Trial of Psilocybin versus Escitalopram for Depression

N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994.

Abstract

Background: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.

Methods: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.

Results: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.

Conclusions: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.).

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / therapeutic use*
  • Antidepressive Agents, Second-Generation / adverse effects
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Citalopram / adverse effects
  • Citalopram / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Double-Blind Method
  • Female
  • Hallucinogens / adverse effects
  • Hallucinogens / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Psilocybin / adverse effects
  • Psilocybin / therapeutic use*
  • Self Report
  • Surveys and Questionnaires
  • Young Adult

Substances

  • Antidepressive Agents
  • Antidepressive Agents, Second-Generation
  • Hallucinogens
  • Citalopram
  • Psilocybin

Associated data

  • ClinicalTrials.gov/NCT03429075