Mirtazapine for Methamphetamine Use Disorder in a Phase 3 Trial

Key Takeaways

• Mirtazapine was associated with a statistically significant reduction in methamphetamine use days on the primary outcome.
• Secondary outcomes, including depression, insomnia, HIV risk behavior, quality of life, and methamphetamine-negative oral fluid samples, were not significantly different.
• Drowsiness and weight gain were more frequent with mirtazapine, but no unexpected safety concerns emerged and no serious adverse events were attributed to study medication.

In adults with moderate to severe methamphetamine use disorder, 12 weeks of mirtazapine 30 mg daily was associated with a greater reduction in self-reported methamphetamine use days than placebo at week 12, with a treatment estimand of -2.2 days (95% CI, -4.2 to -0.2; P = .02). The phase 3, parallel-group, double-blind, placebo-controlled randomized clinical trial was conducted across six outpatient clinics in Australia and enrolled adults receiving routine outpatient addiction care.

Of the 344 randomized participants, 339 received intervention, with 167 assigned placebo and 172 assigned mirtazapine 30 mg daily for 12 weeks. Participants averaged 42 years of age, 37.2% were female, median baseline use was 24 days, and about 49% were depressed at eligibility. The primary end point was change in self-reported methamphetamine use days from baseline to week 12 and the secondary end point was the change in depression, insomnia, HIV risk behavior, and quality of life from baseline to week 12.

Week 12 methamphetamine use results showed mean declines of 7.0 days with mirtazapine and 4.8 days with placebo. Secondary outcomes, including depression, insomnia, HIV risk behavior, quality of life, and methamphetamine-negative oral fluid samples, did not differ significantly between the mirtazapine and placebo groups, although trends generally favored mirtazapine. Median medication adherence was 52% overall and 62% after excluding periods following discontinuation. Investigators noted that the effect appeared smaller than in phase 2 work and may have been diluted by participant heterogeneity, poor adherence, and high discontinuation.

Drowsiness occurred in 47% of the mirtazapine group and 33% of the placebo group, while weight gain occurred in 10% and 3%, respectively. Any adverse event was reported by 90% and 87% and discontinuation due to adverse reaction by 23% and 15%. There were 18 serious adverse events during the trial period, including 7 in the mirtazapine group, and none were considered related to trial medication. Exploratory suicide risk thresholds were exceeded by 11 participants overall, with 5 in the mirtazapine group and 6 in the placebo group. Investigators said the trial extends phase 2 findings to a more diverse outpatient population in routine practice.