Effects of Psilocybin-Assisted Therapy on Major... — Research Summary & Context

Effects of Psilocybin-Assisted Therapy on Major... — Research Summary & Context | Blossom

Abstract

Importance

Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.

Objective

To investigate the effect of psilocybin therapy in patients with MDD.

Design, Setting, and Participants

This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).

Interventions

Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.

Main Outcomes and Measures

The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).

Results

Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.2; 95% CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 3.0; 95% CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9-4.2; P < .001). In the overall sample, 17* participants (71%*) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).

Conclusions and Relevance

Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.

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Research Summary of 'Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder'

Introduction

Major depressive disorder (MDD) is described as a leading global cause of disability with substantial personal and economic burden and limitations in current pharmacotherapies, including incomplete response, adverse effects, and adherence problems. Earlier research highlighted rapid but short-lived antidepressant effects of ketamine and preliminary evidence that one or two administrations of psilocybin, given with psychological support, produced antidepressant effects in patients with cancer-related distress and in small samples of treatment-resistant depression. Psilocybin was noted to act via serotonergic and possibly glutamatergic pathways and to have lower addiction liability and less long-term toxicity than ketamine, motivating further investigation in broader MDD samples. Davis and colleagues designed the present study to test whether psilocybin-assisted therapy reduces depressive symptoms in adults with moderate to severe MDD. The trial used a randomised, waiting list–controlled design to compare immediate administration of two psilocybin sessions (with psychological support) against an 8-week delayed treatment control, with clinician-blinded assessment of depression severity as the primary outcome.

Methods

This single-centre randomised clinical trial was conducted at the Center for Psychedelic and Consciousness Research in Baltimore. Eligible adults were aged 21–75 years, met DSM-5 criteria for current moderate or severe MDD (GRID-Hamilton Depression Rating Scale [GRID-HAMD] score ≥17), and were not using antidepressant medications at screening. Key exclusions included personal or first-/second-degree family history of psychotic or bipolar disorders, recent moderate-to-severe substance use disorders, substantial prior use of ketamine or classic hallucinogens, unstable medical conditions, and pregnancy or nursing in women. Recruitment proceeded from August 2017 to April 2019; 870 people were screened by phone or online, 70 underwent in-person screening, and 27 were randomised. Participants were randomised after baseline assessment using urn randomisation to balance sex, age, baseline depression severity, and treatment-resistance level; 2 participants were allocated to the immediate treatment group and the delayed group using this method (the extracted text reports final allocation of 13 and 11 completers respectively). The immediate treatment period lasted 8 weeks and included preparatory meetings (about 8 hours total) with two facilitators, two daylong psilocybin administration sessions a mean 1.6 weeks apart (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg, given in opaque capsules with water), and follow-up integration meetings (2–3 hours total). Facilitators came from a range of professional backgrounds and remained present during sessions while participants were encouraged to lie down, wear eyeshades and headphones, and focus inward with a music playlist. The delayed treatment (waiting list) group underwent weekly safety monitoring by brief telephone or in-person check-ins during the 8-week delay; GRID-HAMD assessments were obtained at weeks 5 and 8 before they received the active intervention. The primary outcome was GRID-HAMD score assessed by clinician raters blinded to condition at baseline and at the predefined postrandomisation time points that corresponded to week 1 and week 4 after intervention in the immediate-treatment group (these were weeks 5 and 8 for the delayed group). Secondary symptom measures included the Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR), Beck Depression Inventory II, Patient Health Questionnaire-9, clinician-rated Hamilton Anxiety Rating Scale, State-Trait Anxiety Index, and the Columbia–Suicide Severity Rating Scale. Blood pressure and heart rate were monitored during sessions. Interrater reliability for depression assessments through postsession week 4 was reported as 85%. Analyses were conducted on the evaluable population (participants who completed the intervention), with data analysis dated July 1, 2019 to July 31, 2020. The primary between-group test used a repeated-measures analysis of variance with time and condition factors; follow-up independent samples t tests compared corresponding time points between groups. Within-participant changes and rapid effects were examined with paired t tests on GRID-HAMD and QIDS-SR, with effect sizes reported as Cohen's d for t tests and partial eta squared for ANOVA. The trial sample size was justified by prior psilocybin data suggesting a large effect and consequent high power with approximately 24 participants. All tests used a two-sided P < .05 threshold.

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METHODS

This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research in Baltimore, Maryland. The Johns Hopkins Medicine Institutional Review Board approved this trial (the protocol is included in Supplement 1). Written informed consent was obtained from all participants.

