Cannabidiol in Humans—The Quest for Therapeutic Targets A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome Controlled clinical trial of cannabidiol in Huntington's disease A double-blind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. Cannabinoids in the management of difficult to treat pain Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial.
Cannabidiol ( CBD ) , a major phytocannabinoid constituent of cannabis , is attracting growing attention in medicine for its anxiolytic , antipsychotic , antiemetic and anti-inflammatory properties . However , up to this point , a comprehensive literature review of the effects of CBD in humans is lacking . The aim of the present systematic review is to examine the r and omized and crossover studies that administered CBD  to healthy controls and to clinical patients . A systematic search was performed in the electronic data bases PubMed and EMBASE using the key word “ cannabidiol ” . Both monotherapy and combination studies ( e.g. , CBD + ∆9-THC ) were included . A total of 34 studies were identified : 16 of these were experimental studies , conducted in healthy subjects , and 18 were conducted in clinical population s , including multiple sclerosis ( six studies ) , schizophrenia and bipolar mania ( four studies ) , social anxiety disorder ( two studies ) , neuropathic and cancer pain ( two studies ) , cancer anorexia ( one study ) , Huntington ’s disease ( one study ) , insomnia ( one study ) , and epilepsy ( one study ) . Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC . Moreover , some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and /or intensify ∆9-THC-induced effects , whereas others suggest that it may inhibit ∆9-THC-induced effects . Finally , preliminary clinical trials suggest that high-dose oral CBD ( 150–600 mg/d ) may exert a therapeutic effect for social anxiety disorder , insomnia and epilepsy , but also that it may cause mental sedation . Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed 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 & NA ; The objective was to investigate the effectiveness of cannabis‐based medicines for treatment of  chronic pain associated with brachial plexus root avulsion . This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury , pain descriptions and patient demographics . Forty‐eight patients with at least one avulsed root and baseline pain score of four or more on an 11‐point ordinate scale participated in a r and omised , double‐blind , placebo‐controlled , three period crossover study . All patients had intractable symptoms regardless of current analgesic therapy . Patients entered a baseline period of 2 weeks , followed by three , 2‐week treatment periods during each of which they received one of three oromucosal spray preparations . These were placebo and two whole plant extracts of Cannabis sativa L. : GW‐1000‐02 ( Sativex ® ) , containing Δ9tetrahydrocannabinol (THC):cannabidiol ( CBD ) in an approximate 1:1 ratio and GW‐2000‐02 , containing primarily THC . The primary outcome measure was the mean pain severity score during the last 7 days of treatment . Secondary outcome measures included pain related quality of life assessment s. The primary outcome measure failed to fall by the two points defined in our hypothesis . However , both this measure and measures of sleep showed statistically significant improvements . The study medications were generally well tolerated with the majority of adverse events , including intoxication type reactions , being mild to moderate in severity and resolving spontaneously . Studies of longer duration in neuropathic pain are required to confirm a clinical ly relevant , improvement in the treatment of this condition In phase 1 of the study , 3 mg/kg daily of cannabidiol ( CBD ) was given for 30 days to 8 health human volunteers . Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting . Neurological and physical examinations , blood and urine analysis , ECG and EEG were performed at weekly intervals . In phase 2 of the study , 15 patients suffering from secondary generalized epilepsy with temporal focus were r and omly divided into two groups . Each patient received , in a double-blind procedure , 200 - 300 mg daily of CBD or placebo . The drugs were administered for along as 4 1/2 months . Clinical and laboratory examinations , EEG and ECG were performed at 15- or 30-day intervals . Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment , although these drugs no longer controlled the signs of the disease . All patients and volunteers tolerated CBD  very well and no signs of toxicity or serious side effects were detected on examination . 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition .  