisms potentially involved. Although there is currently little clinical evidence for this treatment approach and especially for the effects of CBD alone, our results are consistent with some existing findings, such as those reported by Crippa et al. (2013). Therefore, additional translational studies combining both clinical and basic perspectives are warranted to clarify the therapeutic potential of CBD for cannabinoid withdrawal symptoms. ...
... In a case report, CBD also helped symptoms of cannabis withdrawal in a 19-year-old woman with CUD [107]. Shannon and Opilla-Lehman [108] reported a case where CBD oil decreased the addictive use of marijuana and provided anxiolytic and sleep benefits. ...
Article
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Purpose of review There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines. Recent findings Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity. Summary Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.
... [21,41] Unlike THC, CBD is neglected and obscured [27] but was found to reduce cannabis withdrawal symptoms in an open-label case study. [42] CBD effectively neutralises dosedependent psychosis, [43] THC-induced paranoia, positive psychotic symptoms, [43,44] lessens THC-induced anxiety, [45] and memory impairment. [43,44] The THC: CBD concentration ratios contribute to the overall psychotropic and therapeutic effects [46] while CBD's protective effect on THC is not yet proven. ...
Article
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Cannabis sativa is a complex domesticated plant that has an unstable taxonomy. It is the most utilised illicit substance that has gained prominence in some parts of the world as it is used for therapeutic and recreational purposes. C. Sativa has also been used to manage numerous medical conditions since antiquity. The pharmacological benefits of C. sativa are still subject to intense research due to inconsistent outcomes. C. sativa, like other psychoactive substances, has both medical and psychological side effects. Despite the lack of knowledge, medical practitioners continue to recommend this substance. This review aims to highlight the effects of legalisation and liberalisation on the global trend of cannabis use. A search was conducted on Google Scholar and Medline from 2012 to date. The results showed that cannabis was found to be effective in the management of some medical conditions, though more work is required. Recreational use is rising due to a reduced perception of harm and the availability of more potent species. Cannabis use persists despite the several medical and psychological side effects. It is concluded that there is a shortage of information on the safety and pharmacological properties of C. sativa, and more work is required.
... Cannabidiol significantly reduced cue-induced craving and anxiety, while exerting no significant effect on cognitive function (18). A study on individuals diagnosed with cannabis use disorder found that cannabidiol reduced cannabis-induced withdrawal, anxiety, and dissociative symptoms while decreasing relapse (39). In summary, there seems to be substantial evidence to consider cannabidiol a promising candidate to prevent or treat methamphetamine use disorders. ...
Article
Background: Methamphetamine use is associated with several negative consequences, including neurotoxicity and greater probability of exhibiting a substance use disorder. Sigma1 receptor is involved in the neurobiological basis of several drug use disorders. Cannabidiol has received attention in the treatment of drug use disorders and neurotoxicity. Objectives: To investigate the effects of cannabidiol on methamphetamine-induced conditioned place preference (CPP) and the viability of PC12 cells. Methods: Adult male rats (n = 70) underwent methamphetamine (2 mg/kg, IP) induced CPP, and were administered cannabidiol (10, 20, 40, or 80 mg/kg, IP) during the methamphetamine withdrawal period for five consecutive days. Methamphetamine (0.5 mg/kg) was then injected to reactivate CPP. Four brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, and hippocampus) were extracted after the last test. PC12 cells were treated with cannabidiol, Sigma1R-siRNA, or BD1047 before methamphetamine exposure. Results: Administration of 20, 40, or 80 mg/kg cannabidiol facilitated CPP extinction (80 mg/kg, p < .001) and prevented CPP development (80 mg/kg, p < .0001). This was associated with changes in the expression of Sigma1R (ventral tegmental area, 80 mg/kg, p < .0001) in the four brain regions. Cannabidiol protected the PC12 cell's viability (10 μM, p = .0008) and inhibited the methamphetamine-induced activation of the AKT/GSK3β/CREB signaling pathway by mediating Sigma1R (10 μM, p < .0001). Conclusions: Cannabidiol seems to inhibit the rewarding effects of methamphetamine and the effects of this drug on cell viability. Sigma1R should be given further consideration as a potential target for cannabidiol.
... Currently, there are no FDA-approved treatments for cannabis use disorders, however, research to find one is actively being done [265]. A plethora of drugs such as rimonabant [266][267][268], N-acetyl cysteine [269], Gabapentin [270,271], Cannabidiol [272][273][274][275], Dronabinol [23,[276][277][278][279][280][281], Naltrexone [158,282], Zolpidem (for the treatment of sleep disturbance associated with cannabis withdrawal) [276] are currently under investigation as a potential treatment for cannabis use disorder. Despite all these drugs are currently in preclinical and clinical phases, a few SR preparations have been reported that are discussed below. ...
Article
Substance use disorders (SUDs) are a leading cause of death and other ill health effects in the United States and other countries in the world. Several approaches ranging from detoxification, behavioral therapy, and the use of antagonists or drugs with counter effects are currently being applied for its management. Amongst these, drug therapy is the mainstay for some drug abuse incidence, as is in place specifically for opioid abuse or alcohol dependence. The severity of the havocs observed with the SUDs has triggered constant interest in the discovery and development of novel medications as well as suitable or most appropriate methods for the delivery of these agents. The chronic need of such drugs in users warrants the need for their prolonged or sustained systemic availability. Further, the need to improve patient tolerance to medication, limit invasive drug use and overall treatment outcome are pertinent considerations for embracing sustained release designs for medications used in managing SUDs. This review aims to provide an overview on up-to-date advances made with regards to sustained delivery systems for the drugs for treatment of different types of SUDs such as opioid, alcohol, tobacco, cocaine, and cannabis use disorder. The clinical relevance, promises and the limitations of deployed sustained release approaches along with future opportunities are discussed.
... One of them was an RCT that found no significant changes in BDI scores during the acute treatment period of the trial but found a reduction in BDI scores in the cannabidiol 400 mg/day group compared with the placebo in the follow-up weeks [3]. An open-label trial tested the impact of cannabidiol 200 mg/day on cannabis use, showing a decrease in depressive symptoms according to the BDI [45] and a similar result was found in a single case report that tested cannabidiol 300 to 600 mg/day in cannabis use disorder [46]. ...
