Predictors of the Effectiveness of Psychedelics in Treating Depression—A Scoping Review
James Chmiel, Filip Rybakowski
International Journal of Molecular Sciences February 26, 2026 DOI: 10.3390/ijms27052202 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Scoping review Randomized Open-label Peer reviewed |
|---|---|
| Sample size | 48 |
| Population | Adults with depressive disorders, including treatment-resistant depression |
| Topics | Depression |
| Keywords | Comorbidity Antidepressant Psycinfo Medline Depression economics Meta-analysis Generalizability theory Demographics Clinical psychology |
| Key findings | Antidepressant response in psychedelic-assisted therapies is driven less by static patient characteristics and more by in-session experiences and contextual factors such as therapeutic alliance and music. |
Abstract
Psychedelic-assisted therapies (PATs) can produce rapid and sustained antidepressant effects, yet variability in response remains substantial. Identifying predictors and moderators is essential for optimising patient selection, preparation, and delivery. To map and synthesise the evidence on the predictors of antidepressant response to classic/serotonergic psychedelics administered with psychotherapeutic support in adults with depressive disorders, including treatment-resistant depression. Following PRISMA-ScR principles, we conducted a scoping review of major biomedical and psychology databases (PubMed (MEDLINE), Embase, PsycINFO, and Web of Science) and trial registries (searches September-October 2025), supplemented by reference-list screening. We included randomised trials, open-label studies, and naturalistic cohorts reporting associations between candidate predictors (baseline traits/clinical features, set/setting variables, acute in-session phenomenology, and biological measures) and validated depression outcomes. We charted study characteristics, analytic approaches (including moderation/mediation where available), and indicators of robustness (e.g., adjustment for overall intensity, preregistration, external validation). A total of 48 studies were included in the review. Across study designs, process-level features during the dosing session were the most consistent correlates of antidepressant improvement. Greater emotional breakthrough, mystical/unitive experiences, and ego dissolution-linked reappraisal/insight generally predicted larger and more durable symptom reductions, whereas anxiety-dominant or dysphoric states tended to attenuate benefit, often independent of overall subjective intensity. Set and setting-particularly a stronger therapeutic alliance and music experienced as resonant-predicted both the emergence of therapeutically salient acute experiences and downstream clinical gains. Baseline moderators showed smaller and mixed effects: PTSD comorbidity sometimes weakened trajectories; extensive prior psychedelic exposure was associated with smaller incremental gains; demographics were typically uninformative. Converging biological findings associated better outcomes with markers consistent with increased neural flexibility and plasticity (e.g., less segregated network dynamics; EEG indices), alongside peripheral changes implicating neurotrophic, inflammatory, and HPA axis pathways. Current evidence suggests that antidepressant response in PATs is driven less by static patient characteristics and more by what occurs during dosing and how the context shapes that experience. Optimising preparation, alliance, and music; facilitating emotional breakthrough and meaning making; and mitigating anxious dysregulation are actionable levers. Future trials should harmonise measures, pre-specify and validate moderators/mediators, intensively sample in-session experience and physiology, and report benefits and harms more consistently.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
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- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
and 108 more in the library