Alcohol Use Disorder
Conditions
Brief summary
The goal of this study is to test cannabidiol (CBD) as a potentially effective candidate medication for youth alcohol use disorder (AUD). To accomplish this goal, this study will use a randomized, double-blind, within-subjects crossover design. In counterbalanced order, 50 youth (ages 16-22) will receive 600 mg of CBD or placebo three hours before a neuroimaging and behavioral assessment paradigm. The total amount of time the participant will be in the study is approximately one month.
Interventions
DRUGCannabidiol
In counterbalanced order, 50 youth (ages 16-22) will receive 600mg of cannabidiol or placebo three hours before a neuroimaging and behavioral assessment paradigm, separated by an approximate 18-day washout period.
Sponsors
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 22 Years
Healthy volunteers
Yes
Inclusion criteria
Age 16 to 22. Does or does not drink alcohol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations of Glx (i.e., Glutamate + Glutamine) | Changes 3 hours after administration of 600mg CBD vs. placebo | Using magnetic resonance spectroscopy and a within-subjects design, we measured Concentrations of Glx (i.e., glutamate + glutamine) levels in the anterior cingulate cortex in adolescents during cannabidiol (600mg) or placebo administration. Values provided are absolute values (mmol/kg) measured 3 hours after medication administration. Due to complexities of this method, normal levels of Glx are not known; thus, we cannot make conclusions about the meaning of higher or lower glutamate levels when comparing cannabidiol to placebo. |
| GABA+ | Changes 3 hours after administration of 600mg CBD vs. placebo | Using magnetic resonance spectroscopy and a within-subjects design, we measured GABA+ (GABA plus macromolecules) levels in the anterior cingulate cortex in adolescents during cannabidiol (600mg) or placebo administration. Values provided are absolute values (mmol/kg) measured 3 hours after medication administration. Due to complexities of this method, normal levels of GABA are not known; thus, we cannot make conclusions about the meaning of higher or lower GABA levels when comparing cannabidiol to placebo. |
| Alcohol Cue Reactivity Neural Activation | Changes 3 hours after administration of 600mg CBD vs. placebo | Assessing the change in neural reactivity to alcohol cues after each round of medication: Cannabidiol vs. placebo. Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen. The mean Z-statistic within each ROI mask is reported. A Z-score of 0 represents the population mean (e.g., no activation), where higher absolute Z-scores indicate greater evidence of activation (positive or negative) in the ROI compared to baseline. Z-scores do not have inherent clinical thresholds. Higher Z-scores generally reflect stronger task-related BOLD signal changes. |
| Heart Rate Variability | Changes 2 hours after administration of 600mg CBD vs. placebo | All participants underwent an in vivo, olfactory alcohol cue exposure procedure. Participants smelled water followed by the participant's preferred beverage containing alcohol and apple juice in a counterbalanced order for three minutes each, with a three-minute rest period in between each liquid. The contents were poured into a cup in the participant's presence. During the task, electrocardiogram data were collected and used to create the heart rate variability (HRV) outcome related to the Sympathetic: Vagal ratio, which is the ratio of low-frequency to high-frequency power, derived from spectral HRV analysis. Higher values suggest increased sympathetic activity or reduced vagal activity. |
| PhenX Toolkit Alcohol Urges Questionnaire | Changes 2 hours after administration of 600mg CBD vs. placebo | All participants underwent an in vivo, olfactory alcohol cue exposure procedure. Participants smelled water followed by the participant's preferred beverage containing alcohol and apple juice in a counterbalanced order for three minutes each, with a three-minute rest period in between each liquid. The contents were poured into a cup in the participant's presence. After each beverage exposure, self-reported alcohol craving was collected via the PhenX Toolkit Alcohol Urges Questionnaire (AUQ). The AUQ consists of eight statements about the participant's feelings and thoughts about drinking as they are completing the questionnaire (i.e., right now). The participant was asked to respond to each statement about alcohol craving via a 7-item Likert scale ranging from strongly disagree to strongly agree with a scare range of 8 to 56 where higher scores represent higher alcohol craving. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from September 2022 to April 2024, and data collection was completed in June 2024. Participants were recruited using a mix of approaches, including social media campaigns and in-person events. All participants completed a centralized intake process for youth substance use studies at the Medical University of South Carolina to determine eligibility before consenting for this specific study.
Pre-assignment details
All participants that were eligible and enrolled in the study (N= 36) completed randomized to a group.
