In a double‑blind randomised clinical trial of 30 US frontline clinicians with pandemic‑related depression, a single 25 mg psilocybin session (with preparatory and integration visits) produced a significantly greater reduction in clinician‑rated depressive symptoms at 28 days than 100 mg niacin (mean MADRS change −21.33 vs −9.33; mean difference −12.00, 95% CI −17.67 to −6.33; P < .001). Improvements in burnout and PTSD symptoms were numerically larger with psilocybin but did not reach statistical significance.
Papers cited by this study that are also in Blossom
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Importance
The psychological morbidity experienced by physicians, advanced practice practitioners (APPs), and nurses from working during the COVID-19 pandemic includes burnout, depression, and posttraumatic stress disorder (PTSD).
Objective
To investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic.
Design, Setting, and Participants
This double-blind randomized clinical trial enrolled participants from February to December 2022. Participants included physicians, APPs, and nurses who provided frontline care for more than 1 month during the pandemic and had no prepandemic mental health diagnoses but had moderate or severe symptoms of depression at enrollment. Participants were randomly assigned to either the psilocybin or niacin arm. Data analysis was conducted between December 2023 and May 2024 and was based on the intention-to-treat principle.
Intervention
One intervention episode consisted of 2 preparation visits, 1 medication session, and 3 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally.
Main Outcome and Measures
The primary outcome was a change from baseline (preparation 1 session) to day 28 (after medication administration) in symptoms of depression as measured by the clinician-administered Montgomery-Asberg Depression Rating Scale (MADRS) used by blinded raters. The secondary outcomes were a change in symptoms of burnout (measured with the Stanford Professional Fulfillment Index [SPFI]) and symptoms of PTSD (measured with the Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [PCL-5]).
Results
A total of 30 clinicians (15 females [50%]; mean [range] age, 38 [29-60] years) participated, of whom 15 were randomly assigned to receive psilocybin and 15 to receive niacin. The mean change in symptoms of depression (MADRS scores) from preparation 1 session to day 28 was −21.33 (7.84) in the psilocybin arm compared with −9.33 (7.32) in the niacin arm, with a mean difference between arms of −12.00 (95% CI, −17.67 to −6.33; P &lt; .001), a decrease in MADRS scores indicating improvement. The mean change in SPFI scores from preparation 1 session to day 28 showed a numerically larger improvement in symptoms of burnout in the psilocybin compared with the niacin arm (−6.40 [5.00] vs −2.33 [5.97]; P = .05) but was not statistically significant. Since the SPFI score change did not reach statistical significance, the PCL-5 score change was evaluated descriptively. The mean change in PCL-5 scores showed a numerically larger decrease in symptoms of PTSD from preparation 1 session to day 28 in the psilocybin vs the niacin arm (−16.67 [15.04] vs −6.73 [10.69]), but this difference was not statistically tested.
Conclusions and Relevance
This randomized clinical trial found that psilocybin therapy resulted in a significant, sustained reduction in symptoms of depression experienced by clinicians after frontline work during the COVID-19 pandemic. The findings establish psilocybin therapy as a new paradigm of treatment for this postpandemic condition.
Frontline physicians, advanced practice practitioners, and nurses experienced substantial psychological morbidity during the COVID-19 pandemic, including burnout, depression, and posttraumatic stress disorder (PTSD). At pandemic peaks these clinicians faced prolonged exposure to critically ill patients, high mortality, extended work hours, fear for personal and family safety, isolation, and politically motivated hostility; these stressors contributed to a pandemic-related syndrome with features overlapping first-responder trauma, burnout, and depression. Earlier clinical studies reported that psilocybin administered with psychological support produced reductions in depression and anxiety in populations such as people with major depressive disorder, treatment-resistant depression, or cancer-related distress, but it remained unclear whether psilocybin therapy could help clinicians whose symptoms emerged specifically from pandemic frontline work. Back and colleagues therefore designed a randomized clinical trial to test whether a single episode of psilocybin therapy (25 mg, given with preparation and integration sessions) would improve symptoms of depression, burnout, and PTSD in US clinicians who developed moderate to severe symptoms after providing frontline care during the pandemic. The trial compared psilocybin plus psychological support with an active placebo (niacin, 100 mg) plus the same therapeutic milieu, with change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores from baseline to day 28 specified as the primary outcome.