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Purpose of Review Preclinical studies have demonstrated that cannabidiol improves depressive-like behaviors in animal models, raising its plausibility to be investigated as a treatment for major depressive disorder (MDD) and bipolar disorder (BD). Therefore, our aim is to review the available clinical data of cannabidiol in the treatment of mood disorders. Recent Findings There are no published randomized clinical trials (RCTs) that investigated the efficacy of cannabidiol in mood disorders, either alone or in combination with other cannabinoids. Similarly, there are no published trials with affective symptoms as the primary outcome. There are a few studies which investigated mood symptoms as secondary outcomes within medical conditions or non-mood disorder psychiatric conditions, and the results are conflicting due to the methodological differences between studies. Nevertheless, studies have found cannabidiol to be well-tolerated with few adverse effects such as diarrhea and somnolence. Summary There are no RCT data for the efficacy of cannabidiol in the treatment of MDD or BD, but few studies assessed its efficacy on mood symptoms as secondary outcomes in medical and non-psychiatric disorders populations with conflicting results. Thus, currently, there is insufficient evidence to recommend cannabidiol as a treatment for mood disorders, and high-quality clinical trials are urgently needed.
... A case report of a 19-year-old female with cannabis use disorder showed a quick decrease in cannabis withdrawal symptoms, including anxiety and dissociation, after the patient used oral CBD for 11 days. Although she reported having relapsed at the 6-month follow-up, the frequency of cannabis use was reduced (Crippa et al., 2013). Another case report studied the effects of CBD on cannabis withdrawal symptoms. ...
Article
Introduction Cannabidiol (CBD) is a phytocannabinoid found in the Cannabis plant. CBD has received significant medical attention in relation to its anticonvulsant, anxiolytic, and antipsychotic characteristics. An increasing number of studies focusing on the anti-addictive properties of CBD have recently been published. In this systematic review, we aim to offer a comprehensive overview of animal and human studies regarding the impact of CBD on substance use disorders (SUDs). Methods A systematic search was performed on the PubMed database in February 2021. We included all articles assessing the effects of CBD on substance use disorders. Results The current systematic review suggests that CBD might offer promising therapeutic potential for the treatment of SUD, based on available animal and human studies. Animal studies showed a positive impact of CBD in the context of alcohol, opioids, and methamphetamine use (e.g., diminishing of drug-seeking behaviors). The results for cocaine use were mixed among reviewed studies, and CBD was not found to have an effect in animal studies on cannabis use, No animal study was identified that focused on the impact of CBD on nicotine use. Human studies showed a positive impact of CBD in the context of nicotine, cannabis, and opioid use (e.g., frequency and quantity of consumption). In contrast, CBD was not found to have an effect in human studies on cocaine or alcohol use. No human study was identified that investigated the impact of CBD on methamphetamine use. Conclusions CBD might offer promising therapeutic potential for the treatment of SUD, especially for nicotine, cannabis, and opioid use disorders, based on available human studies. The available research evidence is, however, sparse and more research on humans is needed.
... This process has been described in animal models [24], in clinical studies [22] and in the case of other drugs of abuse or non-drug reinforcers [25][26][27][28]. Clinical studies have reported mild therapeutic effects of CBD or CBD-containing drugs for the treatment of tobacco [29] and cannabis [30][31][32] withdrawal. Nevertheless, a recent study showed that CBD failed to modulate craving and relapse in individuals with cocaine use disorder when administered during withdrawal [33]. ...
Article
Cocaine is a highly consumed drug worldwide which directly targets brain areas involved in reinforcement processing and motivation. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-induced addictive behavior, although many questions about the mechanisms of action and the specific affected processes remain unknown. Moreover, its effects on cue-induced cocaine-craving incubation have never been addressed. The present study aimed to assess the effects of cannabidiol (20 mg/kg, i.p.) administered during the acquisition of cocaine self-administration (0.75 mg/kg/infusion) and demand task or during cocaine abstinence and craving. Moreover, we measured the alterations in expression of AMPAR subunits and ERK1/2 phosphorylation due to cannabidiol treatment or cocaine withdrawal. Our results showed that cannabidiol reduced cocaine intake when administered during the acquisition phase of the self-administration paradigm, increased behavioral elasticity and reduced motivation for cocaine in a demand task. Cannabidiol also reduced GluA1/2 ratio and increased ERK1/2 phosphorylation in amygdala. No effects over cocaine-craving incubation were found when cannabidiol was administered during abstinence. Furthermore, cocaine withdrawal induced changes in GluA1 and GluA2 protein levels in the prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK1/2 phosphorylation in ventral striatum. Taken together, our results show that cannabidiol exerts beneficial effects attenuating the acquisition of cocaine self-administration, in which an operant learning process is required. However, cannabidiol does not affect cocaine abstinence and craving.
... So, CBD is a bicyclic compound, whose breakdown of the tetrahydropyran ring leads to becoming a cannabinoid devoid of psychoactive properties due to low affinity for CB 1 and CB 2 receptors, but with activity at other receptors such as non-endocannabinoid associated to G protein-coupled receptors (GPCR), serotonin receptors (5-HT) and opioid receptors (OR) (Silvestro et al., 2019). Thus, the role of CBD has long been recognized as a therapy in neuronal diseases (anxiety, depression, refractory epilepsy) (Campos et al., 2016;Reddy, 2016;Silvestro et al., 2019), as well as inflammatory disorders and neurodegenerative diseases (Parkinson's, Alzheimer's disease, amyotrophic lateral sclerosis) (Maayah et al., 2020;Petrosino et al., 2018;Pisanti et al., 2017); like, it has been used to treatment of the cannabis withdrawal syndrome (Bonnet and Preuss, 2017;Crippa et al., 2013;Shannon and Opila-lehman, 2015). Likewise, CBD and agonizts, have proven valuable against tumor cell proliferation and angiogenesis, and induce apoptosis in various types of cancer in both in vitro and in vivo studies (Kovalchuk and Kovalchuk, 2020). ...
