The generic tetracyclic antidepressant mirtazapine was associated with a modest but significant reduction in methamphetamine use in adults with moderate-to-severe methamphetamine use disorder in a randomized controlled phase 3 study.

At 3 months, mirtazapine was associated with an average of about 2 fewer days of methamphetamine use per month compared with placebo, researchers found.

“In the absence of an approved medication for methamphetamine use, any traction we can get is critical. This is a good news story,” lead investigator Rebecca McKetin, PhD, with the National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia, told Medscape Medical News.

“There are an estimated 7.4 million people worldwide with a methamphetamine use disorder, and we have found something that doctors can safely prescribe to help people reduce their methamphetamine use,” McKetin said.

The study was published online on April 1 in JAMA Psychiatry.

Promising Candidate

Methamphetamine use, typically in conjunction with opioids, has been on the rise in the US, with some experts suggesting the drug may be driving a “fifth wave” of the opioid epidemic. There is no FDA-approved treatment for methamphetamine use disorder.

Mirtazapine is thought to act on multiple neurobiological pathways relevant to methamphetamine addiction. It modulates dopamine function via its affinity for serotonin receptors, which may mediate its ability to reduce methamphetamine’s effects and help correct underlying dopaminergic dysregulation seen in methamphetamine addiction.

Mirtazapine also blocks central presynaptic alpha-2-adrenergic receptors, which are dysregulated in methamphetamine addiction, while its antihistamine effects may improve the insomnia and anxiety that are common in this population.

Evidence supporting mirtazapine for methamphetamine use disorder comes from earlier phase 2 trials, where it reduced methamphetamine-positive drug tests and improved associated symptoms such as insomnia and depression.

The phase 3 double-blind, placebo-controlled randomized trial was conducted across six outpatient clinics in Australia and included 344 adults (mean age, 42 years; 37% women) with moderate-to-severe methamphetamine use disorder. Baseline methamphetamine use was high, with a median of 24 days of use in the prior 28 days.

Participants received mirtazapine 30 mg daily or matching placebo for 12 weeks. Overall, 339 participants received at least one dose of study medication (172 in the mirtazapine group and 167 in the placebo group) and were included in the analysis.

Mixed Results

The mean reduction in days of methamphetamine use from baseline to week 12 (the primary outcome) was significantly greater with mirtazapine than with placebo (7.0 vs 4.8 days; mean difference, 2.2 days; P = .02). This corresponded to an incidence rate ratio of 0.89, indicating an approximately 8% reduction in the likelihood of methamphetamine use on a given day, investigators found.

However, there were no significant between-group differences on the secondary outcomes of depression and insomnia.

Consistent with the previous phase 2 trials of mirtazapine in methamphetamine use disorder, reductions in methamphetamine use were not contingent on improvements in depression or insomnia, McKetin said.

“This leads us to believe that mirtazapine is acting directly on addictive processes. We cannot be certain of the exact mechanism, but we suspect that mirtazapine is reducing the rewarding effects of methamphetamine,” she said.

Yet mirtazapine did lead to significant improvements in sleep in the subgroup of people who were depressed at the start of the study, with trends toward reduced depression.

“Essentially, if people had sleep problems or depression, mirtazapine was beneficial in alleviating those symptoms,” McKetin said.

Longer treatment may yield more substantial antidepressant effects, which is what was shown in the earlier phase 2 trial that had a treatment period of 24 weeks, McKetin noted.

There were no unexpected safety concerns with mirtazapine, although participants receiving the drug reported more drowsiness (47% vs 33%) and weight gain (10% vs 3%). Medication adherence was modest (52% overall), with adverse events leading to greater discontinuance in the treatment group (23% vs 15%).

“Counseling people on adherence strategies and explaining the benefits of good adherence are key,” McKetin noted.

Drowsiness can have a negative effect on daily activities, so clinicians could recommend patients take the medication before bedtime, she said, adding that clinical monitoring and dose adjustment may also help with adherence.

Promising — but Preliminary

Although the findings offer some evidence of mirtazapine efficacy in methamphetamine use disorder, more research is needed to see how the drug works in a real-world setting, Xiaoduo Fan, MD, MPH, professor of psychiatry, UMass Chan Medical School, Worcester, Massachusetts, told Medscape Medical News.

Fan also felt that the author’s conclusion that the trial results confirm that mirtazapine can be used in routine clinical practice is “an overstatement.”

“So far, contingency management appears to have the best evidence in treating methamphetamine use disorder,” said Fan, who was not part of the study.

Also weighing in, Olivera Bogunovic, MD, assistant professor of psychiatry, Harvard Medical School in Boston, said “although the results of the study were statistically significant they were modest.”

For now, Bogunovic said she would recommend mirtazapine “specifically for patients struggling additionally with anxiety and depression.”