title: Topiramate for treating alcohol dependence: a randomized controlled trial. Effects of Zonisamide in the Treatment of Alcohol Dependence The effect of cannabidiol, alone and in combination with ethanol, on human performance Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial Open Label Trial of the Tolerability and Efficacy of Zonisamide in the Treatment of Alcohol Dependence Interaction of cannabidiol and alcohol in humans Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients. Placebo-Controlled Trial of Zonisamide for the Treatment of Alcohol Dependence Delayed reward discounting predicts treatment response for heavy drinkers receiving smoking cessation treatment. Efficacy and Safety of Levetiracetam for the Prevention of Alcohol Relapse in Recently Detoxified Alcohol-Dependent Patients: A Randomized Trial The Anticonvulsant Zonisamide Reduces Ethanol Self-Administration by Risky Drinkers The use of divalproex in alcohol relapse prevention: a pilot study. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Association of frontal and posterior cortical gray matter volume with time to alcohol relapse: a prospective study.
abstract: CONTEXT Hypothetically , topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol 's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system . OBJECTIVE To determine if topiramate is a safe and efficacious treatment for alcohol dependence . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , placebo-controlled , 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence , conducted between January 27 , 2004 , and August 4 , 2006 , at 17 US sites . INTERVENTIONS Up to 300 mg/d of topiramate ( n = 183 ) or placebo ( n = 188 ) , along with a weekly compliance enhancement intervention . MAIN OUTCOME MEASURES Primary efficacy variable was self-reported percentage of heavy drinking days . Secondary outcomes included other self-reported drinking measures ( percentage of days abstinent and drinks per drinking day ) along with the laboratory measure of alcohol consumption ( plasma gamma-glutamyltransferase ) . RESULTS Treating all dropouts as relapse to baseline , topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 ( mean difference , 8.44 % ; 95 % confidence interval , 3.07%-13.80 % ; P = .002 ) . Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days ( mean difference , 16.19 % ; 95 % confidence interval , 10.79%-21.60 % ; P < .001 ) and all other drinking outcomes ( P < .001 for all comparisons ) . Adverse events that were more common with topiramate vs placebo , respectively , included paresthesia ( 50.8 % vs 10.6 % ) , taste perversion ( 23.0 % vs 4.8 % ) , anorexia ( 19.7 % vs 6.9 % ) , and difficulty with concentration ( 14.8 % vs 3.2 % ) . CONCLUSION Topiramate is a promising treatment for alcohol dependence . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00210925 Objective : Anticonvulsant drugs have been used in the treatment of alcohol dependence . The purpose of the present study was to evaluate tolerance and safety of zonisamide in a sample of patients presenting alcohol dependence . Methods : Open-label zonisamide  was examined in 22 out patients with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition alcohol dependence .  Zonisamide was started at a dose of 50 mg/d and titrated to a maximun dose of 300 mg/d . Subjects received a baseline evaluation including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition and the Severity of Alcohol Dependence Scale . Alcohol craving and alcohol consumption were assessed at weeks 2 , 4 , 6 , 8 , 10 , and 12 . The concentration of & ggr;-glutamyltransferase was used as an indirect measure of alcohol consumption . Results : Significant improvement was observed in visual analog scale for craving severity scores , weekly drink consumption , and & ggr;-glutamyltransferase .  Zonisamide was well tolerated , with only a dropout due to adverse events . Conclusions : Zonisamide is safe and well tolerated in this sample and associated with improvement in alcohol craving and alcohol consumption . A placebo-controlled study would be of interest Fifteen volunteers received cannabidiol ( CBD ) ( 320 μg/kg ) or placebo ( both orally , T0 ) , and 60 min later they consumed an ethanolic beverage ( 0.54 g/kg ) or placebo . The effects were measured at T1 ( 100 min after CBD ingestion ) , T2 ( 160 min ) and T3 ( 220 min ) using cognitive , perceptual and motor function tests . Factorial analysis indicated that test procedures could be adequately expressed by three rotated factors : A reaction speed factor ( I ) , a st and ing steadiness factor ( II ) and a psychomotor coordination/cognitive factor ( III ) . Ethanol produced a significant decrement in factor III . There was no demonstrable effect of CBD , either alone or in combination with ethanol . Neither CBD nor ethanol produced any significant effect on pulse rate . Prior administration of CBD did not significantly affect the blood ethanol levels . Whilst the subjects were able to identify correctly when they were given ethanol , they did not report any subjective effects of CBD AIM Cannabinoid receptor type 1 ( CB1 ) antagonists show central side effects , whereas beneficial effects are most likely peripherally mediated . In this study , the peripherally selective