Mirtazapine for Methamphetamine Use Disorder: A Randomized Double-blind Placebo-controlled Trial on Craving, Mood, and Abstinence

Objectives: Methamphetamine use disorder (MUD) lacks an approved pharmacotherapy. We evaluated the efficacy and safety of adjunctive mirtazapine for reducing craving and relapse during structured inpatient treatment. Methods: In this single-center, randomized, double-blind, placebo-controlled, parallel-group trial, hospitalized adult males with DSM-5–diagnosed MUD were randomized (1:1) to mirtazapine (15–30 mg/day) or matching placebo for 8 weeks plus standardized inpatient psychosocial care. The prespecified primary outcome was change in craving from baseline to week 8 measured by the validated Persian Post-Abstinence Craving Assessment Questionnaire (0–100). The intention-to-treat methodology guided the analysis. The secondary endpoints comprised relapse (self-reported methamphetamine use confirmed by weekly urine toxicology), depressive symptoms, retention, and adverse events. Results: Forty-four participants were randomized; 42 (95.5%) completed 8 weeks. In the ITT analysis, week-8 craving scores were significantly lower with mirtazapine versus placebo (adjusted mean difference: –13.33 points; 95% CI: –16.25 to –10.41; P <0.001; partial η²=0.69). Relapse occurred in 3/22 (13.6%) receiving mirtazapine and 10/22 (45.5%) receiving placebo (Firth logistic regression OR=0.21; 95% CI: 0.04–1.02; P =0.052). The CI included 1.0, indicating statistical uncertainty. Adherence exceeded 95%. Adverse events were mild to moderate; no serious events occurred. Conclusions: Among hospitalized adult males with MUD, adjunctive mirtazapine significantly reduced craving over 8 weeks. Relapse findings were exploratory. Larger multisite trials with longer follow-up are warranted. Trial Registration: Iranian Registry of Clinical Trials (IRCT20240915063046N1). www.irct.ir