Psilocybin with psychotherapeutic support for treatment-resistant depression: a pilot clinical trial
An open‑label pilot trial of two 25 mg psilocybin sessions with preparatory and integration psychotherapy for treatment‑resistant depression produced a clinically meaningful reduction in self‑rated depressive symptoms at three weeks (Hedges’ g = −1.27) that was maintained at 20 weeks, although individual responses varied (two sustained responders, three relapses, two non‑responders). Exploratory analyses linked pre‑dosing mindset, spiritual experiences and perceptual shifts to outcome trajectories, with adverse events consistent with prior studies and no serious adverse events.
Authors
- Paul Liknaitzky
- Olivia Carter
- Martin Williams
Published
Abstract
Background
Depressive disorders are a major global health challenge, with many individuals unresponsive to existing treatments. Novel psychedelic therapies show promise but require further research.
Objectives
This study aimed to evaluate the feasibility, safety and effectiveness of psilocybin with psychotherapeutic support for treatment-resistant depression (TRD), investigate predictors of treatment outcomes and deepen understanding of individual variability in response.
Design
Open-label, single-arm pilot trial with mixed-methods assessment.
Methods
Treatment consisted of two 25 mg psilocybin sessions, alongside three preparatory and six integration sessions. Depression severity was assessed using the self-rated Quick Inventory of Depressive Symptomatology at 3 weeks (primary endpoint) and at 20 weeks post-dose 2 (long-term follow-up). Potential predictors of clinical outcomes were evaluated using questionnaires, and qualitative interviews were used to capture individual experiences.
Results
At the aggregate level, a clinically meaningful reduction in depressive symptoms was observed at the primary endpoint (mean change = –7.14; p = 0.02; Hedges’ g = –1.27; 95% CI [–2.40, –0.37]) and maintained long-term. Individual participant data revealed diverse response patterns. Two participants displayed a sustained treatment response, three relapsed, and two exhibited no substantial improvement. Exploratory analyses identified mindset prior to dosing, spiritual experiences and perceptual shifts during dosing as predictors of treatment trajectory, while treatment expectations were not a reliable predictor. Adverse events were largely consistent with previous studies, with no serious adverse events.
Conclusion
Findings add to the growing evidence base for psilocybin therapy and provide direction for further research on individual variability in response to better tailor treatments and enhance efficacy. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001097831).
Research Summary of 'Psilocybin with psychotherapeutic support for treatment-resistant depression: a pilot clinical trial'
Introduction
Depressive disorders are a leading cause of global non-fatal disease burden and a substantial subset of people with major depressive disorder (MDD) do not remit after successive courses of conventional treatments. Meikle and colleagues note that after two unsuccessful pharmacological interventions the label 'treatment-resistant depression' (TRD) is commonly applied, and that 10%-30% of people with MDD may meet this threshold. Previous clinical trials of psilocybin-assisted therapy in MDD and TRD have generally shown improvements from baseline, though trial results vary and some well-blinded studies have failed to demonstrate superiority over placebo or active comparators, raising concerns about expectancy effects and heterogeneity across protocols (for example single-dose versus two-dose regimens, and differing amounts of preparatory and integration therapy). Safety outside healthy volunteer samples is still being characterised, and unique interpersonal risks in psychedelic therapy (such as therapeutic touch) require further empirical attention. This pilot study aimed to evaluate a two-dose psilocybin protocol (two 25 mg doses) delivered with psychotherapeutic support for people with TRD in an Australian setting. Meikle and colleagues set out to examine effectiveness and safety, to explore individual trajectories of clinical response with mixed quantitative and qualitative methods, and to report a fully disclosed treatment protocol to inform practice and future research in this jurisdiction.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Pro members can view the original manuscript directly in the browser.
Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Meikle, S., Carter, O., Liknaitzky, P., Johansen, L., Iyer, R., Strauss, N., Williams, M., Castle, D., & Rossell, S. L. (2025). Psilocybin with psychotherapeutic support for treatment-resistant depression: a pilot clinical trial. Therapeutic Advances in Psychopharmacology, 15. https://doi.org/10.1177/20451253251377187
References (32)
Papers cited by this study that are also in Blossom
Carhart-Harris, R. L., Bolstridge, &. M., Day, C. M. J. et al. · Psychopharmacology (2017)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Davis, A. K., Streeter Barrett, F., Cosimano, M. P. et al. · Journal of Psychopharmacology (2022)
Sloshower, J. A., Skosnik, P. D., Safi-Aghdam, H. et al. · Journal of Psychopharmacology (2023)
Goodwin, G. M., Croal, M., Feifel, D. et al. · Neuropharmacology (2023)
Yu, C. L., Liang, C. S., Yang, F. et al. · Journal of Clinical Medicine (2022)
Studerus, E., Kometer, M., Hasler, F. et al. · Journal of Psychopharmacology (2010)
Peill, J. M., Trinci, K. E., Kettner, H. et al. · Journal of Psychopharmacology (2022)
Show all 32 referencesShow fewer
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Acevedo, E. C., Uhler, S., White, K. et al. · Journal of Psychoactive Drugs (2024)
Roseman, L., Haijen, E. C. H. M., Idialu-Ikato, K. et al. · Journal of Psychopharmacology (2019)
Low, F., Earleywine, M. · Journal of Psychoactive Drugs (2023)
Nygart, V., Pommerencke, L. M., Haijen, E. et al. · Journal of Psychopharmacology (2022)
Szigeti, B., Heifets, B. D. · Biological Psychiatry (2024)
Muthukumaraswamy, S., Forsyth, B., Lumley, T. · Expert Review of Clinical Pharmacology (2021)
Studerus, E., Gamma, A., Kometer, M. et al. · PLOS ONE (2012)
Haijen, E. C. H. M., Kaelen, M., Roseman, L. et al. · Frontiers in Pharmacology (2018)
Watts, R., Kettner, H., Gandy, S. et al. · Psychopharmacology (2022)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)
Davis, A. K., Barrett, F. S., Griffiths, R. R. · Journal of Contextual Behavioral Science (2020)
Baggott, M. J., Coyle, J. R., Erowid, E. et al. · Drug and Alcohol Dependence (2011)
Knight, G., Rucker, J., Cleare, A. J. et al. · Frontiers in Psychiatry (2022)
Szigeti, B., Weiss, B., Rosas, F. E. et al. · Psychological Medicine (2024)
Van Elk, M., Fried, E. I. · Therapeutic Advances in Psychopharmacology (2023)
Luoma, J. B., Allen, L. R., Gold, V. et al. · Psychedelic Medicine (2024)
Bonson, K. R. · Neuropsychopharmacology (1996)
Erritzoe, D., Barba, T., Spriggs, M. J. et al. · Journal of Psychopharmacology (2024)
Carbonaro, T. M., Hurwitz, E., Johnson, M. W. · Psychopharmacology (2017)
Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.