Mirtazapine Reduces Methamphetamine Use in methamphetamine use disorder: JAMA

A phase III placebo-controlled trial published in the Journal of the American Medical Association demonstrated that mirtazapine use in routine clinical practice significantly reduced methamphetamine use in adults with methamphetamine use disorder. However, it showed no significant benefit on secondary outcomes such as depression, insomnia, HIV risk behavior, or quality of life. 

Methamphetamine use disorder remains a pressing global health challenge, with rising rates of addiction and limited treatment options beyond behavioral therapies. Currently, there are no FDA-approved pharmacological treatments for methamphetamine use disorder. This leaves clinicians with few tools to address the condition in routine practice.

This clinical trial was conducted across 6 outpatient drug and alcohol clinics in Australia from November 2022 to May 2025. The study enrolled 344 adults diagnosed with moderate to severe methamphetamine use disorder, with 339 participants ultimately receiving either mirtazapine or a placebo over a 12-week period.

The  participants, with an average age of 42, reported heavy baseline use (24 out of the previous 28 days). This research tracked changes in usage, along with secondary measures like depression, sleep quality, HIV risk behaviors, and overall quality of life.

By the end of the trial, those receiving mirtazapine showed a greater reduction in methamphetamine use when compared to the placebo group. On average, participants in the treatment group reduced their use by 7 days out of 28, when compared to a 4.8-day reduction in the placebo group. The difference of 2.2 fewer days of use was statistically significant, pointing that the medication had a measurable effect.

The participants taking mirtazapine reported higher rates of side effects, particularly drowsiness (47% versus 33% in the placebo group) and weight gain (10% versus 3%). Also, nearly a quarter of those in the treatment group discontinued the medication due to adverse events, when compared to 15% in the placebo group.

Overall, the findings of this study suggests that while the drug may help reduce methamphetamine use, its broader benefits in this population may be limited. The study also confirmed that mirtazapine can be safely administered in routine clinical settings without unexpected risks for real-world implementation.

Source:

McKetin, R., Shoptaw, S., Saunders, L., Nguyen, L., Clare, P. J., Dore, G. J., Turner, A., Dean, O. M., Kelly, P. J., Arunogiri, S., Koeijers, J., Degan, T. J., Degenhardt, L., Farrell, M., Goodman-Meza, D., Sinclair, B., Reid, D., Cordaro, F., Hill, H., … Berk, M. (2026). Mirtazapine for methamphetamine use disorder: A randomized clinical trial: A randomized clinical trial. JAMA Psychiatry (Chicago, Ill.). https://doi.org/10.1001/jamapsychiatry.2026.0159