This pre-print case study (2022) explores the effects of single-dose psilocybin in an individual with OCD. Treatment led to improvements in OCD symptoms and positive changes to the individuals' emotions, social and work function, and quality of life.
Classic psychedelics, such as psilocybin, act on the brain’s serotonin system and produce striking psychological effects. Early work in the 1950s and 1960s and more recent controlled studies suggest benefits from psychedelic treatment in a number of conditions. A few case reports in recreational users and a single experimental study suggest benefit in patients with obsessive-compulsive disorder (OCD). Still, careful clinical data and long-term follow-up have been lacking. Here we describe a case of a patient with refractory OCD treated with psilocybin and followed prospectively for a year, with marked symptomatic improvement. We provide qualitative and quantitative detail of his experience during and after treatment. Improvement in OCD symptoms (YBOCS declined from 24 to 0-2) was accompanied by broader changes in his relationship to his emotions, social and work function, and quality of life. This individual was an early participant in an ongoing controlled study of psilocybin in the treatment of OCD (NCT03356483). These results are preliminary but promising, motivating ongoing investigations of the therapeutic potential of appropriately monitored and supported psychedelic treatment in the treatment of patients with obsessions and compulsions.
Treatment-resistant major depressive disorder is difficult to treat and carries greater symptom burden, chronicity, disability, suicidality, and costs than treatment-responsive depression. Previous research has shown progressively lower remission rates with successive antidepressant courses, and failure of two adequate courses commonly defines treatment resistance. Preliminary studies have suggested potential antidepressant effects of psilocybin, a tryptamine alkaloid in psilocybe mushrooms, including in patients with life‑threatening cancer and in small pilot studies of major depressive disorder and treatment‑resistant depression. Goodwin and colleagues set out to identify an acceptable and efficacious single dose of a proprietary, synthetic formulation of psilocybin (COMP360) and to assess its safety when given with psychological support to outpatients experiencing a treatment‑resistant major depressive episode. The aim was to evaluate dose–response (25 mg, 10 mg, and 1 mg control) with a primary efficacy assessment at 3 weeks and follow-up to 12 weeks.
Papers cited by this study that are also in Blossom
Passie, T., Seifert, J., Schneider, U. et al. · Addiction Biology (2002)
This was a Phase II, double‑blind, dose‑finding, parallel‑group randomized clinical trial conducted at 22 sites across 10 countries between March 2019 and September 2021. The sponsor, COMPASS Pathfinder, provided the synthetic psilocybin formulation and engaged contract research organisations to supervise conduct and perform assessments; remote blinded raters administered the primary outcome measure. The trial protocol followed ICH Good Clinical Practice and had independent ethics approval at each site. Eligible adults (≥18 years) met DSM‑5 criteria for a single or recurrent episode of major depressive disorder without psychotic features and had a current episode that had failed two to four adequate antidepressant trials, as documented by the MGH Antidepressant Treatment Response Questionnaire. Participants completed a 3–6 week run‑in during which prohibited central nervous system medications were tapered, and they received at least three preparatory sessions with therapists. Two therapists (lead and assisting) were present for the drug administration session; therapists received standardised training and were masked to dose assignment and did not collect efficacy assessments. Participants were randomised centrally in a 1:1:1 ratio, stratified by country and prior psilocybin experience, to receive a single oral dose of 25 mg, 10 mg, or 1 mg psilocybin (control). The administration session lasted 6–8 hours in a nonclinical, calming room; participants wore eyeshades, listened to a curated music playlist, and returned home after effects dissipated. Two integration sessions were provided (day 2 and week 1). Participants were asked to remain off antidepressant medication for the first 3 weeks post‑dosing but could start treatment if clinically necessary. The primary efficacy end point was change from baseline (day −1) to week 3 in the Montgomery‑Åsberg Depression Rating Scale (MADRS) total score, assessed by blinded, experienced raters by telephone at prespecified time points through week 12. Key secondary end points were response (≥50% decrease in MADRS at week 3), remission (MADRS ≤10 at week 3), and sustained response (week 3 response maintained through week 12). Safety assessments included adverse events coded with MedDRA, suicidality monitoring with the Columbia Suicide Severity Rating Scale, vital signs, laboratory tests, urine drug screens, and 12‑lead ECGs. The statistical plan powered the trial for a 6‑point difference in MADRS change with 90% power assuming an SD of 11; 216 participants were planned. Efficacy analyses used a modified intention‑to‑treat set (all randomised participants who received treatment and had at least one postbaseline efficacy assessment). A ‘‘hypothetical strategy’’ imputational approach was applied to MADRS scores after initiation of new antidepressant treatment, treating these as progressively worse (missing‑not‑at‑random); other missing data were handled as missing‑at‑random. The primary analysis used a mixed model for repeated measures (MMRM) comparing each active dose with the 1‑mg control, and a hierarchical testing procedure was prespecified to control type I error across the primary and three key secondary end points. Response and remission were analysed with generalized linear mixed models and sustained response with logistic regression. Safety analyses were descriptive and included all treated participants.