Article
Background Cannabis sativa has been attributed to different pharmacological properties. A number of secondary metabolites such as tetrahydrocannabinol (THC), cannabinol (CBD), and different analogs, with highly promising biological activity on CB1 and CB2 receptors, have been identified. Methods Thus, this study aimed was to evaluate the activity of THC, CBD, and their analogs using molecular docking and molecular dynamics simulations (MD) methods. Initially, the molecules (ligands) were selected by bioinformatics searches in databases. Subsequently, CB1 and CB2 receptors were retrieved from the protein data bank database. Afterward, each receptor and its ligands were optimized to perform molecular docking. Then, MD Simulation was performed with the most stable ligand-receptor complexes. Finally, the Molecular Mechanics-Generalized Born Surface Area (MM-PBSA) method was applied to analyze the binding free energy between ligands and cannabinoid receptors. Results The results obtained showed that ligand LS-61176 presented the best affinity in the molecular docking analysis. Also, this analog could be a CB1 negative allosteric modulator like CBD and probably an agonist in CB2 like THC and CBD according to their dynamic behavior in silico. The possibility of having a THC and a CBD analogue (LS-61176) as a promising molecule for experimental evaluation since it could have no central side-effects on CB1 and have effects of CB2 useful in pain, inflammation, and some immunological disorders. Docking results were validate using ROC curve for both cannabinoids receptor where AUC for CB1 receptor was 0.894 ± 0.024, and for CB2 receptor AUC was 0.832 ± 0,032, indicating good affinity prediction.
... Daily assessments showed a rapid decrease in withdrawal symptoms leading to a score of zero in all tests by day 6. A 6 months follow-up showed a relapse in cannabis use but at a lower frequency (once or twice a week vs. 7 days a week) (Crippa et al., 2013). Another case report study evaluated the use of a CBD oil in a 27 year-old male presenting a long-standing diagnosis of bipolar disorder and a daily addiction to cannabis use. ...
Article
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Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.
... 5 Also, the absence of withdrawal symptoms is consistent with existing evidence from animal and human studies. 11,12 These findings, added to previous evidence of neuroprotective, pneumoprotective, antioxidant, and anti-inflammatory 3 properties of CBD suggest that it can effectively prevent and manage burnout symptoms and other mental health outcomes in health care workers during the COVID-19 pandemic. ...
... 102,104 Os participantes do estudo não foram capazes de diferenciar entre a medicação ativa e o tratamento com placebo, sugerindo que a intoxicação ou alterações subjetivas com nabiximols não foram percebidas como significativamente diferentes do placebo, não constituindo por isso risco de criar abuso ou dependência mesmo em doses altas, tal como previamente descrito. 103,105 Importa referir que até à data não foram identificados estudos que procuraram avaliar o uso isolado de CBD na dependência de canábis, embora tenha sido descrito um case-report de uma mulher de 19 anos cuja dependência terá sido eficazmente tratada apenas com CBD.106 Um recente estudo holandês concluiu que a utilização sob a forma fumada de variantes de canábis medicinal com baixa concentração de THC (0.4% THC e 9% CBD) pode, por vezes, ser dificilmente aceite e eficaz no tratamento de pacientes com uma perturbação psicótica e SUD concomitante, dada a diferença abrupta nas concentrações de THC utilizadas por estes pacientes, tendo alguns deles interrompido o estudo e retomando os consumos de espécies de canábis de alta potência a que estariam habituados, em busca ora do efeito eufórico, ora da sensação de relaxamento.107 Posteriormente, um novo ensaio clínico realizado por outros autores holandeses veio concluir que nos pacientes com esquizofrenia sob antipsicóticos e motivados a interromper o consumo de canábis, uma variante mais branda contendo um mínimo de concentração de THC de 4% (e 8% de CBD) pode representar um passo intermédio para cessar estes consumos, tendo esta formulação uma aceitação bastante satisfatória entre os participantes. ...
Article
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Objetivos: Avaliar o papel do canabidiol (CBD) como tratamento coadjuvante em doentes com psicose inaugural ou esquizofrenia sob tratamento com antipsicóticos, de forma a melhorar a adesão terapêutica. Métodos: Revisão da literatura, realizando uma pesquisa no MedLine por artigos subordinados ao tema, escritos em inglês e português, publicados entre 2005 e 2019. Resultados: A última década apresentou um aumento notável na literatura relativa ao CBD, reconhecidos os seus efeitos anti‑inflamatórios e neuroprotetores. Embora exista uma limitada evidência relativamente ao uso do CBD no tratamento de perturbações psiquiátricas, os estudos disponíveis relataram potencial terapêutico nas perturbações por uso de substâncias (PUSs), psicose e ansiedade. O CBD parece ter a capacidade de reduzir os sintomas psicóticos e o comprometimento cognitivo associado ao uso de canábis e diminuir o risco de desenvolver psicose neste contexto. Os primeiros estudos clínicos utilizando CBD como tratamento em pacientes com sintomas psicóticos confirmam o seu potencial como um composto antipsicótico eficaz com efeitos laterais desprezáveis, com excelente perfil de segurança e tolerabilidade. O canabidiol é também capaz de modular os circuitos neuronais envolvidos nas PUSs, apresentando potencial de reduzir a dependência nestes indivíduos. Resultados recentes vieram reforçar que o tratamento com agonistas canabinóides, em combinação com intervenções psicoterapêuticas, permite reduzir o uso ilícito de canábis. Conclusões: Atualmente, o CBD é um agente terapêutico emergente que demonstrou eficácia potencial no tratamento de distúrbios psicóticos, PUSs e coexistência desses distúrbios, podendo representar um agente terapêutico mais facilmente aceite e tolerável para esta população particularmente vulnerável.
... Study participants were unable to differentiate between active medication and placebo treatment, suggesting that intoxication or subjective changes with nabiximols were not perceived to be significantly different from placebo, and therefore did not constitute a risk of creating abuse or dependence even in doses high, as previously described [103,105] . It should be noted that to date, no studies have been identified that sought to assess the isolated use of CBD in cannabis addiction, although a case report of a 19-year-old woman whose dependence will have been effectively treated with CBD alone has been described [106] . ...
Article
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Background: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been the most studied and debated cannabinoids present in cannabis. The last decade has shown a notable increase in literature regarding CBD, recognizing its anti-inflammatory and neuroprotective effects. Although there is limited evidence regarding the use of CBD in psychiatric disorders' treatment, studies so far available have reported therapeutic potential in substance use disorders (SUDs), psychosis and anxiety. Methods: Literature review, performing a research in MedLine for articles on the subject, written in English and Portuguese, published until 2019, resulting in a total of 108 selected publications. Results: CBD appears to reduce psychotic symptoms and cognitive impairment associated with cannabis use and decrease the risk of developing psychosis in this context. Early clinical studies using CBD as treatment in patients with psychotic symptoms confirm its potential as an effective antipsychotic compound with negligible side effects, with excellent safety profile and tolerability. Cannabidiol is also capable of modulating the neuronal circuits involved in SUDs, presenting the potential to reduce dependence in these individuals. Discussion: CBD is currently an emerging therapeutic agent that has shown potential efficacy in the treatment of psychotic disorders and SUDs, and may represent a more easily accepted and tolerable therapeutic agent for this particularly vulnerable population.