CB1 antagonist TM38837 was studied in humans . METHODS This was a double-blind , r and omized , placebo-controlled , crossover study . On occasions 1 - 4 , 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg , 500 mg or placebo , or placebos only . During occasion 5 , subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups . Blood collection s and pharmacodynamic ( PD ) effects were assessed frequently . Pharmacokinetics ( PK ) and PD were quantified using population PK-PD modelling . RESULTS The TM38837 plasma concentration profile was relatively flat compared with rimonabant . TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high , body sway and heart rate were partly antagonized by rimonabant 60 mg [ -26.70 % [ 90 % confidence interval ( CI ) -40.9 , -12.6 % ] ; -7.10 % , ( 90%CI -18.1 , 5.3 % ) ; -7.30 % , ( 90 % CI -11.5 % , -3.0 % ) respectively ] and TM38837 500 mg [ -22.10 % ( 90 % CI -34.9 , -9.4 % ) ; -12.20 % ( 90 % CI -21.6 % , -1.7 % ) ; -8.90 % ( 90 % CI -12.8 % , -5.1 % ) respectively ] . TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects . CONCLUSIONS Rimonabant showed larger effects than TM38837 , but the heart rate effects were similar . TM38837 100 mg had no impact on CNS effects , suggesting that this dose does not penetrate the brain . This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models . These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders , with a reduced propensity for psychiatric side effects BACKGROUND Topiramate , a sulphamate fructopyranose derivative , might antagonise alcohol 's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function . We aim ed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence . METHODS We did a double-blind r and omised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence . Of these 150 individuals , 75 were assigned to receive topiramate ( escalating dose of 25 - 300 mg per day ) and 75 had placebo as an adjunct to weekly st and ardised medication compliance management . Primary efficacy variables were : self-reported drinking ( drinks per day , drinks per drinking day , percentage of heavy drinking days , percentage of days abstinent ) and plasma gamma-glutamyl transferase , an objective index of alcohol consumption . The secondary efficacy variable was self-reported craving . FINDINGS At study end , participants on topiramate , compared with those on placebo , had 2.88 ( 95 % CI -4.50 to -1.27 ) fewer drinks per day ( p=0.0006 ) , 3.10 ( -4.88 to -1.31 ) fewer drinks per drinking day ( p=0.0009 ) , 27.6 % fewer heavy drinking days ( p=0.0003 ) , 26.2 % more days abstinent ( p=0.0003 ) , and a log plasma gamma-glutamyl transferase ratio of 0.07 ( -0.11 to -0.02 ) less ( p=0.0046 ) . Topiramate-induced differences in craving were also significantly greater than those of placebo , of similar magnitude to the self-reported drinking changes , and highly correlated with them . INTERPRETATION Topiramate ( up to 300 mg per day ) is more efficacious than placebo as an adjunct to st and ardised medication compliance management in treatment of alcohol dependence 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 BACKGROUND Patients with Lennox-Gastaut syndrome , a rare , severe form of epileptic encephalopathy , are frequently treatment resistant to available medications . No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome . We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients . METHODS In this r and omised , double-blind , placebo-controlled trial done at 24 clinical sites in the USA , the Netherl and s , and Pol and , we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome . Eligible patients ( aged 2 - 55 years ) had Lennox-Gastaut syndrome , including a history of slow ( <3 Hz ) spike- and -wave patterns on electroencephalogram , evidence of more than one type of generalised seizure for at least 6 months , at least two drop seizures per week during the 4-week baseline period , and had not responded to treatment with at least two antiepileptic drugs . Patients were r and omly assigned ( 1:1 ) using an interactive voice response system , stratified by age group , to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks . All patients , caregivers , investigators , and individuals assessing data were masked to group assignment . The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period , analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data . All r and omly assigned patients were included in the safety analyses . This study is registered with Clinical Trials.gov , number NCT02224690 . FINDINGS Between April 28 , 2015 , and Oct 15 , 2015 , we r and omly assigned 171 patients to receive cannabidiol ( n=86 ) or placebo ( n=85 ) . 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment ; all r and omly assigned patients received at least one dose of study treatment and had post-baseline efficacy data . The median percentage reduction in monthly drop seizure frequency from baseline was 43·9 % ( IQR -69·6 to -1·9 ) in the cannibidiol group and 21·8 % ( IQR -45·7 to 1·7 ) in the placebo group . The estimated median difference between the treatment groups was -17·21 ( 95 % CI -30·32 to -4·09 ; p=0·0135 ) during the 14-week treatment period . Adverse events occurred in 74 ( 86 % ) of 86 patients in the cannabidiol group and 59 ( 69 % ) of 85 patients in the placebo group ; most were mild or moderate . The most common adverse events were diarrhoea , somnolence , pyrexia , decreased appetite , and vomiting . 