What this trial measures

• Percent change in the alcohol cue-induced Blood-oxygen-level dependent (BOLD) signal in the lateral prefrontal cortex (PFC)Baseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in the alcohol cue-induced BOLD signal change in the caudateBaseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in alcohol cue-induced BOLD signal change in the ventromedial PFC (vmPFC)Baseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in alcohol cue-induced BOLD signal change in the inferior frontal gyrus (IFG)Baseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in alcohol cue-induced BOLD signal change in the insulaBaseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in negative affective cue-induced BOLD signal change in the dorsomedial PFC (dmPFC)Baseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in negative affective cue-induced BOLD signal change in the supramarginal gyrusBaseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the negative affective cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in negative affective cue-induced BOLD signal change in the amygdalaBaseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the negative affective cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in negative affective cue-induced BOLD signal change in the insulaBaseline, Day 2

  Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the negative affective cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

• Percent change in alcohol cue-induced functional connectivity in prespecified regions of interest (ROI)Baseline, Day 2

  ROI include the ventral striatum, lateral PFC (dlPFC and IFG), and caudate with target clusters in the PFC, ACC, and sensorimotor cortex (S1 and M1).

• Percent change in negative affective cue-induced functional connectivity in prespecified regions of interest (ROI)Baseline, Week 4

  ROI include the ventral striatal and amygdala with target clusters in temporal and occipital regions relative to placebo.

• Percent change in the frequency of failed response inhibitionBaseline, Week 4

  A Go/NoGo task will be used as an objective measure of response inhibition. This task includes alcohol, non-alcohol, and neutral stimuli. The Go/No-go task requires participants to respond by pressing a button when they see a "go" signal, and not respond when they see the "no-go" signal. The key behaviour measured with this experiment is the participants' ability to withhold a response on No-go trials and the frequency of their failed responses.

• Change in discounting rate (log(k))Baseline, Week 4

  The discounting rate is derived from the Delay Discounting Task. Delay discounting tasks provide a measure of the temporal window and examine the devaluation of awards as a function of the delay to the receipt. The task includes 80 items requiring a choice between a delayed reward of $100 and smaller immediate rewards (ranging from $10 to $99, at delays ranging from one to 365 days. Discounting rates will be measured and pre-post differences will be assessed. Higher k values indicate higher impulsive decision-making.

• Change in participant-level reference pointsIP Administration (Day 0), Week 24

  A Foraging Task will be used as an objective measure of cognitive flexibility. The task involves making "stay" or "go" decisions to harvest apples from stylized "trees" that have hidden initial rewards. Within each block, trees have a mean initial reward rate. Subjects decide to either harvest the tree ("stay") or search for a new one ("go"), incurring an S second delay penalty for searching. Harvesting reveals the reward, which depletes by a fixed amount, plus a small error term. After a 1-second inter-trial interval, the tree reappears for another "stay" or "go" choice. Rewards on each sequential trial are computed. Rewards are computed dynamically, with optimal strategies varying based on the delay penalty. The optimal reference point is calculated using the marginal value theorem, while the empirical reference point is the participant's cutoff for searching.

• Percentage of no heavy drinking daysBaseline, Week 24

  Outcome will be measured using the Timeline Followback (TLFB) interview-based assessment. The TLFB derives subjects' retrospective daily estimates of alcohol consumption patterns. Using a calendar as a visual aid, special events, and other memory cues, subjects are guided through the process of recalling and reporting daily drinking estimates.

• Change in phosphatidyl ethanol (PEth) blood levelsBaseline, Week 12
• Change in carbohydrate-deficient transferrin (CDT) blood levelsBaseline, Week 12
• Change in the Drinker Inventory of Consequences questionnaire (DrInC-2R) total scoreBaseline, Week 24

  DrInC-2R is a validated self-report questionnaire consisted of 50 questions to measure adverse consequences of alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal as well as frequency of these consequences (answers given on frequency scale grade from 0-3: 0 - never, 1 - once or a few times, 2 - once or twice a week 3 - daily or almost daily). Higher scores indicate greater levels of alcohol-related problems.

• Change in PSQI global scoreBaseline, Week 24

  Sleep quality is measured by the Pittsburgh Sleep Quality Index (PSQI) . The PSQI is a 19-item, self-rated questionnaire designed to measure sleep quality and disturbance over the past month in clinical populations. The 19 items are grouped into 7 components, including (1) sleep duration, (2) sleep disturbance, (3) sleep latency, (4) daytime dysfunction due to sleepiness, (5) sleep efficiency, (6) overall sleep quality, and (7) sleep medication use. Each of the sleep components yields a score ranging from 0 to 3, with 3 indicating the greatest dysfunction. Adding up the average scores of the seven factors gives a global PSQI score from 0 to 21, with 0-4 indicating "good" sleep and 5-21 indicating "poor" sleep.

• Change in patient's self-assessed health-related quality of life (by the SF-36 Questionnaire)Baseline, Week 24

  The Short Form Health Survey (SF-36) is a validated 36 item self-report Quality of Life Questionnaire that measures eight multi-item dimensions of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy/vitality, pain, and general health perception. Scores range from 0 - 100. Lower scores = more disability, higher scores = less disability

• Change in Alcohol craving scoreBaseline, Week 24

  The alcohol cravings score will be assessed using the Penn Alcohol Craving Scale (PACS). The PACS consists of 5 questions with sub-scales ranging from 0 (never) to 6 (nearly all of the time). Scores greater than 20 were considered to meet diagnostic criteria for craving for a diagnosis of Alcohol Use Disorder.

• Change in negative affect scoreBaseline, Week 24

  Negative affect will be assessed using the negative affect scale of the Positive and Negative Affect Schedule (PANAS) which is a 10-item measure of negative emotions on a scale of 1 ("very slightly or not at all) to 5 ("extremely"). Total scores can range from 10 - 50, with higher scores representing higher levels of NA and reflect a dimension of general distress summarizing a variety of negative states such as anger, guilt, or anxiety.

• Change in impulsivity score (Barratt impulsivity scale by the subscales and by the total score)Baseline, Week 24

  Impulsivity will be assessed using the Barratt impulsivity scale (BIS-11), a validated self-report questionnaire composed of 30 items describing common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. Items are scored on a 4-point scale: Rarely/Never = 1, Occasionally = 2, Often = 3, Almost Always/Always = 4. Total score is assessed. The total scores can range from 30 to 120. The higher total score corresponds to the more impulsive behavior