Psilocybin for Depression: Compass Pathways Shares Phase 3 Results

Big industry news as Compass Pathways announces the first results from its Phase 3 clinical trial evaluating synthetic psilocybin for treatment-resistant depression (TRD). The industry and psychedelic medicine advocates have been waiting for these results, as this is the first-ever psilocybin for depression trial to release Phase 3 efficacy data — an important moment for both the company and the psychedelic medicine industry.

Psilocybin for Depression Trial Has Been Years In The Making

Compass Pathways received Breakthrough Therapy designation from the FDA in 2018 for its investigational psilocybin therapy, COMP360, signaling early promise for treatment-resistant depression (TRD). In 2021, Compass completed a landmark Phase 2b trial — the largest study of psilocybin therapy ever conducted. The results showed a rapid and meaningful reduction in depressive symptoms, however, the study also raised some questions. In response, Compass adjusted the design of its Phase 3 trials to address these concerns, including extended follow-up periods and multiple dosing strategies to better assess long-term outcomes.

After last year’s disappointing rejection by the FDA of MAPS’ (Lykos Therapeutics) application of MDMA for PTSD, the sector was anxiously awaiting the results from Compass’ Phase 3 trial. 

Results From Compass’ Phase 3 Depression Trial 

The trial, known as COMP005, assessed the impact of a single 25 mg dose of COMP360 in 258 participants across 32 sites in the U.S. (COMP360 is Compass Pathways’ proprietary form of synthetic psilocybin).

• Compared to placebo, patients who received COMP360 showed a “statistically significant and clinically meaningful improvement in depression symptoms at six weeks”, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Specifically, the psilocybin group had a mean reduction in MADRS scores of 3.6 points greater than the placebo group. This result met the trial’s primary endpoint (the stated main objective of the trial).

• The study’s safety profile was also encouraging. The independent Data Safety Monitoring Board (DSMB) reviewed ongoing data from both the COMP005 and the other COMP006 trials and reported no new or unexpected safety concerns. There was also no clinically meaningful differences in suicidal ideation between the treatment and placebo groups. This is a crucial validation for the study, given concerns around mental health vulnerabilities in study populations.

“The positive top-line results at week 6 from the COMP005 trial underscore the innovative potential of psilocybin treatment in mental health care for which Compass Pathways continues to pave the way,” said Kabir Nath, Chief Executive Officer of Compass Pathways. 

The COMP360 Phase 3 program includes two pivotal studies: COMP005 and COMP006. The recently reported COMP005 trial and second trial, COMP006, which is much larger in scope. The COMP006 trial is enrolling participants across 96 sites in North America and Europe and will involve more than twice the number of participants as COMP005. 9-week and 26-week marks.

“We eagerly anticipate further insights once we have the full dataset, and also look forward to findings from COMP006, which will explore the efficacy of two fixed doses. We remain focused on our goal of transforming the landscape of mental health treatment,” Mr. Nath continued.

Market Reaction: Investors Cautious, Analysts Still Optimistic

While Compass Pathways touted the Phase 3 results as both “highly statistically significant” and “clinically meaningful,” the stock market reacted with skepticism. Following the announcement, Compass shares dropped by more than 30%, reflecting investor disappointment. This reaction echoes the response to the company’s 2021 Phase 2b results, which, though encouraging, were not seen as groundbreaking. The muted enthusiasm highlights the high bar investors have set for psychedelic-based treatments — particularly those still classified as illegal or controlled substances. For many, only dramatic reductions in depression scores may justify confidence in future FDA approval.

However, several Wall Street analysts adopted a more measured perspective. They noted that the results align with expectations for the first part of a multi-phase program and maintained their price targets. Analysts remain optimistic, pointing to the upcoming COMP006 data as potentially more definitive and critical for gauging COMP360’s long-term efficacy and commercial viability.

Investors and industry will have to wait until 2026 for more Phase 3 data and real view on the chances of FDA approval. While further data is needed, these initial findings have given renewed hope to patients, clinicians, and investors alike. If successful, COMP360 could become the first FDA-approved psilocybin therapy, signaling a shift toward integrating psychedelics into mainstream psychiatric care.