Therapist Manual for Psilocybin-Assisted Therapy of Treatment-Resistant Major Depression
Zenodo (CERN European Organization for Nuclear Research) March 30, 2026 DOI: 10.5281/zenodo.19327772 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase IIb randomized clinical trial Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression |
| Intervention | Psilocybin-assisted therapy |
| Topics | Depression Psilocybin |
| Registration | NCT04670081 |
| Key findings | The manual provides a standardized, transparent therapeutic framework for psilocybin-assisted therapy in treatment-resistant depression, including structured music use and safety monitoring. |
Abstract
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.
Comparable studies
Other randomized controlled trials on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
| Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. Adults with treatment-resistant depression | 2022 | Phase 2 double-blind randomized controlled trial | n = 233 |