Participants by arm
| Arm | Count |
|---|---|
| Cannabidiol, Then Placebo In counterbalanced order, 19 youth (ages 17-22) were randomized to receive 600mg of cannabidiol before placebo three hours before a neuroimaging and behavioral assessment paradigm, separated by an approximate 18-day washout period. | 19 |
| Placebo, Then Cannabidiol In counterbalanced order, 17 youth (ages 17-22) were randomized to receive 600mg of placebo before cannabidiol three hours before a neuroimaging and behavioral assessment paradigm, separated by an approximate 18-day washout period. | 17 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Wash-Out Period | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Cannabidiol, Then Placebo | Total | Placebo, Then Cannabidiol |
|---|---|---|---|
| Age, Continuous | 20.4 years STANDARD_DEVIATION 1.5 | 20.5 years STANDARD_DEVIATION 1.5 | 20.5 years STANDARD_DEVIATION 1.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 34 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 31 Participants | 14 Participants |
| Region of Enrollment United States | 19 participants | 36 participants | 17 participants |
| Sex: Female, Male Female | 13 Participants | 25 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 11 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 35 |
| other Total, other adverse events | 2 / 34 | 2 / 35 |
| serious Total, serious adverse events | 0 / 34 | 0 / 35 |
Outcome results
Primary
Alcohol Cue Reactivity Neural Activation
Assessing the change in neural reactivity to alcohol cues after each round of medication: Cannabidiol vs. placebo. Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen. The mean Z-statistic within each ROI mask is reported. A Z-score of 0 represents the population mean (e.g., no activation), where higher absolute Z-scores indicate greater evidence of activation (positive or negative) in the ROI compared to baseline. Z-scores do not have inherent clinical thresholds. Higher Z-scores generally reflect stronger task-related BOLD signal changes.
Time frame: Changes 3 hours after administration of 600mg CBD vs. placebo
Population: 33 participants had complete, usable data (n=3 dropped out before visit 2; n=1 without MRI data at visit 2; n= 1 with head motion at visit 1).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Amygdala (L) | 0.66 Z-score | Standard Deviation 1.23 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Caudate (R) | 0.51 Z-score | Standard Deviation 1 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Nucleus Accumbens (R) | 0.53 Z-score | Standard Deviation 0.91 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Insula (L) | 0.10 Z-score | Standard Deviation 1.37 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Amygdala (R) | 0.68 Z-score | Standard Deviation 1.1 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Insula (R) | 0.12 Z-score | Standard Deviation 1.23 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Nucleus Accumbens (L) | 0.62 Z-score | Standard Deviation 0.85 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Putamen (L) | 0.40 Z-score | Standard Deviation 1.16 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Caudate (L) | 0.29 Z-score | Standard Deviation 1 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Putamen (R) | 0.42 Z-score | Standard Deviation 1.14 |
| Cannabidiol (600mg) | Alcohol Cue Reactivity Neural Activation | Anterior Cingulate Cortex | 1.02 Z-score | Standard Deviation 1.58 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Putamen (R) | 0.37 Z-score | Standard Deviation 1.16 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Anterior Cingulate Cortex | 0.87 Z-score | Standard Deviation 1.37 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Nucleus Accumbens (L) | 0.35 Z-score | Standard Deviation 1.28 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Nucleus Accumbens (R) | 0.56 Z-score | Standard Deviation 1.26 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Amygdala (L) | 0.55 Z-score | Standard Deviation 0.92 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Amygdala (R) | 0.47 Z-score | Standard Deviation 1.09 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Caudate (L) | 0.24 Z-score | Standard Deviation 0.84 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Caudate (R) | 0.35 Z-score | Standard Deviation 1.11 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Insula (L) | 0.33 Z-score | Standard Deviation 1.24 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Insula (R) | 0.30 Z-score | Standard Deviation 1.24 |
| Placebo | Alcohol Cue Reactivity Neural Activation | Putamen (L) | 0.42 Z-score | Standard Deviation 1.12 |
Comparison: Several studies have demonstrated that CBD can modulate resting-state or task-based BOLD signal under similar study design (acute dosing, 600 mg CBD) with sample sizes smaller than our sample. Due to the modeling, only participants with usable data from both medication allocation visits were included. Contrast of interest was alcohol beverages vs. non-alcohol beverages.p-value: >0.05Mixed Models Analysis
Primary
Concentrations of Glx (i.e., Glutamate + Glutamine)
Using magnetic resonance spectroscopy and a within-subjects design, we measured Concentrations of Glx (i.e., glutamate + glutamine) levels in the anterior cingulate cortex in adolescents during cannabidiol (600mg) or placebo administration. Values provided are absolute values (mmol/kg) measured 3 hours after medication administration. Due to complexities of this method, normal levels of Glx are not known; thus, we cannot make conclusions about the meaning of higher or lower glutamate levels when comparing cannabidiol to placebo.
