Effects of Cannabidiol in Alcohol Use Disorder

Study Overview
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Brief Summary
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The goal of the proposed project is to begin rigorous study of the clinically relevant effects of non-psychoactive phytocannabinoid cannabidiol (CBD) in patients with severe alcohol use disorder (AUD). This double-blind, randomized proof-of-concept study (n = 40) is designed to assess feasibility and contrast effects of extended (8 weeks) treatment with CBD to those of placebo in AUD patients. Participants with AUD will be randomized to receive either placebo or 600mg CBD/day (PO) for 4 weeks, immediately followed by 1200mg CBD/day (PO) for an additional 4 weeks (8 total weeks). These doses were chosen to reproduce serum CBD levels reported to reduce alcohol-seeking behavior in animal studies. Measures will include circulating levels of CBD, safety measures (THC serum levels, adverse events, cognitive and motoric function), and physiological and psychological domains relevant to AUD (including self-reported craving, depression, and anxiety, and responses to personalized scripts designed to elicit stress- and cue-induced craving and anxiety). Assessments will be conducted following 1 day, 1 week, and 4 weeks of treatment with each dose of CBD vs. placebo, and 1 and 4 weeks after the cessation of treatment. Drinking outcomes across 8 weeks of treatment and 4 weeks of follow-up will also be assessed as an exploratory outcome.

Detailed Description
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There is increasing recognition of the roles of the endocannabinoid system in neurobiological processes and behavioral domains relevant to addiction. The non-psychoactive phytocannabinoid cannabidiol (CBD) has attracted considerable attention due to its lack of abuse potential, its excellent safety profile, its unique and complex pharmacology, and evidence that it affects anxiety and stress response in animal models and humans. There is a growing body of preclinical data demonstrating that CBD produces marked and persisting decreases in alcohol self-administration and preference for alcohol, and alcohol-, cue- and stress-induced reinstatement of alcohol-seeking behavior, yet there are few studies of the effects of CBD in humans with addictive disorders, and none in alcohol dependent patients.

Official Title
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Effects of Cannabidiol in Alcohol Use Disorder

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Other: Placebo
* Drug: Phytocannabinoid cannabidiol (CBD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females age 18-65 DSM-5 diagnosis of moderate or severe AUD Able to provide voluntary informed consent At least 8 heavy drinking days (4 or more drinks for a woman, 5 or more drinks for a man) in the 30 days prior to screen If of childbearing potential (male or female), are willing to use approved form of contraception from screening for duration of the trial Able to provide at least two locators Endorse desire to cut down or stop drinking Agrees to abstain from all other cannabinoid use for duration of the study Exclusion Criteria: Current alcohol withdrawal (CIWA-Ar score >7) Exclusionary medical conditions (e.g. current severe alcohol withdrawal requiring medical hospitalization, significantly impaired liver function) DSM-5 diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation (e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful social support) Current significant suicidality (assessed using the C-SSRS), any suicidal behavior in the past 12 months, or any history of serious suicide attempts requiring hospitalization, or current significant homicidality History of severe Traumatic Brain Injury (LOC > 24 hours) DSM-5 diagnosis of current mild cannabis use disorder and/or moderate or severe substance use disorder for a substance other than alcohol or nicotine Significant laboratory abnormalities, including significantly impaired liver function, serious abnormalities of complete blood count or metabolic panel Active legal problems likely to result in incarceration within 12 weeks of treatment initiation Pregnancy or lactation Current use of exclusionary medications, including cannabinoids; treatments for addictions including alcohol; moderate to strong inhibitors of CYP3A4 or CYP2C19; medications metabolized primarily by CYP3A4, CYP3A5, or CYP3A7; and medications with a narrow therapeutic index which are substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, CYP2C19, CYP1A2, or CYP2B6. Allergy to any ingredient of the study compound. Current treatment for AUD, with exception of AA/12-step treatment No inpatient psychiatric treatment in the last 12 months, with the exception of detox and extended Emergency Department stays A positive urine drug screen for THC, cocaine and/or opioids at screen

