Inclusion Criteria:
1. Must be ≥18 years of age;
2. Must have moderate to severe OUD;
3. Must, at the time of randomization, be newly initiated on BUP (i.e., within 7 to 60 days) during the current treatment episode, be taking ≥ the recommended target dose for transmucosal BUP (or equivalent for extended-release), and have documentation of receiving BUP, including dose and the start date of the current treatment episode, from their BUP provider, and, for participants prescribed transmucosal BUP, have at least one UDS positive for buprenorphine/norbuprenorphine;
4. Must be willing to be randomized to tirzepatide or placebo and to comply with study procedures, including weekly visits for 6 months;
5. Must be able to understand the study, and having understood, provide written informed consent in English;
6. Must not be breastfeeding; if of child bearing potential, must test negative on the study-administered pregnancy test(s), and if of childbearing potential and engaging /planning to engage in sexual intercourse must agree to effective contraception for the duration of the trial through 30 days after the trial; effective contraception is defined as using: a) birth control injection, an intrauterine device, or implant; or b) two birth control methods - for example birth control pills with a barrier method (e.g., condoms, etc.).
* If ever of childbearing potential, a participant is considered to not be of childbearing potential for the study if they are:
1. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, tubal implants, or tubal ligation), congenital anomaly such as Mullerian agenesis; are
2. post-menopausal defined as ≥ 55 years old not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea;
3. ≥ 55 years old with a diagnosis of menopause prior to starting hormone replacement therapy; or
4. ≥ 40 years old with an intact uterus, not on hormone therapy, who has cessation of menses for at least 1 year without an alternative medical cause, AND a follicle-stimulating hormone ≥ 40 mIU/mL; participants in this category must test negative on the study-administered pregnancy test(s).
Exclusion Criteria:
1. have a history of type 1 or type 2 diabetes mellitus (other than pregnancy-related diabetes);
2. have a BMI \<23.0 kg/m²;
3. have any of the following cardiovascular conditions within 90 days prior to signing consent: acute myocardial infarction, cerebrovascular accident (stroke), unstable angina, or hospitalization due to congestive heart failure (CHF);
4. have a known history of chronic or acute pancreatitis, gallbladder disease, gastroparesis, gastric emptying abnormality, gastroesophageal reflux disease, or other severe gastrointestinal disease;
5. have a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2);
6. have previously taken tirzepatide, have taken any GLP-1 analogue within the 6 months before consent, or have a known history of prior hypersensitivity reaction to any GLP-1 analogue;
7. have renal impairment defined as an estimated glomerular filtration rate (eGFR) value of \< 15 mL/min/1.73 m2 or requiring dialysis;
8. have a current, or within the 30 days prior to signing consent, use of, or plan to start during the course of the trial:
1. medications with glucose lowering properties: GLP-1 analogs, sulfonylurea, insulin, metformin, thiazolidinediones, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors;
2. systemic steroids including prednisone, hydrocortisone, dexamethasone;
9. have a history of suicide attempts in the prior year or significant active suicidal ideation as assessed by a qualified study clinician;
10. have a psychiatric or medical condition that, in the judgment of the site medical clinician (BMC or UMC), would make study participation unsafe or which would make treatment compliance difficult;
11. have current status as a prisoner OR be currently in jail, prison, or any inpatient overnight facility as required by court of law or have pending legal action or other situation (e.g., unstable living arrangements) that, in the judgement of the site investigator, could prevent participation in the study or in any study activities.