Randomized Controlled Trial of Tirzepatide for Methamphetamine Use Disorder

Methamphetamine use disorder (MtUD) affects over 1.5 million U.S. adults annually and has no FDA-approved treatments. Preclinical studies and observational data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce stimulant use. Tirzepatide, a dual GLP-1/glucose-dependent insulinotropic peptide (GIP) receptor agonist approved for type 2 diabetes and weight management, has not been evaluated for MtUD in an adequately-powered randomized controlled trial. This Phase 2 double-blind, randomized controlled trial will enroll 228 adults with moderate or severe MtUD to receive weekly subcutaneous tirzepatide (2.5 mg/week titrated to 15 mg/week or maximally tolerated dose) or placebo for 26 weeks, followed by 6 weeks of follow-up. Safety will be monitored throughout.

The study aims are to: (1) assess tolerability (treatment discontinuation) and safety (serious adverse events) of tirzepatide; and (2) evaluate preliminary efficacy, including reduction in methamphetamine use (Timeline Follow-back), treatment response (≥6 of 8 urine drug screen [UDS] negative in weeks 23-26), and early remission (no longer meeting Diagnostic and Statistical Manual 5th edition [DSM-5] criteria at week 26). Secondary/exploratory aims include assessing reductions in methamphetamine craving and cravings for other substances.

Inclusion criteria

• be aged 18 to 65 years;
• have moderate or severe methamphetamine use disorder;
• have active pattern of methamphetamine use;
• be interested in reducing or stopping methamphetamine use;
• be able and willing to provide informed consent, comply with all study procedures, and adhere to weekly study medication injections;
• be overweight or obese (body mass index ≥25 kg/m²); and
• (only for biological females) agree to use acceptable contraception and undergo urine pregnancy testing unless unable to become pregnant

Exclusion criteria

• report using any glucagon like peptide 1 receptor agonists (GLP-1RA, including tirzepatide), sulfonylureas, or insulin in the past 90 days;
• have a current eating disorder or severe alcohol or substance use disorder;
• have personal or family history of medullary thyroid carcinoma, history of multiple endocrine neoplasia type 2, or hypersensitivity, angioedema, or anaphylaxis to GLP-1RAs or tirzepatide;
• have Stage 3 or higher chronic kidney disease, inadequately controlled diabetes, history of diabetic retinopathy, any unstable or serious medical or psychiatric condition, or any other reason or clinical condition that may either interfere with study participation or make the study participation unsafe (per investigator judgement);
• are currently pregnant, breastfeeding, or planning pregnancy;
• have received an investigational drug within 30 days of informed consent;
• require psychiatric hospitalization;
• have recent suicidal or current homicidal ideation;
• are incarcerated or in court-mandated residential placement;
• have unsafe use of alcohol, benzodiazepines, sedative/hypnotics, or other substances; or
• have use of concurrent medications that may pose safety risks or interfere with study procedures.