RESULTS

Screening evaluation included a preliminary questionnaire administered via telephone or an online survey as well as an inperson medical history and physical examination, electrocardiogram, routine medical blood and urinalysis laboratory tests, and structured assessments (eg, SCID-5, SCID-5 Screening Personality Questionnaire, SCID-5 Personality Disorders, and Personality Assessment Inventory).The primary outcome measure was the GRID-HAMD,a version of the 17-item Hamilton Depression Rating Scale that has high reliability and validity.The GRID-HAMD was administered by blinded clinician raters via telephone at baseline and at postrandomization weeks 5 and 8 for participants in the delayed treatment group and at the weeks 1 and 4 follow-up visits after the second psilocybin session for participants in both the immediate treatment and delayed treatment groups. The primary between-group end point comparison was at weeks 5 and 8 between the immediate treatment and delayed treatment groups (Figure). The primary within-group end point comparison was between baseline and weeks 1 and 4 postsession 2 follow-up visits in both groups. Severity of depression was assessed using the total GRID-HAMD score (0-7: no depression; 8-16: mild depression; 17-23: moderate depression; ≥24: severe depression).A clinically significant response was defined as 50% or greater decrease from baseline; symptom remission was defined as a score of 7 or lower. The GRID-HAMD assessment was audiorecorded to examine interrater reliability (eMethods in Supplement 2). Interrater reliability for all depression assessments (through postsession week 4) was 85%. Rapid and sustained antidepressant effects were examined at baseline; at day 1 and week 1 of postsession-1 follow-up; and at day 1, week 1, and week 4 postsession-2 follow-up using the Quick Inventor y of Depressive Symptomatology-Self-Report (QIDS-SR; score range: 0-27, with higher scores indicating very severe depression).Descriptions of secondary outcome measures and timing of assessment are provided in the eMethods in Supplement 2. Secondary outcome measures for depressive symptoms were the Beck Depression Inventory II (score range: 0-63, with higher scores indicating severe depression)and the 9-item Patient Health Questionnaire (score range: 0-27, with higher scores indicating severe depression).The Columbia-Suicide Severity Rating Scale (severity of ideation subscale score range: 0-5, with higher scores indicating presence of ideation with at least some intent to die)was completed at every visit to assess for potentially worsening suicidal ideation throughout the trial. Anxiety symptoms were measured using the clinician-administered Hamilton Anxiety Rating Scale (score range: 0-56, with higher scores indicating severe anxiety)and the State-Trait Anxiety Index (score range: 0-80, with higher scores indicating greater anxiety).Blood pressure and heart rate were examined before and during the psilocybin sessions.

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Study Details

Study Type
individual
Population
humans
Characteristics
randomizedopen labeldose findingfollow up
Journal
JAMA Psychiatry
Compound
Psilocybin
Topics
Depressive Disorders Older Adults

Results

Twenty-seven participants were randomised and 24 (89%) completed the intervention and postsession assessments; the evaluable sample comprised 13 participants in the immediate treatment condition and 11 in the delayed condition. Among completers the mean (SD) age was 39.8 (12.2) years, 16 were women (67%), and the mean (SD) baseline GRID-HAMD score was 22.8 (3.9), in the moderate-to-severe range. There were no statistically significant baseline differences between conditions on stratification variables reported in the extracted text. A significant time-by-condition interaction on GRID-HAMD scores was observed (partial ηp2 = 0.57; 90% CI, 0.38–0.66; P < .001). Mean (SD) GRID-HAMD scores in the immediate treatment group changed from 22.9 (3.6) at baseline to 8.0 (7.1) at week 5 and 8.5 (5.7) at week 8 (these correspond to weeks 1 and 4 after intervention). The delayed treatment group, before receiving psilocybin, had mean (SD) GRID-HAMD scores of 22.5 (4.4) at baseline, 23.8 (5.4) at week 5, and 23.5 (6.0) at week 8. Between-group effect sizes were large: Cohen d = 2.2 (95% CI, 1.4–3.0; P < .001) at week 5 and Cohen d = 2.6 (95% CI, 1.7–3.6; P < .001) at week 8. Within-participant comparisons among completers showed large reductions from baseline to postsession follow-ups (baseline to week 1: Cohen d = 3.6; 95% CI, 2.2–5.0; P < .001; baseline to week 4: Cohen d = 3.6; 95% CI, 2.2–4.9; P < .001). Rapid change on the QIDS-SR occurred by day 1 after the first psilocybin session, falling from mean (SD) 16.7 (3.5) at baseline to 6.3 (4.4) at day 1 (Cohen d = 3.0; 95% CI, 1.9–4.0; P < .001) and remaining reduced at week 4 after the second session (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9–4.2; P < .001). Clinically significant response (≥50% reduction in GRID-HAMD) was observed in 16 participants (67%) at week 1 and 17 (71%) at week 4, while remission (GRID-HAMD ≤7) occurred in 14 participants (58%) at week 1 and 13 (54%) at week 4. Secondary depression and anxiety measures showed similar patterns of improvement after entry into the active treatment period. Suicidal ideation was reported as low overall and trended lower after enrollment. Safety data indicated no serious adverse events. One session involved a transient blood pressure elevation beyond the protocol threshold (diastolic >100 mm Hg) that resolved without medical intervention. Nonserious adverse events included challenging emotional and physical experiences during sessions, transient headache reported during 33% of sessions and after 29% of sessions, and other events detailed in supplementary tables referenced by the authors. Initiation of antidepressants or psychotherapy after the intervention was documented in supplementary material but specific counts are not clearly reported in the extracted text.

