For the first time in history, a psychedelic compound is entering Phase 3 clinical trials. Compass Pathways has announced it will launch the world’s first Phase 3 trial of psilocybin therapy for treatment-resistant depression by the end of 2022 C.E., enrolling nearly 1,000 participants across two pivotal studies and a long-term follow-up — a milestone that could bring a new class of treatment to patients who have run out of options.
At a glance
- Psilocybin therapy: The Phase 3 program follows Compass Pathways’ Phase 2B results, which showed statistically significant improvements in depression scores after a single 25 mg psilocybin dose in 233 patients with treatment-resistant depression.
- Treatment-resistant depression: Both Phase 3 trials focus exclusively on patients whose depression has not responded to antidepressants or psychotherapy — a population with very few remaining clinical options.
- FDA approval timeline: Compass expects first data from the initial trial in late 2024 C.E. and is targeting an FDA approval application as early as 2025 C.E.
Why this moment matters
The psychedelic research field has generated enormous attention over the past decade, but the excitement has outpaced the clinical evidence. Nearly all studies have remained at Phase 1 or Phase 2 — early-stage trials designed to test safety and initial efficacy in small groups. Phase 3 is the rigorous, large-scale standard required before a drug can be approved for medical use.
That changes now. Moving psilocybin into Phase 3 is not a symbolic step — it is the threshold between promising research and potential medicine.
For the estimated 100 million people worldwide living with depression that doesn’t respond to standard treatments, this matters urgently. Current options for treatment-resistant depression are limited, often invasive, and inconsistently effective. A new tool — especially one that may work after just one or two doses — could represent a genuine shift in care.
How the trials are designed
The Phase 3 program has three parts. The first trial, called Pivotal 1, will enroll 378 participants and compare a single 25 mg psilocybin dose against a placebo. The second trial, Pivotal 2, will enroll 568 participants and explore whether a second dose — given three weeks after the first — improves outcomes, using the same three-dose structure (25 mg, 10 mg, and 1 mg) as the Phase 2B study. Both trials will measure results on the Montgomery–Åsberg Depression Rating Scale six weeks after the first dose.
All participants receive psychological support: three preparation sessions, supervised monitoring on the day of dosing for six to eight hours, and two integration sessions afterward. This is a more streamlined protocol than some other psychedelic-assisted therapy models, but it reflects Compass’s goal of designing something that could scale within existing healthcare systems.
What the Phase 2B results showed — and where caution applies
The Phase 2B trial gave Compass enough evidence to move forward, but it also raised questions that Phase 3 must answer. Among participants in the 25 mg group, 6.3% experienced serious adverse events during the 12-week follow-up, including suicidal ideation and behavior. Compass noted that only one of those 12 serious adverse events occurred within 24 hours of dosing — the rest occurred up to 62 days later — making the causal link to psilocybin unclear. Still, it is a signal that requires careful monitoring at larger scale.
There is also the question of trial blinding. Because the psychedelic experience is unmistakable, participants in both the active and placebo arms will likely know which group they’re in — a limitation that could inflate the apparent difference between groups. Compass’s chief medical officer Guy Goodwin acknowledged this to New Atlas, framing the placebo design as necessary to establish a clear safety profile rather than to achieve perfect blinding.
A cautious but genuine leap forward
It is worth being clear about what Phase 3 does and doesn’t mean. A successful result would not make psilocybin freely available — it would make it an FDA-authorized medicine, prescribed and administered in clinical settings, initially for a specific and severe patient population. That is a meaningful but bounded outcome.
It also doesn’t resolve every open question about long-term use. Goodwin has suggested some patients might need two to three doses per year to maintain improvements, but that estimate lacks clinical evidence yet. Longer-term follow-up data on psilocybin’s durability is still sparse, and Phase 3 will begin to fill that gap.
What’s undeniable is the symbolic and scientific weight of the moment. Psilocybin — a compound used in Indigenous ceremonial contexts across Mesoamerican and other traditions for thousands of years, then stigmatized and legally suppressed for decades — is now being evaluated in the most rigorous clinical setting medicine has. That is not a small thing.
If the data holds, this trial could deliver the first new category of depression treatment in a generation — one that works not by daily chemical maintenance, but by catalyzing change in a small number of guided sessions. For people who have exhausted every other option, that possibility is worth following closely.
The full Phase 3 program design is available from Compass Pathways directly.
Read more
For more on this story, see: New Atlas
For more from Good News for Humankind, see:
- Alzheimer’s risk cut in half by drug in landmark prevention trial
- Ghana establishes a major new marine protected area at Cape Three Points
- The Good News for Humankind archive on mental health
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