... Although different preclinical studies have evaluated the effects of CBD on acquisition of cocaine self-administration (Mahmud et al., 2016;Luján et al., 2018), extinction (Lujan et al., 2020, reinstatement (Mahmud et al., 2016;Gonzalez-Cuevas et al., 2018;Luján et al., 2018;Lujan et al., 2020), and spontaneous cocaine withdrawal (Gasparyan et al., 2020), its effects on abstinence and cocaine-craving incubation have not yet been confirmed. Of note, CBD or CBDcontaining drugs have been clinically tested for the treatment of tobacco (Hindocha et al., 2018) and cannabis (Crippa et al., 2013;Allsop et al., 2014;Trigo et al., 2018) withdrawal, but not for cocaine. Moreover, none of these studies specifically assessed incubation of craving. ...
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Background and Purpose To remain abstinent represents one of the major challenges for the treatment of cocaine use disorder. Cocaine seeking elicited by drug-associated cues progressively intensifies during abstinence in a process termed incubation of craving, representing an aggravating factor for relapse. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-seeking behaviour, although its effects on cocaine-craving incubation have never been elucidated. Experimental Approach We developed a mouse model of behavioural economic analysis of demand curves and incubation of cue-induced cocaine craving. Changes in the protein expression of AMPAR subunits and ERK 1/2 phosphorylation were analysed. We also assessed the effects of cannabidiol (20 mg·kg ⁻¹ ) administered either during acquisition of cocaine self-administration or abstinence. Key Results Mice efficiently performed the demand task and incubation of cocaine craving. Besides, changes in GluA1 and GluA2 protein levels were found along the abstinence in prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK 1/2 phosphorylation in ventral striatum. Cannabidiol reduced ongoing cocaine intake when administered during the acquisition phase of the self-administration, but failed to alter the subsequent demand task performance and incubation of cocaine craving. No effects were found when cannabidiol was administered during the abstinence period. Conclusion and Implications We provide here a novel model of behavioural economic analysis of demand curves and cue-induced incubation of cocaine-seeking behaviour for mice. Moreover, we show that cannabidiol exerts differential effects on the current model depending on the self-administration phase in which it was administered. What is already known Behavioural economics and incubation of cocaine craving are well-stablished paradigms to evaluate cocaine seeking in rats. CBD reduces cocaine-seeking and cocaine-taking behaviours. What this study adds A mouse model of behavioural economic analysis of demand curves and incubation of cue-induced cocaine craving. CBD reduces cocaine self-administration and has no effect over demand task and cocaine-craving incubation. Clinical significance A new behavioural model for studying cocaine addiction in mice. CBD exerts differential effects depending on when it was administered in the addictive process. T ables of L inks
... Additional results supporting the anxiolytic properties of CBD come from clinical trials suggesting that nabiximols, a medication containing THC (2.7 mg) and CBD (2.5 mg) and used to treat spasticity in multiple sclerosis, reduced anxiety, and craving in patients with cannabis use disorder [159]. A previous case report indicated that oral CBD administration reduced cannabis withdrawal, anxiety and dissociative symptoms [166]. Besides, acute CBD vaporization improved emotional processing affect recognition and prevented the impairment of ambiguous face recognition induced by THC [160]. ...
Article
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The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.
... Codzienna ocena wykazała wycofanie się symptomów abstynencyjnych, lękowych i dysocjacyjnych podczas leczenia. Po 6 miesiącach, podczas kontroli, pacjentka stwierdziła, że ilość palonej marihuany po leczeniu zmniejszyła się do 1-2 papierosów z marihuaną tygodniowo [14]. ...
Article
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Addiction is a chronic recurrent disorder characterized by substance abuse and withdrawal syndrome with "hunger." Cannabidiol (CBD), a non-psychoactive cannabinoid, is used to treat neurological conditions, including substance or behavioral addiction (behavioral addiction). This analysis focuses on evaluating the results of available clinical trials, assessing the potential of CBD pharmacotherapy for drug addiction, smoking, cannabis and alcohol use disorders. Clinical trials registered in the clinicaltrials.gov database and the resources of the Pubmed database were analyzed in search of those published in 2010–2020. The review was conducted in July and August 2020. The search terms were for CBD and addiction. The studies sought include randomized controlled and crossover (RCT) studies, open label clinical trials and case studies. 9 articles were identified for review: 6 small RCTs, 2 case studies and 1 open-label clinical study including: 5 studies on CBD in cannabis use disorders (including 63 patients in total; 25 women and 38 men), 2 studies on CBD use for treatment of addiction to smoking (54 patients; 26 women and 28 men), 1 study of CBD in the treatment of heroin dependence (9 patients; 9 men) and 1 study of CBD in drug addiction treatment (38 patients; 19 women and 19 men). Cannabidiol may be a therapeutic option for treating addiction. It is active not only as a substitute, but also supports the treatment of other addictions. Good tolerance and neuroprotective effect determine its high therapeutic potential. aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa
... CBD has been shown to interfere with brain circuits that mediate drug craving and seeking elicited by drug-related enviromental contexts (Koob & Volkow, 2010;Gonzalez-Cuevas et al., 2018). Moreover, CBD has presented therapeutic potential in treating drug and ethanol addiction in patients (Crippa et al., 2013;Hurd, 2015;Sloan, Gowin, Ramchandani, Hurd, & Le Foll, 2017;Batalla, Janssen, Gangadin, & Bossong, 2019). Cannabidiol also reduced the reinforcement properties and motivation and, prevented ethanol-induced relapse in C57 mice (Viudez-Martinez et al., 2018). ...
