Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation
In an open‑label trial of 27 treatment‑resistant depression patients given a single 25 mg psilocybin dose with psychotherapy, those who had discontinued antidepressants before treatment showed comparable reductions in clinician‑rated and self‑reported depression, anxiety and suicidality to patients unmedicated at screening. Both groups experienced clinically significant improvements and similar intensity of psychedelic experience, suggesting medication tapering did not alter short‑term antidepressant effects in this sample.
Authors
- Roger McIntyre
- Jonathan Rosenblat
- Shokouh Meshkat
Published
Abstract
Objective
To compare changes in depression, anxiety, and suicidality symptoms after a single 25 mg oral dose of psilocybin between treatment-resistant depression participants not on antidepressants at screening to participants that discontinued antidepressant medications leading up to receiving psilocybin-assisted psychotherapy (PAP).
Methods
Participants (n = 27) received at least one 25 mg dose of psilocybin accompanied by psychotherapy as part of an exploratory analysis from an open-label, randomized, waitlist-controlled clinical trial. The primary outcome of changes in depression symptoms was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included changes in anxiety symptom severity (Generalized Anxiety Disorder 7-Item [GAD-7]), suicidal ideation (MADRS Item-10), self-reported depression symptoms (Quick Inventory for Depression Symptomology [QIDS-SR]), and intensity of psychedelic experience (Mystical Experience Questionnaire 30-item [MEQ30]). Patients were separated into two groups for analysis; those who were unmedicated at initial screening versus participants that had to taper off antidepressant medications to be eligible for the trial. A mixed analysis of variance was used to evaluate clinical outcomes over time from baseline to 2 months post-dose.
Results
No significant differences were found between medication discontinued (n = 18) and unmedicated at screening (UAS) (n = 9) groups in clinician rated depression (p = 0.759), self-reported depression (p = 0.215), anxiety (p = 0.178), and suicidality (p = 0.882) symptoms over time, with both groups having clinically significant benefits on all outcomes assessed. Both groups also had a similar intensity of psychedelic experience (p = 0.191).
Conclusion
Comparable improvements were observed in depression and anxiety and symptoms between antidepressant discontinued and UAS patients. These findings contrast with and contribute to the growing literature on the effects of medication tapering leading up to PAP. Further clinical research is needed to directly compare efficacy across medication statuses, in addition to evaluating psychedelic effects in individuals continuing antidepressants during PAP.
Research Summary of 'Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation'
Introduction
Treatment-resistant depression (TRD) is defined as a depressive episode that has failed to respond adequately to at least two antidepressant trials and affects an estimated 30% of people diagnosed with depression, producing substantial functional impairment and increased healthcare burden. Psilocybin, a serotonergic psychedelic whose active metabolite psilocin is a high-affinity 5-HT2A receptor agonist, has shown preliminary antidepressant effects when delivered alongside psychological support (psilocybin-assisted psychotherapy, PAP). A practical and scientific debate exists about whether concomitant antidepressant medications—particularly serotonergic agents such as SSRIs and SNRIs—should be tapered before PAP, because continuing these medicines might blunt psychedelic effects or alter therapeutic response, whereas tapering carries risks of discontinuation symptoms and relapse. Chisamore and colleagues report a post-hoc analysis addressing this gap: they compare changes in clinician-rated and self-reported depression, anxiety, suicidal ideation, and intensity of the psychedelic experience between participants who were unmedicated at initial screening (UAS) and participants who tapered off antidepressant medications to join an open-label, randomized, waitlist-controlled trial of PAP. The aim was to evaluate whether antidepressant discontinuation affected clinical outcomes following a single 25 mg oral dose of psilocybin delivered with preparatory and integration psychotherapy.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Chisamore, N., Kaczmarek, E. S., Doyle, Z., Johnson, D. E., Weiglein, G., Meshkat, S., Brudner, R. M., Blainey, M. G., Riva-Cambrin, J., McIntyre, R. S., & Rosenblat, J. D. (2025). Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation. The Canadian Journal of Psychiatry, 70(10), 759-767. https://doi.org/10.1177/07067437251328316
References (17)
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Davis, A. K., Barrett, F. S., May, D. G. et al. · JAMA Psychiatry (2021)
Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
MacLean, K. A., Leoutsakos, J. S., Johnson, M. W. et al. · Journal for the Scientific Study of Religion (2012)
Cameron, L. P., Patel, S. D., Vargas, M. V. et al. · ACS Chemical Neuroscience (2023)
Hesselgrave, N., Troppoli, T. A., Wulff, A. B. et al. · PNAS (2021)
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