Randomized, Triple‑Blind, Active‑Placebo Controlled Trial of Psilocybin (PEX010)‑Assisted Acceptance and Commitment Therapy in Treatment‑Resistant Anorexia Nervosa

The primary objective is to assess the impact of psilocybin administered alongside acceptance and commitment therapy on core clinical symptoms of treatment‑resistant anorexia nervosa, thereby determining its therapeutic potential in this population. The secondary objective is to evaluate the safety profile of the investigational product in individuals with anorexia nervosa, including the incidence of adverse events and relevant clinical safety markers.

The trial enrolled female participants aged 18 to 50 years who met ICD‑11 criteria for Anorexia nervosa or an atypical presentation. Eligibility required a diagnosis of the disorder, suboptimal response to standard psychotherapy (failure of at least one treatment line), no known allergy to study medication components, and the ability to discontinue most psychopharmacologic agents except benzodiazepines and SSRIs. Participants were selected from clinical populations where the diagnosis had been confirmed and were required to have stable general health aside from the target condition; specific lifestyle factors such as diet or physical activity were not stipulated as inclusion criteria. The sponsor did not provide information on the total number of participants.

The Danish Anorexia Nervosa Psilocybin RCT is a phase II, randomized, active‑placebo‑controlled, triple‑blind superiority trial evaluating oral 25 mg PEX010 (dry extract from Psilocybe cubensis) in females aged 18‑50 with ICD‑11 Anorexia nervosa who have failed at least one standard psychotherapy line. After a screening visit to confirm eligibility, participants undergo a baseline assessment, receive the study medication in a supervised session, and are then followed according to a predefined schedule: visits at weeks 1, 2, 4, 6, 8, and 10 for the primary outcome assessment, additional visits at weeks 14, 18, and 22 for secondary outcomes, and a final end‑of‑study visit at week 22. The total participant involvement spans approximately 22 weeks. Randomization assigns participants to either PEX010 or an active placebo, with participants, investigators, and outcome assessors blinded to allocation. Early termination may occur due to serious adverse events, withdrawal of consent, protocol non‑adherence, or inability to discontinue prohibited concomitant psychopharmacology. Recruitment is planned from June 2026 to December 2029.

The investigational product, identified as PEX010, consists of a dry extract derived from Psilocybe cubensis (15‑25:1) with methanol as the extraction solvent. The extract is formulated as oral capsules, each containing 25 mg of the active extract. Capsules are administered by the oral route, with a single dose scheduled at the beginning of the treatment phase. The dosing regimen follows a fixed‑dose approach without titration.

The study incorporates an active‑placebo comparator to maintain blinding, alongside standard‑of‑care psychotherapy consisting of Acceptance and Commitment Therapy (ACT). The active placebo is administered using the same capsule format and oral route to match the investigational product in appearance and dosing schedule. ACT is delivered in structured weekly sessions throughout the trial period, providing a non‑pharmacologic therapeutic component for all participants.

Drug administration occurs under supervised conditions at the clinical site to ensure accurate dosing and to monitor immediate safety. Compliance with the oral capsule regimen is verified by direct observation of ingestion and documented in the study record. For the psychotherapy component, session attendance is recorded, and adherence to the therapeutic protocol is assessed by the treating therapist. All administration details, including timing and any deviations, are captured in the electronic case report form for ongoing monitoring.

Efficacy will be evaluated by comparing the change in anorexia nervosa symptom severity from baseline to the assessment time points defined as the primary endpoint at week 10 and the secondary endpoint at week 22.