Therapeutic alliance and rapport modulate responses to psilocybin assisted therapy for depression
Open accessAbstract
Background:Across psychotherapeutic frameworks, the strength of the therapeutic alliance has been found to correlate with treatment outcomes; however, its role has never been formally assessed in a trial of psychedelic-assisted therapy. We aimed to investigate the relationships between therapeutic alliance and rapport, the quality of the acute psychedelic experience and treatment outcomes. Methods:This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder (N= 59). This analysis focused on the psilocybin condition (n= 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychological preparation, in-session support, and integration therapy. A new psychedelic therapy model, called “Accept-Connect-Embody” (ACE), was developed in this trial. The primary outcome was depression severity 6 weeks post treatment (Quick Inventory of Depressive Symptomatology, QIDS-SR-16). Path analyses tested the hypothesis that therapeutic alliance (Scale To Assess the Therapeutic Relationship Patient Version, STAR-P) would predict depression outcomes via its influence on the acute psychedelic experience, specifically emotional-breakthrough (EBI) and mystical-type experiences (MEQ). The same analysis was performed on the escitalopram arm to test specificity. Results:The strength of therapeutic alliance predicted pre-session rapport, greater emotional-breakthrough and mystical-type experience (maximum EBI and MEQ scores across the two psilocybin sessions) and final QIDS scores (β= −0.22,R2= 0.42 for EBIMax;β= −0.19,R2= 0.32 for MEQMax). Exploratory path models revealed that final depression outcomes were more strongly affected by emotional breakthrough during the first, and mystical experience during the second session. Emotional breakthrough, but not mystical experience, during the first session had a positive effect on therapeutic alliance ahead of the second session (β= 0.79,p< 0.0001). Therapeutic alliance ahead of the second session had a direct impact on final depression scores, not mediated by the acute experience, with a weaker alliance ahead of the second psilocybin session predicting higher absolute depression scores at endpoint (β= −0.49,p< 0.001) Discussion:Future research could consider therapist training and characteristics; specific participant factors, e.g., attachment style or interpersonal trauma, which may underlie the quality of the therapeutic relationship, the psychedelic experience and clinical outcomes; and consider how therapeutic approaches might adapt in cases of weaker therapeutic alliance. Clinical Trial Registration:This trial is registered at http://clinicaltrials.gov , identifier (NCT03429075).
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Integrating MDMA-AT with psychoanalytic principles may establish therapeutic relationship as corrective emotional experience, fostering meaningful psychological change in individuals with PN.
“Integrating MDMA-AT with psychoanalytic principles may further establish the therapeutic relationship as a corrective emotional experience, fostering meaningful psychological change in individuals with PN (170, 171).”
From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [170]
The Discussion’s “The Therapeutic Relationship” section proposes that experiencing care within psychedelic-assisted therapy may change implicit relational patterns and support therapeutic progress. That supports the proposed relationship-based mechanism, but the paper studies psilocybin-assisted therapy for depression; it does not establish this application to MDMA-assisted therapy integrated with psychoanalytic principles or to individuals with PN. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTherapist-patient relationship is one of the strongest predictors of treatment success across psychotherapeutic approaches, including PAT.
“Studies indicate that the therapist-patient relationship is one of the strongest predictors of treatment success across psychotherapeutic approaches, including PAT (166, 169–171).”
From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [170]
The Introduction (page not supplied) calls therapeutic alliance an important predictor of psychotherapy outcomes across approaches. The Discussion reports that alliance and rapport predicted outcomes in a psilocybin-assisted therapy trial for depression. The paper does not establish that the relationship is one of the strongest predictors across approaches. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTherapeutic relationship, alliance, or rapport variables can be assessed with various measures with established validity and reliability.
“These variables can be assessed with various measures with established validity and reliability.89,90,93-95”
From Best Practice Recommendations for Conducting and Reporting Controlled Trials in Clinical Hypnosis Research (2024) · cites this paper as [94]
The Methods (Measures; page unavailable) describe two ways of assessing these variables: the STAR-P for therapeutic alliance and a self-constructed single-item rating for rapport. This supports the claim that they can be measured in different ways, but the paper does not establish the validity and reliability of both measures; in particular, it describes the rapport item as self-constructed. (LLM, conf=0.85)
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References 114 · Cited by 250
Research works printed but not linked: 5
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- Watts R. (2021). Psilocybin for Depression: The ACE Model Manual. Open Science Framework, 10.31234/osf.io/5x2buWesten · DOI
- Authors
- Murphy, R., Kettner, H., Zeifman, R., Giribaldi, B., Kartner, L., Martell, J., Read, T., Murphy-Beiner, A., Baker-Jones, M., Nutt, D., Erritzoe, D., Watts, R., & Carhart-Harris, R.
- Affiliations
- Imperial College London (GB)
- Devon Partnership NHS Trust (GB)
- Royal Holloway University of London (GB)
- University of California, San Francisco (US)
- Corresponding author
- Murphy, Roberta
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2022-03-31
- Volume
- 12
- Pages
- 788155-788155
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC9009076
- OpenAlex
- W4221001769
- Cited by
- 250
- References
- 114
- Citations by year
- 2026: 61 · 2025: 55 · 2024: 72 · 2023: 44 · 2022: 16 · 2021: 1
- FWCI
- 42.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Royal College of Psychiatrists
- National Institute for Health and Care Research (ACF-2013-21-501, CL-2017-21-004)
- Academy of Medical Sciences (SGL019\1063)
- Imperial College London
- King's College London
- NIHR Imperial Biomedical Research Centre
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- alliances, therapeutic rapport, psilocybin-assisted therapy, depression, mystical experience, escitalopram, treatment outcome prediction, attachment styles, interpersonal trauma, therapist training, therapist characteristics
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