Mirtazapine shows some benefit in the treatment of methamphetamine use disorder

Methamphetamine is a highly addictive synthetic stimulant drug of growing global public health concern. About 7.4 million people worldwide are estimated to have methamphetamine use disorder. It is associated with an elevated risk of psychosis, cardiovascular events, accidental injuries, suicide, homicide and suboptimal neonatal outcomes. To date, no approved pharmacotherapies are available for methamphetamine use disorder.The antidepressant mirtazapine (Remeron, generics) is a promising candidate. Mirtazapine modulates dopamine function and may ameliorate the dopaminergic dysregulation seen in methamphetamine addiction. It also blocks central presynaptic α2-adrenergic receptors, which are dysregulated in methamphetamine addiction. In addition, mirtazapine’s antagonism of histamine-1 receptors might provide benefit for insomnia and anxiety, which are often seen in methamphetamine use disorder.The safety and effectiveness of mirtazapine for methamphetamine use disorder has not yet been established. Two single-site phase 2 trials provided preliminary evidence supporting the use of mirtazapine for methamphetamine use disorder. To further examine this issue, Australian researchers investigated the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder in routine clinical practice.The 2.5-year, phase 3, parallel-group, double-blind, placebo-controlled randomized clinical trial was conducted among adults (18–65 years) with moderate to severe methamphetamine use disorder at six outpatient, government-run alcohol and other drug clinics in Australia. All participants had used methamphetamine at least twice weekly in the past four weeks, and had a positive drug screen result for amphetamines. Patients received mirtazapine (30 mg daily for 12 weeks) or a matching placebo. The trial medication was provided to participants in bottles fitted with a medication event monitoring system (MEMS) cap to monitor medication adherence.The primary end point was the change in days of methamphetamine use in the past 28 days from baseline to week 12. Secondary end points were depression, insomnia, HIV risk behaviour, quality of life and methamphetamine-negative oral fluid samples.Key results:The study included 339 participants, with 172 in the mirtazapine group and 167 in the placebo group (mean age 42.0 years, 37.2% female).At baseline, the mean days of methamphetamine use in the past 28 days was 23.1 (95% CI, 21.3–24.9) in the mirtazapine group and 22.0 (95%CI, 20.3–23.8) in the placebo group.The mean reduction in days of methamphetamine use from baseline to week 12 was greater in the mirtazapine group (7.0 days of 28 days) than in the placebo group (4.8 days of 28 days; mean difference, 2.2 days; 95%CI, −4.2 to −0.2 days; p = 0.02). More participants in the mirtazapine group reported drowsiness (47% vs 33%) and weight gain (10% vs 3%). Forty participants (23%) discontinued mirtazapine due to adverse events compared to 25 participants (15%) in the placebo group. No significant effects of mirtazapine on secondary end points were found, but trends were in favour of a benefit of mirtazapine over placebo.The investigators conclude that in this randomized clinical trial in routine clinical practice, mirtazapine reduced methamphetamine use in adults with methamphetamine use disorder. Patients with methamphetamine use disorder had a mean reduction of seven days (out of 28 days) after 12 weeks of mirtazapine (30 mg/day) treatment, which was approximately two days more than the reduction seen with placebo. No unexpected safety concerns were found. The authors believe these findings have important clinical implications, in the absence of any approved pharmacotherapies for methamphetamine use disorder. Although the benefits of mirtazapine therapy were modest in this study, the researchers maintain that any improvement in clinical outcomes for methamphetamine use disorder is critical. The reduction in days of methamphetamine use has a positive effect on functional outcomes, and reduces the risk of methamphetamine-related psychotic symptoms and violent behaviour. The investigators consider mirtazapine to be a safe and inexpensive medication that can be easily and safely prescribed in an outpatient setting to help people reduce methamphetamine use. Reference:McKetin R, Shoptaw S, Saunders L, et al. Mirtazapine for methamphetamine use disorder. A randomized clinical trial. JAMA Psychiatry 2026; published online April 1, 2026. (accessed April 2, 2026).

Mirtazapine shows some benefit in the treatment of methamphetamine use disorder

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