Of 428 individuals screened, 233 were randomised, received study drug, and had at least one postbaseline efficacy assessment (modified intention‑to‑treat and safety sets). Group sizes were 79 in the 25‑mg group, 75 in the 10‑mg group, and 79 in the 1‑mg group. By week 12, withdrawal rates were 6% in the 25‑mg group, 12% in the 10‑mg group, and 13% in the 1‑mg group. Baseline characteristics were similar across groups: mean age 39.8 years, 52% female, 92% White, mean number of lifetime depressive episodes 6.9, and 86% with current episode duration >1 year. Baseline MADRS scores averaged 31.9 (25 mg), 33.0 (10 mg), and 32.7 (1 mg). Prior psilocybin exposure was reported by 6% of participants. The primary efficacy result at week 3 showed a least‑squares mean change in MADRS of −12.0 points in the 25‑mg group, −7.9 points in the 10‑mg group, and −5.4 points in the 1‑mg group. The between‑group difference for 25 mg versus 1 mg was −6.6 points (95% CI −10.2 to −2.9; P<0.001). The 10 mg versus 1 mg comparison was −2.5 points (95% CI −6.2 to 1.2; P=0.18), which was not statistically significant; because of the prespecified hierarchical testing procedure this nonsignificant comparison terminated formal significance testing for the subsequent secondary end points. Observed response rates at week 3 were 37% (25 mg), 19% (10 mg), and 18% (1 mg), with an odds ratio for response of 2.9 (95% CI 1.2 to 6.6) for 25 mg versus 1 mg. Remission rates at week 3 were 29% (25 mg), 9% (10 mg), and 8% (1 mg), with an odds ratio for remission of 4.8 (95% CI 1.8 to 12.8) for 25 mg versus 1 mg. Sustained response at week 12 occurred in 20% (25 mg), 5% (10 mg), and 10% (1 mg); the odds ratio for sustained response for 25 mg versus 1 mg was 2.2 (95% CI 0.9 to 5.4), with the confidence interval including 1. Adverse events were common: reported in 84% of participants in the 25‑mg group, 75% in the 10‑mg group, and 72% in the 1‑mg group. On day 1 the most frequent events in the 25‑mg group were headache (24%), nausea (22%), dizziness and fatigue (6% each). Severe adverse events on day 1 were uncommon. From day 2 to week 3, severe adverse events were reported in 9% (25 mg), 7% (10 mg), and 1% (1 mg). Serious adverse events included suicidal ideation and intentional self‑injury in the 25‑mg and 10‑mg groups; no serious adverse events were reported in the 1‑mg group during that interval. Between week 3 and week 12, three participants in the 25‑mg group reported suicidal behaviour; all three had prior histories of suicidal behaviour or nonsuicidal self‑injury and lacked a treatment response at week 3. Worsening of suicidal state from baseline to week 3 occurred in 14% (25 mg), 17% (10 mg), and 9% (1 mg). No clinically significant changes in vital signs, laboratory tests, or ECGs were observed. Initiation of new antidepressant treatment before week 3 occurred in 5% (25 mg), 12% (10 mg), and 18% (1 mg); additional participants started treatment after week 3.
Goodwin and colleagues interpret the findings as demonstrating the feasibility of single‑session psilocybin monotherapy, with psychological support, for up to 12 weeks in patients with treatment‑resistant major depression. A single 25‑mg dose produced a statistically significant greater reduction in MADRS total score at 3 weeks than a 1‑mg control, whereas the 10‑mg dose did not differ significantly from control. The authors note that response and remission at week 3 were generally directionally consistent with the primary outcome but that the prespecified hierarchical testing stopped after the nonsignificant 10‑mg comparison, so secondary end points cannot be considered definitively statistically significant. Safety considerations are emphasised: headache, nausea, dizziness, and fatigue were common, and there were numerically greater occurrences of suicidal ideation and self‑injurious behaviour in the 25‑mg and 10‑mg groups compared with the 1‑mg group. The investigators highlight the need for clinical vigilance regarding suicidality in future psilocybin trials. They also describe design strengths intended to address limitations of earlier work, including a multicentre, parallel‑group design, remote blinded raters, a manualised but time‑limited preparation and integration protocol, and a trial population largely naïve to psilocybin. The authors propose that dose‑dependent pharmacokinetics and receptor occupancy may account for the greater effect at 25 mg versus 10 mg. Limitations acknowledged include absence of an active comparator, limited ethnic diversity of participants, exclusion of individuals judged to be at significant suicide risk, and challenges to blinding posed by the pronounced subjective effects of higher doses; the trial did not assess participants' ability to guess dose allocation. They also note that whether other psilocybin preparations would yield similar results is unknown. The extracted text ends before the final sentences of the Discussion, and the paper's concluding remarks are thus not fully available in the provided text.
