The study will explore the psychophysiological and neurobiological and mechanisms of CBD in participants with alcohol use disorder
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
20
Four 200mg soft gel capsules of Cannabidiol (CBD) will be taken orally daily for a total of 3 days.
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.
Drug Health Services, Royal Prince Alfred Hospital
Sydney, New South Wales, Australia
RECRUITINGChanges 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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.
Time frame: Up to 43 days
Absence of any Heavy Drinking Day
Measured by Timeline Follow Back
Time frame: Up to 43 days
Mean Alcohol Consumption per Drinking Day
Measured by Timeline Follow Back
Time frame: Up to 43 days
Alcohol Dependence Severity
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Measured by the Alcohol Dependence Scale. The minimum score is 0 and the maximum score is 47. A higher score indicates more severe dependence.
Time frame: 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.
Time frame: Up to 43 days
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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 43 days
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.
Time frame: Baseline
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: Up to 43 days
Risk/Reward Taking Behaviour
To assess an individual's risk taking behaviour measured through the Balloon Analogue Risk Task (BART).
Time frame: Up to 43 days
Decision Making
To assess an individual's decision making skills measured through the Columbia Card Task (CCT).
Time frame: Up to 43 days
Response Inhibition
To assess an individual's ability to inhibit prepotent responses measured through the Stroop task.
Time frame: 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.
Time frame: 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.
Time frame: Up to 43 days
Markers of neuroinflammation
As measured by differences in blood sampling levels of glutathione.
Time frame: 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.
Time frame: Up to 43 days