Article
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The abrupt interruption of ethanol consumption increases anxiety-like behaviors in rodents and may reflect different aspects of ethanol dependence in humans. Measuring emotional behaviors resulting from ethanol withdrawal may aid in testing potential pharmacological agents for the treatment of ethanol dependence. In the present study, we used forced expositon to ethanol 20% during 10 days to mice, followed by abrupt withdrawal of the substance. The animals were evaluated 7, 24 and 35 h after ethanol withdrawal in three different behavioral paradigms, i.e., the open field (OF), light dark (LD) transition and elevated plus maze (EPM), tests usually used to measure anxiety-like behaviors. This was done with the aim of identifying the best interval as well as the most appropriate behavioral test to detect the effects of drugs that can relieve anxiety induced by ethanol withdrawal in mice. We also evaluated the effect of cannabidiol (CBD 10, 30 and 60 mg/kg) in ethanol withdrawn mice because it has been shown to alliviate drug addicton and present anti-anxiety effects. Our results show significant behavioral changes at 24 h following ethanol withdrawal. Diazepam (4 mg/kg), used as a positive control, counteracted the effects of ethanol withdrawal in OF, LD box and EPM. Cannabidiol attenuated anxiety-like behavior produced at 24 h after abstinence from ethanol exposure only in the EPM test.
... Furthermore, 49.1% of cannabis users reporting headaches (type not specified) indicated an association with drug withdrawal. This may be an important observation, as others have noted cannabis withdrawal as a precipitant of migraine (el-Mallakh 1987;Crippa et al. 2013;Adorjan et al. 2020). Caution is warranted in the interpretation of these data as most are derived from case studies or reports of mixed substance abuse. ...
Article
An Industry founded on the promotion of presumed health and wellness benefits of cannabis use continues to grow in the United States, despite the lack of substantial evidence in support of the many claims being made. Several hypotheses exist regarding the role of endocannabinoids in human health and the pertinence of phytocannabinoids as pharmacotherapies for addressing their dysregulation. An opinion is offered regarding the tenuous nature of these assumptions and questions are raised regarding how best to interpret the complex metabolic interplay of the still vaguely defined endocannabinoid system.
... THC and 3% CBD (Di Forti et al., 2009). Higher levels of CBD do not reduce the pleasurable effects of THC (Haney et al., 2016;; however, they may ameliorate adverse effects of THC such as the heightened salience of food , memory impairment , positive symptoms of psychosis (Schubart et al., 2011), and withdrawal symptoms (Crippa et al., 2013). Thus, the use of strains with high-CBD:THC ratios may be beneficial, yet users may gravitate toward high-THC (and low-CBD) strains based on their current understandings. ...
Article
Background: The legal status of cannabis is rapidly evolving, outpacing systematic research and educational efforts. Aims: We investigated knowledge of cannabinoid content and dosages among frequent cannabis users. Methods: A brief survey was administered in April 2019 (N = 472) at a cannabis advocacy event in a state with legal medical and recreational adult cannabis use. Findings: Most participants (67%) used cannabis every day, 85% used cannabis for health or medical purposes. Knowledge of cannabis was mostly from participants’ own experiences (78%), with some receiving information from a medical cannabis caregiver or dispensary (23%) or their primary care provider (18%). The majority reported not knowing the effective dosages of THC (53% of participants) or CBD (68% of participants), other participants gave average estimates of 91 mg and 177 mg, respectively. Participants’ average estimates for high-THC (52%) and high-CBD (53%) as well as low-THC (28%), and low-CBD (30%) strains of cannabis were considerably higher than currently accepted definitions. Men, European Americans, and participants who had medical cannabis cards were more accurate in cannabinoid concentration estimates. Conclusions: Frequent cannabis users reported low knowledge of and substantially overestimated cannabinoid content. The importance of education and research on cannabinoid dosages grows with increasing cannabis accessibility.
... In a case study, CBD was added to the treatment of a cannabis addict with bipolar disorder, while cannabis use was discontinued as well as improved sleep patterns (15). In another case report, CBD has been shown to be useful in cannabis withdrawal symptoms (16). However, it has been reported that CBD may have potential in reducing euphoria associated with cannabis use, despite not directly reducing cannabis use (14). ...
Article
Cannabidiol (CBD) is the second-most common phytocannabinoid found in cannabis plants after tetrahydrocannabinol (THC). Unlike THC, no psychoactive effect has been demonstrated for CBD. Due to its effect on various neurotransmitter systems, it has been tried for the treatment of many physical and psychiatric diseases, considering its neuroprotective and anti-inflammatory properties. In this Editorial, the characteristics of CBD and its place in various psychiatric disorders will be briefly discussed. © 2019 Yerkure Tanitim ve Yayincilik Hizmetleri A.S. All rights reserved.
... 20 Likewise, in another double-blind placebo-controlled study, a dose of 6.7 mg/kg reduced subjective anxiety in 10 adults with generalised SAD. 5 Additionally, in a case report in a child, 0.6 mg/kg/d increased sleep quality and duration, and decreased anxiety secondary to PTSD. 10 Lastly, it was found that doses of 5 mg/kg/d prevented occurrence of graft-vs-host disease in a phase II clinical trial (n = 48) and 5-10 mg/kg/d doses have been shown in a case report to remove withdrawal symptoms from a patient with cannabis dependency. 29,38 Within studies that compared CBD against a placebo or control Analysis of these data revealed that a greater proportion of studies reported a beneficial effect of CBD in the add-on therapy group compared to the monotherapy group (n = 6 and n = 2 respectively). ...
Article
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Aims: Cannabidiol is a cannabis-derived medicinal product with potential application in a wide-variety of contexts, however its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of cannabidiol in a variety of medical contexts. Methods: Publications involving administration of cannabidiol alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov. Results: A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. 23 studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 - 50 mg/Kg/day. Plasma concentrations were not provided in any publication. Cannabidiol was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of cannabidiol on reducing seizure frequency or severity (average 15 mg/Kg/day within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n=6-62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/Kg/day) were used in these studies. Conclusion: This review highlights cannabidiol has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.
... CBD improved subicular and CA1 subfields volumes in the brains of chronic cannabis users, suggesting a protective role of CBD against brain structural harms conferred by chronic cannabis use [40]. Moreover, CBD was shown to have low abuse liability [50,51] and to be effective in decreasing cannabis addiction [52,53]. ...
Article
Background Currently, there is great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex®, a purified CBD medicine formulated for oral administration for treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization is considering rescheduling cannabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake. Methods Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Cochrane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were included to provide balance in estimating risk/benefit. Results CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, hepatocellular injuries, spermatogenesis reduction, organ weight alterations, male reproductive system alterations, and hypotension, although at doses higher than recommended for human pharmacotherapies. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence. Conclusion CBD has proven therapeutic efficacy for serious conditions such as Dravet and Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other conditions. However, AEs and potential drug-drug interactions must be taken into consideration by clinicians prior to recommending off-label CBD.
