¹Keio University School of Medicine, Neuropsychiatry, Tokyo, Japan, ²Monash University School of Psychological Sciences, Turner Institute for Brain and Mental Health, Clayton, Australia

Background: Despite recent advances in the treatment of major depression, approximately 30% of patients show insufficient improvement with conventional antidepressants, a condition commonly referred to as treatment-resistant depression (TRD). Psilocybin is a classic psychedelic compound that has received renewed attention as a promising therapeutic candidate for TRD. Clinical trials conducted primarily in the United States and Europe have demonstrated that psilocybin administered with psychological support can produce rapid and sustained antidepressant effects with a favorable tolerability profile in patients with TRD. However, to date, no clinical trials have yet been conducted in Asia, including Japan.

Aims & Objectives: This study aimed to evaluate the feasibility of psilocybin therapy with psychological support in Japanese patients with TRD and to explore its safety and antidepressant effects.

Method: This single-arm, open-label feasibility study was conducted at Keio University Hospital in Tokyo, Japan, and registered in the Japan Registry of Clinical Trials (jRCTs031230351). Twelve Japanese adults with major depressive disorder, diagnosed according to the DSM-5, who had shown an insufficient response to at least two antidepressants during the current episode, were enrolled. Participants underwent two courses of psilocybin therapy with psychological support. Each course consisted of one preparatory session, one dosing session, and two integration sessions. During each dosing session, the first six participants received 10 mg of psilocybin orally. Following an independent safety review, the subsequent six participants were planned to receive 25 mg at both dosing sessions. The two dosing sessions were administered approximately 2–3 weeks apart. All dosing sessions were conducted in an inpatient setting under the supervision of both a psychiatrist and a clinical psychologist. Participants were followed for up to eight weeks after the second dosing session. The primary outcome was feasibility, defined as completion of both dosing sessions by at least 10 of the 12 participants. Secondary outcomes included adverse events and changes in depressive symptoms assessed using the Montgomery–Åsberg Depression Rating Scale, the 24-item Hamilton Depression Rating Scale, and the Quick Inventory of Depressive Symptomatology Self-Report. Changes in depressive symptoms from baseline to post-treatment were analyzed using paired t-tests.

Results: Enrollment began in November 2024, and the trial is ongoing. As of December 14, 2025, 12 participants had been enrolled: 10 completed all study procedures, 1 withdrew from the study, and 1 is currently undergoing treatment. Study completion, including the follow-up assessments at weeks 4 and 8, is anticipated in February 2026. Final results regarding feasibility, safety, and clinical outcomes will be presented at the conference.

Discussion & Conclusions: This is the first study to evaluate the feasibility of psilocybin therapy with psychological support in Japanese patients with TRD. This study will help address the current evidence gap in Asia by providing preliminary safety and efficacy data on psilocybin treatment in this population. The findings may support future efforts to expand the appropriate clinical application of psilocybin in Japan, and potentially, across Asia.