The Efficacy and Neurobehavioural Mechanism of Cannabidiol (CBD) for Alcohol Dependence

The Efficacy and Neurobehavioural Mechanism of Cannabidiol (CBD) for Alcohol Dependence: An Exploratory Pilot Study

The study will explore the psychophysiological and neurobiological and mechanisms of CBD in participants with alcohol use disorder

Study Overview

• Status: Recruiting
• Conditions: Alcohol Use Disorder (AUD)
• Intervention / Treatment: Drug: Cannabidiol (CBD); Drug: Placebo

Detailed Description

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. Cannabidiol (CBD) may serve as a novel pharmacotherapeutic due to its anxiolytic, anti-epileptic, neuro-protective, antioxidant and neuroprotective properties as well as a particularly safe side effect profile. Further, CBD has been shown to modulate drug craving and seeking behaviours.

This project will examine whether CBD exerts an effect on cue-induced craving by reducing activation in areas of the brain responsive to alcohol cues in comparison to a placebo. This study will use functional magnetic resonance imaging (fMRI) to examine activity in the brain while participants are exposed alcohol related cues and magnetic resonance spectroscopy (MRS) to determine levels of neurotransmitters that may be responsible for craving. In addition, we aim to investigate the effects of CBD on autonomic nervous system parameters associated with alcohol withdrawal symptoms and anxiety, such as heart rate variability and skin conductance. Additionally, clinical outcome measures will be taken to investigate CBDs influence on drinking, sleep

This project uses a randomised, double blind, crossover design with 800mg CBD vs matched placebo. The dosing paradigm will consist of one dose per day for three days per arm with a 18 days washout period in-between arms.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kirsten Morley, PhD; Phone Number: +61295153636; Email: kirsten.morley@sydney.edu.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2050
      • Recruiting
      • Drug Health Services, Royal Prince Alfred Hospital
      • Principal Investigator: Paul Haber, MBBS
      • Contact: Kirsten Morley, PhD; Email: Kirsten.morley@sydney.edu.au
      • Contact: Central Contact Line; Phone Number: 0459877108; Email: sydneyalcoholtreatmentgroup@gmail.com
      • Principal Investigator: Warren Logge, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients between ages of 18 and 65 meeting DSM-5 criteria for current alcohol use disorder
• Adequate cognition and English language skills to give valid consent and complete research interviews;
• A BrAC reading of 0.00
• Must have a stable residence and be able to identify an individual who could locate subject if needed
• Provision of informed consent

Exclusion Criteria:

