Therapist Manual for Psilocybin-Assisted Therapy of Treatment-Resistant Major Depression

Psilocybin-assisted therapy has emerged as a promising intervention for treatment-resistant depression (TRD), yet standardized and transparent therapeutic frameworks remain limited. This therapist manual was developed for the EPIsoDE trial, a phase IIb randomized clinical study investigating the efficacy and safety of psilocybin with adjunct psychotherapy in patients with TRD (NCT04670081). The main results of this trial have been published (doi:10.1001/jamapsychiatry.2026.0132). The manual provides a basic, structured psychotherapeutic framework for delivering psilocybin therapy within a controlled clinical trial setting, as used in the EPIsoDE trial. It outlines therapist qualifications, training procedures, and the use of a therapist dyad model to ensure treatment safety and efficacy. Core components include detailed guidance on preparatory sessions, dosing sessions, and integration sessions. An emphasis is placed on the concepts of “set and setting”, highlighting the importance of psychological preparation, therapeutic alliance and presence, and the design of the physical environment. The manual further describes the phenomenology of the acute psilocybin experience, including both potentially beneficial and challenging psychological states, to be discussed with patients in the preparatory phase. It also provides strategies for therapeutic support, including self-regulation techniques (e.g., breathing or mindfulness exercises), to be applied during the dosing sessions. A distinctive feature of the manual is the structured use of music during dosing sessions, implemented through a phase-specific block system aligned with the experiential trajectory of psilocybin effects. Additionally, the manual includes detailed safety monitoring procedures, including psychological and cardiovascular assessments, as well as standardized checklists for session procedures and documentation tools, as implemented in the EPIsoDE trial. By making this manual publicly available, we aim to enhance transparency, reproducibility, and methodological rigor in psychedelic research, and to contribute to the development of standardized therapeutic approaches in this field of research.