Psilocybin-assisted group psychotherapy and mindfulness-based stress reduction for frontline healthcare provider COVID-19-related depression and burnout: A randomized controlled trial

Background: Depression and burnout, which are common among healthcare workers, were exacerbated by the COVID-19 pandemic. Mindfulness-Based Stress Reduction (MBSR) and psilocybin have been reported to reduce depressive symptoms, but the efficacy of the combination requires comparison to an active treatment control. We sought to evaluate the safety and preliminary efficacy of psilocybin and MBSR versus MBSR alone for frontline healthcare providers with symptoms of depression and burnout related to the COVID-19 pandemic. We hypothesized that psilocybin would augment the antidepressant effects of MBSR in this population. Methods and findings We conducted a randomized controlled trial that enrolled physicians and nurses with frontline clinical work during the COVID-19 pandemic and symptoms of depression and burnout. (ClinicalTrials.gov Identifier: NCT05557643) Participants were enrolled between January 2nd, 2023 and January 16th, 2024, and randomized in a 1:1 ratio to either an 8-week MBSR curriculum alone or an 8-week MBSR curriculum plus group psilocybin-assisted psychotherapy (PAP) with 25 mg psilocybin. Evaluation of safety and feasibility of enrollment and retention was a primary objective of the study. The primary efficacy endpoint was change in depressive symptoms, as measured by the Quick Inventory of Depressive Symptoms (QIDS-SR-16) at 2 weeks post-intervention. Symptoms of depression and burnout were assessed at baseline, and 2 weeks and 6 months post-intervention utilizing the Quick Inventory of Depressive Symptoms (QIDS-SR-16) and Maslach Burnout Inventory Human Services Survey for Medical Professionals (MBI-HSS-MP), respectively. Secondary outcome measures included the Demoralization Scale (DS-II) and the Watt’s Connectedness Scale (WCS). Adverse events (AEs) and suicidality were assessed through a 6-month follow-up. Twenty-five participants were enrolled and randomized. Safety was a study outcome and assessed by rate and severity of AEs and any incident suicidality or significant mental health symptoms. Baseline and outcome data were summarized using descriptive statistics, with continuous variables reported as means and standard deviations. We recorded 12 study-related, Grade 1–2 AEs and no serious AEs. In a linear mixed model analysis (LMM), the MBSR + PAP arm evidenced a significantly larger decrease in QIDS-SR-16 score than the MBSR-only arm from baseline to 2-weeks post-intervention (between-groups effect = 4.6, 95% CI [1.51, 7.70]; p = 0.008). This effect waned at the 6-month follow-up. Secondary outcome measures for burnout (subscales of the MBI-HSS-MP), demoralization (DS II), and connectedness (WCS) favored the MBSR + PAP arm; however, these effects did not survive correction for multiple comparisons. A mixed RM-ANCOVA was conducted to control for baseline differences in outcome measures. Sensitivity analyses were conducted, adjusting for baseline differences in gender and clustering within group cohorts. Study limitations that affect the generalizability of results include a small sample size, homogenous study population, and significant differences in intervention intensity.

Conclusions: This trial met its primary endpoint: group psilocybin-assisted therapy plus MBSR was associated with clinically significant improvement in depressive symptoms without serious AEs and with greater reduction in symptoms than MBSR alone. Our findings suggest that integrating psilocybin with mindfulness training may represent a promising treatment for depression and burnout among physicians and nurses. Larger trials are needed to establish efficacy, generalizability, and durability of these effects.