GLP-1R Agonist Treatment for Opioid Use Disorder

Inclusion Criteria:

• Age 18 to 75 years.

• Body mass index (BMI) > 18.

• Able and willing to provide informed consent prior to any study-related activities.

• Current diagnosis of Diagnostic and Statistical Manual Diploma in Social Medicine (DSM)-5 Opioid Use Disorder (OUD) as per the Mini International NeuropsychiatricInterview (MINI) or per the site clinic diagnosis. Patients are eligible if theyhave a MINI > 3 ("moderate" or "severe" in the "Specify If" box in the Substance UseDisorder (Non-Alcohol) module for the category of opiates).

• Currently receiving outpatient treatment for OUD and at least 2 weeks onbuprenorphine (BUP) or 4 weeks on methadone at the study site and/or at anassociated clinic at the time of enrollment.

• Have at least 1 urine test positive for opioids after 2 weeks on BUP or 4 weeks onmethadone.

• Have positive self-reporting of opioid use after 2 weeks on BUP or 4 weeks onmethadone.

• If anatomically capable of becoming pregnant and of childbearing age, is notpregnant (confirmed) or breastfeeding at the time of enrollment and agrees to use amedically accepted method of birth control or to abstain from sexual intercoursewhile in the study.

• Able to read and communicate in English to the level required to accept standardcare and complete all study requirements.

• Able and willing to engage/adhere to the entirety of the study protocol (19 weeks).

• Not currently a prisoner.

Exclusion Criteria:

• Age < 18 or > 75 years.

• BMI <18.

• Individuals who are pregnant, planning pregnancy, breastfeeding, or unwilling to useadequate contraceptive measures.

• Current use of glucagon-like peptide 1 receptor (GLP-1R) agonist.

• History of angioedema, serious hypersensitivity reaction, or anaphylactic reactionto semaglutide or another GLP-1R agonist.

• Personal or family history of medullary thyroid carcinoma (MTC) or patients withmultiple endocrine neoplasia syndrome Type 2 (MEN 2) or thyroid nodule.

• Type 1 diabetes or history of diabetic ketoacidosis.

• Type 2 diabetes mellitus or current use of a dipeptidyl peptidase-4 (DPP-4)inhibitor.

• Past 30-day use of Sincalide, Sulfonylureas, insulin and insulin products or othermedications that may interact with semaglutide.

• Hypoglycemia on intake visit (blood glucose < 60 mg/dL).

• End-stage renal failure, on dialysis, or glomerular filtration rate (GFR) <30 mL/minper 1.73 square meters or previous renal transplant.

• End stage liver disease or previous liver transplant.

• Current or past diagnosis of pancreatitis, gastroparesis, or other severegastrointestinal (GI) disease.

• Current or past diagnosis of gallbladder disease or gallstones.

• Serious cardiovascular disease within the past 6 months (e.g. uncontrolledhypertension, heart failure, significant cardiac arrhythmias, myocardial infarction,presence of angina pectoris, symptomatic coronary artery disease, deep veinthrombosis, pulmonary embolism, second- or third-degree heart block, mitral valve oraortic stenosis, hypertrophic cardiomyopathy, stroke).

• Severe co-occurring psychiatric disorder (e.g., bipolar disorder, psychoticdisorder, schizophrenia), and/or history or evidence of organic brain disease ordementia that would compromise safety or compliance with the study protocol in theopinion of the site principal investigator (PI) and/or physician. As there is nospecific scale that determines this, this will include the Site PI/physiciandetermining if the potential participant shows consistency in decision making and ifthey are alert and oriented to time, date, day and location.

• Significant risk of suicide requiring a different/higher level of care, according tothe clinical judgment of the study physician or site principal investigator, orhistory of suicide attempts within the past 1 year, unless participation is clearedby clinician assessment and/or judgment. A Columbia-Suicide Severity Rating Scale (C-SSRS) indicating a history of suicide attempts within the past year, or activesuicidal ideation within the past 1 month, will qualify as significant risk ofsuicide.

• Treatment with any investigational drug in the one month preceding the study.

• Any contraindication to both methadone and BUP.

• Any contraindication to a GLP-1R agonist.

• Previous randomization for participation in this trial.

• Any other condition at screening that precludes safe participation in the trial inthe judgment of the site PI or study physician.

• Plans for travel outside of the local area over the 19 weeks (1 week of baseline, 12weeks of medication, 1 week wash-out, and follow-up after a further 28 days) thatwould interfere with visits during the study period or other logistic factors thatwould make it difficult to commit to the entire duration of study.

• Currently a prisoner.