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SAFETY AND TOLERABILITY OF 32-WEEK-LONG TREATMENT WITH TIRZEPATIDE IN INDIVIDUALS WITH MODERATE-TO-SEVERE METHAMPHETAMINE USE DISORDER

Amrita Ghose — Virgilio Garza1, Teresa Slettebo1, Nandini Jha1, Elizabeth Dedrick1, Snoben Kuruvila1, Manish Jha1 1The University of Texas Southwestern Medical Center

2026 ASCP Annual Meeting

Background

Preclinical studies and data from electronic health records suggest potential therapeutic utility of glucagon-like peptide 1 (GLP-1) receptor (R) agonists (GLP1RAs) for individuals with stimulant (such as methamphetamine) use disorder. Yet, the safety and tolerability of this new class of medication in individuals with methamphetamine use disorder (MtUD) has not been assessed previously. In this first study of tirzepatide, a dual agonist of GLP-1R and glucose-dependent insulinotropic peptide (GIP) receptor, for methamphetamine use disorder, safety and tolerability were evaluated after 32 weeks of treatment.

Method

35 adults with moderate to severe methamphetamine use disorder, with obesity or overweight with a comorbid weight condition, were enrolled into the study and treated for up to 32 weeks with tirzepatide according to the FDA label. Tirzepatide was initiated at 2.5 mg/week for 4 weeks and dose increased by 2.5 mg/week in four-week intervals up to 15 mg/week or maximally tolerated dose. A priori, feasibility as a secondary outcome was defined as the number of participants who received at least 5mg/week for at least four weeks. Any spontaneously reported adverse events (AEs) were captured at each weekly visit. The Gastrointestinal Symptom Rating Scale (GSRS) was collected at baseline and each weekly visit to measure symptoms of abdominal pain, constipation, diarrhea, indigestion and reflux. Repeated measures mixed model analyses were used to analyze changes in GSRS scores.

Results

Of the 35 participants who were enrolled and received the first injection of tirzepatide, 32 (91.4%) met the feasibility outcome. Three participants dropped out due to side effects, two were incarcerated before they could finish treatment, one was discontinued from the study due to excessive weight loss, one lost contact, and one was discontinued from the study due to a positive urine pregnancy test. Including those participants who dropped out of the study, the total treatment exposure was 82.4%, with 923 of the planned 1,120 injections administered. A total of 326 AEs were reported with 205, 116, and 4 classified as mild, moderate, and severe, respectively. Most adverse events were GI-related side effects, comprising 52.8% of all AEs. One serious adverse event of hospitalization for influenza occurred which was deemed as unrelated to the treatment. There was a transient, non-significant (p > 0.05) increase across all GSRS domains during the first four weeks of treatment, which resolved by the sixth week of treatment.

Discussion

These Results support good feasibility of using tirzepatide in individuals with moderate-to-severe MtUD. Gastrointestinal symptoms were the most commonly reported side effects, and were predominantly mild-to-moderate in severity. Larger multi-site placebocontrolled randomized controlled trials are needed to further characterize the safety and tolerability of tirzepatide as a potential treatment for MtUD.