Mushroom Psilocybin Shows Promising Results for Treatment-Resistant Depression

Major depressive disorder affects approximately 10% of the general population in the United Kingdom, impairs patients’ lives, and is costly to society. Selective serotonin-reuptake inhibitors are first-line treatments for major depressive disorder; however, these drugs take several weeks to work and, in some patients, do not induce a response. Escitalopram, a selective serotonin-reuptake inhibitor, is representative of the currently used antidepressants in terms of safety and efficacy.

The psychedelic compound psilocybin is the phosphorylated ester of its metabolite, psilocin (4-OH-N,N-dimethyltryptamine). Psilocybin and psilocin occur naturally in the psychoactive psilocybe genus of mushrooms. As with other traditional psychedelic substances, the main effects of psilocin occur through serotonin 5-hydroxytryptamine type 2A (5-HT2A) receptor agonism, which is part of a pathway implicated in depression. Psilocybin showed promise as an adjunct to psychotherapy for mood disorders and addiction in the mid-20th century.

Promising results from psilocybin trial for treatment-resistant depression

Researchers at Trinity College Dublin have participated in the largest and most rigorous clinical trial to date of psilocybin, pointing to the possibility that COMP360 psilocybin with psychological support could be a beneficial therapeutic strategy for people with treatment-resistant depression (TRD).

Prompted by promising preliminary findings, this funded multi-centre, randomized, double-blind, phase 2b clinical trial was launched in 2018 to determine the safety and potential antidepressant effects of a single dose of COMP360 psilocybin (25mg or 10mg), compared to 1mg, with psychological support in people with TRD. The study was sponsored by COMPASS Pathways, a mental health company based in the UK, who also developed COMP360 — their proprietary formulation of synthetic psilocybin administered in conjunction with psychological support.

The trial, which included 233 people with TRD across 10 countries, including the Irish site at Tallaght University Hospital showed that patients who received a single dose of 25mg COMP360 psilocybin experienced a highly statistically and clinically significant rapid reduction in symptoms of depression compared to 1mg at 3 weeks (p<0.001). This offers hope that COMP360 psilocybin with psychological support could be an effective antidepressant treatment paradigm for some people with TRD, if proven effective and safe in larger studies. COMPASS Pathways will be running a larger phase 3 programme of COMP360 psilocybin therapy in TRD, which is on schedule to begin in 2022.


-25mg COMP360 psilocybin with psychological support led to a statistically and clinically significant reduction in symptoms of depression in people with TRD compared to 1mg at week 3.

-37% of people with TRD in the 25mg group met criteria for response at week 3 (≥50% decrease in depressive symptoms).

-Approximately 30% of people with TRD in the 25mg group met criteria for remission at week 3 (29.1%).

-20% of people with TRD in the 25mg group met criteria for sustained response at week 12.

COMP360 psilocybin was generally well-tolerated.

This is the largest and most rigorous clinical trial of psilocybin to date. It shows a promising antidepressant signal for 25 mg COMP360 psilocybin with psychological support and has paved the way for phase 3 clinical trials, which will determine whether it translates into a much-needed complementary treatment strategy in the psychiatry clinic.

Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. 


Guy M. Goodwin, Scott T. Aaronson, Oscar Alvarez, Peter C. Arden, Annie Baker, James C. Bennett, Catherine Bird, Renske E. Blom, Christine Brennan, Donna Brusch, Lisa Burke, Kete Campbell-Coker, Robin Carhart-Harris, (November 3, 2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine. Retrieved from : 

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