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
Interventional Model Description: Double-blind, randomized proof-of-concept study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo for 4 weeks, followed by phytocannabinoid cannabidiol (CBD) for 4 weeks<br>600mg/day Saline taken by mouth (PO) for 4 weeks, immediately followed by 1200mg saline/ day (PO) for an additional 4 weeks (8 total weeks). | Other: Placebo<br>* Saline taken by mouth (PO)<br>|
| Experimental: CBD for 8 weeks<br>600mg CBD/day (PO) for 4 weeks, immediately followed by 1200mg CBD/day (PO) for an additional 4 weeks (8 total weeks). | Drug: Phytocannabinoid cannabidiol (CBD)<br>* CBD taken by mouth (PO)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough CBD Plasma Levels | CBD trough plasma levels measured before dosing with CBD. | Baseline | 
| Trough CBD Plasma Levels | CBD trough plasma levels measured before dosing with CBD. | Week 1 | 
| Trough CBD Plasma Levels | CBD trough plasma levels measured before dosing with CBD. | Week 4 | 
| Trough CBD Plasma Levels | CBD trough plasma levels measured before dosing with CBD. | Week 5 | 
| Trough CBD Plasma Levels | CBD trough plasma levels measured before dosing with CBD. | Week 8 | 
| Trough CBD Plasma Levels | CBD trough plasma levels measured before dosing with CBD. | Week 9 | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Baseline | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Day 1 | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Week 1 | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Week 4 | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Week 4 + 1 Day | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Week 5 | 
| Peak CBD Plasma Levels | CBD peak plasma levels measured 45 minutes after dosing with CBD. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Baseline | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 1 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 2 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 3 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 4 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 5 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 6 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 7 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 8 | 
| Percent of Heavy Drinking Days | The percent of heavy drinking days will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of days in the past 7 days in which they drank heavily. | Week 9 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Baseline | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 1 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 2 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 3 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 4 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 5 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 6 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 7 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 8 | 
| Number of Drinks Per Day | The number of drinks per day will be assessed by Timeline Follow Back (TLFB) methodology over the previous week. The TLFB methodology allows participants to report the number of drinks per day over the last 7 days. | Week 9 | 
| Penn Alcohol Craving Scale (PACS) Score | 5-item self-report measure of alcohol craving. Items are ranked on a Likert scale ranging from 0 (not at all) to 6 (severely). The total score is a sum of all the responses and ranges from 0 to 30. Higher scores indicate greater alcohol craving. | Baseline | 
| Penn Alcohol Craving Scale (PACS) Score | 5-item self-report measure of alcohol craving. Items are ranked on a Likert scale ranging from 0 (not at all) to 6 (severely). The total score is a sum of all the responses and ranges from 0 to 30. Higher scores indicate greater alcohol craving. | Week 1 | 
| Penn Alcohol Craving Scale (PACS) Score | 5-item self-report measure of alcohol craving. Items are ranked on a Likert scale ranging from 0 (not at all) to 6 (severely). The total score is a sum of all the responses and ranges from 0 to 30. Higher scores indicate greater alcohol craving. | Week 4 | 
| Penn Alcohol Craving Scale (PACS) Score | 5-item self-report measure of alcohol craving. Items are ranked on a Likert scale ranging from 0 (not at all) to 6 (severely). The total score is a sum of all the responses and ranges from 0 to 30. Higher scores indicate greater alcohol craving. | Week 5 | 
| Penn Alcohol Craving Scale (PACS) Score | 5-item self-report measure of alcohol craving. Items are ranked on a Likert scale ranging from 0 (not at all) to 6 (severely). The total score is a sum of all the responses and ranges from 0 to 30. Higher scores indicate greater alcohol craving. | Week 8 | 
