Randomized Controlled Trial of Tirzepatide for Methamphetamine Use Disorder

Overview

This is a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial evaluating the tolerability, safety, and preliminary efficacy of tirzepatide for the treatment of individuals with moderate or severe methamphetamine use disorder (MtUD). The central hypothesis of the proposed research is that tirzepatide is a safe and potentially efficacious treatment of MtUD. Participants will undergo study procedures over 32 weeks, including: 1. completing self-assessments 2. undergo brief physical and review of medical and psychiatric history 3. provide urine and blood samples 4. medical management sessions 5. weekly subcutaneous study medication injections

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.