Safety, tolerability, and efficacy of orally administered cannabinoids in MS A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews Cannabinoids in the management of difficult to treat pain Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. A multi-center, randomized controlled trial of a group psychological intervention for psychosis with comorbid cannabis dependence over the early course of illness The impact of cannabis use on clinical outcomes in recent onset psychosis. Clinical profile of participants in a brief intervention program for cannabis use disorder. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Controlled clinical trial of cannabidiol in Huntington's disease Does occasional cannabis use impact anxiety and depression treatment outcomes?: Results from a randomized effectiveness trial. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia Primary outcomes in two randomized controlled trials of treatments for cannabis use disorders.
Abstract —The authors conducted a r and omized , double-blind , placebo-controlled , twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety , tolerability , and efficacy of oral & Dgr;9-Tetrahydrocannabinol ( THC ) and Cannabis sativa plant extract . Both drugs were safe , but adverse events were more common with plant-extract treatment . Compared with placebo , neither THC nor plant-extract treatment reduced spasticity . Both THC and plant-extract treatment worsened the participant ’s global impression Objectives : To determine whether plant-derived cannabis medicinal extracts ( CME ) can alleviate neurogenic symptoms unresponsive to st and ard treatment , and to quantify adverse effects . Design : A consecutive series of double-blind , r and omized , placebo-controlled single-patient cross-over trials with two-week treatment periods . Setting : Patients attended as out patients , but took the CME at home . Subjects : Twenty-four patients with multiple sclerosis ( 18 ) , spinal cord injury ( 4 ) , brachial plexus damage ( 1 ) , and limb amputation due to neurofibromatosis ( 1 ) . Intervention : Whole-plant extracts of delta-9-tetrahydrocannabinol ( THC ) , cannabidiol ( CBD ) , 1:1 CBD : THC , or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5–120 mg/24 hours . Measures used : Patients recorded symptom , well-being and intoxication scores on a daily basis using visual analogue scales . At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales , administered st and ard measures of disability ( Barthel Index ) , mood and cognition , and recorded adverse events . Results : Pain relief associated with both THC and CBD was significantly superior to placebo . Impaired bladder control , muscle spasms and spasticity were improved by CME in some patients with these symptoms . Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME . Conclusions : Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to st and ard treatments . Unwanted effects are predictable and generally well tolerated . Larger scale studies are warranted to confirm these findings We conducted a review of systematic review s ( SRs ) and r and omized-controlled trials ( RCTs ) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders . Five data bases were systematic ally search ed ( 2006—August 2018 ) ; 4 SRs ( of 11 RCTs ) and 14 RCTs ( 1629 participants ) were included . Diagnoses were : dementia , cannabis and opioid dependence , psychoses/schizophrenia , general social anxiety , posttraumatic stress disorder , anorexia nervosa , attention-deficit hyperactivity disorder , and Tourette`s disorder . Outcome variables were too heterogeneous to conduct a meta- analysis . A narrative synthesis method was applied . The study quality was assessed using the risk-of-bias tool and SIGN-checklists . THC- and CBD-based medicines , given as adjunct to pharmaco- and psychotherapy , were associated with improvements of several symptoms of mental disorders , but not with remission . Side effects occurred , but severe adverse effects were mentioned in single cases only . In order to provide reliable treatment recommendations , more and larger RCTs with follow-up assessment s , consistent outcome measures and active comparisons are needed Medicinal cannabis has already entered mainstream medicine in some countries . This systematic review ( SR ) aim ed at evaluating the efficacy , acceptability and safety of cannabis-based medicines for chronic pain management . Qualitative systematic review of SRs of r and omized controlled trials with cannabis-based medicines for chronic pain management . The Cochrane data bases of SRs , Data base of Abstract s of Review s of Effects and PubMed were search ed for SR published in the period January 2009 to January 2017 . Assessment of the method ological quality of SR was performed by the AMSTAR checklist . Out of 748 papers identified , 10 SRs met the inclusion criteria . The method ological quality was high in four and moderate in six SRs . There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis . There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases ( three SRs ) and in cancer pain ( two SRs ) . Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions . It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the st and ard of 21st century clinical care . SIGNIFICANCE We provide an overview of systematic review s on the efficacy , tolerability and safety of cannabis-based medicines for chronic pain management . There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis . There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain This article review s recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms , as well as r and omized clinical trials employing cannabinoids in pain treatment .  Tetrahydrocannabinol ( THC , Marinol ® ) and nabilone ( Cesamet ® ) are currently approved in the United States and other countries , but not for pain indications . Other synthetic cannabinoids , such as ajulemic acid , are in development . Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation . Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC ( partial CB1 receptor agonist ) and cannabidiol ( CBD , a non-euphoriant , anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects ) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis , and in 2007 for intractable cancer pain . Numerous r and omized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain , rheumatoid arthritis and cancer pain . An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006 . Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles . Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise Objective : To test the effectiveness and long term safety of cannabinoids in multiple sclerosis ( MS ) , in a follow up to the main Cannabinoids in Multiple Sclerosis ( CAMS ) study . Methods : In total , 630 patients with stable MS with muscle spasticity from 33 UK centres were r and omised to receive oral Δ9-tetrahydrocannabinol ( Δ9-THC ) , cannabis extract , or placebo in the main 15 week CAMS study . The primary outcome was change in the Ashworth spasticity scale . Secondary outcomes were the Rivermead Mobility Index , timed 10 metre walk , UK Neurological Disability Score , postal Barthel Index , General Health Question naire-30 , and a series of nine category rating scales . Following the main study , patients were invited to continue medication , double blinded , for up to12 months in the follow up study reported here . Results : Intention to treat analysis of data from the 80 % of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months ( Δ9-THC mean reduction 1·82 ( n = 154 , 95 % confidence interval ( CI ) 0.53 to 3.12 ) , cannabis extract 0.10 ( n = 172 , 95 % CI −0.99 to 1.19 ) , placebo −0.23 ( n = 176 , 95 % CI −1.41 to 0.94 ) ; p = 0.04 unadjusted for ambulatory status and centre , p = 0.01 adjusted ) . There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability . There were no major safety concerns . Overall , patients felt that these drugs were helpful in treating their disease . Conclusions : These data provide limited evidence for a longer term treatment effect of cannabinoids . A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS Context Because the same systems metabolize cannabinoids and protease inhibitors , cannabinoids might alter viral loads in HIV-infected patients taking protease inhibitors . Contribution In this r and omized trial , 62 HIV-infected patients taking indinavir or nelfinavir  received a marijuana cigarette , dronabinol capsule , or placebo capsule three times daily for 21 days . Half of the patients in all three groups had undetectable viral loads during the study , and average changes in viral load with marijuana and dronabinol , relative to placebo , were small . Caution s The findings of no large harmful effects on viral loads with either smoked or oral cannabinoids need to be confirmed in larger and longer trials . The Editors Marijuana has been smoked for medicinal purpose s for centuries ( 1 ) . Introduced into western medicine in 1842 , marijuana was used to treat various illnesses on the basis of its purported analgesic , anticonvulsant , sedative , hypnotic , and antispasmodic properties . With the passage of the Marihuana Tax Act in 1937 , use of marijuana as a therapeutic agent in the United States waned until the substance was removed from the U.S. Pharmacopoeia in 1942 . The Controlled Substances Act of 1970 placed marijuana in the Schedule I category along with other substances deemed to have no medicinal value and high potential for abuse . In 1986 , the U.S. Food and Drug Administration approved a synthetic , oral form of marijuana 's main psychoactive component , delta-9-tetrahydrocannabinol ( dronabinol , Marinol , Roxane Laboratories , Columbus , Ohio ) , for treating chemotherapy-induced nausea and vomiting ( 2 - 5 ) . A r and omized , controlled trial demonstrated that dronabinol increased self-reported appetite but not weight in patients with AIDS-related wasting syndrome ; these findings led to an expansion of the labeling indication for this use in 1992 ( 6 , 7 ) . Before the advent of highly active antiretroviral therapy in the 1990s , many patients infected with HIV-1 experienced wasting as a preterminal manifestation of the disease ( 8) . Patients with AIDS-related wasting syndrome often reported that they preferred smoked marijuana to dronabinol because it was easier to titrate the dose to achieve the desired effect ; smoked marijuana delivers cannabinoids to the bloodstream much more rapidly than dronabinol ( 9 ) . By the mid-1990s , cannabis buyers ' clubs in the San Francisco Bay area were