This open-label pilot trial (n=7) of psilocybin-assisted therapy (2x25mg sessions with preparatory and integration psychotherapy) for treatment-resistant depression found clinically meaningful aggregate reductions in depressive symptoms at 3 weeks (mean change=-7.14; Hedges’ g=-1.27) maintained at 20 weeks. Exploratory analyses identified pre-dosing mindset, spiritual experiences, and perceptual shifts, but not expectations, as potential predictors of response, with no serious adverse events.
Abstract of Psilocybin with psychotherapeutic support for treatment-resistant depression
“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.”
Authors: Sally Meikle, Olivia Carter, Paul Liknaitzky, Lauren Johansen, Ravi Iyer, Nigel Strauss, Martin Williams, David Castle & Susan L. Rossell
Summary of Psilocybin with psychotherapeutic support for treatment-resistant depression
Meikle and colleagues situate the study in the long-standing problem of major depressive disorder (MDD), where only about half of patients benefit from established antidepressants or psychotherapy, and outcomes worsen after multiple failed treatments. After two ineffective pharmacological trials in the current episode, the label used is treatment-resistant depression (TRD), which carries higher morbidity, healthcare use, and suicide risk. Against this backdrop, modern trials of psilocybin therapy have shown symptom reductions in MDD and TRD, but effect sizes and remission rates vary, and at least one rigorously blinded study failed to outperform placebo, raising concerns about expectancy effects. Reported response rates differ across designs, with two-dose protocols and more extensive non-dosing sessions tentatively associated with stronger or more durable effects. Safety in patient populations is still being mapped: while adverse events are typically transient (headache, nausea, anxiety), recent trials have reported post-dose suicidal ideation and self-injury, and there is a growing focus on interpersonal risks, including the boundaries of therapeutic touch.
The authors note Australia’s 2023 regulatory shift permitting psilocybin for TRD under specific safeguards, creating an urgent need for locally generated evidence and practice protocols. This pilot open-label trial therefore set out to test feasibility, safety, and effectiveness of psilocybin with psychotherapeutic support in Australian TRD, and to probe individual variability using mixed methods: quantitative predictors (e.g., mindset, altered states) and qualitative interviews to understand participants’ trajectories.
Methods
Study design and oversight
Find this paper
Psilocybin with psychotherapeutic support for treatment-resistant depression: a pilot clinical trial
https://doi.org/10.1177/20451253251377187
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Cite this paper (APA)
Meikle, S., Carter, O., Liknaitzky, P., Johansen, L., Iyer, R., Strauss, N., ... & Rossell, S. L. (2025). Psilocybin with psychotherapeutic support for treatment-resistant depression: a pilot clinical trial. Therapeutic Advances in Psychopharmacology, 15, 20451253251377187.
Study details
Compounds studied
Psilocybin
Topics studied
Treatment-Resistant Depression
Depression
Study characteristics
Original
Open-Label
Participants
7
Humans
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 25 mg | 2xLinked Clinical Trial
An open-label study of the efficacy and feasibility of psilocybin-assisted psychotherapy for treatment-resistant depression (TRD)This open-label trial (n=15) will investigate the efficacy and feasibility of psilocybin-assisted psychotherapy for treatment-resistant depression (TRD).