| Penn Alcohol Craving Scale (PACS) Score | 5-item self-report measure of alcohol craving. Items are ranked on a Likert scale ranging from 0 (not at all) to 6 (severely). The total score is a sum of all the responses and ranges from 0 to 30. Higher scores indicate greater alcohol craving. | Week 9 | 
| Beck Anxiety Inventory (BAI) Score | 21-item self-report measure of anxiety. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of anxiety. Scores are interpreted as follows: 0 - 21 = low anxiety; 22 - 35 = moderate anxiety; 36 and above = potentially concerning levels of anxiety. | Baseline | 
| Beck Anxiety Inventory (BAI) Score | 21-item self-report measure of anxiety. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of anxiety. Scores are interpreted as follows: 0 - 21 = low anxiety; 22 - 35 = moderate anxiety; 36 and above = potentially concerning levels of anxiety. | Week 1 | 
| Beck Anxiety Inventory (BAI) Score | 21-item self-report measure of anxiety. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of anxiety. Scores are interpreted as follows: 0 - 21 = low anxiety; 22 - 35 = moderate anxiety; 36 and above = potentially concerning levels of anxiety. | Week 4 | 
| Beck Anxiety Inventory (BAI) Score | 21-item self-report measure of anxiety. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of anxiety. Scores are interpreted as follows: 0 - 21 = low anxiety; 22 - 35 = moderate anxiety; 36 and above = potentially concerning levels of anxiety. | Week 5 | 
| Beck Anxiety Inventory (BAI) Score | 21-item self-report measure of anxiety. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of anxiety. Scores are interpreted as follows: 0 - 21 = low anxiety; 22 - 35 = moderate anxiety; 36 and above = potentially concerning levels of anxiety. | Week 8 | 
| Beck Anxiety Inventory (BAI) Score | 21-item self-report measure of anxiety. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of anxiety. Scores are interpreted as follows: 0 - 21 = low anxiety; 22 - 35 = moderate anxiety; 36 and above = potentially concerning levels of anxiety. | Week 9 | 
| Beck Depression Inventory (BDI) Score | 21-item self-report measure of depression. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of depression. Scores are interpreted as follows: 0 - 10 = normal ups and downs; 11-16 = mild mood disturbance; 17-20 = borderline clinical depression; 21-30 = moderate depression; 31-40 = severe depression; over 40 = extreme depression. | Baseline | 
| Beck Depression Inventory (BDI) Score | 21-item self-report measure of depression. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of depression. Scores are interpreted as follows: 0 - 10 = normal ups and downs; 11-16 = mild mood disturbance; 17-20 = borderline clinical depression; 21-30 = moderate depression; 31-40 = severe depression; over 40 = extreme depression. | Week 1 | 
| Beck Depression Inventory (BDI) Score | 21-item self-report measure of depression. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of depression. Scores are interpreted as follows: 0 - 10 = normal ups and downs; 11-16 = mild mood disturbance; 17-20 = borderline clinical depression; 21-30 = moderate depression; 31-40 = severe depression; over 40 = extreme depression. | Week 4 | 
| Beck Depression Inventory (BDI) Score | 21-item self-report measure of depression. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of depression. Scores are interpreted as follows: 0 - 10 = normal ups and downs; 11-16 = mild mood disturbance; 17-20 = borderline clinical depression; 21-30 = moderate depression; 31-40 = severe depression; over 40 = extreme depression. | Week 5 | 
| Beck Depression Inventory (BDI) Score | 21-item self-report measure of depression. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of depression. Scores are interpreted as follows: 0 - 10 = normal ups and downs; 11-16 = mild mood disturbance; 17-20 = borderline clinical depression; 21-30 = moderate depression; 31-40 = severe depression; over 40 = extreme depression. | Week 8 | 
| Beck Depression Inventory (BDI) Score | 21-item self-report measure of depression. Items are ranked on a Likert scale ranging from 0 (Not at all) to 3 (Severely). The total score is the sum of responses and ranges from 0 to 63, where higher scores indicate greater levels of depression. Scores are interpreted as follows: 0 - 10 = normal ups and downs; 11-16 = mild mood disturbance; 17-20 = borderline clinical depression; 21-30 = moderate depression; 31-40 = severe depression; over 40 = extreme depression. | Week 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cannabidiol, Alcohol Use Disorder