reportedly selling marijuana to 11 000 patients with HIV infection ( 10 - 12 ) . With the increased availability of protease inhibitorcontaining antiretroviral regimens in the mid-1990s , the incidence of AIDS-related wasting syndrome decreased markedly , as did most of the other late-stage opportunistic manifestations of advanced HIV disease ( 13 - 15 ) . Protease inhibitors , which can inhibit or stimulate the hepatic cytochrome P-450 enzyme system , are subject to many significant drugdrug interactions with other agents used in treating HIV infection and its complications ( 16 , 17 ) . The potential for a drugdrug interaction between protease inhibitors and marijuana is worrisome since many HIV-infected patients continue to smoke marijuana as an appetite stimulant or to decrease nausea associated with their antiretroviral therapy ( 18 , 19 ) . The likelihood of such an interaction is supported by the facts that cannabinoids are metabolized by some of the same cytochrome P-450 enzyme isoforms that metabolize the more widely prescribed protease inhibitors and that tetrahydrocannabinol has been shown to inhibit the metabolism of other drugs ( 20 - 23 ) . Although few recent clinical trials have evaluated the potential therapeutic effects of smoked marijuana , significant progress has been made in underst and ing the pharmacology of cannabinoids in humans . Of the two cannabinoid receptors identified , CB1 ( found mainly in cells of the central nervous system ) is thought to be responsible for the neurologic and behavioral effects of marijuana ( 24 , 25 ) . The identification of a CB2 receptor , found predominantly on B lymphocytes and natural killer cells , suggests that cannabinoids may also affect the immune response . Some studies suggest that marijuana can impair the immune system through B-lymphocyte modulation , tumor necrosis factor inhibition , or changes in the phenotype and function of circulating lymphocytes ( 26 - 29 ) . The hallmark of successful antiretroviral therapy is sustained suppression of HIV RNA levels associated with increasing CD4 + cell counts ( 30 - 32 ) . Considering the potential for both a protease inhibitorcannabinoid interaction and an effect of smoked marijuana on the immune system , we design ed a study to determine the safety or toxicity profile of cannabinoids ( smoked and oral ) in persons with HIV infection . We chose HIV RNA levels as our primary outcome because an intervention that interacted unfavorably with either the antiretroviral agent pharmacokinetics or the immune system directly could cause a perturbation of viral suppression . We report the overall safety results of this r and omized , controlled inpatient clinical trial . Methods Study Group Study participants were recruited by referrals from local physicians and advertisements in newspapers . Volunteers from across the country telephoned to determine whether they might be eligible to participate . Participants were required to be at least 18 years of age , have documented HIV infection , and be receiving a stable antiretroviral treatment regimen of either indinavir ( Crixivan , Merck & Co. , Inc. , North Wales , Pennsylvania ) or nelfinavir ( Viracept , Agouron Pharmaceuticals , Inc. , La Jolla , California ) for at least 8 weeks before enrollment . When enrolled , participants who had been taking the recently recommended dose of nelfinavir  , 1250 mg twice daily , were switched to 750 mg three times daily for consistency of our pharmacokinetic evaluations ( 33 ) . No additional protease inhibitors were allowed for the duration of the study . Participants were also required to have a stable viral load , defined as less than a threefold ( 0.5 log10 ) change in HIV RNA level for the 16 weeks before enrollment . All participants were required to have previous experience smoking marijuana ( defined as six or more times ) to ensure that they knew how to inhale and what neuropsychiatric effects to expect . The institutional review board of the University of California , San Francisco , approved the study , and signed , informed consent was obtained from each participant before enrollment . Exclusion criteria included any active opportunistic infection or malignant condition requiring acute treatment , unintentional loss of 10 % or more of body weight during the previous 6 months , current substance dependence ascertained by completion of a confidential drug screening form and an alcohol screening form , methadone maintenance , use of tobacco or cannabinoids ( smoked or oral ) within 30 days of enrollment , history of serious pulmonary disease , pregnancy , or stage II or higher AIDS dementia complex . Laboratory exclusion criteria were hematocrit less than 0.25 and elevation of hepatic aminotransferase levels to greater than five times the upper limit of normal . Therapeutic exclusions were concurrent use within the past 8 weeks of anabolic hormones , prednisone , interleukin-2 , or other agents known to alter immune system function . Study Medications The National Institute on Drug Abuse provided prerolled marijuana cigarettes , weighing on average 0.9 g and containing 3.95 % delta-9-tetrahydrocannabinol . These cigarettes were kept in a locked and alarmed freezer until they were dispensed to a locked freezer in the General Clinical Research Center at