... For example, several preclinical studies have shown that CBD reduces opiate intoxication and reward, and may prevent opioid Prud'homme, Cata, & Jutras-Aswad, 2015;Ren, Whittard, Higuera-Matas, Morris, & Hurd, 2009) and stimulant relapse (Fischer et al., 2015;Karimi-Haghighi & Haghparast, 2018;Prud'homme et al., 2015). CBD also appears to be a promising intervention for other addictive drugs, reducing the number of cigarettes smoked in tobacco smokers (Morgan, Das, Joye, Curran, & Kamboj, 2013), and ameliorating symptoms of cannabis withdrawal in a case report (Crippa et al., 2013). Furthermore, there is some evidence that CBD oil may be effective in tapering off daily marijuana use in individuals dependent on cannabis (Shannon & Opila-Lehman, 2015), although CBD-containing capsules did not influence self-administration of smoked cannabis in a laboratory setting (Haney et al., 2016). ...
Article
Increased access to medicinal and recreational cannabis will be accompanied by greater exposure to its chemical constituents, including Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the primary nonpsychoactive compound. Increasing attention has focused on CBD, in part, due to its potential therapeutic properties. Relatively little is known about how CBD might interact with other commonly used drugs. While a number of studies have explored the influence of cannabis or Δ9-THC on alcohol consumption and treatment outcomes, few have examined the effects of CBD on alcohol-related outcomes. This article reviews preclinical and human studies examining the effects of CBD administration on alcohol responses. Preliminary preclinical results suggest that CBD can attenuate alcohol consumption and potentially protect against certain harmful effects of alcohol, such as liver and brain damage. Also reviewed herein are the few existing studies involving CBD and alcohol coadministration in humans. The paucity of such studies precludes any definitive conclusions relating to CBD-alcohol interactions. Effects of CBD on alcohol use and potential therapeutic implications for alcohol use disorder are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
... Therefore, it is suggested that treatment with low doses of CB1 receptor agonists could reduce the severity of withdrawal symptoms [61]. Low doses of Δ9-THC were tested to improve withdrawal symptoms; however, these doses exhibited reinforcing properties in chronic Cannabis users, eliminating THC as a viable treatment [62]. ...
... The fi rst case report describing that CBD use could reduce cannabis withdrawal syndrome was published in 2013 (Crippa et al., 2013). The case involved a 19-year-old woman with cannabis withdrawal syndrome treated with oral CBD for 10 days. ...
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The history of the use of cannabis for the treatment of substance-related disorders and harm reduction is relatively recent. Although evidence of the use of cannabis for the treatment of multiple disorders, including such varied conditions as pain and malaria, has been documented across time and cultures (Landa, Jurica, Sliva, Pechackova, & Demlova, 2018), the use of herbal cannabis for the treatment of drug abuse and dependence emerged with the legalization of medicinal cannabis in Canada and several states of the United States in the last 20 years. California was the first state to legalize medical cannabis in 1996. Since then evidence has emerged from preclinical research, ethnographical research, observational studies, and a few clinical trials, some of them still in development. Moreover, in the last decade, several preclinical and clinical studies are showing evidence that cannabidiol (CBD) could be a treatment option for substance-related disorders. After delta9-tetrahydrocannabinol (or simply THC), CBD is the second most abundant cannabinoid in the cannabis plant. In contrast to THC, CBD does not produce euphoria or cognitive deficits, and so has no potential for abuse. In this chapter we will discuss both the treatment of substance use disorders and harm reduction, acknowledging that these are concepts that refer to completely different issues and practices. We decided to use this approach because almost all evidence coming from observational studies suggests that herbal cannabis is not always used to reach complete abstinence from other drugs, but rather to improve quality of life or as a substitute for more dangerous drugs such as cocaine and heroin.
... To date, only a few case reports have evaluated the therapeutic usefulness of CBD alone for CUD. Crippa et al. [154] administered CBD for 11 days (300 mg on day 1, 600 mg on days 2-10, and 300 mg on day 11) to a 19-year-old female with cannabis dependence who experiences withdrawal symptoms when she tried to cease cannabis use. Daily assessments showed a rapid decrease in withdrawal symptoms, leading to a score of zero in all tests by day 6. ...
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Cannabis use disorders (CUD) represent a serious public health problem in occidental societies. Despite their devastating social, health, and economic impact, to date no pharmacological treatment has been approved for the clinical management of cannabis dependence.
Article
Cannabidiol’s (CBD) safety profile and broad action has made it a popular treatment option for anxiety and co-occurring sleep disturbance. However, its efficacy in healthy and clinical populations, treatment duration, formulation and doses for optimal therapeutic benefits remains unclear. Selected databases were examined from inception to October 2022. Study selection, data extraction and Cochrane Risk of Bias assessments were conducted according to PRISMA guidelines and registered on the PROSPERO database (CRD42021247476) with 58 full-text studies meeting the eligibility criteria and administered CBD only or with Δ-9-tetrahydrocannabinol (THC) across healthy and clinical populations. In healthy populations and certain non-cannabis using clinical populations, CBD had greater anxiolytic effects without prominent effects on sleep. An inverted U-shaped dose relationship, and CBD ratio to THC in combined treatments likely moderated these effects. Mechanistically, observed CBD effects occurred via primary modulation of the endocannabinoid system and secondary regulation of neuroendocrine function. Additional research is needed to understand CBD mechanisms of action across diverse groups.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Chapter
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
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Research suggests that cannabis-derived delta-9- tetrahydrocannabinol (THC) can be linked to the worsening of psychosis and/or other symptoms of schizophrenia. However, studies have shown that another major cannabinoid found in cannabis, cannabidiol (CBD), may be a potential alternative or adjunctive treatment for psychosis and schizophrenia. As such, herein we review the relevant literature relating to the safety and efficacy of CBD treatment in patients with schizophrenia, including the effects of CBD in treating the positive, negative, and cognitive symptoms of the disorder, as well as the molecular mechanisms by which CBD can reduce schizophrenic symptoms. The potential utility of CBD for mitigating cannabis cravings and cannabis withdrawal in this patient population will also be reviewed. Lastly, the dosing, method of drug delivery, length of treatment, and adverse effects of CBD in patients with schizophrenia are also discussed. Thus, the goal of this narrative review is to help clinicians and researchers better understand the risks and benefits of this potential therapy for this patient population.
