Psilocybin Efficacy and Mechanisms of Action in Major Depressive Disorder: a Review

Curr Psychiatry Rep. 2022 Oct;24(10):573-581. doi: 10.1007/s11920-022-01361-0. Epub 2022 Aug 12.


Purpose of the review: We aim to provide an overview of the current state of knowledge about the efficacy of psilocybin in the treatment of depression, as well as its mechanisms of action.

Recent findings: Psilocybin has a large, rapid, and persistent clinical effect in the treatment of resistant or end-of-life depression. Tolerance is good, with mild side effects limited to a few hours after dosing. The studies conducted to date have had small sample sizes. One clinical trial has been conducted against a reference treatment (escitalopram) without showing a significant superiority of psilocybin in the main outcome. The neurobiological mechanisms, mostly unknown, differ from those of SSRI antidepressants. Psilocybin represents a promising alternative in the treatment of depression. Further research with larger sample sizes, particularly against reference treatments, is needed to better understand the neurobiological factors of its effects and to investigate its potential for use in everyday practice.

Keywords: 5-HT2A agonists; Hallucinogen; Mood disorder; Narrative review; Neuroimaging; Psychedelic.

Publication types

  • Review

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major* / drug therapy
  • Hallucinogens* / adverse effects
  • Humans
  • Psilocybin / pharmacology
  • Psilocybin / therapeutic use


  • Antidepressive Agents
  • Hallucinogens
  • Psilocybin