T reatment-resistant depression is a challenging disorder to treat, as shown in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.Incidences of remission became progressively lower from the first course of antidepressant treatment (36.8%) to the second course (30.6%), third course (13.7%), and fourth course (13.0%).Failure of two courses of treatment has generally been considered to define a group of patients who have treatment-resistant depression. Patients with treatment-resistant depression have greater severity and duration of illness, disability, physical illness, incidences of hospitalization, risk of suicide, and economic costs than patients with treatment-responsive depression.Psilocybin is a tryptamine alkaloid found in several species of psilocybe mushrooms.Its potential antidepressant efficacy was suggested by preliminary studies involving patients with life-threatening cancer.Amelioration of symptomatic depression in pilot studies of major depressive disorder, including those that compared psilocybin with escitalopramand that investigated its use in treatment-resistant depression,has suggested therapeutic potential for this agent. The objective of the current trial was to identify an acceptable efficacious dose and assess the safety of a synthetic, proprietary formulation of psilocybin, administered together with psychological support,in patients with a treatmentresistant major depressive episode.
This was a phase 2 double-blind, dose-finding, parallel-group, randomized clinical trial. The sponsor, COMPASS Pathfinder, designed and funded the trial and provided a proprietary pharmaceutical-grade synthetic psilocybin formulation, COMP360, which was analyzed for stability and purity. A contract research organization (Worldwide Clinical Trials), paid by the sponsor, supervised the conduct of the trial. An independent contract research organization (MedAvante-ProPhase) was responsible for assessment of participants using the Montgomery-Åsberg Depression Rating Scale (MADRS),performed by trained remote raters who were unaware of the details of the trial and the trial-group assign-ments. The statistical analysis of the data was performed by the contract research organization and reviewed by the sponsor, and the interpretation and post hoc statistical analyses of the data were performed by the sponsor. The sponsor paid for professional writing assistance for the first draft of the manuscript. All the authors reviewed and approved the manuscript before submission and vouch for the adherence of the trial to the protocol (available with the full text of this article at NEJM.org), the completeness and accuracy of the data, and the reporting of adverse events. Confidentiality agreements were in place between the investigators and COMPASS Pathfinder. The roles of the authors are listed in the Supplementary Appendix, available at NEJM.org. The trial was conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. The trial protocol was approved by independent ethics committees or institutional review boards at each participating site. All the participants provided written informed consent.
Men and women 18 years of age or older were eligible if they met Diagnostic and Statistical Manual of Mental Disorders (fifth edition) criteria for a single or recurrent episode of major depressive disorder, without psychotic features, on the basis of clinical assessment and medical records and as documented by the Mini-International Neuropsychiatric Interview (version 7.0.2).Recruitment was conducted through referrals from primary care and specialized psychiatry services, online advertisements, and word of mouth. Participants were outpatients who met criteria for the diagnosis of treatment-resistant depression and had a current episode of depression that had not responded to two to four adequate trials in terms of both dose and duration (≥8 weeks) of treatment according to the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ).Augmentation agents, or other antidepressants not included in the MGH ATRQ, qualified as a treatment failure if they failed to ameliorate depression, provided they had local regulatory approval as a treatment for major depressive disorder. Additional selec-
The trial was conducted at 22 sites in 10 countries in Europe (the Czech Republic, Denmark, Germany, Ireland, the Netherlands, Portugal, Spain, and the United Kingdom) and North America (Canada and the United States) from March 1, 2019, through September 27, 2021. All but one of the principal investigators was a psychiatrist. Both assisting and lead therapists, whose roles are described below, were recruited as psychologists with at least master's-level qualifications, psychiatrists, master's-level practitioners, nurses, diploma-level cognitive behavioral therapists, or doctorate-level mental health specialists. These therapists had experience in adult mental health, addiction, dementia, physical health, child or developmental health, family therapy, or eating disorders and experience with patients having severe psychological distress. The therapist-training program that was expressly prepared for the trial had four components: an online learning platform, in-person training, clinical training, and ongoing individual mentoring and webinars. Therapists were required to complete the first three components of the training program before they could lead sessions independently and to engage in the fourth component to continue their professional development.Therapists in training could act as assisting therapists so that there were always two therapists present on the day of drug administration. All the therapists were unaware of the trial-group assignments, did not collect efficacy assessments, and were discouraged from speculating about doses. Eligible participants completed a run-in period of 3 to 6 weeks, during which