The Take Control intervention is a structured CBT intervention or manualised digital therapy designed to support alcohol reduction.

Take Control will be completed using a computer interface with headphones in a private room. Participants will complete one module per week during treatment Weeks 1 to 8. Each module is approximately 30-45 minutes in length and will be completed independently by the participant under the supervision of a research assistant. Program content is fixed and self-paced, eliminating the need for fidelity monitoring of therapist behaviour.

Take Control is an evidence-informed cognitive-behavioural intervention originally developed for use in pharmacotherapy trials for AUD and has demonstrated feasibility and acceptability in similar populations. The intervention content draws on established CBT strategies for alcohol reduction, including motivational enhancement, managing triggers, coping skills, and relapse prevention.

Participants in the placebo condition will receive visually-matched sham injections, where by the placebo container and contents will be identical in appearance to Tirzepatide, except without the active ingrediant.

As measured the Visual Analogue Scale (VAS) weekly and also at pre-, during-, and post- psychophysiological cue-reactivity task completion. Scored from to 0 to 100, where higher scores indicate more severe craving.

The WHO drinking risk level scale categorizes alcohol consumption based on average daily intake of pure alcohol (in grams) and its associated health risk.

There are 5 levels that differ based on gender:

• For men, very high risk >100 grams/day or; high risk as >60 to 100 grams/day ; moderate risk as >40 to 60 grams/day; and low risk as 1 to 40 grams/day.
• For women, very high risk was defined as >60 grams/day; high risk as >40 to 60 grams/day; moderate risk as >20 to 40 grams/day ; and low risk as 1 to 20 grams/day.

Proportion of participants with zero heavy drinking days measured by the TLFB.

Changes in body weight in kilograms (kg) from baseline to week 9 (end of treatment).

Changes in waist circumference in centimetres (cm) from baseline to week 9 (end of treatment).

Systolic and diastolic blood pressure measured weekly from baseline to end of treatment (week 8).

Clinical metabolic monitoring for cardiometabolic risk and drug safety. Measures glycated haemoglobin in a blood in percentages (%). Collected at screening (Week 0) and again at the end-of-treatment visit (Week 9). Additional testing may be conducted at follow up (week 12) if clinically indicated.

A cardiometabolic biomarker providing an estimation of 10-year atherosclerotic cardiovascular disease (ASCVD) risk score, based on pooled cohort equations. This is a composite risk score derived from traditional cardiovascular risk factors, including gender, age, race, total cholesterol, total HDL cholesterol, systolic BP, previous receipt of treatment for high blood pressure (if SBP > 120 mmHg), diabetes and smoking status.

This is used to provide a risk score of atherosclerotic cardiovascular disease.

Safety outcomes including adverse events (AEs), serious adverse events (SAEs), and vital sign abnormalities, will be summarised descriptively across the study period. Feasibility outcomes (e.g., recruitment and retention rates, session attendance) will be analysed using proportions with corresponding 95% confidence intervals.

As a measure of safety, the number of treatment-related discontinuations will be measured.

Clinical metabolic monitoring for total cholesterol in millimoles per litre (mmol/L). Collected at screening (Week 0) and again at the end-of-treatment visit (Week 9). Additional testing may be conducted at follow up (week 12) if clinically indicated.

Clinical metabolic monitoring for triglycerides in blood sample, measured via millimoles per litre (mmol/L) as a measure of cardiometabolic risk and drug safety. Collected at screening (Week 0) and again at the end-of-treatment visit (Week 9). Additional testing may be conducted at follow up (week 12) if clinically indicated.

Mood states before/after ketamine sessions assessed by PANAS (Positive and Negative Affect Schedule). This will be measured during neuroimaging and psychophysiology sessions. Used to measure an individual's emotional state, assessing two dimensions: Positive Affect (PA; captures feelings like enthusiasm and alertness), and Negative Affect (NA; measures distress and negative emotions like anger and anxiety).

As measured by the Penn Alcohol Craving Scale (PACS). 5-item self-report questionnaire that evaluates alcohol craving over the past week. Measures frequency, intensity, duration of craving, perceived control over drinking, and overall craving severity. Each item is rated on a 7-point Likert scale (0-6). Total scores range from 0 to 30, with higher scores indicating greater craving.

