Exploratory safety, tolerability, and feasibility of psilocybin-assisted psychotherapy for adults with co-occurring treatment-resistant depression and cluster B personality disorders

Psilocybin therapy can reduce depression in patients with comorbid Cluster B personality disorders.

In this small study, Lipsitz et al. (2026) conducted an exploratory secondary analysis of 10 adults with treatment-resistant depression (TRD) and co-occurring personality disorders who received psilocybin-assisted psychotherapy.

Nine participants had Cluster B personality disorders and one had a Cluster C disorder. Mean depressive symptoms, measured using the Montgomery–Åsberg Depression Rating Scale (MADRS), decreased from 30.4 at baseline to 22.3 at 6-month follow-up, while mean suicidal-ideation scores also decreased from 3.2 to 1.2.

No serious adverse events were reported, although three participants discontinued the study and considerable variability in individual outcomes was observed. These findings provide preliminary evidence that psilocybin-assisted psychotherapy may be feasible and tolerable in this clinically complex population and may be associated with reductions in depressive symptoms and suicidal-ideation ratings.

However, the very small sample, absence of a control group for this subgroup, and exploratory design mean that the study cannot establish the efficacy or causal effects of psilocybin, and larger controlled studies are needed.

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.

Lipsitz, O., Brudner, R.M., Doyle, Z. et al. Exploratory safety, tolerability, and feasibility of psilocybin-assisted psychotherapy for adults with co-occurring treatment-resistant depression and cluster B personality disorders. npj Mental Health Res (2026). Read Paper

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