Abstract
Monoamine oxidase inhibitors (MAOIs) remain an important option for patients with treatment-resistant depression (TRD) and other psychiatric conditions, despite potentially serious drug–drug interactions and associated dietary tyramine restrictions. However, they are rarely prescribed in patients with comorbid substance use disorders (SUDs) due to concerns about potential drug interactions and limited research in these populations. This narrative review investigates the use of MAOIs in patients who use psychoactive substances, exploring potential interactions while summarizing the relatively scant literature on using MAOIs as treatments for SUDs. It synthesizes data from 219 peer-reviewed publications investigating MAOI/psychoactive substance interactions or the use of MAOIs to treat SUDs or psychiatric conditions in patients with comorbid SUDs, including 20 randomized controlled trials, 18 non-randomized interventional trials, 32 observational studies/case series, 56 case reports, 85 preclinical studies, and 8 reviews, with publication years spanning from 1955 to 2025. Data from 28 non-peer-reviewed user-submitted reports from drug use/harm reduction forums are also included. Suspected cases of serotonin toxicity have been reported for MAOIs in combination with amphetamine, dextromethorphan, 3,4-methylenedioxymethamphetamine (MDMA), meperidine (pethidine), methadone, and tramadol. Hypertensive urgency/emergency has been reported for MAOIs in combination with alcohol (varieties containing significant amounts of tyramine), amphetamine, cocaine, dextroamphetamine, khat, methamphetamine, and psilocybin mushrooms. Other notable adverse events associated with MAOIs in combination with psychoactive substances include agitation (4-bromo-2,5-dimethoxyphenethylamine [2C-B] 5-methoxy-N,N-dimethyltryptamine [5-Meo-DMT]), N,N-dimethyltryptamine [DMT]), delirium/confusion (DMT, propoxyphene, and tramadol), edema (chlordiazepoxide), intracranial hemorrhage (amphetamine, khat, and methamphetamine), mania/psychosis (DMT), rhabdomyolysis (5-MeO-DMT, DMT, and propoxyphene), and sedation/stupor/loss of consciousness (amobarbital, amphetamine, cocaine, dextroamphetamine, and propoxyphene). Fatalities have been reported for MAOIs in combination with 5-MeO-DMT, amphetamine, dextroamphetamine, dextromethorphan (in overdose), MDMA, methamphetamine, meperidine, and tramadol (in overdose). Based on our findings, some substances, such as alcoholic beverages containing significant tyramine quantities (uncommon today), amphetamines, opioids with significant serotonergic reuptake inhibition, and some hallucinogens such as the empathogen/entactogen MDMA, can pose potentially fatal risks in combination with MAOIs. However, MAOI treatment of patients who use alcoholic beverages low in tyramine, caffeine, cannabis, nicotine, sedatives, some (primarily classic) hallucinogens, and some other substances can likely be appropriately managed with careful monitoring, although psychoactive substance dose and route of administration are important safety considerations. While there was initially hope MAOIs might effectively treat some SUDs, there are no robust human data to support their efficacy in this context. Given growing levels of substance use and an increasing number of novel illicit compounds being produced, more research on MAOI safety in patients with psychiatric conditions and comorbid psychoactive substance use/misuse is essential to determining their appropriateness in this complex patient population.
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B.S. Barnett holds stock in Atai Life Sciences N.V. and CB Therapeutics (options). He has served as an advisor for AbbVie, Cerebral, CB Therapeutics, Compass Pathways, GH Research, Janssen Pharmaceuticals, Livanova, and MindMed. He receives monetary compensation from DynaMed Plus (EBSCO Industries, Inc.) for editorial work and speaker’s fees from TD Cowen. Dr Barnett receives research support from Abbott Laboratories, Compass Pathways, MindMed, and Reunion Neuroscience. V. Van den Eynde has received consulting fees from PsychoTropical Research, NeuraWell Therapeutics, Aristo Pharma GmbH, and a speaker’s fee from the Flemish Psychiatric Association (donated to a charitable trust for monoamine oxidase inhibitor [MAOI] research). He has acquired a grant from Neon Healthcare for PsychoTropical Research and for the International MAOI Expert Group, and has stock options in NeuraWell Therapeutics. P.K. Gillman has equity interests in, and serves on the advisory board of, NeuraWell Therapeutics, the company holding the patent for a modified form of tranylcypromine. He has received a speaker’s fee from the Flemish Psychiatric Association (donated to a charitable trust for MAOI research). The other authors declare no potential conflicts of interest.
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B.S. Barnett conceptualized the study and provided critical revisions. G. Rached drafted the manuscript and conducted the literature review. A. Campana, D. Fiani, and C. Nguyen contributed to data extraction and synthesis. V. Van den Eynde and P.K. Gillman provided expert review of the pharmacological and safety content. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.
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Rached, G., Campana, A., Fiani, D. et al. Safety and Efficacy of Monoamine Oxidase Inhibitors in Patients Who Use Psychoactive Substances: Potential Drug Interactions and Substance Use Disorder Treatment Data. CNS Drugs 40, 359–417 (2026). https://doi.org/10.1007/s40263-025-01256-7
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DOI: https://doi.org/10.1007/s40263-025-01256-7