This open label pilot study will assess the feasibility and preliminary efficacy of tirzepatide which will be prescribed under its FDA approved weight management indication in adults with moderate or severe methamphetamine, cocaine or prescription stimulant use disorder (MUD) who also meet criteria for obesity or overweight with comorbidities. Up to 30 participants will receive 20 weeks of once weekly tirzepatide, followed by an observational follow up period.

The study also incorporates MRI at seven time points to explore neural biomarkers associated with treatment response. All participants will receive 12 weeks of contingency management (CM) combined with cognitive behavioral therapy (CBT). Together, these pharmacologic, neuroimaging, and behavioral components will evaluate tirzepatide's potential to improve health and substance use outcomes in individuals with MUD.

This is a phase two, open-label study to evaluate the feasibility and preliminary efficacy of using tirzepatide when prescribed for its United States (US) Food and Drug Administration (FDA) approved weight-related indication as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 1) 30 kg/m2 or greater (obesity) or 2) 27kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease) in individuals with comorbid moderate/severe methamphetamine, cocaine, or prescription stimulant use disorder. The study will screen up to 45 individuals and enroll up to N=30 individuals with moderate/severe methamphetamine, cocaine or prescription stimulant use disorder who meet FDA-approved weight-related indication of tirzepatide for a 20-week-long, once-weekly treatment with tirzepatide (dose optimized for each individual, with a minimum of 5mg/week after week-4) that will be followed by an observational follow-up period (Weeks 24, 28 and 32) after the last dose of tirzepatide. In addition, all participants will undergo magnetic resonance imaging (MRI), including structural and functional (fMRI) scans, at screening and baseline, as well as at Weeks 6, 20, 24, 28, and 32, for a total of seven scans over the course of the trial. The screening scan may be completed same day as the screening visit or scheduled on another day based on scanner availability. Participants will also receive 12 weekly contingency management (CM) in conjunction with cognitive behavioral therapy (CBT) during the 12 weeks. These combined measures will provide us with a comprehensive evaluation of tirzepatide and its potential impact on behavior and brain function/patterns in individuals with moderate/severe methamphetamine, cocaine, and stimulant use disorder.

Inclusion Criteria:

1. Be 18 to 65 years of age, inclusive.

2. Be able to provide informed consent and ask relevant questions.

3. Stated willingness to comply with all study procedures and availability for the duration of the study.

4. Be willing to adhere to the study medication regimen

5. Meet DSM-5 criteria for moderate or severe methamphetamine, cocaine or prescription stimulant use disorder.

6. Self-report methamphetamine, cocaine or prescription stimulant use on 18 or more days in the 30-day period prior to written informed consent using the Timeline Followback (TLFB).

7. Have an initial body mass index (BMI) at screening of:

   1. 30 kg/m2 or greater (obesity)
   2. 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

8. If biologically female and is or becomes sexually active with a biological male, must agree to use acceptable methods of contraception and have urine pregnancy testing during participation in the study, unless unable to get pregnant

   a. Appropriate birth control methods include: i. Oral contraceptives, contraceptive patch, hormonal vaginal contraceptive ring (with restrictions related to dose change given the medication interactions between tirzepatide and oral contraceptives).

   ii. Barrier (diaphragm or condom) iii. Contraceptive implant iv. Medroxyprogesterone acetate injection v. Intra-uterine device vi. Complete abstinence from sexual intercourse vii. Surgical sterilization

9. Agreement to adhere to Lifestyle Considerations throughout study duration

Exclusion Criteria:

1. Current or recent use (within 3 months prior to consent) of other tirzepatide-containing products or any other GLP-1 receptor agonist
2. Current or recent use (within 30 days) of sulfonylureas, other concomitantly administered insulin secretagogue, or insulin
3. Current or recent use (within 3 months prior to consent) of other weight loss agents
4. Weight loss surgery within 12 months prior to consent
5. Current eating disorder per clinician evaluation
6. Personal or family history of Medullary Thyroid Carcinoma
7. History of Multiple Endocrine Neoplasia syndrome type 2
8. Known serious hypersensitivity (e.g., anaphylaxis, angioedema) to tirzepatide or any of the excipients in tirzepatide
9. History of angioedema or anaphylaxis with a GLP-1 receptor agonist
10. Current Stage 3 or higher Chronic Kidney Disease, defined as eGFR <60 at Screening
11. Current inadequately controlled diabetes, defined as HbA1c > 7.0 at Screening
12. History of diabetic retinopathy
13. Current pregnancy or lactation
14. Treatment with another investigational drug or intervention within the past one month (30 days prior to consent)
15. Have any condition for which study participation would not be in their best interest (e.g., cognitive impairment, unstable general medical condition, intoxication, active psychosis) or that could prevent, limit, or confound the protocol-specified assessments, in the opinion of the investigator or their designee.
16. Require immediate hospitalization for psychiatric disorder or suicidal risk as assessed by a licensed study clinician.
17. Any contraindications to MRI, including pacemakers or metallic objects in the body.
18. Any claustrophobia or other conditions which may result in inability to lie still in the MRI scanner for 1 hour or more.

No individual participant data is planned to be shared with other researchers.