Mirtazapine modestly cut methamphetamine use in an Australian phase 3 trial

Methamphetamine use disorder has no approved medication anywhere in the world [s1]. Against that backdrop, an Australian phase 3 trial has found that mirtazapine — a cheap, generic antidepressant — modestly reduced methamphetamine use when it was prescribed in ordinary outpatient clinics, though the effect was small and side-effects drove more people to stop the drug [s1].

The trial, published in JAMA Psychiatry, was deliberately built to test the drug under everyday conditions rather than in a tightly controlled research setting — an effectiveness question rather than a pure efficacy one [s1]. Mirtazapine is off-patent and carries no commercial sponsor pushing it toward this use, which makes a positive signal easier to take at face value than a manufacturer-funded result.

How the trial was run

Between 16 November 2022 and 1 May 2025, six outpatient alcohol and other drug clinics in Australia enrolled adults with moderate-to-severe methamphetamine use disorder [s1]. Of 344 people randomised, 339 received the intervention: 172 assigned to mirtazapine, 30 mg once daily for 12 weeks, and 167 to matching placebo [s1]. Their mean age was 42.0 years, 126 (37.2%) were female, and at baseline they had used methamphetamine on a median of 24 of the previous 28 days — heavy, frequent use [s1].

The primary outcome was the change in days of methamphetamine use in the past 28 days, from baseline to week 12 [s1]. Secondary outcomes included depression, insomnia, HIV-risk behaviour, quality of life, and methamphetamine-negative oral-fluid samples [s1].

What the numbers showed

Use fell in both groups, but further on the drug. The mean reduction was 7.0 of 28 days with mirtazapine versus 4.8 days with placebo — a mean difference of 2.2 days (95% confidence interval, −4.2 to −0.2; P=.02) [s1]. That is a real but modest effect: roughly two fewer days of use a month, on top of what placebo and clinic contact already achieved.

None of the secondary outcomes separated significantly [s1]. The trial found no meaningful effect of mirtazapine on depression, insomnia, HIV-risk behaviour, quality of life, or the proportion of drug-negative oral-fluid samples — a caution against reading too much into the primary result, since the reduction in self-reported use was not corroborated by the biological measure.

Tolerability was the other constraint. More people on mirtazapine reported drowsiness (47% versus 33%) and weight gain (10% versus 3%) [s1]. And more stopped the drug because of adverse events: 40 participants (23%) discontinued mirtazapine for that reason, against 25 (15%) on placebo [s1]. The investigators reported no unexpected safety concerns from delivering the drug in routine practice, but the higher dropout is a practical limit on how useful even a modest benefit can be if a substantial share of patients cannot stay on the medication long enough to gain it [s1].

An older signal, now tested in the clinic

Mirtazapine did not come from nowhere. A San Francisco trial published in JAMA Psychiatry in 2020 had tested the same 30 mg daily dose against placebo in cisgender men and transgender women who have sex with men and who had methamphetamine use disorder, following an earlier phase 2a study that reported reductions in both methamphetamine use and sexual-risk behaviour [s2]. That work established mirtazapine as one of the more promising candidates in a field with none approved [s2].

The new trial's contribution is that it moved the question out of a specialised research clinic and into general outpatient services, in a broader population, and still found a positive primary result [s1]. Effectiveness trials like this one usually show smaller effects than efficacy trials, because real-world adherence and follow-up are messier — which makes even a two-day difference notable, and also explains why it is not larger.

What it does and does not settle

It settles that, in routine Australian clinics, adding mirtazapine to standard care modestly reduced self-reported methamphetamine use over 12 weeks [s1]. It does not establish that the drug changes the harder outcomes that matter most: the biological marker of use did not move, the secondary outcomes were null, and nearly a quarter of those on the drug stopped it because of side-effects [s1]. Whether a two-day monthly reduction translates into meaningful gains in health or function is the question a longer trial would need to answer.

For a disorder with no licensed pharmacotherapy, a modest, replicated signal from a cheap generic is worth having on the table — but it is a modest signal, not a cure [s1][s2]. This article describes trial findings and is not medical advice; anyone struggling with stimulant use can seek help from a doctor or a local alcohol and drug service.

Sources

• Mirtazapine for Methamphetamine Use Disorder — JAMA Psychiatry, 2026-06-01
• Effects of Mirtazapine for Methamphetamine Use Disorder Among Cisgender Men and Transgender Women Who Have Sex With Men — JAMA Psychiatry, 2020-03-01