Discussion

Davis and colleagues interpret their findings as evidence that two administrations of psilocybin given with supportive psychotherapy produced rapid, large, and sustained antidepressant effects in adults with moderate to severe MDD. The authors contrast psilocybin with ketamine by noting that ketamine's antidepressant effects are typically brief (days to about 2 weeks) whereas the current study documented clinically significant response that persisted at least through the 4-week follow-up after the second session, with 71% of participants still meeting response criteria at that time. Psilocybin was further described as having lower addiction potential and a comparatively mild adverse-event profile in this trial, which the authors suggest could confer therapeutic advantages relative to some existing pharmacotherapies. The trial's results were presented as consistent with prior reports of antidepressant effects of psilocybin in patients with cancer-related distress and in open-label studies of treatment-resistant depression. The authors also highlight associations observed between intensity of mystical-type, personally meaningful, or insightful experiences occasioned by psilocybin and reductions in depressive symptoms, and they reference emerging evidence that psilocybin may reduce negative affect and related neural correlates as a possible mechanism. Consequently, the authors recommend further research into psychological and neural mechanisms that might underlie transdiagnostic efficacy. The paper acknowledges several limitations. The delayed treatment control did not account for non-drug elements of the intervention such as preparatory and integration meetings or expectancy effects; the investigators noted difficulties in implementing placebo or active control conditions given the highly discriminable effects of psilocybin. The study had a small sample, short follow-up, limited demographic diversity (predominantly White, non-Hispanic), and excluded individuals at higher suicide risk, restricting generalisability. Facilitators varied in training and professional background, and the authors signalled that the optimal psychotherapy approach and therapist characteristics require further study. They also called for larger, longer, and placebo- or active-controlled trials to better determine safety concerns (including abuse potential, suicide risk, and psychosis emergence) and efficacy across more diverse clinical populations.

CONCLUSION

This randomized clinical trial documented the substantial rapid and enduring antidepressant effects of psilocybin-assisted therapy among patients with MDD. Although the rapid antidepressant effects of psilocybin are similar to those reported with ketamine,the therapeutic effects are different: ketamine effects typically last for a few days to 2 weeks, whereas the current study showed that clinically significant antidepressant response to psilocybin therapy persisted for at least The mean (SD) GRID-HAMD score was 22.8 (3.9) at baseline, 8.7 (7.6) at week 1, and 8.9 (7.4) 4 weeks, with 71% of the participants continuing to show a clinically significant response (≥50% reduction in GRID-HAMD score) at week 4 of follow-up. Furthermore, psilocybin was found to have low potential for addictionand a minimal adverse event profile,suggesting therapeutic advantages with less risk for associated problems than ketamine.The present findings in patients with MDD are consistent with results of studies that reported on the effectiveness of psilocybinassisted therapy in producing antidepressant effects among patients with cancer who had psychological distressand a small open-label study of patients with treatment-resistant depression.The mounting evidence of the use of psilocybin as an adjunct to treatment of a variety of psychiatric conditions (eg, depression,tobacco use disorder,and alcohol use disorder) suggests a transdiagnostic mechanism of action. In several studies in patientsand in healthy volunteers,the intensity of mystical-type experiences reported after psilocybin sessions was associated with favorable outcomes. Furthermore, cross-sectional studies have suggested that mystical-type and psychologically insightful experiences during a psychedelic session predict positive therapeutic effects.Consistent with these previous studies, the current trial showed that psilocybin-occasioned mysticaltype, personally meaningful, and insightful experiences were associated with decreases in depression at 4 weeks (eResults in Supplement 2). Furthermore, a recent report suggested that psilocybin may decrease negative affect and the neural correlates of negative affect,which may be a mechanism underlying transdiagnostic efficacy. Taken together, these findings suggest that further studies into psychological and neural mechanisms across different psychiatric conditions are warranted. The present trial showed that psilocybin administered in the context of supportive psychotherapy (approximately 11 hours) produced large, rapid, and sustained antidepressant effects. The effect sizes reported in this study were approximately 2.5 times greater than the effect sizes found in psychotherapyand more than 4 times greater than the effect sizes found in psychopharmacological depression treatment studies.These findings are consistent with literature that showed that combined pharmacotherapy and psychotherapy were more efficacious in the treatment of MDD than either intervention alone.Furthermore, given that psilocybin was associated with nonserious adverse effects that were frequently reported as mild-to-moderate headache and challenging emotions that were limited to the time of sessions (eTables 8 and 9 in Supplement 2), this intervention may be more acceptable to patients than widely prescribed antidepressant medications that confer substantially more problematic effects (eg, suicidal ideation, decrease in sexual drive, and weight gain). The effectiveness of psilocybin therapy after a single or only a few administrations represents another substantial advantage over commonly used antidepressants that require daily administration.

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