The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis.
Level 3 - non-randomized controlled study
Post hoc correlational and path analysis of a single trial cohort
PubMed 41881122 · doi:10.1016/j.jad.2026.121662
What was done
Post hoc correlation and path analysis of data from 79 individuals with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support in a multicenter clinical trial. The study evaluated relationships between pre-dosing therapeutic alliance (Scale to Assess Therapeutic Relationship-Patient version; STAR-P), acute psychedelic experience (5D-ASC and EBI), and clinical outcome change at Week 3 (Montgomery-Åsberg Depression Rating Scale; MADRS).
What was found
Week 3 MADRS score change correlated weakly with pre-dosing therapeutic alliance (-0.178) compared to acute psychedelic experience measures: EBI (-0.637), Oceanic Boundlessness (-0.508), and Visual Restructuralization (-0.516). Path analysis revealed no nominally significant direct effects of therapeutic alliance on Week 3 MADRS scores. Therapeutic alliance showed nominally significant effects on psychedelic experiences: Oceanic Boundlessness (β = 0.28), Visual Restructuralization (β = 0.27), and Auditory Alterations (β = 0.25). Only one indirect effect of alliance on MADRS was nominally significant (via Visual Restructuralization, β = -0.15). Direct effects of psychedelic experiences on clinical outcome were larger: EBI (β = -0.59), Oceanic Boundlessness (β = -0.53), Visual Restructuralization (β = -0.54), and Auditory Alterations (β = -0.24).
Why it matters
These findings suggest that pre-treatment therapeutic alliance supports antidepressant response primarily by facilitating acute psychedelic experiences rather than exerting a direct therapeutic effect.
Limits
This was an exploratory post hoc path analysis limited to a single 25 mg cohort (n = 79) without a comparison arm, restricting causal inferences. Findings relied on subjective self-report questionnaires and yielded only nominally significant results.
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