COMP360 Psilocybin in Treatment-Resistant Depression: Insights From Gus Alva, MD, DFAPA

Gus Alva, MD, discussed the current state of psychedelic research in psychiatry, with particular focus on the clinical trial program for COMP360 psilocybin by Compass Pathways in treatment-resistant depression (TRD), at the 2026 Southern California Psychiatry Conference.

Alva framed the emergence of psychedelic research as a welcome change following decades of stigma and methodological deficiencies in early-era substance research. He argued that the field's return to rigorous investigational trial design is essential to establishing a credible evidence base. Mechanistically, he described psychedelics as potentially enabling patients to "reset" pathological patterns of neural activity—specifically disrupting the ruminative, self-referential processing associated with hyperactivation of the default mode network (DMN) and restoring salience network connectivity in ways that may allow patients to access more adaptive psychological states.

As an investigator in the COMP005 and COMP006 phase 3 trials of COMP360 psilocybin for TRD, Alva offered firsthand clinical observations. He noted that the COMP006 open-label data confirmed enduring antidepressant benefit at 6 months—corroborating the primary endpoint results of the double-blind COMP005 trial—with 39% of participants in COMP006 achieving a clinically meaningful response after 2 doses administered 3 weeks apart, with an effect maintained through 26 weeks.¹ He emphasized that the transformational clinical responses he witnessed required anchoring with psychotherapy and trained therapist supervision, and acknowledged that the administration setting and duration of supervision represent logistical challenges likely to require a risk evaluation and mitigation strategy framework if the compound receives regulatory approval. He characterized Compass Pathways as potentially the first company positioned to commercialize a psilocybin-based treatment.

Alva also noted an expanding pipeline of other investigational psychedelic compounds—including synthetic psilocybin analogs, MDMA, LSD, and 5-MeO-DMT—and identified patient selection as a critical and underexplored research question, arguing that psychological traits such as openness and curiosity are likely to predict positive treatment experiences and outcomes.²

Dr Alva is a board-certified psychiatrist and the Mood Disorders Section Editor for Psychiatric Times.

References

1. Kuntz L. New 6-month data from second phase 3 trial confirms rapid effect of COMP360 for TRD. Psychiatric Times. July 7, 2026. https://www.psychiatrictimes.com/view/new-6-month-data-from-second-phase-3-trial-confirms-rapid-effect-of-comp360-for-trd

2. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402–1411.