• Active major psychological disorder associated with psychosis, significant suicide risk
• 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;
• Dependence on any substance other than nicotine (eg methadone)
• Diagnosis of epilepsy, and/or current use of anti-epileptic drugs (AED)
• Liver failure with jaundice or prolonged INR above 1.3
• Medical complications such as liver failure, cardiac ischemia or conduction abnormalities, renal impairment or unstable elevated vital signs (systolic blood pressure > 180, diastolic blood pressure > 120 or heart rate > 150)
• Severe cognitive impairment or insufficient English or literacy to complete study processes
• Concurrent use of drugs potentially exacerbated by CBD via CYP3A5 including cardiac medication (e.g. betablockers, calcium channel blockers and statins), macrolides and recent antihistamine use.
• Claustrophobia;
• Extreme obesity;
• Previous brain surgery;
• Ever employed as a machinist, a welder or a metal worker;
• Metal items such as pacemakers; aneurysm clips in the brain; metal dental implants; metallic fragments in the eye or anywhere else; insulin pump; metal implants; hearing aid or a prosthetic device.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cannabidiol (CBD); For a total of three days, so that both study participants and staff are blind to treatment condition	Drug: Cannabidiol (CBD); Four 200mg soft gel capsules of Cannabidiol (CBD) will be taken orally daily for a total of 3 days.
Placebo Comparator: Placebo; For a total of three days, so that both study participants and staff are blind to treatment condition	Drug: Placebo; The placebo will be identical in appearance, taste, and composition except for the active ingredient of pure CBD. So, four 200mg soft gel capsules of the placebo will be taken orally daily for a total of 3 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in High Frequency Heart Rate Variability	To assess whether acute ingestion of CBD can modulate heart rate variability when responding to alcohol cues compared to neutral cues	22 days
Changes in Skin Conductance Levels	To assess whether acute ingestion of CBD modulates skin conductance levels when responding to alcohol cues compared to neutral cues	22 days
Changes in Brain Activation	To assess whether acute ingestion of CBD can attenuate brain activation via blood oxygen level dependent (BOLD) in areas associated with alcohol cue-elicited craving measured by an fMRI machine	22 days
Changes in Neurotransmitter levels in the Brain	To assess whether CBD treatment leads to changes in brain levels of the neurotransmitters: glutamate, gamma-aminobutyric acid (GABA), N-acetylaspartate (NAA) and glutathione (GSH)	22 days
Heavy Drinking Days	Reduction in Heavy Drinking Days (HDD; defined as 4 or more drinks in a day for women and five or more drinks in a day for men). This will be measured by the Timeline Follow Back.	Up to 43 days
Absence of any Heavy Drinking Day	Measured by Timeline Follow Back	Up to 43 days
Mean Alcohol Consumption per Drinking Day	Measured by Timeline Follow Back	Up to 43 days
Alcohol Dependence Severity	Measured by the Alcohol Dependence Scale. The minimum score is 0 and the maximum score is 47. A higher score indicates more severe dependence.	Baseline
Alcohol Craving	As measured by the Penn Alcohol Craving Scale (PACS), which measures the amount of time spent thinking and craving for alcohol, difficulty in resisting consumption of alcohol if present and hypothetical pleasure associated with consumption of alcohol. This scale has a minimum score of 0 and a maximum score of 6. A higher score indicates greater levels of craving.	Up to 43 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lifetime Consequences related to Drinking	To examine the adverse consequences a participant has experienced in their lifetime due to alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. This is measured using the Drinker Inventory of Consequences Lifetime Edition (DrInC-2L). Higher scores indicate more consequences.	Baseline
Changes in Alcohol Craving	To assess whether acute ingestion of CBD can modulate subjective measures of alcohol cue elicited craving. This will be measured during the fMRI scan using the Visual Analogue Scale. This scale will assess alcohol craving, thirst and anxiety.	22 days
Changes in Alcohol Craving in response to alcohol cues	To assess whether acute ingestion of CBD can modulate subjective measures of alcohol cue elicited craving. This will be measured before and after the fMRI scan using the Alcohol Urge Questionnaire (AUQ). This Questionnaire consists of 8 questions that are scored on a Likert scale of 7 points. Two of the questions are reversed scored. Total score is computed by averaging the item scores. A greater score indicates greater craving.	22 days
Changes in Positive and Negative Mood States	To assess whether acute ingestion of CBD can modulate subjective measures of positive and negative mood states following alcohol cues. This will be measured before and after the fMRI scan using the Positive and Negative Affect Schedule (PANAS).	22 days
Changes in Anxiety	Measured by cumulative scores on the DASS-21 Anxiety Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more anxiety.	Up to 43 days
Changes in Depression	Measured by cumulative scores on the DASS-21 Depression Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates greater depression.	Up to 43 days
Changes in Stress	Measured by cumulative scores on the DASS-21 Stress Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more stress.	Up to 43 days
