Mapping psilocybin therapy: A systematic review of therapeutic frameworks, adaptations, and standardization across contemporary clinical trials
Mary E. Kittur, Mingyao Liu, Brett D. M. Jones, Daniel M. Blumberger, Benoit H. Mulsant, Joshua D. Rosenblat, Muhammad Ishrat Husain
Journal of Affective Disorders July 18, 2025 DOI: 10.1016/j.jad.2025.119952 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Sample size | 22 |
| Population | Participants in 22 recent clinical trials of psilocybin for mental health conditions including major depression, treatment-resistant depression, medical condition-related distress, substance use disorders, obsessive-compulsive disorders, and eating disorders |
| Topics | Psilocybin |
| Keywords | Standardization Clinical trial Systematic review Medline Psychotherapist |
| Citations | 12 |
| Key findings | Trials of psilocybin therapy show broad consistency in therapeutic structure but vary in intensity, diagnostic adaptations, and use of evidence-based psychotherapies, with fewer than half reporting standardization measures. |
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.
Comparable studies
Other systematic reviews and meta-analyses on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern‐era clinical studies Patients with cancer- or illness-related anxiety and depression, major depressive... | 2020 | Systematic review | n = 188 |
| Blinding and expectancy confounds in psychedelic randomized controlled trials | 2021 | Systematic review | |
| Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years Patients from included clinical trials | 2016 | Systematic review | |
| The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis People with elevated symptoms of anxiety and depression | 2020 | Meta-analysis | n = 117 |
| Default Mode Network Modulation by Psychedelics: A Systematic Review Participants from included studies | 2022 | Systematic review |
Citations in the library
Cited by 15
- The CAnadian Network for Psychedelic-Assisted Cancer Therapy (CAN-PACT): A Multi-Phase Program Overview. Current Oncology December 22, 2025
- Psilocybin in the real world: Regulatory, ethical, and operational challenges in Australia’s clinical landscape Australian & New Zealand Journal of Psychiatry December 17, 2025
- Psilocybin in Treatment-Resistant Depression: Weighing Rapid Antidepressant Effects Against Uncertain Durability Therapeutics October 19, 2026
- Connectedness as a Mechanism of Change in Psilocybin-Assisted Cognitive Behavioral Therapy for Major Depressive Disorder Psychedelics October 1, 2026
- From regulation to practice: A scoping review of prescribers’ roles in psilocybin-assisted therapy Drug Science Policy and Law October 1, 2026
and 10 more in the library
Cites 57
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
and 52 more in the library