COMP360 Psilocybin Shows Rapid, Durable Effect in TRD, With Steve Levine, MD

Following positive topline results from the phase 3 COMP006 trial, HCPLive spoke with Steve Levine, MD, chief patient officer of Compass Pathways, to contextualize the clinical relevance of COMP360 (synthetic psilocybin) for treatment-resistant depression (TRD).1,2

“One of the most striking things about the data we've just presented from our 05 and 06 studies is the rapidity of onset,” Levine told HCPLive. “In both cases, we were able to detect a clinically and statistically significant difference in MADRS reduction as of day 2, which is the first day after administration of COMP360. That is a rapidity of effect that we've never seen before.”

Levine said the rapid onset may reflect acute, network-level effects mediated through 5-HT2A receptor agonism. He noted that this mechanism appears distinct from those underlying currently available treatments for TRD.

In COMP006, two 25-mg doses of COMP360 administered 3 weeks apart demonstrated a –3.8-point least squares mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6 compared with a 1-mg control (P <.001). According to Levine, a 3-point MADRS difference is generally considered clinically meaningful in TRD, placing the 3.8-point separation above the accepted threshold for relevance.

He noted that the magnitude of effect is comparable to that observed in pivotal trials of esketamine (Spravato), currently the only FDA-approved medication specifically indicated for TRD. However, whereas esketamine’s approximately 4-point treatment difference was achieved after multiple administrations over 4 weeks, COMP360 demonstrated a similar effect size 6 weeks after a single administration in COMP005 and after 2 administrations in COMP006.

In Part B of COMP005, participants who achieved ≥ 25% reduction in MADRS at week 6 and received a second treatment demonstrated sustained benefit through week 26. Among those with an initial clinically meaningful response who underwent re-treatment, approximately 40% achieved remission. These findings suggest that 1 or 2 administrations may support symptom improvement lasting up to 6 months in responders.

Furthermore, in COMP005, 25% of participants receiving 25 mg achieved a ≥ 25% MADRS reduction versus placebo. In COMP006, 39% reached this threshold after a second administration.

“This is a level of improvement that is very likely to translate into really meaningful benefit for patients, particularly those who have treatment-resistant depression,” Levine said. “Even modest decreases in symptoms can have an outsized impact on the course of their care and the quality of their life.”

A relevant disclosure for Levine includes Janssen Pharmaceuticals, Inc.

References

1. Compass Pathways Successfully Achieves Primary Endpoint in Second Phase 3 Trial Evaluating COMP360 Psilocybin for Treatment-Resistant Depression. Compass Pathways. Published on February 17, 2026. Accessed on February 19, 2026. https://ir.compasspathways.com/News--Events-/news/news-details/2026/Compass-Pathways-Successfully-Achieves-Primary-Endpoint-in-Second-Phase-3-Trial-Evaluating-COMP360-Psilocybin-for-Treatment-Resistant-Depression/default.aspx

2. Derman C. COMP360 Psilocybin Meets Primary Endpoint in Second Phase 3 Trial for TRD. HCPLive. Published on February 19, 2026. Accessed on February 20, 2026. https://www.hcplive.com/view/comp360-psilocybin-meets-primary-endpoint-second-phase-3-trial-trd