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.