Changes in PEth (phosphatidylethanol) from baseline to Week 9 will be analysed using MMRM, with baseline PEth as a covariate. Collected at week 0, 9 (end-of-treatment) and optionally at week 12.

Measured by cumulative scores on the Center for Epidemiologic Studies Depression Scale (CES-D). This scale consists of 20 items with a minimum score of 0 and a maximum score of 60. A higher score indicates greater depressive symptomatology. Items are rated according to how often the feeling or behavior occurred in the past week (e.g. 0 = Rarely or none of the time (less than 1 day; 1 = Some or a little of the time (1-2 days); 2 = Occasionally or a moderate amount of the time (3-4 days) and 3 = Most or all of the time (5-7 days))

As measured by cumulative scores Insomnia Severity Index (ISI). This scale consists of 7 items with a minimum total score of 0 and a maximum score of 28. A higher score indicates greater insomnia severity. Items are rated on a 0-4 scale based on the severity or impact of sleep difficulties over the past two weeks (e.g., 0 = No problem; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very severe).

A total score of 0-7 indicates "no clinically significant insomnia," 8-14 means "sub-threshold insomnia," 15-21 is "clinical insomnia (moderate severity)," and 22-28 means "clinical insomnia (severe)."

As measured by cumulative scores on the 36-Item Short Form Health Survey (SF-36). Consists of 36 items grouped into 8 domains of health:

1. Physical Functioning (10 items)
2. Role Limitations due to Physical Health (4 items)
3. Role Limitations due to Emotional Problems (3 items)
4. Energy/Fatigue (4 items)
5. Emotional Well-being (5 items)
6. Social Functioning (2 items)
7. Pain (2 items)
8. General Health (5 items)

Each item is scored from 0 to 100, with higher scores indicating better health status. Items are rated based on experiences over the past 4 weeks using Likert-type response options (e.g., ranging from "All of the time" to "None of the time" or "Excellent" to "Poor").

Items within a domain are summed and averaged, then transformed to a 0-100 scale. Refer to the following reference for specific transformations needed for each item: https://www.rand.org/health/surveys/mos/36-item-short-form/scoring.html

Measured through the use of Ecological Momentary Assessment (SEMA) via smartphone prompts.

Collected via structured post-treatment feedback at Week 9 and optional qualitative interviews at Week 12.

To assess short term alcohol urge, the Alcohol Urge Questionnaire (AUQ) will be used. This is a brief 8-item self-report questionnaire that evaluates acute alcohol craving as a single factor (unidimensional). Each item is rated on a Likert scale of 7 points, with higher scores indicating stronger urges to consume alcohol. Two of the questions are reversed scored.

Measured by cumulative scores on the GAD-7 (Generalised Anxiety Disorder 7-item scale). Measures anxiety symptom severity over the last two weeks, and the extent to which the participant is bothered by these symptoms.

Each item is scored from 0 to 3 (where 0 = not at all, 1= several days, 2= more than half of days, 3=nearly every day). This scale has a minimum score of 0 and a maximum score of 21. A higher score indicates greater severity of generalized anxiety symptoms (The total score indicates anxiety severity: 0-4 is minimal anxiety, 5-9 is mild, 10-14 is moderate, and 15-21 is severe).

The C-SSRS is a structured clinician-administered instrument with strong predictive validity for suicidal behavior, used in clinical and research settings to assess the presence, severity, and intensity of suicidal ideation and behavior. The C-SSRS is administered by trained clinicians. C-SSRS scoring includes four subscales: ideation severity (items 1-5, scored by the most severe type endorsed); intensity of ideation (sum of five items including frequency, duration, controllability, deterrents, and reasons for ideation; range 2-25; higher number indicates more intense ideation); suicidal behavior (presence or absence of actual, interrupted, aborted, or preparatory behavior recorded separately); and potential lethality (medical damage rated 0-5, potential lethality rated 0-2). At baseline, this is measured by the baseline version. Higher scores indicate more severe suicidality.

