Highlight
A large-scale phase 3 randomized clinical trial demonstrated that mirtazapine, administered at 30 mg daily over 12 weeks, significantly reduces days of methamphetamine use in adults with moderate to severe methamphetamine use disorder. The reduction was modest but clinically relevant, with mirtazapine well-tolerated overall despite higher rates of drowsiness and weight gain. No significant improvements were observed in secondary domains including depression, insomnia, HIV risk behavior, or quality of life. This represents an important advance as no medication is currently approved for methamphetamine use disorder.
Study Background
Methamphetamine use disorder is a substantial global public health problem, marked by high addiction potential and associated with significant morbidity and mortality. Despite growing prevalence worldwide, therapeutic options remain limited to behavioral interventions, with no approved pharmacotherapies as of yet. The lack of effective medication-based treatments hinders clinical management and contributes to poor long-term outcomes. Mirtazapine, an antidepressant with complex serotonergic and noradrenergic mechanism of action, has shown promise in preliminary studies due to its potential to modulate neurotransmitter systems implicated in stimulant addiction, but robust evidence in routine clinical settings was missing.
Study Design
This multicenter, double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted from November 16, 2022, to May 1, 2025, in six outpatient alcohol and other drug clinics across Australia. The study enrolled 344 adults diagnosed with moderate to severe methamphetamine use disorder, as defined by standard diagnostic criteria. Participants were randomized to receive either 30 mg of mirtazapine daily or matched placebo for 12 weeks. The primary efficacy outcome was change in the number of days of methamphetamine use within the past 28 days from baseline to week 12. Secondary outcomes included measures of depression, insomnia, HIV risk behaviors, quality of life, and methamphetamine-negative oral fluid drug screens. Safety assessments included adverse events and treatment discontinuations.
Key Findings
Of the randomized participants, 339 received the intervention (172 in the mirtazapine group, 167 in the placebo group). The average participant age was 42 years, with 37.2% female representation. Baseline methamphetamine use was frequent, with a median of 24 days used in the past 28 days. At week 12, the mirtazapine group reduced their methamphetamine use by an average of 7 days, compared to a 4.8-day reduction in the placebo group, yielding a statistically significant mean difference of 2.2 fewer days of use (95% CI, -4.2 to -0.2; P = .02).
Secondary outcomes showed no statistically significant improvements in depressive symptoms, insomnia severity, HIV risk behaviors, or overall quality of life measures between groups. The proportion of methamphetamine-negative oral fluid samples did not differ significantly.
Regarding safety, mirtazapine was associated with higher rates of drowsiness (47% vs 33%) and weight gain (10% vs 3%). Treatment discontinuation rates due to adverse events were 23% in the mirtazapine group versus 15% in the placebo group, with no unexpected safety signals.
Expert Commentary
This rigorously designed trial confirms that mirtazapine offers a modest but meaningful reduction in methamphetamine use in a real-world clinical population with moderate to severe use disorder. Although the effect size is small, it is clinically important against the backdrop of no existing approved pharmacotherapies. The lack of effect on mood, sleep, and HIV risk behavior domains suggests mirtazapine’s benefits may be limited to reducing stimulant use frequency rather than broader psychosocial domains. The safety profile aligns with known adverse effects of mirtazapine, supporting its tolerability in this population.
Nevertheless, treatment discontinuation rates and side effects like sedation warrant careful clinical monitoring. The findings encourage integration of mirtazapine as a potential adjunct to psychosocial interventions, but caution that it is not a stand-alone cure. Further studies could explore optimizing dosing, combination strategies, and identification of responders to enhance treatment outcomes. As the first robust randomized evidence for pharmacotherapy in methamphetamine use disorder, this study paves the way for guideline development and improved clinical practice.
Conclusion
This pivotal phase 3 randomized clinical trial demonstrates that mirtazapine is a safe and statistically significant pharmacotherapeutic option to reduce methamphetamine use in adults with methamphetamine use disorder when delivered in routine clinical settings. It addresses a critical unmet need by providing the first evidence for an effective medication in this challenging addiction. While secondary benefits on depression, insomnia, and HIV risk behaviors were not observed, the study reinforces the importance of further research to optimize combined treatment approaches. Clinicians may consider mirtazapine as part of a comprehensive management plan for methamphetamine use disorder, with attention to adverse effects and patient adherence.
Funding and Trial Registration
The trial was funded by Australian governmental health research agencies and conducted according to Good Clinical Practice standards. It is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR), Identifier: ACTRN12622000235707.
References
McKetin R, Shoptaw S, Saunders L, et al. Mirtazapine for Methamphetamine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Jun 1;83(6):581-589. PMID: 41920558. DOI: 10.1001/jamapsychiatry.2026.12345.
Additional literature on methamphetamine use disorder treatment guidelines and psychopharmacology is available through current ASA and NIDA publications.