Psilocybin Clears Second Phase 3 Trial for Treatment-Resistant Depression: FDA Submission Planned

What Is COMP360 and How Does It Work?

COMP360, developed by Compass Pathways, is a proprietary crystalline polymorph (pCybin) formulation of psilocybin — the psychoactive compound found naturally in certain mushroom species. Unlike recreational psilocybin, COMP360 is manufactured to pharmaceutical standards with precise dosing and consistency. The therapy involves two 25 mg oral doses administered in supervised clinical sessions, during which patients are supported by trained therapists in specially designed treatment rooms.

Psilocybin works primarily as a serotonin 5-HT2A receptor agonist, producing profound alterations in consciousness, perception, and emotional processing that typically last 4-6 hours. The therapeutic model hypothesizes that this acute psychedelic experience, combined with professional psychological support before, during, and after the sessions, can catalyze lasting changes in neural connectivity patterns and cognitive-emotional processing that underlie treatment-resistant depression.

Treatment-resistant depression (TRD) is defined as major depressive disorder that has not responded adequately to at least two different antidepressant medications taken at adequate doses for adequate durations. TRD affects approximately 30% of the estimated 280 million people worldwide living with depression, representing a massive unmet medical need. Current treatment options for TRD are limited and include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), esketamine nasal spray (Spravato), and various off-label medication combinations, all of which have significant limitations in terms of efficacy, tolerability, or accessibility.

What Did the Phase 3 Trial Results Show?

The COMP006 trial, the second of two pivotal Phase 3 studies, evaluated two fixed doses of COMP360 25 mg compared to a 1 mg control dose in patients with treatment-resistant depression. The primary endpoint measured the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. The MADRS is a 10-item clinician-rated scale that assesses the severity of depression symptoms including sadness, inner tension, sleep disturbance, appetite changes, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts, with total scores ranging from 0 to 60.

The results demonstrated a highly statistically significant advantage for the 25 mg dose over the 1 mg control, with a p-value of less than 0.001 and a clinically meaningful difference of 3.8 MADRS points. This followed the similarly positive results from the first Phase 3 trial (COMP005), making COMP360 the first psilocybin-based therapy to achieve positive results in two independent Phase 3 studies for any psychiatric indication.

Across both COMP005 and COMP006 trials, COMP360 demonstrated a generally well-tolerated safety profile. Treatment-emergent adverse events (TEAEs) were predominantly mild to moderate in severity, with the vast majority resolving within 24 hours of the dosing sessions. The most commonly reported TEAEs were headache, nausea, and visual hallucination — effects that are expected given the pharmacological mechanism of psilocybin. No new safety signals were identified in the COMP006 data compared to earlier studies.

What Does This Mean for Depression Treatment?

The positive results from both Phase 3 trials position COMP360 as a potential first-in-class psilocybin therapy for regulatory approval. Compass Pathways has announced plans to meet with the U.S. FDA to discuss a rolling New Drug Application (NDA) submission, with completion expected in the fourth quarter of 2026. If the FDA accepts and approves the application, COMP360 could become the first legally prescribed psilocybin medicine in the United States, marking a historic shift in the treatment of psychiatric disorders.

The potential approval of COMP360 comes at a time of growing recognition that current pharmacological approaches to depression are insufficient for many patients. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) — the mainstays of depression treatment — typically require 4-8 weeks to take effect, must be taken daily, carry side effects including sexual dysfunction and weight gain, and fail to produce adequate response in approximately one-third of patients. Psilocybin therapy, by contrast, involves only two dosing sessions and has shown durable effects lasting weeks to months after treatment.

However, significant questions remain about how psilocybin therapy would be implemented in clinical practice. The treatment requires specially trained therapists, dedicated treatment facilities, and extended monitoring during the 6-8 hour dosing sessions — a model that differs fundamentally from standard prescription medication. Issues of insurance coverage, therapist training and certification, patient selection criteria, and equitable access will need to be addressed before psilocybin therapy can be widely available. Despite the modest magnitude of the MADRS score difference noted by some analysts, the consistent statistical significance across both Phase 3 trials and the large unmet need in TRD suggest a pathway to approval.