This was a double-blind, randomized clinical trial conducted at the University of Washington between February and December 2022, approved by the institutional review board and conducted according to CONSORT guidelines. Eligible participants were physicians, APPs, or nurses who had provided more than 1 month of direct frontline COVID-19 care, endorsed at least 2 of 4 high-exposure items on a COVID-19 occupational exposure index, reported no prepandemic mental health diagnosis (self-reported), and had persistent moderate to severe depressive symptoms (participant-scored MADRS ≥ 21) for at least 6 months despite at least one prior trial of medication and/or therapy. Key exclusions included a first-degree family history of schizophrenia, bipolar or paranoid disorder, current substance use disorder, recent psychedelic use (within 12 months), pregnancy, and unstable medical conditions. Recruitment used a study website and newsletters; screening combined web surveys, telephone screening, and in-person medical and psychiatric assessment including ECG and labs. Randomisation was performed by a faculty member unaffiliated with the study using block sizes of 6; an investigational pharmacist dispensed numbered envelopes and both participants and study staff (including facilitators and raters) were blinded. The intervention episode comprised two 60–90 minute preparation sessions (day −8 and day −1), a medication session (day 0) of approximately 7 hours, and three integration sessions (days 1, 8, and 15 reported in some places, with follow-up at days 28, 56, 84, and 180). Facilitators were interprofessional and used a facilitator manual with specified elements for preparation, medication, and integration. Sessions combined secular ceremonial elements, a curated music programme matched to the pharmacologic trajectory, encouragement of eyeshades, and explicit guidance on touch and support. The experimental medication was a fixed oral psilocybin dose of 25 mg; the control was oral niacin 100 mg, both provided in identical capsules by Usona Institute. Participants were intentionally not given a diagnostic label in records; the study obtained a certificate of confidentiality. The prespecified primary outcome was the change in MADRS score (blinded clinician-administered) from baseline (preparation 1) to day 28. Secondary outcomes, in a hierarchical order, were change in burnout measured by the Stanford Professional Fulfillment Index (SPFI) burnout subscale and change in PTSD symptoms measured by the PCL-5. The SPFI burnout subscale assesses work exhaustion and interpersonal disengagement; the PCL-5 is a 0–80 symptom checklist for PTSD. The Mystical Experience Questionnaire (MEQ-30) and adverse events including suicidal ideation (Columbia Suicide Severity Rating Scale) were collected at the medication session. The trial was powered a priori for the primary outcome assuming an effect size of 1.06 SD; with 15 participants per arm the study had 80% power at a two-sided α = .05. Analyses followed the intention-to-treat principle, used two-sample t tests for mean change comparisons after testing assumptions, applied the prespecified hierarchical testing sequence to control type I error, and evaluated the correlation between MEQ-30 and MADRS change with linear regression (Pearson coefficient). Participants were unblinded after completing day 28 questionnaires; those assigned to niacin were offered open-label psilocybin with the same protocol and follow-up.
INTERVENTION One intervention episode consisted of 2 preparation visits, 1 medication session, and 3 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally. participated, of whom 15 were randomly assigned to receive psilocybin and 15 to receive niacin. The mean change in symptoms of depression (MADRS scores) from preparation 1 session to day 28 was -21.33 (7.84) in the psilocybin arm compared with -9.33 (7.32) in the niacin arm, with a mean difference between arms of -12.00 (95% CI, -17.67 to -6.33; P < .001), a decrease in MADRS scores indicating improvement. The mean change in SPFI scores from preparation 1 session to day 28 showed a numerically larger improvement in symptoms of burnout in the psilocybin compared with the niacin arm (-6.40 [5.00] vs -2.33 [5.97]; P = .05) but was not statistically significant. Since the (continued)
The psychological morbidity experienced by physicians, advanced practice practitioners (APPs), and nurses working during the COVID-19 pandemic included burnout, depression, and posttraumatic stress disorder (PTSD). At the peaks of the pandemic, these clinicians were exposed to intense suffering, high death rates, decision-making under extreme uncertainty, prolonged work shifts, fear for their own and their families' safety, and isolation due to self-quarantine.These experiences were psychologically challenging for some clinicians, even in the absence of preexisting mental health diagnoses.This pandemic-related syndrome has features of first-responder trauma, burnout, and depression.During the first peak of the pandemic, physicians, APPs, and nurses served as first responders.As the value of face masks became clear and as the vaccines arrived, these clinicians became the targets of politically motivated attacks.These incidences occurred on top of worsening burnout.While PTSD, moral distress, burnout, and depression are different constructs, there are associations between them.In earlier studies, psilocybin administered in the context of psychological support or therapy demonstrated improvements in individuals with major depressive disorder and treatment-resistant depression.Psilocybin therapy has also improved symptoms of depression and anxiety in patients with cancer,whose symptoms also followed a life event and involved confrontations with mortality.In this randomized clinical trial, we aimed to investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic.