12 ( 14 % ) patients in the cannabidiol group and one ( 1 % ) patient in the placebo group withdrew from the study because of adverse events . One patient ( 1 % ) died in the cannabidiol group , but this was considered unrelated to treatment . INTERPRETATION Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated . The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial . FUNDING GW Pharmaceuticals Objectives : The objectives of this study are to assess the tolerability and efficacy of the anticonvulsant  zonisamide in an open label trial of the treatment of alcohol dependence . Methods : In this trial , zonisamide ( 400-mg daily ) was administered to alcohol-dependent subjects ( ADS ) ( n = 16 ) over 13 weeks . The mean daily consumption of st and ard alcoholic drinks and performance on a verbal fluency task , the COWAT , and on a measure of attention and visuomotor speed , the DSMT were assessed , and the occurrence of adverse events was monitored weekly . Results : The mean number of drinks consumed daily was significantly reduced from baseline levels during the treatment period . Performances on the COWAT and on the DSMT were not significantly reduced by zonisamide treatment . Overall , zonisamide was well tolerated by the study subjects . Conclusion : These results indicate that zonisamide administration may not impair verbal fluency in ADS , and are consistent with other studies that found zonisamide administration may reduce alcohol intake Six male and four female healthy volunteers were given oral placebo ( glucose capsule and orange juice ) , cannabidiol ( CBD 200 mg capsule and orange juice ) , alcohol ( 1 g/kg in orange juice and glucose capsule ) , and CBD ( 200 mg capsule ) plus alcohol ( 1 g/kg in orange juice ) in a double-blind , crossover , r and omized design . Treatments were spaced one week apart . Parameters measured were a finger tap test ( motor performance ) , cancellation and differential aptitude tests ( psychomotor performance ) , a 1-min time production task , subjective effects ( 66 item adjective-pair semantic differential ) , and breathalyzer estimations of blood alcohol levels . Compared to placebo , alcohol and alcohol plus CBD , but not CBD alone , produced significant impairments of motor and psychomotor performances , overestimations of time production and subjective responses indicating an accurate self-perception of their intoxication and deficits . The combination of alcohol plus CBD result ed in significantly lower blood alcohol levels compared to alcohol given alone , however , there were few differences observed between the pharmacological effects of the two alcohol conditions . Thus , the inactivity of CBD , a major marijuana constituent , on motor and mental performance and effects also extends to its interaction with alcohol Background Cannabidiol has been used for treatment‐resistant seizures in patients with severe early‐onset epilepsy . We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox – Gastaut syndrome , a severe developmental epileptic encephalopathy . Methods In this double‐blind , placebo‐controlled trial conducted at 30 clinical centers , we r and omly assigned patients with the Lennox – Gastaut syndrome ( age range , 2 to 55 years ) who had had two or more drop seizures per week during a 28‐day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight ( 20‐mg cannabidiol group ) or 10 mg per kilogram ( 10‐mg cannabidiol group ) or matching placebo , administered in two equally divided doses daily for 14 weeks . The primary outcome was the percentage change from baseline in the frequency of drop seizures ( average per 28 days ) during the treatment period . Results A total of 225 patients were enrolled ; 76 patients were assigned to the 20‐mg cannabidiol group , 73 to the 10‐mg cannabidiol group , and 76 to the placebo group . During the 28‐day baseline period , the median number of drop seizures was 85 in all trial groups combined . The median percent reduction from baseline in drop‐seizure frequency during the treatment period was 41.9 % in the 20‐mg cannabidiol group , 37.2 % in the 10‐mg cannabidiol group , and 17.2 % in the placebo group ( P=0.005 for the 20‐mg cannabidiol group vs. placebo group , and P=0.002 for the 10‐mg cannabidiol group vs. placebo group ) . The most common adverse events among the patients in the cannabidiol groups were somnolence , decreased appetite , and diarrhea ; these events occurred more frequently in the higher‐dose group . Six patients in the 20‐mg cannabidiol group and 1 patient in the 10‐mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial . Fourteen patients who received cannabidiol ( 9 % ) had elevated liver aminotransferase concentrations . Conclusions Among children and adults with the Lennox – Gastaut syndrome , the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen result ed in greater reductions in the frequency of drop seizures than placebo . Adverse events with cannabidiol included elevated liver aminotransferase concentrations . ( Funded by GW Pharmaceuticals ; GWPCARE3 Clinical Trials.gov number , NCT02224560 . BACKGROUND Despite advances in the development of medications to treat alcohol dependence , few medications have been approved by the U.S. Food and Drug Administration . The use of certain anticonvulsant medications has demonstrated potential efficacy in treating alcohol dependence . Previous research suggests that the anticonvulsant levetiracetam may be beneficial in an alcohol-dependent population of very heavy drinkers . METHODS In this double-blind , r and omized , placebo-controlled clinical trial , 130 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites . Patients received either levetiracetam extended-release ( XR ) or placebo and a Brief Behavioral Compliance Enhancement Treatment intervention . Levetiracetam XR was titrated during the first 4 weeks to 2,000 mg/d . This target dose was maintained during weeks 5 through 14 and was tapered during weeks 15 and 16 . RESULTS No significant differences were detected between the levetiracetam XR and placebo groups in either the primary outcomes ( percent heavy drinking days and percent subjects with no heavy drinking days ) or in other secondary drinking outcomes . Treatment groups did not differ on a number of nondrinking outcomes , including depression , anxiety , mood , and quality of life . The only difference observed was in alcohol-related consequences . The levetiracetam XR treatment group showed significantly fewer consequences than did the placebo group during the maintenance period ( p = 0.02 ) . Levetiracetam XR was well tolerated , with fatigue being the only significantly elevated adverse event , compared with placebo ( 53 % vs. 24 % , respectively ; p = 0.001 ) . CONCLUSIONS This multisite clinical trial showed no efficacy for levetiracetam XR compared with placebo in reducing alcohol consumption in heavy drinking alcohol-dependent patients Introduction : Zonisamide is an anticonvulsant medication with GABAergic , glutamatergic , and monoaminergic effects . Zonisamide has also been shown to reduce alcohol intake in rodents and in risky drinkers in the context of a laboratory study . This pilot clinical trial evaluated the safety , tolerability , and efficacy of zonisamide for the treatment of alcohol dependence . Methods : Forty alcohol-dependent subjects ( 23 men ) were r and omly assigned to receive treatment with either placebo or zonisamide in a 12-week double-blind trial . Zonisamide was initiated at a dosage of 100 mg/d , which was increased by 100 mg/d every 2 weeks for 8 weeks to a maximum dosage of 500 mg/d . The medication was continued for 4 weeks at the target dosage and then tapered and discontinued . The primary outcomes were drinks per week , heavy drinking days per week , and abstinent days per week , which were measured using the Timeline Follow-Back method . Results : There was a significant medication by treatment week interaction effect favoring the zonisamide group for heavy drinking days ( HDD ; P = 0.012 ) , drinks per week ( P = 0.004 ) , and alcohol urge scores ( P = 0.006 ) . There was not a significant effect on the number or rate of increase in abstinent days . There were no serious adverse events reported and zonisamide treatment was well tolerated . Conclusion : The findings provide preliminary support for the use of zonisamide to treat alcohol dependence . Efforts to replicate and extend these findings are warranted Delayed reward discounting ( DRD ) is a behavioral economic index of impulsivity that reflects the extent to which an individual devalues a reward based on its delay in time ( i.e. , preference for smaller immediate rewards relative to larger delayed rewards ) . Current smokers exhibit greater DRD compared to non-smokers , but also exhibit greater DRD compared to ex-smokers , suggesting that either DRD is inversely associated with successful smoking cessation or that smoking cessation itself reduces DRD . In a sample of treatment-seeking smokers ( n=57 , 61 % male , 85 % Caucasian ) participating in a r and omized controlled smoking cessation trial , the current study prospect ively examined  DRD  for money in general and at three magnitudes in relation to time to the participants ' first lapse to smoking . Survival analysis using Cox proportional-hazards regression revealed that DRD predicted days to first lapse ( ps<.05-.01 ) and did so beyond nicotine dependence , sensation-seeking , and income in covariate analyses , with the exception of small magnitude discounting . In addition , dichotomous comparisons revealed significantly more impulsive baseline discounting for individuals who had lapsed by the two-week and eight-week follow-up visits . These findings indicate that high levels of DRD reflect a risk factor for poor smoking cessation treatment response . Interrelationships among the variables assessed and clinical strategies to improve outcomes for smokers who are high in DRD are discussed Background Antiepileptics have been shown to reduce alcohol intake or to prevent relapse in patients with alcoholism . Goal To investigate if the new antiepileptic levetiracetam ( LEV ) prevents relapse after detoxification compared with placebo in patients with alcohol dependence . Methods Two hundred one patients were included in the prospect i ve , r and