Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review

Psychopharmacology (Berl). 2022 Jun;239(6):1945-1976. doi: 10.1007/s00213-022-06083-y. Epub 2022 Mar 7.


Rationale & objectives: ± 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration's phased drug development process for psychiatric treatment indications: posttraumatic stress disorder and depression, respectively. The current standard of care for these disorders involves treatment with psychiatric medications (e.g., selective serotonin reuptake inhibitors), so it will be important to understand drug-drug interactions between MDMA or psilocybin and psychiatric medications.

Methods: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the MEDLINE database via PubMed for publications of human studies in English spanning between the first synthesis of psilocybin (1958) and December 2020. We used 163 search terms containing 22 psychiatric medication classes, 135 specific psychiatric medications, and 6 terms describing MDMA or psilocybin.

Results: Forty publications were included in our systematic review: 26 reporting outcomes from randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports. Publications of studies describe interactions between MDMA (N = 24) or psilocybin (N = 5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants. We focus our results on pharmacodynamic, physiological, and subjective outcomes of drug-drug interactions.

Conclusions: As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drug-drug interactions with MDMA or psilocybin.

Keywords: Depression; Drug interactions; Hallucinogens; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Psychopharmacology; Serotonin uptake inhibitors; Stress disorders, Post-traumatic.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Drug Interactions
  • Hallucinogens* / pharmacology
  • Hallucinogens* / therapeutic use
  • Humans
  • N-Methyl-3,4-methylenedioxyamphetamine* / pharmacology
  • Psilocybin / adverse effects
  • Psychotherapy / methods
  • Stress Disorders, Post-Traumatic* / psychology


  • Hallucinogens
  • Psilocybin
  • N-Methyl-3,4-methylenedioxyamphetamine