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Papers in Blossom that reference this study
Lewis, B. R., Hendrick, J., Byrne, K. et al. · PLOS Medicine (2025)
Williams, Z. J., Barnett, H., Szigeti, B. · OSF Preprints (2025)
Thirty US clinicians were enrolled and randomised, 15 to psilocybin and 15 to niacin; the sample was 50% female and 50% male with a mean age of 38 years (range 29–60). All participants completed the intervention sessions. For the primary outcome, the mean (SD) change in MADRS score from preparation 1 to day 28 was −21.33 (7.84) in the psilocybin arm and −9.33 (7.32) in the niacin arm, yielding a mean difference in change scores of −12.00 (95% CI, −17.67 to −6.33; P < .001), favouring psilocybin. The reduction in depressive symptoms in the psilocybin arm was sustained through month 6 (mean decrease −24.00; 95% CI, −26.87 to −21.13). For context, the authors note that a 6–9 point MADRS change is typically considered clinically meaningful and that the minimum clinically important difference is around 1.6–1.9 points. For the first secondary outcome, burnout measured by the SPFI burnout subscale decreased more in the psilocybin arm than the niacin arm (mean [SD] change −6.40 [5.00] vs −2.33 [5.97]; reported P = .05), though the authors state this did not meet their prespecified significance threshold for continuing hierarchical testing. Because that secondary outcome did not reach the prespecified significance, the PCL-5 PTSD outcome was reported descriptively: mean change in PCL-5 was −16.67 (15.04) in the psilocybin arm versus −6.73 (10.69) in the niacin arm, a numerically larger decrease in PTSD symptoms that was not formally hypothesis-tested under the hierarchical plan. Immediate post-session MEQ-30 scores indicated a much deeper subjective medication experience after psilocybin than niacin (mean 129.40 [range 88–119] vs 15.07 [0–52]), and higher MEQ-30 scores correlated modestly with greater MADRS improvement (R = 0.701). Safety outcomes showed no serious adverse events. Common acute adverse events on the day of psilocybin included mild nausea (4 participants, 27%), mild headache (reported as 27% in the text), mild tachycardia (2 participants, 13%), and transient hypertension (mild in 6 [40%], moderate in 8 [53%], severe in 1 [7%]); these cardiovascular changes resolved within 20 minutes without medical intervention. There were no psychosis episodes or attempts to leave the treatment room. One participant experienced transient passive death wishes on day 28 after open-label psilocybin but reported no intent or plan and symptoms did not recur. Functional unblinding was evident: immediately after ingesting the capsule 100% of participants reported not knowing which treatment they had received, but by the end of the medication session 100% reported knowing and were correct. Illustrative participant comments from preparatory and integration sessions described feelings of disposability and guilt and, after the intervention, increased openness to support, perspective, and realignment of professional meaning; examples included “I feel more disposable than a used COVID-19 swab” and “I'm reaching out and leaning on others…and trusting that the people around me can support me.” Of the 15 participants initially randomised to niacin, 12 (80%) later received open-label psilocybin; in those open-label episodes the mean baseline MADRS was 20.17 (10.11) and the mean MADRS change from preparation 1 to day 28 was −12.83 (95% CI, −18.29 to −7.38). During follow-up 21 participants (70%) reported substantial changes in work role or full-time equivalent status, 8 (27%) remained in the same position, and 1 (3%) remained unemployed; no participants left health care.