To determine changes in the severity of alcohol withdrawal symptoms the Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) will be used. This 10-item scale evaluates common withdrawal symptoms including nausea/vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache and orientation. Each item is rated on a scale from 0 to 7 (except orientation, which is rated 0-4), with a total score ranging from 0 to 67. Higher scores indicate more severe withdrawal symptoms.

As measured by the Patient Health Questionnaire-9 (PHQ-9). A 9-item self-report instrument that assesses the severity of depressive symptoms over the past two weeks. Items correspond to DSM-5 criteria for major depressive disorder, including mood, interest, sleep, energy, appetite, self-worth, concentration, psychomotor changes, and suicidal thoughts. Each item is rated on a 4-point Likert scale (0 = "Not at all" to 3 = "Nearly every day"). Total scores range from 0 to 27, with higher scores indicating greater depressive symptom severity.

As measured by the Short Alcohol Withdrawal Scale (SAWS). A self-report questionnaire designed to assess the severity of alcohol withdrawal symptoms over the past 24 hours. It consists of 10 items covering common withdrawal symptoms such as anxiety, tremor, sweating, nausea, sleep disturbance, and sensory sensitivity. Each item is rated on a 4-point Likert scale (0 = "Not at all" to 3 = "Severe"). Total scores range from 0 to 30, with higher scores indicating greater withdrawal severity.

As measured by the Prediction of Alcohol Withdrawal Severity Scale (PAWSS). A clinician-administered screening tool designed to predict the risk of developing severe alcohol withdrawal complications (e.g., seizures, delirium tremens) in patients. Consists of 10 items which assess recent alcohol use, history of withdrawal complications, and clinical risk factors (e.g., elevated blood alcohol level, concurrent use of sedatives). Each item is scored as 0 (absent) or 1 (present). Total scores range from 0 to 10, with higher scores indicating greater risk. A score of ≥4 suggests high risk for severe withdrawal.

As measured by the Alcohol Use Disorders Identification Test (AUDIT). A 10-item screening questionnaire used to identify hazardous and harmful alcohol consumption, as well as possible alcohol dependence. Items cover three domains:

1. Alcohol consumption (frequency, quantity, binge drinking)
2. Alcohol-related problems (injury, guilt, concern from others)
3. Dependence symptoms (impaired control, morning drinking)

Each item is scored from 0 to 4, giving a total score range of 0-40, with higher scores indicating greater risk. Common interpretation thresholds:

0-7: Low risk 8-12: Risky drinking 13+: High risk

As measured by the Fagerström Test of Nicotine Dependence (FTND). A 6-item self-report questionnaire which assess the intensity of physical addiction to nicotine. Items evaluate behaviors such as time to first cigarette after waking, daily cigarette consumption, difficulty refraining from smoking in forbidden places, and smoking patterns during the day. Each item is scored on a scale (0-1 or 0-3 depending on the question), with a total score range of 0-10, where higher scores indicate greater nicotine dependence.

Common interpretation thresholds:

0-2: Very low dependence 3-4: Low dependence 5: Medium dependence 6-7: High dependence 8-10: Very high dependence

As measured by the UPPS Impulsive Behavior Scale. This is a self-report questionnaire designed to assess multidimensional impulsivity across five distinct facets:

1. Negative Urgency (acting rashly under distress)
2. Positive Urgency (acting rashly under extreme positive emotions)
3. Lack of Premeditation (difficulty thinking before acting)
4. Lack of Perseverance (difficulty staying focused on tasks)
5. Sensation Seeking (tendency to seek excitement and novel experiences) This version contains 59 items. Responses are rated on a Likert scale (typically 1 = "Strongly agree" to 4 = "Strongly disagree"). Scores are calculated for each facet, with higher scores indicating greater impulsivity in that domain.

As measured by the Impaired Control Scale (ICS). A self-report questionnaire which assesses difficulty in controlling alcohol consumption. It includes items evaluating perceived inability to stop drinking once started, failure to adhere to drinking limits, and loss of control over drinking behavior. Responses are typically rated on a Likert scale, with higher scores indicating greater impaired control.

