Investigational Psilocybin for PTSD and Ongoing Trials

Gary Small, MD, discussed recent developments in psychedelic therapies for posttraumatic stress disorder (PTSD), with a focus on psilocybin-based treatments under investigation by Compass Pathways.¹ Small noted that Compass Pathways has received Investigational New Drug application acceptance by the US Food and Drug Administration to proceed with clinical trials of COMP360, a proprietary psilocybin formulation, for PTSD. PTSD was emphasized to affect millions of individuals in the United States and to represent a major area of unmet clinical need, with no disorder-specific pharmacologic treatments currently approved.

Small summarized findings from a phase 2, 12-week open-label study evaluating the safety and preliminary efficacy of a single 25-mg dose of psilocybin in individuals with PTSD.² The primary endpoint was safety of the drug, which was demonstrated to be favorable, with good tolerability and no unexpected adverse events. Secondary analyses suggested significant symptom improvement; however, Small emphasized that efficacy conclusions were limited by the open-label design. He described the results as reassuring and supportive of progression to larger, randomized, blinded trials.

He further outlined the design of subsequent phase 2b/3 studies, which included a 12-week blinded component followed by a 40-week unblinded extension. This design was intended to provide more rigorous data on efficacy as well as longer-term safety and durability of response. Additional blinded studies in PTSD were cited as having demonstrated both safety and efficacy signals.

Small highlighted the substantial burden of PTSD, particularly among veterans and individuals exposed to trauma, noting associated symptoms such as nightmares, avoidance, depression, and suicidality. He also discussed diagnostic complexity in veteran populations, where traumatic brain injury and chronic traumatic encephalopathy may present with symptoms overlapping with PTSD.

The treatment protocol described relied primarily on psychoeducation and close monitoring rather than intensive psychotherapy, which raised important questions about the active mechanisms of psilocybin and the optimal level of psychotherapeutic support. Small emphasized the need for future research to clarify biological versus experiential mechanisms, refine adjunctive psychotherapy models, and improve accessibility while maintaining safety and effectiveness.

Dr Small is the director of Breakthrough Health Behavioral Therapies at Hackensack Meridian Health, and a professor of psychiatry and behavioral health at the Hackensack Meridian School of Medicine.

References

1. Duerr HA. FDA accepts Investigational New Drug Application for COMP360 for PTSD. Psychiatric Times. January 6, 2026. https://www.psychiatrictimes.com/view/fda-accepts-investigational-new-drug-application-for-comp360-for-ptsd

2. Duerr HA. Phase 2 study of COMP360 psilocybin finds improved PTSD symptoms. Psychiatric Times. https://www.psychiatrictimes.com/view/phase2-study-of-comp360-psilocybin-finds-improved-ptsd-symptoms