the San Francisco General Hospital , where the inpatient study was conducted . The frozen marijuana cigarettes required rehydration overnight in a humidifier . Participants r and omly assigned to the smoked marijuana group were housed in a room with a fan ventilating to the outside . To maximize st and ardization of inhaled doses , research staff monitored participants while they followed the uniform puff procedure outlined by Foltin and colleagues ( 34 ) . Research staff weighed the marijuana cigarettes immediately before and after they were administered to participants and returned all leftover material to the pharmacy . Study participants smoked up to three complete marijuana cigarettes daily , as tolerated , 1 hour before meals . Study participants were r and omly assigned in a double-blind fashion to the oral regimens , which were given on the same schedule as the smoked marijuana . Research staff observed participants taking all treatments . Research Design and Procedures Study clinicians admitted study participants to the General Clinical Research Center for a 4-day lead-in period to obtain baseline variables . A urine sample obtained on the day of admission ( day 4 ) had to be negative for tetrahydrocannabinol . The second phase of the trial was a 21-day intervention period beginning with r and om assignment of treatments on day 0 . Patients were stratified by protease inhibitor ( indinavir or nelfinavir ) and then allocated with equal probability in blocks of 12 to the study agents ( marijuana , dronabinol , and placebo ) . The statistician generated the r and om allocation sequences , and the pharmacists maintained the sequences in a secure location and distributed the assignments to the study coordinator on day 0 . Study participants were not permitted to have visitors or to leave the General Clinical Research Center unless accompanied by research personnel during the 25-day study . All clinical laboratory tests and study procedures were obtained or performed in the center . Patients were weighed on the same calibrated scale each morning while wearing a hospital gown . Baseline blood specimens were collected on days 4 and 0 to examine within-participant variation in HIV RNA level in the absence of experimental therapies . Follow-up specimens were obtained on days 2 , 5 , 8 , 11 , 14 , 17 , 19 , and 21 . Sample s were stored at 70 C and batch-tested for HIV RNA at the end The objective was to determine whether a cannabis-based medicinal extract ( CBME ) benefits a range of symptoms due to multiple sclerosis ( MS ) . A parallel group , double-blind , r and omized , placebo-controlled study was undertaken in three centres , recruiting 160 out patients with MS experiencing significant problems from at least one of the following : spasticity , spasms , bladder problems , tremor or pain . The interventions were oromucosal sprays of matched placebo , or whole plant CBME containing equal amounts of delta-9- tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) at a dose of 2.5- 120 mg of each daily , in divided doses . The primary outcome measure was a Visual Analogue Scale ( VAS ) score for each patient ’s most troublesome symptom . Additional measures included VAS scores of other symptoms , and measures of disability , cognition , mood , sleep and fatigue . Following CBME the primary symptom score reduced from mean ( SE ) 74.36 ( 11.1 ) to 48.89 ( 22.0 ) following CBME and from 74.31 ( 12.5 ) to 54.79 ( 26.3 ) following placebo [ ns ] . Spasticity VAS scores were significantly reduced by CBME ( Sativex ) in comparison with placebo ( P- 0.001 ) . There were no significant adverse effects on cognition or mood and intoxication was generally mild Symptoms relating to spasticity are common in multiple sclerosis ( MS ) and can be difficult to treat . We have investigated the efficacy , safety and tolerability of a st and ardized oromucosal whole plant cannabis-based medicine ( CBM ) containing delta-9 tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , upon spasticity in MS . A total of 189 subjects with definite MS and spasticity were r and omized to receive daily doses of active preparation ( n = 124 ) or placebo ( n = 65 ) in a double blind study over 6 weeks . The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity . Secondary endpoints included a measure of spasticity ( Ashworth Score ) and a subjective measure of spasm . The primary efficacy analysis on the intention to treat ( ITT ) population ( n = 184 ) showed the active preparation to be significantly superior ( P = 0.048 ) . Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance . The responder analysis favoured active preparation , 40 % of subjects achieved > 30 % benefit ( P = 0.014 ) . Eight withdrawals were attributed to adverse events ( AEs ) ; six were on active preparation and two on placebo . We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS BACKGROUND Patients who experience the onset of psychotic illness with a comorbid diagnosis of cannabis dependence experience poor clinical outcomes . Few studies have identified interventions that reduce cannabis use and improve clinical outcome in this population . AIMS We undertook a multi-center , r and omized controlled trial of a group psychological intervention for psychosis with comorbid cannabis dependence to determine whether there was any impact on cannabis use symptoms , global functioning , insight , attitudes to treatment and subjective quality of life . METHOD Across three centers , we compared a group psychological intervention , based on cognitive behavioral therapy and motivational interviewing , with treatment as usual among patients experiencing their first psychotic episode or early in the course of psychotic illness . Substance misuse and indices of clinical outcome were assessed at baseline , 3months and 1year . RESULTS At 3month and 1year follow-ups , there was no evidence for an intervention effect on cannabis use , symptoms , global functioning insight or attitude to treatment . However , the intervention improved subjective quality of life at 3months and this effect was sustained at 1year . CONCLUSIONS Over the early phase of psychotic illness , group psychological interventions for those with comorbid cannabis dependence improved subjective quality of life . However , this was not associated with reduction in use of cannabis or improvement in clinical outcomes BACKGROUND There are inconsistencies in findings as to whether cannabis use has a negative impact on clinical outcomes for people with established psychosis . Effects may be more evident on patients with recent onset psychosis . AIM To investigate the relationship between cannabis use and clinical outcome , including whether change in cannabis use affects psychotic symptoms , affective symptoms , functioning and psychotic relapse in a sample of people in early psychosis with comorbid cannabis abuse or dependence . METHODS One hundred and ten participants were examined prospect ively with repeated measures of substance use antecedent to psychopathology at baseline , 4.5 , 9 , and 18 months . We used r and om intercept models to estimate the effects of cannabis dose on subsequent clinical outcomes and whether change in cannabis use was associated with change in outcomes . RESULTS There was no evidence of a specific association between cannabis use and positive symptoms , or negative symptoms , relapse or hospital admissions . However , a greater dose of cannabis was associated with subsequent higher depression and anxiety . Change in the amount of cannabis used was associated with statistically significant corresponding change in anxiety scores , but not depression . Additionally , reductions in cannabis exposure were related to improved patient functioning . CONCLUSIONS Reducing cannabis may be directly associated with improvements in anxiety and functioning , but not other specific symptoms The increasing dem and for cannabis dependence treatment has led to the identification of significant gaps in the knowledge of effective interventions . A r and omized controlled trial of brief cognitive-behavioral interventions ( CBT ) for cannabis dependence was undertaken to address this issue . A total of 229 participants were assessed and allocated to either a 6-session CBT program , a single-session brief intervention , or a delayed-treatment control group . This paper demonstrates that individuals with cannabis use disorder will present for a brief intervention program . While they report similar patterns of cannabis use to nontreatment sample s , they report a range of serious health and psychosocial consequences . While they appear relatively socially stable , they typically demonstrated severe cannabis dependence and significantly elevated levels of psychological distress , with the most commonly cited reason for cannabis use being stress relief . There were clinical ly relevant gender differences among the sample . This study provides more evidence of the dem and for , and nature of issues relevant to , interventions for cannabis use disorders , and supports the need for further research into how best to assist individuals with these disorders BACKGROUND Multiple sclerosis is associated with muscle stiffness , spasms , pain , and tremor . Much anecdotal evidence suggests that cannabinoids could help these symptoms . Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis . METHODS We did a r and omised , placebo-controlled trial , to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity . 630 participants were treated at 33 UK centres with oral cannabis extract ( n=211 ) , Delta9-tetrahydrocannabinol ( Delta9-THC ; n=206 ) , or placebo ( n=213 ) . Trial duration was 15 weeks . Our primary outcome measure was change in overall spasticity scores , using the Ashworth scale . Analysis was by intention to treat . FINDINGS 611 of 630 patients were followed up for the primary endpoint . We noted no treatment effect of cannabinoids on the primary outcome ( p=0.40 ) . The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 ( 95 % CI -1.04 to 1.67 ) , and for those taking Delta9-THC versus placebo it was 0.94 ( -0.44 to 2.31 ) . There was evidence of a treatment effect on patient-reported spasticity and pain ( p=0.003 ) , with improvement in spasticity reported in 61 % ( n=121 , 95 % CI 54.6 - 68.2 ) , 60 % ( n=108 , 52.5 - 66.8 ) , and 46 % ( n=91 , 39.0 - 52.9 ) of participants on cannabis extract , Delta9-THC , and placebo , respectively . INTERPRETATION Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale . However , though there was a degree of unmasking among the patients in the active