Back and colleagues interpret their findings as evidence that a single episode of psilocybin therapy administered with structured preparation and integration can produce large, rapid, and sustained reductions in depressive symptoms among clinicians who developed moderate to severe depression while providing frontline COVID-19 care. The authors propose a biological rationale—psilocybin is a partial 5-HT2A receptor agonist that facilitates neuroplasticity—together with a therapeutic rationale that the structured psychotherapeutic context enabled participants to process complex pandemic-related emotions. They emphasise that both arms received the same counselling and support, suggesting that the pharmacologic component substantially augmented the therapeutic effect. Compared with prior trials of psilocybin in major depressive disorder and treatment-resistant depression, the present sample differed in that participants generally had no prepandemic mental health diagnoses; nonetheless, most had previously tried counselling and more than half had used antidepressants. The authors highlight that the observed 21-point mean MADRS decrease exceeds typical thresholds for clinical meaningfulness and is larger than many prior reported effects. Although the SPFI burnout outcome did not reach the prespecified significance threshold, the authors note that the trial was small and possibly underpowered for burnout; similarly, the 16-point PCL-5 decrease in PTSD symptoms exceeded commonly used thresholds for clinical meaningfulness (10 points) but was not formally tested under the hierarchical analysis. The investigators acknowledge several limitations. Chief among them is the small sample size and consequent limits on generalisability. Recruitment interest greatly exceeded enrolment (2,247 expressing interest vs 30 enrolled), raising the possibility of selection biases despite randomisation at each recruitment step. Functional unblinding—participants and facilitators could accurately distinguish psilocybin from niacin by the end of the medication session—was a limitation inherent to psychedelic trials and complicates interpretation of expectancy effects. The trial also did not include a psilocybin arm without therapy, so the independent contribution of the psychological support cannot be separated from the pharmacologic effect. Finally, the authors report that participants were unblinded after day 28 and many in the control group received open-label psilocybin, which affects longer-term between-group comparisons. Despite these caveats, the study team concludes that psilocybin therapy was associated with substantial improvements in depressive symptoms in this specific clinician population and that the intervention was generally well tolerated.
The University of Washington Institutional Review Board approved this trial (trial protocol in Supplement 1). Written informed consent was obtained from all participants. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Between February and December 2022, this double-blind randomized clinical trial enrolled physicians, APPs, and nurses who were frontline workers during the pandemic. To be eligible, clinicians had to have more than 1 month of direct frontline clinical care experience and had to endorse at least 2 of 4 items from a COVID-19 occupational exposure index as occurring more than half of the day during that time. These items included caring for a patient critically ill with COVID-19,
Psilocybin Therapy for Clinicians With Symptoms of Depression After the Pandemic working longer hours to provide care to patients with COVID-19, witnessing or responding to a death from COVID-19, or caring for a patient who died without their family present due to pandemicrelated precautions.Additional eligibility criteria included absence of prepandemic mental health diagnosis (self-reported), moderate or severe symptoms of depression (score Ն21) on a participantscored version of the Montgomery-Asberg Depression Rating Scale (MADRS; score range: 0-60, with higher scores indicating worse symptoms),persistent depression symptoms for at least 6 months despite 1 or more trials of medication and/or therapy, nonpregnant, agreement to use contraception, and willingness to taper antidepressant use. Exclusion criteria included a first-degree family history of schizophrenia, bipolar disorder, or paranoid disorder; current substance use disorder; use of psychedelics within 12 months; and unstable medical conditions. Recruitment was conducted through a study website and online newsletters. Screening for potential participants included a web-based survey; a telephone screening call; and an in-person visit with an interview, medical and psychiatric history, physical examination, laboratory tests, and an electrocardiogram. Randomization was performed by a University of Washington faculty member not associated with the study, who generated a random number sequence using Research Randomizer in block sizes of 6. An investigational pharmacist placed the study medication in numbered envelopes, which were dispensed in the order that medication sessions occurred. Study facilitators were given an envelope containing the study medication immediately before each medication session. The participants, facilitators, principal investigator, study coordinator, and outcome raters were all blinded to the treatment group assignment. Participants were assigned to either the psilocybin (experimental) or niacin (active placebo) arm (Figure). The last outcome measure from the randomized cohort was completed in August 2023.
