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 Peer reviewed DOI: 10.1016/j.jad.2026.121662 via PubMed
Summary
The study examined the role of patient support in the antidepressant effects of psilocybin for individuals with treatment-resistant depression. While therapeutic alliance had limited direct effects on clinical outcomes measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), it was found to facilitate certain aspects of the psychedelic experience. Notably, stronger correlations were observed between the psychedelic experience and clinical outcomes than with therapeutic alliance. The findings suggest that the therapeutic alliance may enhance the psychedelic experience, which in turn drives better clinical results.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 79 |
| Population | individuals with treatment-resistant depression receiving psilocybin |
| Key finding | Therapeutic alliance had limited direct effects on clinical outcomes, while the psychedelic experience showed stronger correlations with improvements in depression scores. |
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.