Mapping psilocybin therapy: A systematic review of therapeutic frameworks, adaptations, and standardization across contemporary clinical trials

Abstract

Accumulating evidence suggests that psilocybin can produce rapid and sustained clinical benefits when administered in conjunction with psychological support. Though non-pharmacological procedures are considered integral, the field lacks therapeutic guidelines and little is known about current practices. This systematic review sought to provide a comprehensive and cross-diagnostic synthesis of current psilocybin therapy (PT) protocols across contemporary mental health related trials. Primary objectives were to define and compare PT models with respect to overall therapeutic framework, evidence-based psychotherapeutic adaptations, and therapeutic standardization measures. Database search identified 22 recent trials assessing psilocybin as treatment for major and treatment-resistant depression, medical condition-related distress, substance use, obsessive-compulsive disorders, and eating disorders. Cross-diagnostic review revealed broad consistency in therapeutic structure (i.e. before, during, and after psilocybin treatment), session themes, and external context during drug administration. However, trials varied in therapeutic intensity, diagnostic adaptations, and incorporation of evidence-based psychotherapies. Less than half of reviewed trials reported standardization measures such as manualized procedures, PT-specific training, or adherence and fidelity monitoring. With non-pharmacological treatment mechanisms still unclear, results highlight potential confounds and standardization gaps that undermine the replicability and generalizability of recent psilocybin interventions. Until adjunctive support protocols are adequately operationalized, mechanistic insight and uptake into clinical practice will remain a challenge.