One intervention episode consisted of 2 preparation sessions, 1 medication session, and 3 integration sessions or visits (eFigure in Supplement 2). The study facilitators were diverse, interprofessional,including a residential retreat with experiential breathwork.At least 1 preparation session and 1 integration session were conducted in person; the rest of the sessions were provided on video. All sessions lasted 60 to 90 minutes. The 2 preparation sessions occurred on day -8 and day -1 prior to the medication (psilocybin or niacin) session. The medication session (day 0) lasted approximately 7 hours, and the 3 integration sessions occurred on days 1, 8, and A facilitator manual outlined process-specific elements for each session. For the preparation sessions, these elements included the participant's professional story, unfinished business from their work during the pandemic, personal strengths and challenges, and intentions for the medication session. That session focused on allowing the participant to have their own experience of the medication, with minimal dialogue unless support was requested. For the integration sessions, the elements were the experience with the medication; insights or lessons from that experience; and how to take lessons forward, with an emphasis on embodied practices.Cases were reviewed in weekly meetings that included supervision. In the experimental arm, the medication was a fixed dose of psilocybin, 25 mg, orally. In the control arm, the medication was niacin, 100 mg, orally. The medication was provided in identical white capsules (by Usona Institute) and administered with elements of secular ceremony,such as participants bringing in a photograph or keepsake. The purpose of ceremony was to reinforce the participant's belief that they could change and to incorporate their own spirituality. During the medication session, participants could sit in a chair or lie down on a bed, and using an eyeshade was encouraged. Both facilitators were present. The music was streamed from Wavepaths,played through speakers and headphones, and was a study-specific curated mix of adaptively generated and fixed musical segments with a consistent trajectory matching the pharmacologic effects of psilocybin. Facilitators instructed participants about the use of touch (eg, taking blood pressure and offering a hand for support) and elicited touch preferences. Participant-reported measurement data were collected prior to the first preparation (preparation 1) session, the day of the medication session (day 0), and the day after the medication session (days 1, 8, 15, 28, 56, 84, and 180). Measures at the medication session were collected on paper (medication experience using Mystical Experience Questionnaire, 30 Questions [MEQ-30; 0-150, with higher scores indicating more intense symptoms]; adverse events; and suicidal ideation and behavior using Columbia Suicide Severity Rating Scale [score range varies]). Other measures were collected on a mobile secure data platform (Quantified Citizen).
Participants received check-in text messages in the evening after their medication session. In addition to the 3 planned integration sessions, additional supportive visits were available. Participants were unblinded after they completed the day 28 questionnaires; those who received niacin could then schedule an open-label psilocybin session. Participants who were randomly assigned to the niacin arm had no further questionnaires to complete after day 28; those randomly assigned to the psilocybin arm completed questionnaires until month 6. The open-label psilocybin sessions had the same intervention structure and follow-up questionnaire schedule as the randomized psilocybin sessions.
Psilocybin Therapy for Clinicians With Symptoms of Depression After the Pandemic
The prespecified primary outcome was a change in symptoms of depression from baseline (preparation 1 session) to day 28 (after the medication session). The primary measure was the MADRS administered by blinded raters,licensed clinicians who were trained in the MADRS for this study (provided by Valis Bioscience) and passed a qualifying examination. Participants were intentionally not given a diagnosis of depression so that they would not be obliged to report a mental health diagnosis to a licensing board. No information about study participation was entered into an electronic medical record. A certificate of confidentiality was obtained. The prespecified secondary outcomes were change from preparation 1 session to day 28 in symptoms of burnout, measured using the Stanford Professional Fulfillment Index (SPFI; burnout subscale score range: 0-10, with higher scores indicating worse symptoms),and symptoms of PTSD, measured using the Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5; score range: 0-80, with higher scores indicating worse symptoms).The SPFI has 2 subscales: burnout and fulfillment. For this analysis, the SPFI burnout subscale (work exhaustion and interpersonal disengagement) and the PCL-5 are reported. Functional unblinding was assessed using 2 questions (eTable in Supplement 2).
The null hypothesis was that the mean change in MADRS score from the preparation 1 session to day 28 would be the same in both niacin and psilocybin groups. The alternative hypothesis was that the change in the psilocybin group would be greater than the change in the niacin group, with an assumed true effect size of 1.06 SD units based on findings in prior studies.With 15 participants per group, this study had 80% power to observe a statistically significant difference between groups in mean MADRS score change from baseline to day 28 (at the 2-sided significance level of .05). Change scores were calculated as the difference between baseline and day 28 scores, with a decrease in scores indicating improvement. The difference in mean change between the 2 treatment groups was assessed with a 2-sample, 2-tailed t test of equal variances using the intent-to-treat principle (after testing for normality and equality of variances). A hierarchical approach was prespecified for the analysis of the primary and secondary end points in the following order: MADRS, SPFI, and then PCL-5.When one of the outcome analyses did not reach statistical significance, further outcomes were analyzed descriptively to maintain the overall type I error rate of .05. The correlation between the MEQ-30 and MADRS scores was evaluated using linear regression and summarized with a Pearson coefficient. All reported P values were 2-sided, and statistical tests used a 2-sided α = .05. All analyses were performed between December 2023 and May 2024 using SAS, version 9.4 (SAS Institute Inc). No changes were made to the methods after trial commencement.
