Semaglutide Therapy for Alcohol Reduction (STAR)

• INCLUSION CRITERIA:

This study will enroll adult individuals with a current diagnosis of AUD. Participants will be recruited without any preference to sex, race, religion, or other social variables, but sociodemographic data will be collected for sample characterization and potential use in the analyses. Since self-reported psychological measures that have been validated in English constitute major part of the study assessments, participants need to be able to speak, read, write, and understand English to be in the study.

The information needed to assess eligibility will be collected under an IRB-approved NIDA IRP

screening protocol, led by the Office of the Clinical Director (OCD) at the NIDA IRP to assess

potential research participants' eligibility for entering clinical protocols. Additional details can be found in the NIDA screening protocol documents. Furthermore, NIH medical records (from other NIH clinical protocols) and outside medical records may also be used, if available, to determine whether participants fulfill the eligibility criteria.

To be eligible for this study, an individual must meet all of the following criteria:

• At least 18 years old

• Alcohol Use Disorder (minimum 2 symptoms on a validated diagnostic tool, e.g., theMini-International Neuropsychiatric Interview (MINI) or the Structured ClinicalInterview for DSM Disorders (SCID))

• Self-reported drinking, according to alcohol Timeline Follow-Back (TLFB), of > 7drinks per week for females or > 14 drinks per week for males during the 28-dayperiod prior to screening plus at least four days with > 3 drinks for females or > 4drinks for males during the 28-day period prior to screening

• Most recent Clinical Institute Withdrawal Assessment for Alcohol - revised (CIWA-Ar)score < 10

• Able to speak, read, write, and understand English as demonstrated by ability tounderstand and sign the NIDA screening protocol consent

• Normal or corrected-to-normal (e.g., wearing glasses or contacts) vision and normalor corrected-to-normal (e.g., with the use of a hearing aid) hearing

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from enrolling in this study:

• BMI < 23 kg/m^2 or BMI >= 50 kg/m^2

• Evidence of malnutrition as determined by the Nutrition Risk Screening 2002 (NRS-2002)

• Most recent blood tests: creatinine >= 2 mg/dL, eGFR <45 mL/min/1.73 m^2,triglycerides > 500 mg/dl, ALP > 4x the upper limit of normal, clinically abnormallipase levels per study clinician

• Present diagnosis of diabetes mellitus or blood hemoglobin A1c (HbA1c) >= 6.5 %

• Current (within the past 30 days) use of the following medications with glucoselowering properties: GLP-1 analogues, sulfonylurea, insulin, metformin,thiazolidinediones, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucosecotransporter-2 (SGLT-2) inhibitors

• Current or prior use of semaglutide or tirzepatide

• Current (within the past 30 days) use of weight-lowering medications

• Current (within the past 30 days) use of FDA-approved pharmacotherapy for AUD (oralor intramuscular naltrexone, acamprosate, disulfiram)

• Current (within the past 30 days) use of medications with known interaction withsemaglutide

• Personal or family history of medullary thyroid carcinoma (MTC) or MultipleEndocrine Neoplasia syndrome type 2 (MEN 2)

• Known ongoing history of alcohol ketoacidosis, gastroparesis, pancreatitis (eitheracute or chronic), pancreatic carcinoma, gallbladder disease, jaundice,Mallory-Weiss syndrome (esophageal tears secondary to vomiting), esophageal varices,cirrhosis

• Known history of gastric bypass surgery

• Known history of prior hypersensitivity reaction to semaglutide, any of the productcomponents, or any other GLP-1 analogue

• Known history of suicidal attempts (within the past 24 months) or active suicidalideation

• Known history of clinically significant vestibular disorders or motion sickness

• Known history of clinically significant noise-induced hearing loss or tinnitus

• Contraindication(s) for brain fMRI

• Unstable cardiovascular conditions (e.g., arrhythmias, clinically significant ECGabnormalities)

• Physical and/or mental health conditions that are clinically unstable, as determinedby the study clinicians, including (but not limited to) major depressive disorder orgeneralized anxiety disorder unstable during the past three months or otherpsychiatric conditions (e.g., schizophrenia, bipolar disorder) unstable during thepast twelve months prior to screening.

• Female who is pregnant, breast-feeding, or intends to become pregnant or is ofchild-bearing potential and not using a highly effective contraceptive method

• Any other reason or clinical condition that the investigators judge may interferewith study participation and/or be unsafe for a participant