Exploratory safety, tolerability, and feasibility of psilocybin-assisted psychotherapy for adults with co-occurring treatment-resistant depression and cluster B personality disorders
Orly Lipsitz, Ryan M Brudner, Zoe Doyle, Erica Kaczmarek, Shakila Meshkat, Rickinder Sethi, Roger S McIntyre, Joshua D. Rosenblat
npj Mental Health Research September 16, 2026 DOI: 10.1038/s44184-026-00248-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of a clinical trial Peer reviewed |
|---|---|
| Sample size | 10 |
| Population | Participants with treatment-resistant depression and a comorbid personality disorder (9 cluster B, 1 cluster C) |
| Intervention | Psilocybin-assisted psychotherapy |
| Duration | Follow-up to 6 months |
| Measures | MADRS, MADRS Suicidal ideation (SI) item |
| Topics | Depression Psilocybin Psychedelic-assisted therapy |
| Registration | NCT05029466 |
| Key findings | In ten participants with treatment-resistant depression and comorbid personality disorder, mean MADRS scores declined from 30.4 pre-treatment to 22.3 at six months, and the mean suicidal ideation item fell from 3.2 to 1.2, with substantial heterogeneity between individuals and no serious adverse events. The authors state this is the first clinical trial evidence that psilocybin-assisted psychotherapy may reduce depression and suicidal ideation in comorbid cluster B personality disorders, suggesting further trials may be warranted. |
Abstract
Cluster B personality disorders (PDs) are highly comorbid with depression and are associated with attenuated antidepressant response. No clinical trials to date have reported on psilocybin-assisted psychotherapy (PAP) in comorbid treatment-resistant depression (TRD) and PDs. This is the first clinical trial to describe a subgroup of ten participants with a comorbid PD ( n = 9 cluster B; n = 1 cluster C) and TRD who underwent PAP, representing a secondary analysis of a larger trial. The trial was registered on clinicaltrials.gov under the identifier NCT05029466 (Registration Date: 2021-08-26). Three participants dropped out of the trial. Mean MADRS scores decreased from 30.4 pre-treatment to 22.5 at day 1, 24.9 at week 2, and 22.3 at month 6. Mean MADRS Suicidal ideation (SI) item declined from 3.2 to 1.6 at day 1, 2.3 at week 2, and 1.2 at month 6. There was substantial heterogeneity in outcomes amongst participants. No serious adverse events were recorded. This is the first clinical trial evidence that PAP may reduce depression and SI in comorbid cluster B PDs, suggesting further trials may be warranted.