Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: Evidence from the bench and the bedside

Steven M. Graves, Roueen Rafeyan, Jeffrey Watts, T. Celeste Napier

Research output: Contribution to journalReview articlepeer-review

33 Scopus citations


Understanding substance use disorders (SUDs) and the problems associated with abstinence has grown in recent years. Nonetheless, highly efficacious treatment targeting relapse prevention has remained elusive, and there remains no FDA-approved pharmacotherapy for psychostimulant dependence. Preclinical and clinical investigations assessing the utility of classical antidepressants, which block monoamine reuptake, show mixed and often contradictory results. Mirtazapine (Remeron®) is a unique FDA-approved antidepressant, with negligible affinity for reuptake proteins, indirectly augments monoamine transmission presumably through antagonist activity at multiple receptors including the norepinephrine (NE)α2, and serotonin (5-HT) 2A/C receptors. Historically, mirtazapine was also considered to be a 5-HT2C antagonist, but recent evidence indicates that mirtazapine is an inverse agonist at this receptor subtype. Suggesting a promising role for mixed-action serotonergic drugs for addiction pharmacotherapy, mirtazapine attenuates psychostimulant-induced behaviors in several rodent models of substance abuse, and antagonizes methamphetamine-induced biochemical and electrophysiological alterations in rats. Preclinical findings are confirmed through published case studies documenting successful outcomes with mirtazapine therapy across a number of SUDs. To date, a large scale clinical trial assessing the utility of mirtazapine in substance abuse pharmacotherapy has yet to be conducted. However, as reviewed here, accumulating preclinical and clinical evidence argues that mirtazapine, or compounds that emulate aspects of its pharmacological profile, may prove useful in helping treat addictions.

Original languageEnglish (US)
Pages (from-to)343-353
Number of pages11
JournalPharmacology and Therapeutics
Issue number3
StatePublished - Dec 2012
Externally publishedYes

Bibliographical note

Funding Information:
Work reported in this review was supported by USPHSGs R01 DA015760 and F31 DA024923 , and the Daniel F. and Ada L. Rice Foundation . The authors thank the Program Officer of our R01, Dr. Nathanial Appel for his insightful discussions on this topic throughout the life of the project. The authors also wish to thank Dr. Kathryn Cunningham for her valuable discussions.


  • Atypical antidepressant
  • Cue reactivity
  • Methamphetamine
  • Methamphetamine-seeking
  • Self-administration
  • Serotonin


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