For decades, successive waves of antidepressants have promised relief to millions suffering from mood disorders. And while many psychiatrists find clinical utility across a range of treatment options, the process for patients who don’t respond often remains what it has been since the SSRI era began: try one drug, wait weeks, and if it doesn’t work, try the next. For the roughly 4 million Americans whose depression resists two or more treatments, that cycle can stretch for years.
Pioneering research at Johns Hopkins, beginning with Roland Griffiths’ landmark 2006 psilocybin study, helped spark interest in psychedelics as a fundamentally different approach, one that might break the cycle with a single transformative experience rather than daily medication. Small trials produced striking results. Investors poured in. The FDA granted breakthrough therapy designation. But Phase 3 data, the gold standard required for approval, remained elusive. The wellspring of interest also heightened attention in MDMA, also known as ecstasy for its potential in post-traumatic stress disorder. But then in August 2024, the FDA rejected Lykos Therapeutics’ bid to make MDMA-assisted therapy a legitimate option for PTSD. The regulators cited trial design concerns and demanding a third pivotal study.
Now the first Phase 3 psilocybin data is in. On February 17, Compass Pathways reported that both of its pivotal trials for COMP360 psilocybin in treatment-resistant depression met their primary endpoints — results positive enough to send the company’s stock surging and prompt plans for an NDA filing by year’s end. But the numbers underneath the headline tell a more complicated story: modest effect sizes, a non-standard response threshold, and undisclosed remission rates that raise a pointed question for patients, clinicians and payers alike. Is psilocybin meaningfully better than what we already have?
Compass Pathways (Nasdaq: CMPS) on Feb. 17 reported that its second pivotal trial, COMP006, met its primary endpoint, making COMP360 the first classic psychedelic to produce two positive Phase 3 results. The multi-dose trial enrolled 581 participants across North America and Europe and tested two fixed 25 mg doses of its synthetic psilocybin, administered three weeks apart, against 10 mg and 1 mg comparator arms. At Week 6, the 25 mg group showed a mean treatment difference of -3.8 points on the Montgomery-Åsberg Depression Rating Scale versus the 1 mg group (p<0.001). Compass said 39% of participants on the high dose achieved what the company defines as a clinically meaningful MADRS reduction of at least 25%, a lower bar than the 50% threshold typically used to define response in antidepressant trials.
The results echo the company’s first Phase 3 trial, COMP005, reported in June 2025, which tested a single 25 mg dose against placebo in 258 U.S. participants and produced a similar separation of -3.6 MADRS points (p<0.001). In that trial, 25% of participants in the active arm met the same 25% response threshold at Week 6. Compass has not disclosed remission rates for either Phase 3 study. By comparison, the company’s earlier Phase 2b trial, published in the New England Journal of Medicine, showed a 37% response rate at three weeks using the standard 50% MADRS reduction cutoff, but that figure fell to 20% by 12 weeks.
Across more than 800 dosed participants in both Phase 3 trials, the company reported a generally favorable safety profile. Most adverse events, headache, nausea and visual hallucinations, were mild to moderate and resolved within 24 hours. Serious adverse events involving suicidal ideation occurred at a rate below 1%, and an independent safety monitoring board found no clinically meaningful imbalance in suicidality between treatment and control arms. There was one case of suicidal behavior, which occurred in the 1 mg arm of COMP006.
Shares surged as much as 50% in early trading before settling around 34% higher, with the stock trading near $7.66 after closing at $5.81 the prior session. Compass said it has requested a meeting with the FDA to discuss a rolling submission and review, with a New Drug Application targeted for the fourth quarter. Longer-term durability data from COMP006, tracking outcomes through 26 weeks,is expected in early Q3 2026.
Filed Under: Psychiatric/psychotropic drugs
