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Randomized Controlled Trial
. 2025 Sep 1:274:112769.
doi: 10.1016/j.drugalcdep.2025.112769. Epub 2025 Jun 24.

Mirtazapine reduces hypothetical methamphetamine demand in humans

Craig R Rush  1 , Glenn-Milo Santos  2 , Vanessa M McMahan  3 , Annie Fraser  3 , Jesse Clark  4 , Xochitl Luna Marti  3 , John E Walker  3 , Steve Shoptaw  5 , Phillip O Coffin  6
Affiliations
Randomized Controlled Trial

Mirtazapine reduces hypothetical methamphetamine demand in humans

Craig R Rush et al. Drug Alcohol Depend. .

Abstract

Background: Previous trials showed mirtazapine reduces methamphetamine use. The present study determined the influence of mirtazapine treatment on the acute effects of methamphetamine.

Methods: We conducted a placebo-controlled, crossover, double-blind trial to determine the pharmacodynamic effects of intravenous methamphetamine (0, 30mg) after 5 days of mirtazapine (0, 30mg/day) treatment. Healthy adults with moderate to severe methamphetamine use disorder who had a positive baseline urine test for methamphetamine were enrolled. The order of mirtazapine and placebo was randomly assigned, and participants received a methamphetamine infusion during each treatment condition. Acute effects of methamphetamine were assessed using a drug purchasing task, a subjective effect questionnaire, and cardiovascular indices.

Results: Fifteen (15) participants (10 cisgender males, 4 cisgender females, 1 transgender female) enrolled in the trial. Intravenous methamphetamine produced prototypical stimulant-like effects (e.g., hypothetical drug demand; increased ratings of Like Effect, heart rate, blood pressure) when participants were treated with placebo. Mirtazapine significantly decreased methamphetamine demand. The subjective and cardiovascular effects of methamphetamine were similar during mirtazapine and placebo treatment. Mirtazapine and infusions of methamphetamine, alone and combined, were well tolerated.

Conclusions: Mirtazapine reduced hypothetical drug demand and was well tolerated with saline or methamphetamine infusions. Considering these favorable findings, along with those from previous clinical trials, mirtazapine should continue to be tested as a putative pharmacotherapy for methamphetamine use disorder.

Keywords: Cardiovascular effects; Hypothetical drug demand; Methamphetamine; Mirtazapine; Subjective effects.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shoptaw was Editor-in Chief of this journal; Shoptaw receives clinical supplies for his research from: Alkermes, Indivior, and Gilead; Shoptaw consults for Clear Scientific. The author is a previous Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for this journal and was not involved in the editorial review or the decision to publish this article.

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