The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis.
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez, Robin Carhart-Harris, Megan Croal, David Feifel, David J Hellerstein, Muhammad I Husain, John R. Kelly, Namik Kirlic, Rasmus W Licht, Lindsey Marwood, Ania Nowakowska, Tomáš Páleníček, Dimitris Repantis, Robert A Schoevers, Hollie Simmons, Jair C Soares, Metten Somers, Joyce Tsai, Mourad Wahba, Ella Williams, Allan H. Young, Matthew B Young, Sidney Zisook, Ekaterina Malievskaia
Journal of Affective Disorders August 1, 2026 DOI: 10.1016/j.jad.2026.121662 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort with correlation and path analysis Peer reviewed |
|---|---|
| Sample size | 79 |
| Population | Individuals with treatment-resistant depression |
| Intervention | psilocybin |
| Dose | 25 mg |
| Duration | Change from baseline to Week 3 |
| Topics | Depression Psilocybin |
| Keywords | Psychedelic experience Psychological support Therapeutic alliance |
| Citations | 2 |
| Registration | NCT03775200 |
| Key findings | Therapeutic alliance facilitated the psychedelic experience, but the psychedelic experience itself had stronger direct effects on depression outcomes than the alliance. |
Abstract
The contribution of patient support to psilocybin's antidepressant effects remains uncertain. Relationships between therapeutic alliance (Scale to Assess Therapeutic Relationship-Patient version; STAR-P), psychedelic experience (Five-Dimensional Altered States of Consciousness Questionnaire and Emotional Breakthrough Inventory; 5D-ASC and EBI) and clinical outcomes (Montgomery-Åsberg Depression Rating Scale; MADRS) were explored using correlation and path analysis for individuals with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support (N = 79). Change from Baseline to Week 3 MADRS scores showed weaker correlations with pre-dosing therapeutic alliance (-0.178) than with measures of the psychedelic experience: EBI (-0.637), Oceanic Boundlessness (-0.508), and Visual Restructuralization (-0.516). Path analysis showed no nominally significant direct effects of therapeutic alliance on Week 3 MADRS scores, but there were nominally significant effects of therapeutic alliance on psychedelic experience (Oceanic Boundlessness (β = 0.28), Visual Restructuralization (β = 0.27), and Auditory Alterations (β = 0.25)). Only one indirect effect of therapeutic alliance on clinical outcome reached nominal significance (via Visual Restructuralization; β = -0.15). Stronger effects were seen on clinical outcomes for psychedelic experience (EBI (β = -0.59), Oceanic Boundlessness (β = -0.53), Visual Restructuralization (β = -0.54), and Auditory Alterations (β = -0.24)). The therapeutic alliance appeared to facilitate the psychedelic experience, and these experiences in turn had stronger nominally significant direct effects on clinical outcomes. The effects of the alliance itself on therapeutic efficacy were either limited or absent. EudraCT number: 2017-003288-36; Clinicaltrials.gov identifier: NCT03775200.
Comparable studies
Other observational and cohort studies on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Patients with treatment-resistant depression | 2017 | Observational cohort | n = 19 |
| Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression Patients with treatment-resistant depression and healthy controls | 2017 | Observational cohort | n = 33 |
| More Realistic Forecasting of Future Life Events After Psilocybin for Treatment-Resistant Depression Patients with treatment-resistant depression (TRD) | 2018 | Observational cohort | n = 15 |
| Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression. 17 patients with treatment-resistant depression and 18 untreated age-matched healthy... | 2018 | Observational cohort with machine learning classification | n = 35 |
| Brain dynamics predictive of response to psilocybin for treatment-resistant depression. Responders and non-responders to psilocybin therapy for depression | 2024 | Observational cohort |