Sleep Disturbances	As measured by the ISI (Insomnia Severity Index). This Index has a minimum score of 0 and a maximum score of 28. The higher the score indicates more severe insomnia.	Up to 43 days
Sleep Disturbances	To assess whether acute ingestion of CBD has any impact of sleep. This will be measured by an Actiwatch. The Actiwatch records motion and light to determine information about participants sleep and wake patterns. The participants will wear this watch for 48 hours on two separate occasions.	22 days
Changes in Tension Reduction Alcohol Expectancies	To assess whether CBD treatment can reduce participants need to use alcohol to attenuate tension states (such as anxiety) as measured by the Tension Reduction subscale of the Alcohol Expectancy Questionnaire. Higher scores indicate greater reliance on alcohol to reduce tension/ anxiety.	Up to 43 days
Recent Consequences related to Drinking	To examine the adverse consequences a participant has experienced in the last 3 months due to alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. This is measured using the Drinker Inventory of Consequences Recent Edition (DrInC-2R). Higher scores indicate more consequences.	Baseline
Behavioural Inhibition/Avoidance Scales	The BIS/BAS Scale is a 20-item self-report questionnaire designed to measure two motivational systems: the behavioral inhibition system (BIS), which corresponds to motivation to avoid aversive outcomes, and the behavioral activation system (BAS), which corresponds to motivation to approach goal-oriented outcomes.	22 days
Obsessive Compulsive Drinking	To assess an individuals obsessive thoughts about alcohol use and compulsive behaviours towards drinking as measured by the Obsessive Compulsive Drinking Scale. Six of the questions measure to obsession and eight of the questions measure compulsivity. Higher scores on these subscales indicate more obsession and compulsion, respectively.	22 days
Self-Confidence to Remain Abstinent	To measure an individual's self-confidence in avoiding alcohol through the Alcohol Abstinence Self-Efficacy Scale (AASE). There are 20 questions and each is scored from 0 to 4. Higher scores on this scale indicate more self-confidence.	22 days
Intolerance of Uncertainty	To assess an individual's reactions to situations that are ambiguous, the consequences of being uncertain, and attempts the individual might make to control the future. This will be measured through the Intolerance of Uncertainty Scale (IUS). This scale includes 27-items that are scored on a Likert scale (1 - Not at all characteristic of me to 5 - entirely characteristic of me). All scores are summed up and a higher score indicates greater inability to deal with uncertainty.	22 days
Impulsivity	To assess an individual's impulsivity across four domains: urgency, lack of premeditation and perseverance, and sensation seeking. This will be measured through the Impulsivity Scale (UPPS). Greater scores on this scale indicate greater impulsivity.	22 days
Alcohol Withdrawal	To assess an individual's severity of alcohol withdrawal through the Clinical Institute Withdrawal Assessment of Alcohol Scale - Revised (CIWA-Ar). Greater scores on this scale indicate the participant is experiencing greater alcohol withdrawal symptoms.	22 days
Approach and Avoidance towards Alcohol	To assess an individual's automatic action tendencies (either approve or avoid) towards alcohol. This will be measured through the Approach Avoidance Task (AAT).	Up to 43 days
Response Time and Visuospatial Skills	To assess an individual's response time and visuospatial skills through the Trail Making Test Part A (TMT-A).	Up to 43 days
Set-shifting Flexibility, Attention, and Inhibition	To assess an individual's set-shifting flexibility, attention and inhibition through the Trail Making Test Part B (TMT-B).	Up to 43 days
Risk/Reward Taking Behaviour	To assess an individual's risk taking behaviour measured through the Balloon Analogue Risk Task (BART).	Up to 43 days
Decision Making	To assess an individual's decision making skills measured through the Columbia Card Task (CCT).	Up to 43 days
Response Inhibition	To assess an individual's ability to inhibit prepotent responses measured through the Stroop task.	Up to 43 days
Working Memory Capacity to Update Information	To assess an individual's capacity to update working memory information measured through the N-back task.	Up to 43 days
Working Memory Capacity to Shift Information	To assess an individual's capacity to shift between two tasks measured by the Number Letter task.	Up to 43 days
Markers of neuroinflammation	As measured by differences in blood sampling levels of glutathione.	Up to 43 days
Markers of Stress	As measured by differences in blood sampling levels of cortisol. This will be measured at rest, before the fMRI scan and following the fMRI scan.	Up to 43 days

Collaborators and Investigators

• Sponsor: South West Sydney Local Health District
• Collaborators: University of Sydney; Lambert Initiative for Cannabinoid Therapeutics

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2022
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: May 15, 2022
• First Submitted That Met QC Criteria: May 18, 2022
• First Posted (Actual): May 24, 2022

Study Record Updates

• Last Update Posted (Actual): June 3, 2022
• Last Update Submitted That Met QC Criteria: May 31, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Alcohol-Related Disorders; Mental Disorders; Substance-Related Disorders; Alcohol Withdrawal
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Anticonvulsants; Cannabidiol
• Other Study ID Numbers: X19-0416

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No