Cannabidiol (CBD) for the Treatment of Alcohol Withdrawal

Study Overview
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Brief Summary
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This study will explore the effectiveness and tolerability of Cannabidiol (CBD) in the treatment of alcohol withdrawal symptoms in an inpatient setting, in a double-blind randomised placebo-controlled trial.

Detailed Description
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New treatment strategies for treating symptoms of alcohol dependence are urgently needed. Although alcohol related disorders are a leading cause of preventable death in Australia, their treatment is generally not evidence-based. Contemporary treatment for managing alcohol withdrawal in Australia involves administration of benzodiazepines that, while often effective for managing withdrawal symptoms, have concerns regarding their use including: a major abuse liability potential in this population; their sedating effects and potential for adverse events (e.g. falls, overdose, cognitive impairment) if used in combination with other sedatives; and an increased risk of relapse due to symptoms of alcohol dependence that return after cessation of treatment (e.g. increased sleep problems and anxiety). However, no other safe and effective alternatives to benzodiazepines in treating alcohol withdrawal have yet been demonstrated. This project will pilot the clinical efficacy and tolerability of Cannabidiol (CBD) relative to placebo in the treatment of alcohol withdrawal in an inpatient setting across two study sites. This is a double-blind, randomised controlled design. The trial will recruit 52 participants undergoing alcohol withdrawal, using a 1:1 random allocation into one of two treatment groups as follows: (1) CBD (Day 1: 1200 mg/day; Day 2-4: 800 mg/day; Day 5: placebo washout; n = 26), or (2) matched placebo (n = 26). All participants will be administered a symptom triggered diazepam medication regimen, as per conventional best-practice management of alcohol withdrawal.

Official Title
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A Randomised Controlled Trial of Cannabidiol (CBD) for the Treatment of Alcohol Withdrawal

Conditions
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Alcohol Withdrawal, Alcohol Dependence

Intervention / Treatment
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* Drug: Cannabidiol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-65 years; At least one prior episode 2 days or longer in duration during which the participant experienced withdrawal symptoms that caused significant incapacitation (e.g. inability to work or do normal activities) OR at least one prior inpatient or outpatient medical detoxification during which the participant exhibited withdrawal symptoms of significant magnitude that sedative-hypnotic or anticonvulsant medication was required at least once on 2 consecutive days after cessation of or reduction in the use of alcohol following 2 weeks or more of heavy daily consumption; Average consumption of at least 8 standard drinks per day for at least 2 weeks prior to enrolment in the study; Adequate cognition and English language skills to give valid consent and complete research interviews; Willingness to give written informed consent Exclusion Criteria: Treatment/ingestion during the previous week of benzodiazepines or other sedative-hypnotic medications or history of recent chronic treatment with sedative-hypnotic medication as evidenced by a negative urine drug screen at baseline History of alcohol withdrawal related seizures Substance use in the previous week, defined as > 3 times per week (not including nicotine or caffeine), inclusive of non-prescribed pharmaceuticals (ATOP to be collected at screening) Active major psychiatric disorder associated with psychosis, or significant suicide risk (e.g. Bipolar, Schizophrenia) Pregnancy or lactation - Women shall be advised to use reliable contraception for the duration of drug therapy and a urine pregnancy test will be performed where necessary History of confirmed seizures during adulthood, and/or current use of anti-epileptic drugs (AED) Diagnosis of epilepsy, and/or current use of anti-epileptic drugs (AED) Serious medical illness impacting on safety/participation, defined as an unstable medical state in the opinion of the trial medical officer Low body weight (body mass index < 17) Severe cognitive impairment or insufficient English or literacy to complete study processes Concurrent use of drugs potentially exacerbated by CBD via CYP3A5

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabidiol (CBD)<br>Drug: Cannabidiol (day 1: 1200 mg (800 mg BD); day 2-4: 800 mg (400 mg BD); day 5: placebo BD). | Drug: Cannabidiol<br>* CBD capsules administered BD for 4-days (800-1200 mg/day), placebo day 5<br>|
| Placebo Comparator: Placebo<br>Drug: Placebo (days 1-5: placebo matched BD) | Drug: Placebo<br>* Placebo capsules administered BD for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diazepam | Diazepam use over the 5-day withdrawal period (which due to symptom triggered regimen is a proxy measure for withdrawal severity). Measured by total diazepam use over 5 day period. | 5 day admission period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alcohol Withdrawal Severity | Measured by Alcohol Withdrawal Scale (AWS), minimum score is 0, maximum score is 27 where higher scores indicate greater withdrawal severity. | 5 day admission period | 
| Self-reported Alcohol Withdrawal Severity | As measured by the Alcohol Withdrawal Severity Checklist (AWSC), a self-report measure of withdrawal severity, minimum score is 0, maximum score is 64 where higher scores indicate greater self-reported withdrawal severity. | 5 day admission period (twice daily) | 
| Self-reported alcohol craving | As measured by the Penn Alcohol Craving Scale (PACS), minimum score is 0, maximum score is 30 where higher scores indicate greater alcohol craving | Baseline, Day 5, and Day 12 and 33 Follow Up | 
| Self-reported urges to drink | As measured by the Alcohol Urge Questionnaire (AUQ), minimum score is 8, maximum score is 56, where higher scores indicate greater urges to drink | Twice Daily, days 1-5 | 
| Actiwatch for sleep quality | as measured using data obtained from the actiwatch worn by participants for duration of inpatient stay | 5 day admission period | 
| Self-reported sleep quality | as measured using the Insomnia Severity Index (ISI), minimum score is 0, maximum score is 28, where higher scores indicate greater insomnia severity. | Baseline, Day 5, and Follow Up (Day 12, Day 33) | 
| Subjective measure of patient satisfaction | Measured using the Treatment Satisfaction Questionnaire for Medication (TSQM), minimum score is 13, maximum score is 80, where higher scores indicate greater treatment satisfaction. | Day 5 and follow up (day 12 and 33) | 
| Liver function tests for clinical markers of liver injury | as measured by levels of liver enzymes, Alanine Transaminase (ALT), Alkaline Phosphatase (ALP) and Aspartate Transaminase (AST) in blood | Baseline and follow up (day 12 and 33). | 
| Plasma levels of benzodiazepines | As measured by concentration of benzodiazepines in blood plasma | Daily (days 1-5) | 
| Plasma levels of cannabidiol | As measured by concentration of cannabidiol in blood plasma | Daily (days 1-5) | 
| Mood | Depression, Anxiety and Stress Symptoms measured by the Depression, Anxiety and Stress Scale (DASS-21), minimum score is 0, maximum score is 63, where higher scores indicate greater levels of depression, anxiety and stress. | Baseline, day 5 and follow up day 12 and 33. | 
| Cognitive Functioning | As measured by the Montreal Cognitive Assessment (MoCA), maximum score is 30 and where higher scores indicate greater cognitive functioning. | Baseline, day 5 and follow up day 12 and 33. | 
| Cognitive Functioning | Executive functioning measured by time taken to complete the Trail Making Test A and B (in seconds), where lower scores indicate greater functioning. | Baseline, day 5 and follow up day 12 and 33. | 
| Comorbid Anxiety Disorders | Assessed using the MINI Neuropsychiatric Interview indicating the presence or absence of anxiety disorders | 4 week follow up (day 33) |