omized , double-blind , multicenter , placebo-controlled trial . After detoxification treatment and a screening period of 7 days , patients were r and omized to treatment with LEV or placebo . Medication was administered in a fixed-dose schedule for 16 weeks . Primary outcome parameters were the overall rate and time to relapse with heavy drinking . Secondary outcome parameters were time to the first drink , craving , adherence , tolerability , and safety data ( mean corpuscular volume , serum alanine aminotransferase , serum aspartate aminotransferase , & ggr;-glutamyltransferase ) . Results The rate of relapse and the time to relapse did not differ significantly between both groups , but less patients treated with LEV terminated treatment early compared with patients receiving placebo .  Tolerability and safety data were similar in the LEV group compared with placebo . Conclusions Our data do not support a significant effect of LEV on relapse prevention in patients with alcohol dependence during the first 16 weeks of abstinence Objective : The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm . Method : We conducted a double-blind , placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers ( N = 10 ) ( 1 ) . Result : During the second hour of a 2-hour self-administration session ethanol consumption was 50 % lower in the zonisamide group as compared to the placebo group . Urge to drink was also significantly lower under the zonisamide condition . Conclusion : These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol . Scientific Significance : Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol Anticonvulsant agents show promise in the treatment of the acute symptoms of alcohol withdrawal and may also treat some symptoms associated with the protracted abstinence syndrome . Impulsivity , hostility and irritability are common characteristics of alcohol-dependent individuals , and there is some evidence that anticonvulsant agents decrease these traits in individuals with a number of different psychiatric disorders . This pilot study is a 12-week , double-blind , placebo-controlled trial of an anticonvulsant agent , divalproex ( DVPX ) , in alcohol-dependent individuals .  Alcohol use ( Timeline Follow Back ) , impulsivity ( Barratt Impulsivity Scale ) , irritability and aggression ( Buss-Durkee Hostility Index ; and Anger , Irritability , Aggression Scale ) were measured at baseline and throughout the 12-week treatment period . Drinking decreased significantly in both the placebo and the DVPX-treated groups . In the DVPX group , a significantly smaller percentage of individuals relapsed to heavy drinking , but there were no significant differences in other alcohol-related outcomes . There were significantly greater decreases in irritability in the DVPX-treated group and a trend towards greater decreases on measures of lability and verbal assault . There were no significant between-group differences on measures of impulsivity . While DVPX did not have a robust effect on alcohol-related outcomes , it did have modest impact on a measure of irritability . This is consistent with the findings of other investigators exploring the use of DVPX in schizophrenia , personality disorder and a number of other psychiatric disorders 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 Alcoholism is associated with gray matter volume deficits in frontal and other brain regions . Whether persistent brain volume deficits in abstinence are predictive of subsequent time to alcohol relapse has not been established . The authors measured gray matter volumes in healthy volunteers and in a sample of treatment-engaged , alcohol-dependent patients after 1 month of abstinence and assessed whether smaller frontal gray matter volume was predictive of subsequent alcohol relapse outcomes . METHOD Forty-five abstinent alcohol-dependent patients in treatment and 50 healthy comparison subjects were scanned once using high-resolution ( T(1)-weighted ) structural MRI , and voxel-based morphometry was used to assess regional brain volume differences between the groups . A prospect i ve study design was used to assess alcohol relapse in the alcohol-dependent group for 90 days after discharge from 6 weeks of inpatient treatment . RESULTS Significantly smaller gray matter volume in alcohol-dependent patients relative to comparison subjects was seen in three regions : the medial frontal cortex , the right lateral prefrontal cortex , and a posterior region surrounding the parietal-occipital sulcus . Smaller medial frontal and parietal-occipital gray matter volumes were each predictive of shorter time to any alcohol use and to heavy drinking relapse . CONCLUSIONS These findings are the first to demonstrate that gray matter volume deficits in specific medial frontal and posterior parietal-occipital brain regions are predictive of an earlier return to alcohol use and relapse risk , suggesting a significant role for gray matter atrophy in poor clinical outcomes in alcoholism . Extent of gray matter volume deficits in these regions could serve as useful neural markers of relapse risk and alcoholism treatment outcome
target: 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 .
background: 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 ) .