Mirtazipine for methamphetamine? (McKetin 2026)

Addictions are incredibly challenging to treat in the emergency department, although hopefully everyone has accumulated a few wins with suboxone over recent years, and so maintains at least a modicum of optimism. Methamphetamine is much less common around me, but the primary drug of abuse in many areas of the world, and, unlike opioids, methamphetamine addiction does not have approved pharmacotherapeutic options. Based on its actions at a number of chemical receptors, and early phase 2 trials, it is thought that mirtazapine might help patients with methamphetamine use disorder. 

The question

Does mirtazapine reduce methamphetamine use in patients with moderate to severe methamphetamine use disorder?

The paper

McKetin R, Shoptaw S, Saunders L, Nguyen L, Clare PJ, Dore GJ, Turner A, Dean OM, Kelly PJ, Arunogiri S, Koeijers J, Degan TJ, Degenhardt L, Farrell M, Goodman-Meza D, Sinclair B, Reid D, Cordaro F, Hill H, Lundin R, Hayllar J, Christmass M, Liaw W, Liu D, Woods A, Brewerton B, Holyoak E, Wu BT, Maher H, O’Dea N, Keygan J, Kontogiannis A, Palmer L, Morrison C, Wrobel A, Hyland B, Kiden G, Romeo V, Kyaw KWY, Byrne M, Colledge-Frisby S, Zahra E, Berk M. Mirtazapine for Methamphetamine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Apr 1:e260159. doi: 10.1001/jamapsychiatry.2026.0159. PMID: 41920558

The methods

This is a phase 3, double-blind, placebo-controlled RCT based in 6 outpatient addictions clinics in Australia. 

Patients

Adult patients aged 18 to 65 with moderate or severe methamphetamine use disorder, and who had used methamphetamine at least twice weekly for the last 4 weeks, with a positive urine test. 

Intervention

Mirtazapine (30mg/day for 12weeks).

Comparison

Matching placebo.

Outcome

The primary outcome was the change in self-reported days of methamphetamine use at 28 days.

The results

They randomized 344 patients, 339 of whom attended the baseline assessment, and 28 day outcome data was available for 293 (86%). The mean age was 42 and 37% were female.

25% of patients discontinued the trial medication. 19% were due to reasons related to the trial medication. The rate was higher with mirtazapine than with placebo (23% vs 15%). 

At baseline, the groups were using methamphetamine 22-23 days out of the 28 days prior to starting the trial. Mirtazapine resulted in a statistical improvement of their primary outcome, with 7 days fewer use (95% CI 5.5-8.5) as compared to 5 days with placebo (95% CI 3.5-6.2).

There was no difference in the rate of methamphetamine negative oral fluid samples.

None of the secondary outcomes were statistically significant. 

The trial is too small to identify all adverse events, but they do seem to be increased in the mirtazapine group – with both weight gain and drowsiness being statistically and clinically significant. (Although I guess whether weight gain is a good or bad thing would depend on the baseline in this population.)  

My thoughts

It is not emergency medicine research, and the study is underwhelming in a number of ways, but I thought a double blind RCT showing benefit in the very difficult to treat methamphetamine use disorder was interesting enough to take note of. Whether this trial has any impact on your practice will depend greatly on where you work, the popularity of methamphetamine locally, and the availability of addictions follow-up.

This is a placebo-controlled double-blind RCT, and so has better methodology than 90% of the research discussed here. Of course, every study has limitations. 

In emergency medicine, we are used to a sample of patients who just show up. These patients are more select, as recruiting was done via social media, flyers, and word of mouth. Obviously, all addictions interventions require motivation from patients, but the patients here are probably a lot more motivated than anyone we are seeing in the emergency department, and so the results might not generalize.

A 14% loss to follow-up is incredibly good for research in patients with methamphetamine use disorder, but again emphasizes the likelihood of selection bias. 

Overall adherence to trial medications was low. They used an intention to treat analysis, which gives us an appropriate estimate of the expected effect when prescribing the medication to all comers, but this might be an under-estimation of the benefit seen in patients who actually take or tolerate the medication. A lot depends on whether the medication was stopped because of adverse events, or simply because adherence to an oral medication regimen will always be imperfect in a population of patients with methamphetamine use disorder.  

Self-report addictions data is always going to be subject to a degree of bias. A double-blind trial design should really limit the impacts of that bias, but I wonder whether there was some unmasking, given the more objective test (methamphetamine saliva samples) was completely unchanged, but the subjective self-report was significantly different. Of course, my faith in saliva drug testing is about as high as my faith in urine drug testing, so who knows?

Overall, we have a statistically significant but modest decrease in self reported use of methamphetamine, which is nothing to scoff at. However, other clinical outcomes were clinically negative, and the modest benefit needs to be weighed against harms. Given the lack of alternatives, I certainty think this is worth discussing with patients.

Bottom line

In this double-blind placebo-controlled RCT, mirtazapine resulted in less self-reported days using methamphetamine in the next 28 days. The benefit was modest, and there were adverse events, so this is not a slam dunk game changer, but it is interesting and worth discussing with patients as we await more data.

Other FOAMed

Evidence based medicine is easy

The EBM bibliography

Evidence based medicine resources

EBM deep dives

References

McKetin R, Shoptaw S, Saunders L, Nguyen L, Clare PJ, Dore GJ, Turner A, Dean OM, Kelly PJ, Arunogiri S, Koeijers J, Degan TJ, Degenhardt L, Farrell M, Goodman-Meza D, Sinclair B, Reid D, Cordaro F, Hill H, Lundin R, Hayllar J, Christmass M, Liaw W, Liu D, Woods A, Brewerton B, Holyoak E, Wu BT, Maher H, O’Dea N, Keygan J, Kontogiannis A, Palmer L, Morrison C, Wrobel A, Hyland B, Kiden G, Romeo V, Kyaw KWY, Byrne M, Colledge-Frisby S, Zahra E, Berk M. Mirtazapine for Methamphetamine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Apr 1:e260159. doi: 10.1001/jamapsychiatry.2026.0159. PMID: 41920558