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Original Investigation
December 11, 2019

Effects of Mirtazapine for Methamphetamine Use Disorder Among Cisgender Men and Transgender Women Who Have Sex With Men: A Placebo-Controlled Randomized Clinical Trial

Author Affiliations
  • 1San Francisco Department of Public Health, San Francisco, California
  • 2Department of Medicine, University of California, San Francisco, San Francisco
  • 3School of Nursing, University of California, San Francisco, San Francisco
  • 4Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco
  • 5Department of Psychiatry, University of California, San Francisco, San Francisco
JAMA Psychiatry. Published online December 11, 2019. doi:10.1001/jamapsychiatry.2019.3655
Key Points

Question  Does treatment with mirtazapine reduce the use of methamphetamine and sexual HIV risk behaviors among cisgender men and transgender women who have sex with men?

Findings  In this analysis, mirtazapine reduced the use of methamphetamine over 24 weeks of treatment and 12 weeks of follow-up after treatment was concluded. Mirtazapine also reduced several sexual HIV risk behaviors; both findings were consistent with a previous study.

Meaning  Mirtazapine is the first medication to demonstrate efficacy in treating methamphetamine use disorder in 2 independent randomized clinical trials.


Importance  Methamphetamine use is increasingly prevalent and associated with HIV transmission. A previous phase 2a study of mirtazapine demonstrated reductions in methamphetamine use and sexual risk behaviors among men who have sex with men.

Objective  To determine the efficacy of mirtazapine for treatment of methamphetamine use disorder and reduction in HIV risk behaviors.

Design, Setting, and Participants  This double-blind randomized clinical trial of mirtazapine vs placebo took place from August 2013 to September 2017 in an outpatient research clinic in San Francisco, California. Participants were community-recruited adults who were sexually active; cisgender men, transgender men, and transgender women who (1) had sex with men, (2) had methamphetamine use disorder, and (3) were actively using methamphetamine were eligible. Participants were randomized to receive the study drug or placebo for 24 weeks, with 12 more weeks of follow-up. Data analysis took place from February to June 2018.

Exposures  Mirtazapine, 30 mg, or matched placebo orally once daily for 24 weeks, with background counseling.

Main Outcomes and Measures  Positive urine test results for methamphetamine over 12, 24, and 36 weeks (primary outcomes) and sexual risk behaviors (secondary outcomes). Sleep, methamphetamine craving, dependence severity, and adverse events were assessed.

Results  Of 241 persons assessed, 120 were enrolled (5 transgender women and 115 cisgender men). The mean (SD) age was 43.3 (9.8) years; 61 (50.8%) were white, 31 (25.8%) were African American, and 15 (12.5%) were Latinx. A mean (SD) of 66% (47%) of visits were completed overall. By week 12, the rate of methamphetamine-positive urine test results significantly declined among participants randomized to mirtazapine vs placebo (risk ratio [RR], 0.67 [95% CI, 0.51-0.87]). Mirtazapine resulted in reductions in positive urine test results at 24 weeks (RR, 0.75 [95% CI, 0.56-1.00]) and 36 weeks (RR, 0.73 [95% CI, 0.57-0.96]) vs placebo. Mean (SD) medication adherence by WisePill dispenser was 38.5% (27.0%) in the mirtazapine group vs 39.5% (26.2%) in the placebo group (P = .77) over 2 to 12 weeks and 28.1% (23.4%) vs 38.5% (27.0%) (P = .59) over 13 to 24 weeks. Changes in sexual risk behaviors were not significantly different by study arm at 12 weeks, but those assigned to receive mirtazapine had fewer sexual partners (RR, 0.52 [95% CI, 0.27-0.97]; P = .04), fewer episodes of condomless anal sex with partners who were serodiscordant (RR, 0.47 [95% CI, 0.23-0.97]; P = .04), and fewer episodes of condomless receptive anal sex with partners who were serodiscordant (RR, 0.37 [95% CI, 0.14-0.93]; P = .04) at week 24. Participants assigned to mirtazapine had net reductions in depressive symptoms (Center for Epidemiologic Studies Depression Scale score, 6.2 [95% CI, 1.3-11.1] points lower; P = .01) and insomnia severity (Athens score, 1.4 [95% CI, 0.1-2.7] points lower; P = .04) at week 24. There were no serious adverse events associated with the study drug.

Conclusions and Relevance  In this expanded replication trial, adding mirtazapine to substance use counseling reduced methamphetamine use and some HIV risk behaviors among cisgender men and transgender women who have sex with men, with benefits extending after treatment despite suboptimal medication adherence.

Trial Registration  ClinicalTrials.gov identifier: NCT01888835.

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    1 Comment for this article
    Data inconsistency, table-header confusion
    Daniel Bloch, MD, FASAM | PrimaryOne Health (Federally-Qualified Health Center)
    Figure 1 shows 241 subjects assessed for eligibility, 153 excluded, 120 randomized; those numbers don't add up
    Table 2 would be easier to understand if the column-2 header were rewritten for each section.
    For example, the first section (Primary Outcomes) could say "Risk Ratio", the second section (Secondary Outcomes) could say "Coefficient", and so forth
    The continuation of Table 2 on page 6 was especially confusing because the header was duplicated as "Risk Ratio or Coefficient" and the true outcome ("No.(%)") was less prominent
    That said, the findings are provocative and give hope for a treatment for this difficult problem.