treatment groups , objective improvement in mobility and patients ' opinion of an improvement in pain suggest cannabinoids might be clinical ly useful Based on encouraging preliminary findings , cannabidiol ( CBD ) , a major nonpsychotropic constituent of Cannabis , was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients with Huntington 's Disease ( HD ) . The effects of oral CBD ( 10 mg/kg/day for 6 weeks ) and placebo ( sesame oil for 6 weeks ) were ascertained weekly under a double-blind , r and omized cross-over design . A comparison of the effects of CBD and placebo on chorea severity and other therapeutic outcome variables , and on a Cannabis side effect inventory , clinical lab tests and other safety outcome variables , indicated no significant ( p greater than 0.05 ) or clinical ly important differences . Correspondingly , plasma levels of CBD  were assayed by GC/MS , and the weekly levels ( mean range of 5.9 to 11.2 ng/ml ) did not differ significantly over the 6 weeks of CBD administration . In summary , CBD , at an average daily dose of about 700 mg/day for 6 weeks , was neither symptomatically effective nor toxic , relative to placebo , in neuroleptic-free patients with HD This study investigated the extent to which occasional cannabis use moderated anxiety and depression outcomes in the Collaborative Care for Anxiety and Panic ( CCAP ) study , a combined cognitive-behavioral therapy ( CBT ) and pharmacotherapy r and omized effectiveness trial . Participants were 232 adults from six university-based primary care outpatient clinics in three West Coast cities r and omized to receive either the CCAP intervention or the usual care condition .  Results showed significant ( P<.01 ) evidence of an interaction between treatment group ( CCAP vs. usual care ) and cannabis use status ( monthly vs. less than monthly ) for depressive symptoms , but not for panic disorder or social phobia symptoms ( all P>.05 ) . Monthly cannabis users ' depressive symptoms improved in the CCAP intervention just as much as those who used cannabis less than monthly , whereas monthly users receiving usual care had significantly more depressive symptoms than those using less than monthly . A combined CBT and medication treatment intervention may be a promising approach for the treatment of depression among occasional cannabis users Cannabidiol is a component of marijuana that does not activate cannabinoid receptors , but moderately inhibits the degradation of the endocannabinoid an and amide . We previously reported that an elevation of an and amide levels in cerebrospinal fluid inversely correlated to psychotic symptoms . Furthermore , enhanced an and amide 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 , r and omized 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 an and amide levels , which was significantly associated with clinical improvement . The results suggest that inhibition of an and amide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia BACKGROUND While several r and omized controlled trials evaluating a range of treatments for cannabis use disorders have appeared in recent years , these have been marked by inconsistency in selection of primary outcomes , making it difficult to compare outcomes across studies . METHOD With the aim of identifying meaningful and reliable outcome domains in treatment studies of cannabis use disorders , we evaluated multiple indicators of marijuana use , marijuana problems , and psychosocial functioning from two independent r and omized controlled trials of behavioral treatments for cannabis use disorders ( Ns=450 and 136 ) . RESULTS Confirmatory factor analysis indicated that the best-fitting model of outcomes in both trials encompassed three distinct factors : frequency of marijuana use , severity of marijuana use , and psychosocial functioning . In both trials , frequency of marijuana use and longest period of abstinence during treatment were most strongly associated with outcome during follow-up . Using two categorical definitions of " clinical ly significant improvement , " individuals who demonstrated improvement differed on most end-of-treatment and long-term outcomes from those who did not improve . CONCLUSIONS Results may guide future r and omized controlled trials of treatments for cannabis use disorders in the collection of relevant end-of-treatment outcomes and encourage consistency in the reporting of outcomes across trials
Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials .
There was an increased risk of short-term AEs with cannabinoids , including serious AEs .
Common AEs included dizziness , dry mouth , nausea , fatigue , somnolence , euphoria , vomiting , disorientation , drowsiness , confusion , loss of balance , and hallucination .
CONCLUSIONS AND RELEVANCE There was moderate- quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity .
There was low- quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy , weight gain in HIV infection , sleep disorders , and Tourette syndrome .
Cannabinoids were associated with an increased risk of short-term AEs
IMPORTANCE Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms , but their efficacy for specific indications is not clear .
OBJECTIVE To conduct a systematic review of the benefits and adverse events ( AEs ) of cannabinoids .