CBD was ineffective in 1 patient . The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved . The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed Objective To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol ( CBD ) in children with Dravet syndrome . Methods Patients aged 4–10 years were r and omized 4:1 to CBD ( 5 , 10 , or 20 mg/kg/d ) or placebo taken twice daily . The double-blind trial comprised 4-week baseline , 3-week treatment ( including titration ) , 10-day taper , and 4-week follow-up periods . Completers could continue in an open-label extension . Multiple pharmacokinetic blood sample s were taken on the first day of dosing and at end of treatment for measurement of CBD , its metabolites 6-OH-CBD , 7-OH-CBD , and 7-COOH-CBD , and antiepileptic drugs ( AEDs  ; clobazam and metabolite N-desmethylclobazam [ N-CLB ] , valproate , levetiracetam , topiramate , and stiripentol ) . Safety assessment s were clinical laboratory tests , physical examinations , vital signs , ECGs , adverse events ( AEs ) , seizure frequency , and suicidality . Results Thirty-four patients were r and omized ( 10 , 8 , and 9 to the 5 , 10 , and 20 mg/kg/d  CBD  groups , and 7 to placebo )  ; 32 ( 94 % ) completed treatment . Exposure to CBD and its metabolites was dose-proportional ( AUC0–t ) . CBD did not affect concomitant AED levels , apart from an increase in N-CLB ( except in patients taking stiripentol ) . The most common AEs on CBD were pyrexia , somnolence , decreased appetite , sedation , vomiting , ataxia , and abnormal behavior . Six patients taking CBD and valproate developed elevated transaminases ; none met criteria for drug-induced liver injury and all recovered . No other clinical ly relevant safety signals were observed . Conclusions Exposure to CBD and its metabolites increased proportionally with dose . An interaction with N-CLB was observed , likely related to CBD inhibition of cytochrome P450 subtype 2C19 . CBD result ed in more AEs than placebo but was generally well-tolerated . Classification of evidence This study provides Class I evidence that for children with Dravet syndrome , CBD result ed in more AEs than placebo but was generally well-tolerated 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 Δ9-Tetrahydrocannabinol ( Δ9-THC ) , the most prominent psychoactive cannabinoid in Cannabis sativa L. ( marijuana ) , has been reported to have properties of appetite stimulation , promotion of weight gain , and antiemetic efficacy in selected patient population s. In this 4-week , double-blind , crossover study , 11 female patients with primary anorexia nervosa ( PAN ) were evaluated on Δ9-THC and on an active placebo , diazepam . All patients participated in a st and ardized behavior modification treatment program . The following data were obtained : ( 1 ) daily weight , ( 2 ) daily caloric intake , and ( 3 ) weekly psychiatric assessment s. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales . The only significant differences found between the changes over time on Δ9-THC versus diazepam were more pathology on Δ9-THC for somatization , interpersonal sensitivity , and sleep disturbance . Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during Δ9-THC administration . One week after the study ended , each subject was given the highest dose level of Δ8-THC achieved in the study , and periodic blood sample s were obtained coincident with self-rated “ subjective high ” assessment s and pulse measurements . Quantitative analyses of these sample s indicated peak times of 1 to 5 hours postdose for Δ9- THC and for its primary active metabolite , 11-hydroxy-THC , which generally coincided with peak times for “ subjective high ” and pulse rate . The results of this clinical investigation suggest that Δ9-THC is not efficacious , in short-term administration , in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients 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 Research in both animals and humans indicates that cannabidiol ( CBD ) has antipsychotic properties . The authors assessed the safety and effectiveness of CBD in patients with schizophrenia . METHOD In an exploratory double-blind parallel-group trial , patients with schizophrenia were r and omized in a 1:1 ratio to receive CBD ( 1000 mg/day ; N=43 ) or placebo ( N=45 ) alongside their existing antipsychotic medication . Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale ( PANSS ) , the Brief Assessment of Cognition in Schizophrenia ( BACS ) , the Global Assessment of Functioning scale ( GAF ) , and the improvement and severity scales of the Clinical Global Impressions Scale ( CGI-I and CGI-S ) . RESULTS After 6 weeks of treatment , compared with the placebo group , the CBD group had lower levels of positive psychotic symptoms ( PANSS : treatment difference=-1.4 , 95 % CI=-2.5 , -0.2 ) and were more likely to have been rated as improved ( CGI-I : treatment difference=-0.5 , 95 % CI=-0.8 , -0.1 ) and as not severely unwell ( CGI-S : treatment difference=-0.3 , 95 % CI=-0.5 , 0.0 ) by the treating clinician . Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance ( BACS : treatment difference=1.31 , 95 % CI=-0.10 , 2.72 ) and in overall functioning ( GAF : treatment difference=3.0 , 95 % CI=-0.4 , 6.4 ) . CBD was well tolerated , and rates of adverse events were similar between the CBD and placebo groups . CONCLUSIONS These findings suggest that CBD has beneficial effects  in patients with schizophrenia . As CBD 's effects do not appear to depend on dopamine receptor antagonism , this agent may represent a new class of treatment for the disorder 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 Sativex ( ® ) , a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , is currently in phase III trials as an adjunct to opioids for cancer pain treatment , and recently received United Kingdom approval for treatment of spasticity . There are indications that CBD modulates THC 's effects , but it is unclear if this is due to a pharmacokinetic and /or pharmacodynamic interaction . METHODS Cannabis smokers provided written informed consent to participate in this r and omized , controlled , double-blind , double-dummy institutional review board-approved study . Participants received 5 and 15 mg synthetic oral THC , low-dose ( 5.4 mg THC and 5.0 mg CBD ) and high-dose ( 16.2 mg THC and 15.0 mg CBD ) Sativex , and placebo over 5 sessions . CBD , THC , 11-hydroxy-THC , and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS . Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions . Significant differences ( P < 0.05 ) in maximum plasma concentrations ( C(max ) ) and areas under the curve from 0 - 10.5 h postdose ( AUC(0→10.5 ) ) for all analytes were found between low and high doses of synthetic THC and Sativex . There were no statistically significant differences in C(max ) , time to maximum concentration or in the AUC(0→10.5 ) between similar oral THC and Sativex doses . Relative bioavailability was calculated to determine the relative rate and extent of THC absorption ; 5 and 15 mg oral THC bioavailability was 92.6 % ( 13.1 % ) and 98.8 % ( 11.0 % ) of low- and high-dose Sativex , respectively . CONCLUSION These data suggest that CBD modulation of THC 's effects is not due to a pharmacokinetic interaction at these therapeutic doses Worldwide cannabis dependence is increasing , as is the concentration of Δ9-tetrahydrocannabinol ( THC ) in street cannabis . At the same time , the concentration of the second most abundant cannabinoid in street cannabis ,  cannabidiol  ( CBD ) , is decreasing . These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory . No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans . A total of 94 cannabis users were tested 7 days apart , once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures . Using an unprecedented methodology , a sample of cannabis ( as well as saliva ) was collected from each user and analyzed for levels of cannabinoids . On the basis of CBD : THC ratios in the cannabis , individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs , explicit liking , and implicit attentional bias to drug stimuli . When intoxicated , smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC . Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days . Our findings suggest that CBD has potential as a treatment for cannabis dependence . The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders BACKGROUND Cannabis use disorder ( CUD ) is a prevalent and impairing condition , and established psychosocial treatments convey limited efficacy . In light of recent findings supporting the efficacy of N-acetylcysteine ( NAC ) for CUD in adolescents , the objective of this trial was to evaluate its efficacy in adults . METHODS In a 12-week double-blind r and omized placebo-controlled trial , treatment-seeking adults ages 18 - 50 with CUD ( N=302 ) , enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites , were r and omized in a 1:1 ratio to a 12-week course of NAC 1200 mg ( n=153 ) or placebo ( n=149 ) twice daily . All participants received contingency management ( CM ) and medical management . The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment , compared between NAC and placebo participants . RESULTS There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence ( odds ratio=1.00 , 95 % confidence interval 0.63 - 1.59 , p=0.984 ) . Overall , 22.3 % of urine cannabinoid tests in the NAC group were negative , compared with 22.4 % in the placebo group . Many participants were medication non-adherent ; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group . CONCLUSIONS In contrast with prior findings in adolescents , there is no evidence that NAC 1200 mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM . This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development , cannabis use