A total of 30 US clinicians were enrolled and randomized, of whom 15 (50%) were females and 15 (50%) were males with a mean (range) age of 38 (29-60) years. All participants completed all intervention sessions. Fifteen participants were randomized to psilocybin and 15 were randomized to niacin. For the primary outcome, the mean (SD) change in MADRS score from preparation 1 session to day 28 was -21.33 (7.84) in the psilocybin arm and -9.33 (7.32) in the niacin arm, with a mean difference in change scores of -12.00 (95% CI, -17.67 to -6.33; P < .001) (Tableand Figure). The decrease in MADRS scores (indicating improvement) in the psilocybin arm was sustained through the month 6 follow-up (mean decrease, -24.00; 95% CI, -26.87 to -21.13) (Figure). To put these MADRS score decreases into context, the minimum clinically important difference in change scores is 1.6 to 1.9.For the secondary outcomes, the mean change in SPFI scores from preparation 1 session to day 28 showed a numerically larger decrease (indicating improvement) in burnout symptoms in the psilocybin arm compared with the niacin arm (mean [SD] score change, -6.40 [5.00] vs -2.33 [5.97]; Montgomery-Asberg Depression Rating Scale (MADRS) scores ranged from 0 to 60, with the higher scores indicating worse symptoms. P = .05). This improvement did not reach the prespecified significance level of .05, however (Table). Since the first secondary outcome did not meet the prespecified significance level, the next secondary outcome, measured with PCL-5, was evaluated descriptively only. The mean change in PCL-5 scores from preparation 1 session to day 28 showed a numerically larger improvement in PTSD symptoms in the psilocybin arm compared with the niacin arm (mean score change, -16.67 [15.04] vs -6.73 [10.69]). Due to the prespecified hierarchical analysis, this difference was not statistically tested (Table). The MEQ-30 scores immediately after the medication session showed a numerically greater depth of the medication experience in the psilocybin arm compared with the niacin arm (mean [range] score, 129.40 [88-119] and 15.07 [0-52]). Higher MEQ-30 scores showed a modest correlation with improvement in MADRS scores from preparation 1 session to 28 (R = 0.701). No serious adverse events occurred. Other adverse events were managed without medical intervention except for 1 instance of nausea in the psilocybin group. On the day of the psilocybin administration, other adverse events occurred, such as mild nausea (4 [27%]), mild headache ([27%]), mild tachycardia (2 [13%]), and hypertension (mild, 6 [40%], moderate, 8 [53%], or severe, 1 [7%], which resolved in <20 minutes without medical treatment). There were no episodes of psychosis or attempts to leave the room without permission. For the niacin sessions, 1 participant experienced a mild headache. After day 0, there were no episodes of thought distortion (derealization or depersonalization) or perceptual disturbances. The most serious psychiatric adverse event involved 1 participant on day 28 after receiving open-label psilocybin; the individual had transient thoughts that they might be "better off dead," without suicidal intention or plans; these thoughts did not recur. The functional unblinding questions showed that just after they swallowed the capsule, 100% of participants said they did not know whether they received psilocybin or niacin. At the end of the session, however, 100% stated they knew-and were correct (eTable in Supplement 2). Illustrative comments from the preparation sessions included the following: "I feel more disposable than a used COVID-19 swab"; "It got to the point where I felt like I was participating in the torture of people"; and "I found myself waking up in the middle of the night and logging on to Epic to see if anyone I'd sent home had come back and died or gone to the ICU [intensive care unit]." Illustrative comments from the integration sessions were as follows: "I'm reaching out and leaning on others…and trusting that the people around me can support me. I don't have to carry it all by myself"; "I'm learning to just embrace dystopia…you have to adapt"; and "I was shown my tendency to be a superhero…[during my trip I received] messaging that 'It's not about you'-that was done with grace, love, and accountability." Of the 15 participants in the niacin group, 12 (80%) received an episode of open-label psilocybin therapy. These open-label episodes had preparation, medication, and integration sessions and follow-up questionnaires, as in the randomized psilocybin arm. In these open-label episodes, the mean (SD) baseline MADRS score was 20.17 (10.11), and the mean change in MADRS score from preparation 1 session to day 28 was -12.83 (95% CI, -18.29 to -7.38) (Figure). Employment changes over the course of the trial follow-up were notable. Because most participants assigned to the niacin group went on to receive open-label psilocybin, these results are reported for the entire group. During their follow-up, 21 participants (70%) reported a change in their work role or full-time equivalent status that substantially changed their responsibility or institution; 8 (27%) remained in the same position; and 1 (3%) remained unemployed. No one left the health care field.
