Mirtazapine Reduces Meth Use

The first med with phase III evidence for methamphetamine use disorder

STUDY: McKetin R et al, JAMA Psychiatry 2026; doi:10.1001/jamapsychiatry.2026.0159

STUDY TYPE: Randomized, double-blind, placebo-controlled trial

FUNDING: Australian Government Medical Research Future Fund

Background

Mirtazapine is an antidepressant that may reduce methamphetamine cravings and withdrawal problems by modulating dopamine, as well as serotonin and norepinephrine transmission. It has shown promise in two small trials of methamphetamine use disorder, but only in men who have sex with men at a single site. This study furthers the case with a large, phase III trial.

The Study

This multicenter randomized controlled trial enrolled 339 adults with moderate-to-severe methamphetamine use disorder at six outpatient clinics in Australia, randomizing them to mirtazapine 30 mg/day or placebo for 12 weeks. The primary outcome was change in days of methamphetamine use in the past 28 days. The sample was diverse — 37% women, 49% with comorbid depression — filling a major gap left by prior trials.

By week 12, the mirtazapine group reduced use by 7.0 days compared to 4.8 days with placebo — a difference of 2.2 days (p = .02), representing an 8% reduction in daily use risk. The effect was consistent regardless of sex or depression status:

No secondary outcomes (depression, insomnia, HIV risk, quality of life) reached significance overall, though insomnia improved significantly in participants with comorbid depression.

Drowsiness was more common with mirtazapine (47% vs 33%), as was weight gain (10% vs 3%). Discontinuation due to adverse effects was higher in the mirtazapine group (23% vs 15%).

Practice Implications

1. Two fewer use days per month isn’t dramatic — and it’s a smaller effect than the earlier phase 2 trials showed. But in a disorder with zero approved options, any improvement matters.
2. Mirtazapine is cheap, generic, and manageable in outpatient settings without the close supervision required by bupropion/naltrexone or stimulant-based approaches.
3. If your patient has methamphetamine use disorder — especially with prominent insomnia or depression — mirtazapine 30 mg nightly is a low-barrier option worth offering. Counsel them upfront about drowsiness and appetite changes, and set realistic expectations: this won’t stop use, but it may help reduce it.