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Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and glutamatergic pathways play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for new treatment is mandatory. This review focuses on the potential effects of cannabidiol (CBD), as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which CBD provides its benefit properties. CBD medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. The activation of the WNT/β-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway and circadian rhythms dysregulation in OCD. Future prospective clinical trials could focus on CBD and its different and multiple interactions in OCD.
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Methamphetamine (MET) is one of the most prevalently abused psychostimulants in the world with drastic repercussions. Several studies emphasized the inhibitory effect of Cannabidiol (CBD) on the reward properties of psychostimulants. The current investigation utilized conditioned place preference (CPP) to assay CBD's impact on MET's reward characteristic, including acquisition and expression phases of MET-induced CPP. Like our prior researches, animals received MET (1 mg/kg; sc) in a five-day schedule to induce CPP. The rats were given intracerebroventricular (ICV) microinjection of CBD (2, 10, and 50 µg/5 µl DMSO) during the 5-day conditioning phase in the CPP paradigm to highlight the CBD's impact on the development (acquisition) of MET-induced place preference. Furthermore, animals were treated with CBD (2, 10 and 50 µg/5 µl) in the lateral ventricle on the post-conditioning day to elucidate the effect of ICV injection of CBD on the expression of MET-induced CPP. It was revealed that CBD (10 and 50 µg/5 µl) microinjection profoundly inhibited both phases of MET-induced CPP without any side effect on the locomotion in animals were treated by MET injection over conditioning phase. Also, CBD's inhibitory impact was more potent in the acquisition phase than the expression phase of MET-induced CPP. Ultimately, the current research reported that CBD could be a beneficial compound to treat drug abuse however more investigations are needed.
Chapter
Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders. In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse. In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies. Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington's disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson's disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future. Currently, there are no human studies that investigated the effects of CBD in either Alzheimer's disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies. Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.
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Importance There are no effective medications for treating dependence on cannabis. Objective To examine the safety and efficacy of nabiximols in the treatment of patients with cannabis dependence. Design, Setting, and Participants This parallel double-blind randomized clinical trial comparing nabiximols with placebo in a 12-week, multisite outpatient study recruited participants from February 3, 2016, to June 14, 2017, at 4 outpatient specialist alcohol and drug treatment services in New South Wales, Australia. Participants had cannabis dependence (as defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and were seeking treatment, were nonresponsive to prior treatment attempts, were 18 to 64 years of age, had no other substance use disorder, had no severe medical or psychiatric conditions, were not pregnant, were not mandated by a court to undergo treatment, and provided informed consent. Results for primary efficacy measures and all secondary outcomes were obtained using a modified intention-to-treat data set. Interventions Participants received 12-week treatment involving weekly clinical reviews, structured counseling, and flexible medication doses—up to 32 sprays daily (tetrahydrocannabinol, 86.4 mg, and cannabidiol, 80 mg), dispensed weekly. Main Outcomes and Measures Primary outcome was self-reported number of days using illicit cannabis during the 12-week period. Other outcomes included alternate cannabis use parameters (periods of abstinence, withdrawal, cravings, and problems), safety parameters (adverse events and aberrant medication use), health status, other substance use, and treatment retention. Results A total of 128 participants (30 women and 98 men; mean [SD] age, 35.0 [10.9] years) were randomized and received at least 1 dose of study medication. Participants had used a mean (SD) of 2.3 (2.1) g of cannabis on a mean (SD) of 25.7 (4.5) days in the past 28 days. Treatment retention was comparable for the 2 groups (placebo, 30 of 67 participants [44.8%]; nabiximols, 30 of 61 participants [49.2%]), and both groups used similar mean (SD) doses (placebo, 18.5 [9.5] sprays daily; nabiximols, 17.6 [9.5] sprays daily, equivalent to a mean [SD] of 47.5 [25.7] mg of tetrahydrocannabinol and 44.0 [23.8] mg of cannabidiol). For the primary end point, the placebo group reported significantly more days using cannabis during the 12 weeks (mean [SD], 53.1 [33.0] days) than the nabiximols group (mean [SD], 35.0 [32.4] days; estimated difference, 18.6 days; 95% CI, 3.5-33.7 days; P = .02). Both groups showed comparable improvements in health status, with no substantial changes in other substance use. Medication was well tolerated with few adverse events. Conclusions and Relevance This study demonstrates that cannabinoid agonist treatment, in this case using nabiximols, in combination with psychosocial interventions is a safe approach for reducing cannabis use among individuals with cannabis dependence who are seeking treatment. Trial Registration anzctr.org.au Identifier: ACTRN12616000103460
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Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.
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The effects of ipsapirone and cannabidiol (CBD) on healthy volunteers submitted to a simulated public speaking (SPS) test were compared with those of the anxiolytic benzodiazepine diazepam and placebo. Four independent groups of 10 subjects received, under a double-blind design, placebo or one of the following drugs: CBD (300 mg), diazepam (10 mg) or ipsapirone (5 mg). Subjective anxiety was evaluated through the Visual Analogue Mood Scale (VAMS) and the State-trait Anxiety Inventory (STAI). The VAMS anxiety factor showed that ipsapirone attenuated SPS-induced anxiety while CBD decreased anxiety after the SPS test. Diazepam, on the other hand, was anxiolytic before and after the SPS test, but had no effect on the increase in anxiety induced by the speech test. Only ipsapirone attenuated the increase in systolic blood pressure induced by the test. Significant sedative effects were only observed with diazepam. The results suggest that ipsapirone and CBD have anxiolytic properties in human volunteers submitted to a stressful situation.
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Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.
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The authors review the literature examining the validity and significance of cannabis withdrawal syndrome. Findings from animal laboratory research are briefly reviewed, and human laboratory and clinical studies are surveyed in more detail. Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome reliably follows discontinuation of chronic heavy use of cannabis or tetrahydrocannabinol. Common symptoms are primarily emotional and behavioral, although appetite change, weight loss, and physical discomfort are also frequently reported. The onset and time course of these symptoms appear similar to those of other substance withdrawal syndromes. The magnitude and severity of these symptoms appear substantial, and these findings suggest that the syndrome has clinical importance. Diagnostic criteria for cannabis withdrawal syndrome are proposed.
