The objective of this Phase 2 randomized controlled trial is to evaluate the effects of weekly tirzepatide (vs. placebo) on alcohol consumption and cardiometabolic outcomes in adults with alcohol use disorder and overweight or obesity.

Inclusion Criteria:

1. Meeting past-year DSM-5 criteria for AUD with at least moderate severity (≥ 4 symptoms)
2. Average daily consumption of ≥40g (women) / ≥ 60 g (men) per day in the 28 days prior to baseline
3. Body mass index ≥ 27kg/m2
4. Willingness to attend weekly medication visits and complete all study procedures
5. Ability to read and communicate in English
6. Age 21-65
7. Treatment-seeking (i.e., currently seeking assistance to reduce or stop drinking)
8. Stable housing status

Exclusion Criteria:

1. Meeting past-year DSM-5 criteria for another substance use disorder (except tobacco use disorder or mild cannabis use disorder)
2. Recent (past 30 day) self-report of illicit drug use (excluding cannabis) or non-prescribed opioids; or positive urine screen for illicit drugs. A positive screen for opioids will be allowed if the participant is prescribed an opioid replacement therapy medication and can provide documentation.
3. History of significant alcohol withdrawal, as indicated by history of seizure, delirium tremens; history of hospitalization for withdrawal-related symptoms; a CIWA score >9 at assessment; or a baseline score 4+ on the Prediction of Alcohol Withdrawal Severity (PAWS) scale.
4. Recent (past 3 months) engagement in behavioral or pharmacological alcohol use treatment or currently mandated to receive treatment
5. History of chronic or acute pancreatitis
6. History of Type 1 or Type 2 diabetes, or diabetes-related conditions (e.g., diabetic retinopathy), or baseline HbA1C ≥ 6.5%
7. History of suicide attempt or report of current (past 2 weeks) active suicidal ideation
8. Lifetime diagnosis of severe mental illness (e.g., psychosis or bipolar disorder)
9. Evidence of a significant anxiety or depressive disorder that is currently interfering with daily functioning, based on GAD-7 and PHQ-9 scores and physician judgement. (Anxiety or depression are not exclusionary if symptoms are stable/non-interfering with daily activities, or if the participant is receiving treatment, i.e., psychiatric medications have not changed for at least 3 months prior to baseline)
10. Treatment for eating disorder in the past 12 months
11. Report of significant medical, neurological, or psychiatric illness that would preclude safe or full study participation based on the judgement of the study physicians
12. History of known liver disease
13. Elevated serum lipase, amylase, bilirubin, or ALP, ALT, or AST (>3x upper limit of normal range)
14. History of malignant neoplasms in the last 5 years, except for non-melanoma skin cancer
15. Inability to attend weekly clinic visits as scheduled (i.e., based on travel or work schedule)
16. Weight loss > 5% in the 30 days prior to screening
17. Currently enrolled in another clinical trial involving an investigational product
18. Current contact or co-habitation with a current or former participant in the present trial
19. Current co-habitation with a person taking GLP-1RA therapy
20. Planned surgical procedures requiring anesthesia within 90 days post-entry into the study
21. History of treatment with tirzepatide or a GLP-1RA within 6 months of screening
22. Treatment with any weight loss medications (e.g., orlistat, bupropion-naltrexone) or medications known to reduce alcohol consumption (e.g., naltrexone, topiramate, acamprosate, varenicline) in the past 3 months
23. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) type I or type II
24. Estimated glomerular filtration rate (eGFR) <60 (indicated impaired kidney function)
25. Use of prescribed or non-prescribed medications that would preclude safe use of tirzepatide in the judgement of the study physicians
26. Known bone, muscle, or wasting conditions (e.g., osteoporosis, sarcopenia) aa. Presence of significant or uncontrolled GI conditions (e.g., GERD) that would interfere with treatment in the judgement of study physicians bb. Any other significant disease, disorder, or finding that in the opinion of the investigator(s) may increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.

cc. Currently pregnant or nursing, or inability to adhere to a reliable method of birth control (applies to female participants of childbearing age) dd. Uncontrolled hypertension at baseline, as indicated by an average blood pressure reading of >180/110 after three successive readings ee. History of heart attack or stroke in the 6 months prior to screening ff. A pre-treatment reduction in alcohol consumption to < 40g/day (males) or <20g/day (females) in the interval between baseline screening and randomization