Time frame: Changes 3 hours after administration of 600mg CBD vs. placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (600mg) | Concentrations of Glx (i.e., Glutamate + Glutamine) | 18.76 mmol/kg | Standard Deviation 0.98 |
| Placebo | Concentrations of Glx (i.e., Glutamate + Glutamine) | 18.57 mmol/kg | Standard Deviation 1.15 |
Comparison: An a priori power analysis was conducted to ensure power to detect differences in neurometabolite levels in the dACC. Due to type of modeling, participants were included even if they did not complete the second medication allocation.p-value: 0.33Mixed Models Analysis
Primary
GABA+
Using magnetic resonance spectroscopy and a within-subjects design, we measured GABA+ (GABA plus macromolecules) levels in the anterior cingulate cortex in adolescents during cannabidiol (600mg) or placebo administration. Values provided are absolute values (mmol/kg) measured 3 hours after medication administration. Due to complexities of this method, normal levels of GABA are not known; thus, we cannot make conclusions about the meaning of higher or lower GABA levels when comparing cannabidiol to placebo.
Time frame: Changes 3 hours after administration of 600mg CBD vs. placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (600mg) | GABA+ | 4.25 mmol/kg | Standard Deviation 0.26 |
| Placebo | GABA+ | 4.22 mmol/kg | Standard Deviation 0.34 |
Comparison: Due to type of modeling, participants were included even if they did not complete the second medication allocation.p-value: 0.75Mixed Models Analysis
Primary
Heart Rate Variability
All participants underwent an in vivo, olfactory alcohol cue exposure procedure. Participants smelled water followed by the participant's preferred beverage containing alcohol and apple juice in a counterbalanced order for three minutes each, with a three-minute rest period in between each liquid. The contents were poured into a cup in the participant's presence. During the task, electrocardiogram data were collected and used to create the heart rate variability (HRV) outcome related to the Sympathetic: Vagal ratio, which is the ratio of low-frequency to high-frequency power, derived from spectral HRV analysis. Higher values suggest increased sympathetic activity or reduced vagal activity.
Time frame: Changes 2 hours after administration of 600mg CBD vs. placebo
Population: Some participants did not have usable data based on data quality markers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (600mg) | Heart Rate Variability | 0.84 frequency ratio | Standard Deviation 0.37 |
| Placebo | Heart Rate Variability | 0.81 frequency ratio | Standard Deviation 0.41 |
Comparison: We were not able to complete a power calculation for this task. We used linear mixed effects models, containing the main effect of medication (CBD vs. placebo), visit (visit 1 vs. visit 2), and sequence (CBD/placebo vs. placebo/CBD) and cue-by-medication interaction terms. Random intercepts were included to account for individual differences.p-value: 0.82Mixed Models Analysis
Primary
PhenX Toolkit Alcohol Urges Questionnaire
All participants underwent an in vivo, olfactory alcohol cue exposure procedure. Participants smelled water followed by the participant's preferred beverage containing alcohol and apple juice in a counterbalanced order for three minutes each, with a three-minute rest period in between each liquid. The contents were poured into a cup in the participant's presence. After each beverage exposure, self-reported alcohol craving was collected via the PhenX Toolkit Alcohol Urges Questionnaire (AUQ). The AUQ consists of eight statements about the participant's feelings and thoughts about drinking as they are completing the questionnaire (i.e., right now). The participant was asked to respond to each statement about alcohol craving via a 7-item Likert scale ranging from strongly disagree to strongly agree with a scare range of 8 to 56 where higher scores represent higher alcohol craving.
Time frame: Changes 2 hours after administration of 600mg CBD vs. placebo
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabidiol (600mg) | PhenX Toolkit Alcohol Urges Questionnaire | Alcohol Cue | 23.18 score on a scale | Standard Deviation 11.73 |
| Cannabidiol (600mg) | PhenX Toolkit Alcohol Urges Questionnaire | Apple Juice Cue | 18.56 score on a scale | Standard Deviation 9.65 |
| Cannabidiol (600mg) | PhenX Toolkit Alcohol Urges Questionnaire | Water Cue | 16.47 score on a scale | Standard Deviation 7.64 |
| Cannabidiol (600mg) | PhenX Toolkit Alcohol Urges Questionnaire | Baseline | 16.18 score on a scale | Standard Deviation 7.3 |
| Placebo | PhenX Toolkit Alcohol Urges Questionnaire | Baseline | 14.94 score on a scale | Standard Deviation 6.8 |
| Placebo | PhenX Toolkit Alcohol Urges Questionnaire | Alcohol Cue | 21.40 score on a scale | Standard Deviation 11.22 |
| Placebo | PhenX Toolkit Alcohol Urges Questionnaire | Water Cue | 15.50 score on a scale | Standard Deviation 7.14 |
| Placebo | PhenX Toolkit Alcohol Urges Questionnaire | Apple Juice Cue | 17.63 score on a scale | Standard Deviation 10.26 |
Comparison: We were not able to complete a power calculation for this task. We used linear mixed effects models, containing the main effect of medication (CBD vs. placebo), visit (visit 1 vs. visit 2), and sequence (CBD/placebo vs. placebo/CBD) and cue-by-medication interaction terms. Random intercepts were included to account for individual differences.p-value: 0.21Mixed Models Analysis