profiles , responses to embedded behavioral treatment , medication adherence , and other factors BACKGROUND Peripheral neuropathic pain ( PNP ) associated with allodynia poses a significant clinical challenge . The efficacy of Δ(9 ) -tetrahydrocannabinol/cannabidiol ( THC/CBD ) oromucosal spray , a novel cannabinoid formulation , was investigated in this 15-week r and omized , double-blind , placebo-controlled parallel group study . METHODS In total , 303 patients with PNP associated with allodynia were screened ; 128 were r and omized to THC/CBD spray and 118 to placebo , in addition to their current analgesic therapy . The co- primary efficacy endpoints were the 30 % responder rate in PNP 0 - 10 numerical rating scale ( NRS ) score and the mean change from baseline to the end of treatment in this score . Various key secondary measures of pain and functioning were also investigated . RESULTS At the 30 % responder level , there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis ( intention-to-treat ) data set [ p = 0.034 ; 95 % confidence interval ( CI ) : 1.05 - 3.70 ] . There was also a reduction in mean PNP 0 - 10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group , but which failed to reach statistical significance . Secondary measures of sleep quality 0 - 10 NRS score ( p = 0.0072 ) and Subject Global Impression of Change ( SGIC ) ( p = 0.023 ) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment . CONCLUSIONS These findings demonstrate that , in a meaningful proportion of otherwise treatment-resistant patients , clinical ly important improvements in pain , sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray . THC/CBD spray was well tolerated and no new safety concerns were identified Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol ( THC ) but low in cannabidiol ( CBD ) are particularly hazardous for mental health . Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form , under controlled conditions . In a between-subjects design , we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment . Healthy participants were r and omised to receive oral CBD 600 mg ( n=22 ) or placebo ( n=26 ) , 210 min ahead of intravenous ( IV ) THC ( 1.5 mg ) . Post-THC , there were lower PANSS positive scores in the CBD group , but this did not reach statistical significance . However , clinical ly significant positive psychotic symptoms ( defined a priori as increases ≥3 points ) were less likely in the CBD group compared with the placebo group , odds ratio (OR)=0.22 ( χ2=4.74 , p<0.05 ) . In agreement , post-THC paranoia , as rated with the State Social Paranoia Scale ( SSPS ) , was less in the CBD group compared with the placebo group ( t=2.28 , p<0.05 ) . Episodic memory , indexed by scores on the Hopkins Verbal Learning Task-revised ( HVLT-R ) , was poorer , relative to baseline , in the placebo pre-treated group ( -10.6±18.9 % ) compared with the CBD group ( -0.4%±9.7 % ) ( t=2.39 , p<0.05 ) . These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health Animal and human studies have suggested that cannabidiol ( CBD ) may possess anxiolytic properties , but how these effects are mediated central ly is unknown . The aim of the present study was to investigate this using functional neuroimaging . Regional cerebral blood flow ( rCBF ) was measured at rest using 99mTc-ECD SPECT in 10 healthy male volunteers , r and omly divided into two groups of five subjects . Each subject was studied on two occasions , 1 week apart . In the first session , subjects were given an oral dose of CBD ( 400 mg ) or placebo , in a double-blind procedure . SPECT images were acquired 90 min after drug ingestion . The Visual Analogue Mood Scale was applied to assess subjective states . In the second session , the same procedure was performed using the drug that had not been administered in the previous session . Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping ( SPM ) . CBD significantly decreased subjective anxiety and increased mental sedation , while placebo did not induce significant changes . Assessment of brain regions where anxiolytic effects of CBD were predicted a priori revealed two voxel clusters of significantly decreased ECD uptake in the CBD relative to the placebo condition ( p<0.001 , uncorrected for multiple comparisons ) . These included a medial temporal cluster encompassing the left amygdala – hippocampal complex , extending into the hypothalamus , and a second cluster in the left posterior cingulate gyrus . There was also a cluster of greater activity with CBD than placebo in the left parahippocampal gyrus ( p<0.001 ) . These results suggest that CBD has anxiolytic properties , and that these effects are mediated by an action on limbic and paralimbic brain areas BACKGROUND Central neuropathic pain ( CNP ) , pain initiated or caused by a primary lesion or dysfunction of the