Background:
Clinical trials have shown that psilocybin therapy with psychological support can improve depression, anxiety, and well-being. However, concerns have been raised that findings from clinical trials may not generalize to real-world practice due to exclusion criteria, sampling bias, controlled environments, and limited participant diversity. Oregon's Psilocybin Services Act established the first legal framework for psilocybin therapy outside clinical trials, providing a unique opportunity to evaluate outcomes in community settings. This ongoing longitudinal study assesses the real-world safety and effectiveness of psilocybin therapy and examines factors associated with therapeutic outcomes across multiple follow-up periods.


Methods:
Up to 3,000 adults receiving psilocybin therapy from licensed facilitators across 10 treatment sites in Oregon are being enrolled prior to treatment and followed for 12 months through online assessments. The primary outcome is well-being (WHO-5) at the primary endpoint of one month post-treatment. Secondary outcomes include depression (PHQ-9), anxiety (GAD-7), and psychological flexibility (Psy-Flex), with additional disorder-specific measures based on clinical presentation (e.g., borderline personality disorder, posttraumatic stress disorder, substance use). Safety is tracked throughout using the Swiss Psychedelic Side Effects Inventory (SPSEI) and measurement of symptom exacerbation. Acute experiences are assessed with the Mystical Experience Questionnaire, Emotional Breakthrough Inventory, and Challenging Experience Questionnaire. Analyses include ANCOVAs and linear mixed-effects models controlling for baseline characteristics, and latent variable modeling to identify predictors and mechanisms of change. The study also examines variation in psychotherapeutic approach and level of psychological support, offering insight into process factors that influence outcomes and guide training.


Results:
Data collection is ongoing. Preliminary findings on feasibility, safety, and early effectiveness outcomes will be presented.


Conclusions:
This first large-scale, multi-site, prospective evaluation of psilocybin therapy in naturalistic practice will generate crucial real-world evidence. Findings will guide safe implementation, refine therapeutic frameworks, inform training and regulation, and advance applied psychological science in psychedelic-assisted therapy.