To our knowledge, this trial is the first to demonstrate the utility of psilocybin therapy in the treatment of physicians, APPs, and nurses who developed moderate to severe symptoms of
Psilocybin Therapy for Clinicians With Symptoms of Depression After the Pandemic depression in the course of frontline work during the COVID-19 pandemic. Biologically, psilocybin is a partial agonist of the 5-HT2A receptor, with downstream effects of inducing neuroplasticity, which likely underlies these benefits.Therapeutically, psilocybin in this study was administered within the context of preparation, medication, and integration sessions by specially trained clinicians.These facilitators used session-specific protocols that emphasized the possibility of change, allowing emotions typically avoided, in-the-moment unfolding of the medication session, insights emerging from that experience, and cultivation of practices to bring those insights into daily life. The statistically significant difference between the psilocybin and niacin arms, both of which had the same counseling, attests to how much psilocybin added to the therapeutic intervention. The results for the primary outcome showed a statistically significant improvement in symptoms of depression (as measured by the for participants in the psilocybin arm, which was sustained for most of the participants for 6 months. This 21-point decrease in MADRS scores is striking when a 6-to 9-point change in the MADRS is considered clinically meaningful.The change in symptoms of burnout did not reach statistical significance, but this small trial may have been inadequately powered for this outcome. A recent systematic review of interventions for physician burnout tested in randomized clinical trials found numerical changes that were "unlikely [to] result in meaningful changes in clinical burnout"; in contrast, a number of participants described their study experience as life-changing. Furthermore, while the significance of the change in PTSD symptoms was not analyzed due to the hierarchical analytic plan, the 16-point decrease in PCL-5 scores for the psilocybin arm was well above the 10-point decrease considered clinically meaningful.This trial builds on past studies showing that psilocybin therapy was effective for depression and treatment-resistant depression in individuals with much longer durations of illness and often multiple regimens of antidepressants. By contrast, participants in this study had no prepandemic mental health history other than moderate to severe symptoms of depression, burnout, and PTSD. The efficacy of psilocybin in this study is notable given that 100% of the participants had previously tried counseling and more than 50% had tried an antidepressant. Their rapid and sustained response indicates that psilocybin therapy is a new paradigm of treatment for the postpandemic depressive symptoms in clinicians. Although the trial did not include an arm of psilocybin without therapy, the issues that emerged suggest a complex psychological landscape that would be difficult for any individual to navigate alone. Clinicians described a sense of betrayal by health systems, leaders, and colleagues; guilt from feeling that they had not been able to do enough; and grief from witnessing innumerable deaths and suffering. The question that repeatedly came up, in different forms, was "Do I matter?" What psilocybin-assisted therapy did, when it was successful in this trial, was enable participants to take some time amid the urgency of their professional and personal lives to feel all of their feelings, find some perspective on their recent past, and come to terms with what they were unable to do-and what they were able to accomplish-for patients, families, colleagues, and society. Following their experience, many participants were able to locate their own resources, give themselves permission to take care of themselves, and start to reconstruct the meaning that their work still holds. While most participants intentionally made major changes to their clinical work during their participation in the trial, none left health care altogether.
This study has limitations. Because it was a small trial, its findings might not be generalizable. Many more clinicians indicated interest (2247) than could be enrolled (30), and while we selected participants randomly at each step of recruitment, unknown biases may be present. Additionally, the participants and facilitators, all of whom reported not knowing which medication was given at the moment of ingestion, found that after 2 hours they could distinguish niacin from psilocybin with 100% precision. Functional unblinding is an issue for all studies involving psychedelic therapies; in