Mirtazapine for Methamphetamine Use Disorder

"In this randomized clinical trial, people with methamphetamine use disorder had a mean reduction of 7 days (out of 28 days) after 12 weeks of mirtazapine (30 mg/day) treatment, which was approximately 2 days more than the reduction seen with placebo. In this trial, we confirm the preliminary observed benefits of mirtazapine from phase 2 trials and generalize these to routine clinical practice and a broader population of people with methamphetamine use disorder. We did not find any unexpected safety concerns associated with prescribing mirtazapine to people with methamphetamine use disorder, although participants receiving mirtazapine reported more drowsiness (47% vs 33%) and weight gain (10% vs 3%).

"The clinical significance of these findings lies in identifying a safe and cheap generic medication that can be prescribed to help people reduce methamphetamine use. The well-established safety profile of mirtazapine means it can be easily and safely prescribed in an outpatient setting with limited clinical oversight. Other pharmacotherapy agents under investigation (eg, high-dose prescription stimulant medications,²⁵ long-acting opioid antagonists⁶) are usually prescribed by addiction medicine specialists and require close clinical supervision to manage potential risks (eg, overdose, toxicity, and abuse liability). The potential of mirtazapine for broader application addresses questions of accessibility and scalability inherent to other agents under investigation.

"The impact of mirtazapine on methamphetamine use in routine clinical practice appeared diluted compared to the previous phase 2 trials.⁷ We found an 8% reduction in the risk of using methamphetamine on a given day compared to a 14% reduction in the risk of a methamphetamine-positive urine test in the previous phase 2 trials.⁷ However, in the absence of an approved pharmacotherapy, any leverage on improving clinical outcomes for methamphetamine use disorder is critical. Reductions in days of methamphetamine use impacts positively on functional outcomes²⁶ and reduces the risk of methamphetamine-related psychotic symptoms²⁷ and violent behavior.²⁸ We also found preliminary evidence of benefits for insomnia among people with co-occurring depression, supporting the findings of the previous phase 2 trial by Coffin and colleagues.¹³

"Consistent with the previous phase 2 trials of mirtazapine on methamphetamine use disorder,^12,13 we found that reductions in methamphetamine use were not contingent on improvements in depression or insomnia. This finding implies that mirtazapine has a direct effect on addictive processes, consistent with animal models of addiction⁹ and human preclinical research.⁸ The neural mechanism behind this interaction is not known; however, mirtazapine has a high antagonism affinity for 5-HT_2A receptors, and antagonizing these receptors has been found to attenuate the rewarding properties of methamphetamine.^29,30 Mirtazapine also enhances monoamine signaling, and this may help correct the downregulation of dopamine function seen following chronic methamphetamine use.⁹"