As measured by the Environmental Reward Observation Scale (EROS). A self-report measure assessing the degree to which individuals experience positive reinforcement from their environment, and evaluates engagement in rewarding activities and perceived availability of environmental rewards. Items are rated on a Likert scale, with higher scores indicating greater environmental reinforcement.

As measured by a multi-item questionnaire titled Inventory of Drinking Situation scale. This scale assesses high-risk situations for drinking, such as coping with negative emotions, social pressure, and positive mood states. Responses indicate frequency or likelihood of drinking in these contexts. Higher scores suggest greater vulnerability to relapse.

As measured by the Reward-Based Eating Drive Scale (R-BEDS). A self-report tool assessing compulsive eating behaviors driven by reward sensitivity. It evaluates loss of control over eating, lack of satiety, and preoccupation with food. It consists of 9 items, each rated on a Likert scale from 1 to 5:

• 1 = Strongly Disagree
• 5 = Strongly Agree

Items are grouped into three subscales:

1. Loss of Control Over Eating
2. Lack of Satiety
3. Preoccupation With Food

Total Scores range from 9 to 45, where higher scores indicate greater reward-driven eating tendencies.

As measured by the Yale Food Addiction Scale (YFAS). Assesses addictive-like eating behaviors based on DSM criteria for substance use disorders. It measures symptoms such as tolerance, withdrawal, loss of control, and continued use despite negative consequences. Scoring identifies 1) symptom count ranging from 0 to 7 reflecting number of addiction like criteria endorsed with higher scores indicating greater food addiction severity; and 2) a dichotomous "diagnosis" that indicates whether a threshold of 3/< "symptoms" plus clinically significant impairment or distress is satisfied.

Measured by the General Food Craving Questionnaire - Trait (G-FCQ-T). This is a self-report measure that assesses the general tendency to experience food cravings over time. It includes multiple subscales. Items are rated on a Likert scale, with higher scores indicating stronger trait-level food cravings. There are 21 items scored on a Likert scale ranging from 1 = never to 6 = always, with a score range between 21 and 126. Higher scores are indicative of more frequent and intense trait food cravings.

As measured by the Snaith-Hamilton Pleasure Scale (SHPS). A self-report questionnaire which assesses anhedonia across domains such as social interactions, food and drink, sensory experiences, and hobbies. Items are rated on a Likert scale, with the final score ranging from 14 to 56. Higher scores indicate greater anhedonia. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree.

As measured by the Alcohol Abstinence Self-Efficacy Scale (AASE). Self report measure assessing confidence in resisting alcohol use across high-risk situations (e.g., negative emotions, social pressure). Items are rated on a Likert scale, with higher scores indicating greater self-efficacy for maintaining abstinence. Each item is scored on a scale from 1 (not at all confident) to 5 (extremely confident) relating to the level of confidence a participant has to not drink alcohol.

As measured by the Obsessive-Compulsive Drinking Scale (OCDS). A 14-item questionnaire that measures an individual's severity of obsessive thoughts and compulsions to use alcohol. Includes two subscales 1. obsessions (thoughts, urges) and 2. compulsions (drinking behaviors). Higher scores indicate greater cognitive and behavioral preoccupation with alcohol. Each item is scored on a scale of 0 to 4.

As measured by the General Food Craving Questionnaire-State (G-FCQ-S). A self-report measure assessing momentary food cravings at a specific point in time. Items capture craving intensity, desire, and preoccupation. Higher scores indicate stronger state-level cravings.

As measured by the Tiffany Questionnaire of Smoking Urges (QSU). Measures the intensity and nature of cigarette craving, assessing 2 dimensions:

1. Desire and intention to smoke for positive reinforcement (e.g., pleasure, satisfaction) and....
2. Urgency to smoke to relieve negative affect or withdrawal symptoms There are 32 items, each rated on a 7-point Likert scale ranging from 1= strongly disagree to 7 = strongly agree. Higher total summed scores are indicative of a stronger craving and motivation to smoke.

As measured by the Alcohol Purchase Task (APT). Measure assesses demand and motivation for alcohol under varying price conditions. Participants indicate how many drinks they would purchase at different prices. Outcomes include indices such as intensity, elasticity, and breakpoint, reflecting motivation and valuation of alcohol.