The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder
In a randomised, waiting‑list‑controlled psilocybin‑assisted therapy trial for major depressive disorder (N = 24), therapeutic alliance strengthened over time and higher alliance ratings before and shortly after dosing predicted stronger acute mystical and psychological‑insight experiences and significantly greater reductions in depressive symptoms up to 12 months. These results highlight the therapeutic relationship as an important predictor of both acute psychedelic experiences and long‑term clinical outcomes.
Authors
- Roland Griffiths
- Alan Davis
- Frederick Barrett
Published
Abstract
We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final preparation session predicted depression scores at 4 weeks (r = -.65, p = .002), 6 months (r = -.47, p = .036), and 12 months (r = -.54, p = .014) post-intervention. A stronger total alliance in the final preparation session was correlated with higher peak ratings of mystical experiences (r = .49, p = .027) and psychological insight (r = .52, p = .040), and peak ratings of mystical experience and psychological insight were correlated with depression scores at 4 weeks (r = -.45, p = .030 for mystical; r = -.75, p < .001 for insight). Stronger total alliance one week after the final psilocybin session predicted depression scores at 4 weeks (r = -.85, p < .001), 3 months (r = -.52, p = .010), 6 months (r = -.77, p < .001), and 12 months (r = -.61, p = .001) post-intervention. These findings highlight the importance of the therapeutic relationship in PAT. Future research should explore therapist and participant characteristics which maximize the therapeutic alliance and evaluate its relationship to treatment outcomes. Trial registration: Registration: Clinicaltrials.gov NCT03181529. https://classic.clinicaltrials.gov/ct2/show/NCT03181529.
Research Summary of 'The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder'
Introduction
Levin and colleagues situate this study within the growing literature on psychedelic-assisted therapy (PAT), which has shown promise across several psychiatric conditions including major depressive disorder (MDD). They note that beyond pharmacology, aspects of the therapeutic context—commonly framed as 'set and setting'—and the psychotherapeutic work surrounding dosing sessions are widely believed to shape acute psychedelic experiences and downstream clinical outcomes. The therapeutic alliance, a central "common factor" in psychotherapy defined as the collaborative bond between clinician and patient, has robust associations with outcomes in conventional therapies but has been little empirically examined in modern clinical trials of PAT. The researchers set out to replicate and extend prior findings linking alliance, acute psychedelic experiences, and clinical outcomes. Specifically, they aimed to test whether participant-rated therapeutic alliance changes across the course of a psilocybin-assisted therapy trial for MDD, whether alliance ratings predict clinician-rated depression outcomes up to 12 months post-intervention, whether alliance is related to peak mystical-type and psychological insight effects during psilocybin sessions, and how those acute effects relate to subsequent depression scores. This analysis used data from a previously reported randomized, waitlist-controlled trial of psilocybin-assisted therapy in adults with moderate-to-severe MDD.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Levin, A. W., Lancelotta, R., Sepeda, N. D., Gukasyan, N., Nayak, S., Wagener, T. L., Barrett, F. S., Griffiths, R. R., & Davis, A. K. (2024). The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder. PLOS ONE, 19(3), e0300501. https://doi.org/10.1371/journal.pone.0300501
References (37)
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Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
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Aday, J. S., Davis, A. K., Mitzkovitz, C. M. et al. · ACS Pharmacology and Translational Science (2021)
Haijen, E. C. H. M., Kaelen, M., Roseman, L. et al. · Frontiers in Pharmacology (2018)
Murphy, R., Murphy-Beiner, A., Kettner, H. et al. · Frontiers in Pharmacology (2022)
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Carbonaro, T. M., Johnson, M. W., Griffiths, R. R. · Psychopharmacology (2020)
Pontual, A. A. D. D., Tófoli, L. F., Corradi-Webster, C. M. et al. · Frontiers in Psychology (2022)
Kettner, H., Rosas, F. E., Timmermann, C. et al. · Frontiers in Pharmacology (2021)
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Nikolaidis, A., Lancelotta, R., Gukasyan, N. et al. · Journal of Affective Disorders (2023)
Passie, T., Guss, J., Kraehenmann, R. · Frontiers in Psychiatry (2022)
Oehen, P., Gasser, P. · Frontiers in Psychiatry (2022)
Pokorny, T., Preller, K. H., Kometer, M. et al. · International Journal of Neuropsychopharmacology (2017)
Watts, R., Day, C. M., Krzanowski, J. et al. · Journal of Humanistic Psychology (2017)
Preller, K. H., Pokorny, D., Hock, A. et al. · PNAS (2016)
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