Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin

Introduction

Over the past two decades, psychedelics have re-emerged as a promising treatment for numerous psychiatric disorders, including major depressive disorder, treatment-resistant major depression, and cancer.

Results from psilocybin-for-TRD randomized clinical trials have been promising, but several important limitations have been observed. These limitations may in part contribute to the large effect sizes observed in many trials completed to date, and the strict eligibility criteria used in clinical trials reduces the generalizability into real-world clinical settings.

The durability of the clinical benefits of psilocybin in acute responders who later experience a relapse of depression is still unknown. However, intuitively, a repeat course of treatment may be advantageous.

The required ”dose” of psychotherapy for safe and effective use of psilocybin remains unknown, and a therapy protocol that is brief would benefit scalability, cost effectiveness, and feasibility.

The researchers conducted an RCT to evaluate the feasibility of a brief four-session model of PAP for TRD with broader eligibility criteria, and to evaluate the feasibility, efficacy, and safety of repeat psilocybin sessions for participants showing signs of relapse.

Results

Participants were recruited from November 1, 2021, to February 1, 2023, and were randomized to receive immediate treatment or delayed treatment. A total of 21 participants were retained for the 6-month follow-up period.

Baseline characteristics of the sample show that the mean age was 44.4 years, that the mean depression duration was 18.3 years, that the majority of participants had failed numerous forms of psychotherapy, and that the immediate treatment group was more severe than the control group.

All four feasibility criteria were met: only 1/30 participants dropped out before week-2, there were zero serious adverse events, and only one treatment-emergent adverse event persisted past 48 h.

Rosenblat et al. evaluated open-label data showing sustained reductions in MADRS scores over time, with the greatest reduction observed with the third dose. However, self-reported symptoms of anxiety had only improved slightly, with symptom severity returning close to baseline levels after 2 months.

Discussion

The present study demonstrated feasibility for evaluating psilocybin in a more complex patient population including ultra-refractory depression, both MDD and BDII, substantial comorbidity, and baseline suicidality. Improvements in depressive symptoms aligned with improvements in the primary clinician-rated measure.

The authors recently completed a systematic review and meta-analysis of 13 clinical trials evaluating PAP in MDD, TRD, and life-threatening illness. Two trials have evaluated PAP specifically in TRD. The second trial found that a single 25-mg dose of psilocybin was associated with greater reductions in the MADRS compared to 1 mg. Still, the control arm would be expected to have a larger effect with psychotherapy and placebo compared to this open-label waitlist control arm.

The present trial included patients with MDD and BDII, and did not exclude comorbid personality disorders, complex cases, the presence of baseline suicidality, or higher levels of treatment resistance. It included one participant with 4 failed medication trials, whereas all other participants had greater than 4 failed medication trials.

The study included patients with borderline personality disorder II and TRD with comorbid borderline personality in a rapid-acting treatment trial. No treatment-emergent mania, hypomania, or psychosis was observed, and no additional safety concerns were observed in this group.

The present study was the first to allow for flexible repeat doses of psilocybin, and established feasibility for providing additional doses upon relapse as long as antidepressant effects were observed and there were no additional adverse events or safety concerns.

The authors anticipate that psilocybin will still be clinically significant in a complex population, and that the optimal number of psilocybin doses will still be a priority research question.

Limitations of the study

The present study has several major limitations, including an open-label design, small sample size, use of waitlist controls, and substantial sample heterogeneity. Nevertheless, the results may contribute toward regulatory approval of psilocybin for TRD.

The present study modified several critical aspects of study design compared to previous trials, and it is difficult to determine which of these modifications contributed to the observed clinical effects.

Star ★ Methods

Experimental model and study participant details

Study design

This randomised, waiting list-controlled clinical trial was conducted at Braxia Health in Mississauga, Ontario, Canada. It was the first Canadian psilocybin clinical trial, and the investigators carefully considered how they would envision PAP being used clinically in the future.

Participants

This trial included participants with a primary diagnosis of MDD or BDII with a current Major Depressive Episode (MDE) of at least three months duration. No depression severity cut-off was used for this trial.

Eligible candidates were aged 18 to 75 who had failed at least two pharmacological treatments for depression and were willing to taper off current pharmacotherapy.

Candidates were required to refrain from using antidepressants, antipsychotics, ketamine, esketamine or any augmenting medications for at least 5 half-lives before the screening and for the 6-month follow-up period. However, participants could continue using conventional mood stabilisers.

Participants had to be medically stable and have no uncontrolled cardiovascular conditions or major concurrent illnesses. They could not be pregnant, nursing, or planning a pregnancy, and must have stopped using ketamine at least 30 days prior to enrollment.

Method details

Randomisation and masking

Blocked randomisation was used to form the allocation list for the two comparison groups. There was no blinding of researchers, therapists or participants.

Procedures

Synthetic psilocybin was obtained from Usona Institute in powder form and combined with 100mL of water for each dosing session. Screening consisted of verbal and written informed consent, a comprehensive evaluation of physical and mental health by a study doctor, and a structured clinical interview. Patients were also required to undergo an electrocardiogram, routine blood tests, drug urine toxicology test, pregnancy test, and physical examination.

Participants were randomised to begin treatment immediately or after a 2-week delay. They had one, two or three psilocybin sessions with a fixed dose of 25 mg synthetic psilocybin powder dissolved in water.

Psychotherapy was provided by multidisciplinary therapist dyads with licences to practise psychotherapy in the local jurisdiction of Ontario. The therapists underwent a training program specifically designed for the present trial, which consisted of extensive pre-reading, didactic teaching, supervised cases and ongoing peer group supervision.

The participant was provided with food and beverages during the first 1 – 3 h of treatment, and a journal to document any points they deemed significant or noteworthy during the psilocybin experience. One week later, a final integration session occurred.

Participants were eligible for a second psilocybin dose after 10 weeks if they showed clinical benefits from the first dose and adequate tolerability/safety of the prior dose.

Participants were assessed in person or virtually for all study visits and psychotherapy sessions. Psilocybin administration visits were conducted on site (no virtual option).

Quantification and statistical analysis

Outcomes

Three sets of outcome measures were collected: safety and tolerability, antidepressant efficacy, and exploratory outcomes. Blood and serum samples were collected for future exploratory analysis that has not been conducted to date.

A feasibility study was conducted to determine if a new medication could reduce suicidality.

Statistical analysis

In this feasibility study, the author didn’t perform a formal power calculation, and selected 12 participants per arm based on the n = 12 rule-of-thumb for feasibility studies. They assessed preliminary efficacy of treatment using MADRS scores, and calculated effect sizes using the Hedges’ g formula.