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Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.
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Anxiety reactions and panic attacks are the acute symptoms most frequently associated with cannabis use. Understanding the relationship between cannabis and anxiety may clarify the mechanism of action of cannabis and the pathophysiology of anxiety. Aims of the present study were to review the nature of the relationship between cannabis use and anxiety, as well as the possible clinical, diagnostic and causal implications. Systematic review of the Medline, PsycLIT and EMBASE literature. Frequent cannabis users consistently have a high prevalence of anxiety disorders and patients with anxiety disorders have relatively high rates of cannabis use. However, it is unclear if cannabis use increases the risk of developing long-lasting anxiety disorders. Many hypotheses have been proposed in an attempt to explain these relationships, including neurobiological, environmental and social influences. The precise relationship between cannabis use and anxiety has yet to be established. Research is needed to fully clarify the mechanisms of such the association.
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Cannabis is the most widely used illicit drug in the world. Treatment admissions for cannabis use disorders have risen considerably in recent years, and the identification of medications that can be used to improve treatment outcomes among this population is a priority for researchers and clinicians. To date, several medications have been investigated for indications of clinically desirable effects among cannabis users (e.g. reduced withdrawal, attenuation of subjective or reinforcing effects, reduced relapse). Medications studied have included those: (i) known to be effective in the treatment of other drug use disorders; (ii) known to alleviate symptoms of cannabis withdrawal (e.g. dysphoric mood, irritability); or (iii) that directly affect endogenous cannabinoid receptor function. Results from controlled laboratory studies and small open-label clinical studies indicate that buspirone, dronabinol, fluoxetine, lithium and lofexidine may have therapeutic benefit for those seeking treatment for cannabis-related problems. However, controlled clinical trials have not been conducted and are needed to both confirm the potential clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications. Although the recent increase in research towards the development of pharmacotherapy for cannabis use disorders has yielded promising leads, well controlled clinical trials are needed to support broad clinical use of these medications to treat cannabis use disorders.
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Cannabis use can both increase and reduce anxiety in humans. The neurophysiological substrates of these effects are unknown. To investigate the effects of 2 main psychoactive constituents of Cannabis sativa (Delta9-tetrahydrocannabinol [Delta9-THC] and cannabidiol [CBD]) on regional brain function during emotional processing. Subjects were studied on 3 separate occasions using an event-related functional magnetic resonance imaging paradigm while viewing faces that implicitly elicited different levels of anxiety. Each scanning session was preceded by the ingestion of either 10 mg of Delta9-THC, 600 mg of CBD, or a placebo in a double-blind, randomized, placebo-controlled design. Fifteen healthy, English-native, right-handed men who had used cannabis 15 times or less in their life. Regional brain activation (blood oxygenation level-dependent response), electrodermal activity (skin conductance response [SCR]), and objective and subjective ratings of anxiety. Delta9-Tetrahydrocannabinol increased anxiety, as well as levels of intoxication, sedation, and psychotic symptoms, whereas there was a trend for a reduction in anxiety following administration of CBD. The number of SCR fluctuations during the processing of intensely fearful faces increased following administration of Delta9-THC but decreased following administration of CBD. Cannabidiol attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing intensely fearful faces, and its suppression of the amygdalar and anterior cingulate responses was correlated with the concurrent reduction in SCR fluctuations. Delta9-Tetrahydrocannabinol mainly modulated activation in frontal and parietal areas. Delta9-Tetrahydrocannabinol and CBD had clearly distinct effects on the neural, electrodermal, and symptomatic response to fearful faces. The effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety, whereas the anxiogenic effects of Delta9-THC may be related to effects in other brain regions.
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The aim of this review is to describe the historical development of research on cannabidiol. This review was carried out on reports drawn from Medline, Web of Science and SciELO. After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis. In the 1970's the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with delta9-THC and its antiepileptic and sedative effects. The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects. The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer. In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials.
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The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.
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In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.
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In the present study, we investigated the effects of cannabidiol (CBD) on plasma prolactin, growth hormone and cortisol of 11 normal volunteers who received placebo or CBD at the doses of 300 mg (N = 7) or 600 mg (N = 4), po, in a double-blind manner during two experimental sessions separated by an interval of at least one week. The sessions were held in the morning and consisted of blood collection and application of self-evaluation scales before and after drug injection (-35 to 180 min). Hormonal measurements were performed by radioimmunoassay. Basal prolactin (11.5 +/- 4.3 ng/ml) and growth hormone (1.5 +/- 0.7 ng/ml) levels were unchanged after placebo and CBD. In contrast, plasma cortisol levels decreased significantly during the placebo sessions (basal measurement = 11.0 +/- 3.7 micrograms/dl; 120 min after placebo = 7.1 +/- 3.9 micrograms/dl), in agreement with the normal circadian rhythm of this hormone. This decrease in cortisol levels was significantly attenuated after CBD (basal measurement = 10.5 +/- 4.9 micrograms/dl; 120 min after 300 mg CBD = 9.9 +/- 6.2 micrograms/dl; 120 min after 600 mg CBD = 11.6 +/- 11.6 micrograms/dl). CBD was also found to have a sedative effect as determined by the self-evaluation scales. The present results suggest that CBD interferes with cortisol secretion.
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Although withdrawal symptoms are commonly reported by persons seeking treatment for marijuana dependence, the validity and clinical significance of a marijuana withdrawal syndrome has not been established. This controlled outpatient study examined the reliability and specificity of the abstinence effects that occur when daily marijuana users abruptly stop smoking marijuana. Twelve daily marijuana smokers were assessed on 16 consecutive days during which they smoked marijuana as usual (days 1-5), abstained from smoking marijuana (days 6-8), returned to smoking marijuana (days 9-13), and again abstained from smoking marijuana (days 14-16). An overall measure of withdrawal discomfort increased significantly during the abstinence phases and returned to baseline when marijuana smoking resumed. Craving for marijuana, decreased appetite, sleep difficulty, and weight loss reliably changed across the smoking and abstinence phases. Aggression, anger, irritability, restlessness, and strange dreams increased significantly during one abstinence phase, but not the other. Collateral observers confirmed participant reports of these symptoms. This study validated several specific effects of marijuana abstinence in heavy marijuana users, and showed they were reliable and clinically significant. These withdrawal effects appear similar in type and magnitude to those observed in studies of nicotine withdrawal.
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