Psilocybin Therapy Clears Second Phase 3 Trial for Treatment-Resistant Depression

A second successful Phase 3 trial has brought psilocybin-assisted therapy to the threshold of regulatory approval for one of psychiatry's most intractable conditions.

Compass Pathways announced this week that COMP360, a synthetic psilocybin administered alongside psychological support, met its primary endpoint in a large-scale trial of patients with treatment-resistant depression — people for whom at least two conventional antidepressants have failed.

Patients receiving COMP360 showed significantly greater improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) at six weeks compared to those receiving a control. The result replicates findings from the company's first Phase 3 trial, providing the kind of consistent evidence regulators require before granting approval.

The scale of the unmet need is staggering. Treatment-resistant depression affects an estimated 100 million people worldwide. Current options — electroconvulsive therapy, ketamine infusions, deep brain stimulation — are either invasive, expensive, or inconsistently effective. For many patients, the reality is a revolving door of medications that don't work, side effects that compound suffering, and a medical system that has largely run out of ideas.

A single-dose psilocybin session with trained therapists represents a fundamentally different model: brief, experiential, and potentially long-lasting. Unlike daily antidepressants, the treatment is administered once in a supervised clinical setting, with preparatory and follow-up psychological support sessions.

The science behind psilocybin's therapeutic effects is still being elucidated, but brain imaging studies at Imperial College London and Johns Hopkins have shown that psilocybin temporarily disrupts the brain's default mode network — a set of interconnected regions associated with self-referential thinking and rumination. In depression, this network often becomes hyperactive, creating rigid patterns of negative thought. Psilocybin appears to loosen these patterns, creating a window of neuroplasticity during which therapy can be particularly effective.

The path from here is regulatory submission, likely to both the FDA and EMA. Compass Pathways holds breakthrough therapy designation from the FDA, which provides an expedited review pathway. If approved, COMP360 would become the first psychedelic therapy licensed for a major psychiatric condition — a moment that would have seemed unimaginable a decade ago, when psilocybin research was confined to a handful of academic centres operating under heavy restrictions.

The broader psychedelic medicine landscape provides both encouragement and caution. MDMA-assisted therapy for PTSD showed impressive trial results but was rejected by the FDA in 2024 when Lykos Therapeutics' application raised methodological concerns about trial blinding and data integrity. That setback demonstrated that even promising psychedelic therapies face a high regulatory bar — and that the quality of trial design matters as much as the results themselves.

For Compass Pathways, the fact that two independent Phase 3 trials have now produced consistent results is precisely the kind of replication that addresses regulatory scrutiny. It is the strongest evidence base any psychedelic therapy has assembled to date.

Key Facts

• COMP360 met its primary endpoint in a second Phase 3 trial, replicating results from the first
• Treatment-resistant depression is defined as failure of two or more antidepressant treatments
• Primary measure: Montgomery-Åsberg Depression Rating Scale (MADRS) at week 6
• Compass Pathways holds breakthrough therapy designation from the FDA
• An estimated 30% of depression cases are treatment-resistant (WHO)
• An estimated 100 million people worldwide live with treatment-resistant depression

Why This Matters

This isn't just about one company's drug trial. A successful psilocybin approval would validate an entirely new class of psychiatric treatment — one based on guided, transformative experiences rather than daily medication. It would likely accelerate investment in psychedelic therapies for conditions ranging from PTSD to anorexia to end-of-life anxiety.

More fundamentally, it would offer hope to millions of people trapped in a treatment paradigm that has failed them. For someone who has tried five, six, seven antidepressants without relief, the promise of a single therapeutic session that could shift the trajectory of their illness is not abstract — it's the difference between a life defined by depression and one that isn't.

What We Don't Know Yet

Full trial data have not yet been published in a peer-reviewed journal. The announcement is based on a company press release, and independent analysis of the methodology, effect sizes, and adverse event profiles will be essential.

The therapy requires trained facilitators and controlled clinical settings. Even if approved, scaling access will be a major challenge — there are currently far more patients who need this treatment than there are trained therapists to deliver it.

Long-term safety and durability data beyond six months remain limited. How long the benefits last, how many patients relapse, and whether repeat dosing is safe are open questions.

And regulatory approval is not guaranteed. The FDA's rejection of Lykos Therapeutics' MDMA therapy in 2024 demonstrated that promising results don't automatically translate to market access.

Sources: Compass Pathways · Psychiatric Times
Published 21 February 2026 · Category: Health & Medicine