Mirtazapine Trial Finds Modest Reduction in Methamphetamine Use

A phase 3 randomized trial has strengthened the evidence that mirtazapine can help some people with methamphetamine use disorder reduce their use. The advantage over placebo was statistically significant but modest: 2.2 fewer days of methamphetamine use during a 28-day period after 12 weeks of treatment.

The result comes from the Tina Trial, conducted at six government-run outpatient alcohol and drug clinics in Australia. JAMA Psychiatry published the study online on April 1, 2026. It tested an established antidepressant in routine clinical settings because no medication is specifically approved to treat methamphetamine use disorder.

The finding is not evidence that mirtazapine ends dependence, produces abstinence or should be started without medical assessment. The primary outcome was a reduction in self-reported days of use. Several secondary outcomes, including drug-negative oral-fluid samples, depression, insomnia and quality of life, did not show a statistically significant overall benefit.

The Trial Compared Daily Mirtazapine With Placebo

Researchers randomized 344 adults with moderate to severe methamphetamine use disorder. Of those, 339 received an intervention: 172 were assigned mirtazapine and 167 received placebo. Participants were 18 to 65 years old and had used methamphetamine at least twice a week during the four weeks before enrollment.

The study included a broader population than two earlier San Francisco trials. Women made up 37 percent of participants, and about half met the study threshold for depression at entry. The six clinics were in Wollongong, Geelong, Townsville, Perth, Brisbane and Adelaide.

Participants took a 30-milligram tablet each evening for 12 weeks, followed by a taper. Medication bottles had electronic caps to record openings. Researchers assessed outcomes at baseline and after four, eight and 12 weeks. The primary measure used a structured timeline method in which participants reported the number of days they had used methamphetamine during the previous 28 days.

At baseline, participants had used methamphetamine on a median of 24 of the prior 28 days. By week 12, the estimated reduction was 7.0 days in the mirtazapine group and 4.8 days in the placebo group. The adjusted between-group difference was 2.2 days, with a 95 percent confidence interval from 0.2 to 4.2 fewer days and a P value of .02.

The Main Result and the Biological Test Diverged

The primary outcome favored mirtazapine, but the oral-fluid result did not confirm a significant separation. Methamphetamine-negative samples were estimated at 13.2 percent in the mirtazapine group and 12.0 percent with placebo. The 1.3 percentage-point difference had a wide confidence interval and a P value of .68.

Researchers reported no significant overall treatment effects on depression, insomnia, HIV-risk behavior or quality of life. A subgroup analysis found an insomnia signal among participants who were depressed at baseline, but subgroup findings do not change the neutral overall secondary outcomes.

The use measure was self-reported rather than derived solely from laboratory tests. The investigators said the method has performed well against biological measures and found agreement with oral-fluid results in this study. Even so, self-report can be affected by recall, and the 12-week follow-up cannot establish whether the reduction lasts after treatment ends.

Medication adherence was another practical limitation. The researchers described poor adherence and high discontinuation as factors that may have diluted the effect. They also argued that the result may better reflect what clinics can expect outside a tightly controlled research environment than a trial limited to highly adherent patients.

Drowsiness, Weight Gain and Discontinuation Matter

No serious adverse event was judged related to the trial medication, and the investigators reported no unexpected safety concern. That does not mean the two groups had identical tolerability. Drowsiness was reported by 47 percent of participants receiving mirtazapine and 33 percent receiving placebo. Weight gain was reported by 10 percent and 3 percent, respectively.

Forty participants in the mirtazapine group, or 23 percent, stopped medication because of adverse reactions, compared with 25 participants, or 15 percent, in the placebo group. The difference in discontinuation was not statistically significant in the trial, but it remains relevant when considering how a daily medicine might perform in practice.

Mirtazapine is already approved for depression and is available as a generic medicine. Its established use may make it easier to study and prescribe than a new compound. For methamphetamine use disorder, however, prescribing is off label. A clinician must weigh other medicines, health conditions, suicide risk, pregnancy, side effects and the person's treatment goals rather than treating the trial dose as a general instruction.

The study excluded people already taking antidepressants, those who had attempted suicide in the prior year, pregnant or breastfeeding people, and patients needing acute or inpatient care. Those exclusions limit how directly the results apply to individuals in those groups.

A New Trial Does Not Replace the Treatment System

The ASAM and AAAP stimulant-use guideline, published before this phase 3 result, gives mirtazapine a conditional recommendation based on low-certainty evidence. It gives contingency management, which uses structured incentives tied to treatment goals, a strong recommendation with high-certainty evidence and places it alongside other psychosocial care.

The new trial gives clinicians better evidence from a larger and more diverse population. It does not establish mirtazapine as a universally effective first-line treatment, prove abstinence or justify replacing behavioral support with a prescription. The absolute difference was about two use days per month, and the biological secondary measure was inconclusive.

That modest effect can still matter in a disorder with no approved medication. A scalable generic option that helps some patients reduce use would be clinically useful, especially where specialist services are scarce. Its value depends on honest expectations, tolerability, adherence and integration with evidence-based care.

The responsible reading is neither dismissal nor celebration. Three randomized trials now point in the same direction, and the phase 3 study extends the signal to routine Australian clinics. Regulators and guideline panels still need to decide how the evidence changes practice. Until then, this is a credible incremental advance, not a cure and not a dosing instruction for readers.