central nervous system , occurs in ~28 % of patients with multiple sclerosis ( MS ) . Delta(9)-Tetrahydrocannabinol/cannabidiol ( THC/CBD ) , an endocannabinoid system modulator , has demonstrated efficacy for up to 4 weeks in r and omized controlled trials in the treatment of CNP in patients with MS . OBJECTIVE The purpose of this extension was to establish long-term tolerability and effectiveness profiles for THC/CBD ( Sativex ( R ) , GW Pharmaceuticals plc , Salisbury , United Kingdom ) oromucosal spray in CNP associated with MS . METHODS This uncontrolled , open-label trial was an indefinite- duration extension of a previously reported 5-week r and omized study in patients with MS and CNP . In the initial trial , patients were r and omized to placebo or THC/CBD . Patients were only required to maintain their existing analgesia in the r and omized study . In the open-label trial they could vary their other analgesia as required . All patients ( placebo and THC/CBD ) who completed the r and omized trial commenced the open-label follow-up on THC/CBD ( 27 mg/mL : 25 mg/mL ) . Patients titrated their dosage , maintaining their existing analgesia . The primary end point of the trial was the number , frequency , and type of adverse events ( AEs ) reported by patients . Secondary end points included changes from baseline in 11-point numerical rating scale ( NRS-11 ) neuropathic pain score , hematology and clinical chemistry test results , vital signs , trial drug usage , and intoxication visual analogue scale scores . RESULTS Sixty-six patients were enrolled in the r and omized trial ; 64 ( 97 % ) completed the r and omized trial and 63 ( 95 % ) entered the open-label extension ( race , white , 100 % ; sex , male , 14 [ 22 % ] ; mean [ SD ] age , 49 [ 8.4 ] years [ range , 27 - 71 years [ ) . The mean ( SD ) duration of open-label treatment was 463 ( 378 ) days ( median , 638 days ; range , 3 - 917 days ) , with 34 ( 54 % ) patients completing > 1 year of treatment with THC/CBD and 28 ( 44 % ) patients completing the open-label trial with a mean ( SD ) duration of treatment of 839 ( 42 ) days ( median , 845 days ; range , 701 - 917 days ) . Mean NRS-11 pain scores in the final week of the r and omized trial were 3.8 in the treatment group and 5.0 in the placebo group . In the 28 ( 44 % ) patients who completed the 2-year follow up , the mean ( SD ) NRS-11 pain score in the final week of treatment was 2.9 ( 2.0 ) ( range , 0 - 8.0 ) . Fifty-eight ( 92 % ) patients experienced > or = 1 treatment-related AE . These AEs were rated by the investigator as mild in 47 ( 75 % ) patients , moderate in 49 ( 78 % ) , and severe in 32 ( 51 % ) . The most commonly reported AEs were dizziness ( 27 % ) , nausea ( 18 % ) , and feeling intoxicated ( 11 % ) . Two treatment-related serious AEs ( ventricular bigeminy and circulatory collapse ) were judged to be treatment-related . Both serious AEs occurred in the same patient and resolved completely following a period of discontinuation . Eleven ( 17 % ) patients experienced oral discomfort , 4 persistently . Regular oral examinations revealed that 7 ( 11 % ) patients developed white buccal mucosal patches and 2 ( 3 % ) developed red buccal mucosal patches ; all cases were deemed mild and resolved . Seventeen ( 25 % ) patients withdrew due to AEs . The mean number of sprays and patients experiencing intoxication remained stable throughout the follow-up trial . CONCLUSIONS THC/CBD was effective , with no evidence of tolerance , in these select patients with CNP and MS who completed approximately 2 years of treatment ( n = 28 ) . Ninety-two percent of patients experienced an AE , the most common of which were dizziness and nausea . The majority of AEs were deemed to be of mild to moderate severity by the investigators
In both rodent and cell culture models , CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus .
In rodent models , CBD was found to attenuate alcohol-induced hepatotoxicity , specifically , alcohol-induced steatosis .
Finally , findings from pre clinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking , alcohol self-administration , withdrawal-induced convulsions , and impulsive discounting of delayed rewards .
In human studies , CBD was well tolerated and did not interact with the subjective effects of alcohol .
Collectively , given its favorable effects on alcohol-related harms and addiction phenotypes in pre clinical models , CBD appears to have promise as a c and i date AUD pharmacotherapy .
This is further bolstered by the absence of abuse liability and its general tolerability .
There is substantial interest in the therapeutic potential of cannabidiol ( CBD ) , a nonpsychoactive cannabinoid found in plants of the genus Cannabis .
The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a c and i date pharmacotherapy for alcohol use disorder ( AUD ) .