antidepressants and other prohibited medications affecting the central nervous system were tapered and discontinued at least 2 weeks before the baseline visit (the day before psilocybin administration). During this period, the participant met with a therapist at least three times to build trust, receive psychoeducation, and prepare for the psychedelic experience. Participants who continued to meet eligibility criteria were randomly assigned in a 1:1:1 ratio to receive a single dose of psilocybin of 25 mg, 10 mg, or 1 mg (control). Ran-domization was performed at a central location and stratified according to country and the participant's previous experience with psilocybin. The administration session (day 1) lasted 6 to 8 hours, with the lead therapist who had prepared the participant for the intervention and an assisting therapist in attendance. A trial psychiatrist was available on site for consultation. Administration rooms were designed to provide a nonclinical, calming atmosphere. During the administration session, participants listened to a specially designed music playlist while wearing eyeshades to help direct attention internally. After at least 6 hours and when the psychedelic effects of the drug had fully dissipated, participants returned home. The trial followed participants for 12 weeks after treatment. Participants received two integration sessions, with the same lead and assisting therapists at the day 2 visit and with the lead therapist at the week 1 visit. The goal of the integration sessions was to support participants in deriving their own insights and solutions from the experience with psilocybin. Therapists were advised to remain open and supportive, without active guiding.Participants were requested to remain off antidepressant treatment during the first 3 weeks after the trial-drug administration; however, these medications could be started at any time during the trial if deemed clinically necessary by a physician investigator. (A schedule of the assessments is provided in Tablein the Supplementary Appendix.)
The primary end point was the change from baseline (day -1, the day before trial-drug administration) to 3 weeks in the MADRS total score (range, 0 to 60, with higher scores indicating greater severity of depression).The primary analysis was of the 25-mg dose and 10-mg dose each compared with the 1-mg dose. The MADRS was administered by experienced mental health clinician raters by telephone at baseline, on day 2, and at weeks 1, 3 (primary end-point assessment), 6, 9, and 12. The Structured Interview Guide for the MADRS provided structured probes to ensure standardization of administration and comprehensive coverage of the 10 questions.Three key secondary efficacy end points were response (≥50% decrease from baseline to week 3 in the MADRS total score), remission (MADRS total score ≤10 at week 3), and sustained response (week 3 response maintained through week 12).
Adverse events were evaluated at every visit and were recorded and coded with the use of the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0. All visits were in conducted in person except for the week 6 and 9 visits, which were conducted remotely. Adverse events that emerged or worsened after trial-drug administration were categorized as serious adverse events on the basis of the ICH Good Clinical Practice criteria and with the use of additional information from the Columbia Suicide Severity Rating Scale.Suicidal ideation with intent or endorsement of any items in the suicidal-behavior section, including nonsuicidal self-injurious behavior, was reported as a serious adverse event. Safety assessments also included evaluation of vital signs (at screening, baseline, day 1, and day 2), clinical laboratory tests (including urine drug screening) (at screening, day 2, and week 3), and 12-lead electrocardiography (ECG) at screening and day 2.
Using a two-sample t-test, we calculated that a sample of 216 participants (72 per group) would provide 90% power at a two-sided alpha level of 0.05 to detect a 6-point difference in the mean change from baseline to week 3 in the MADRS total score between the 25-mg group or the 10-mg group and the 1-mg group, assuming a common standard deviation of 11.0 (see the Supplementary Appendix). Efficacy analyses were performed in the modified intention-to-treat analysis set, which included all randomly assigned participants who received treatment and had at least one postbaseline efficacy assessment. A "hypothetical strategy" estimand was applied in which MADRS total scores for participants who initiated a new antidepressant treatment were imputed at visits after initiation with the use of a missing-not-at-random mechanism that progressively worsened the MADRS total score. The aim was to hypothesize what would have happened to the MADRS total score had a new treatment for depression not been available to use. This same method was also applied to missing MADRS total scores after trial with-drawal for reasons of lack of efficacy or adverse events. All other missing data on MADRS total scores, both intermittent and after trial withdrawal for other reasons, were imputed with the use of a missing-at-random mechanism. The primary efficacy end point (change from baseline to week 3 in the MADRS total score) was evaluated with the use of a mixed model for repeated measures (MMRM) analysis comparing the 25-mg dose with the 1-mg dose and comparing the 10-mg dose with the 1-mg dose. The MMRM analysis included treatment, visit, pooled trial site, treatment-by-visit interaction, baseline MADRS total score, and an unstructured correlation matrix. The estimates of the least-squares means and mean differences and 95% confidence intervals were then pooled with the use of Rubin's combination rules. This analysis method combined the between-imputation variability with the within-imputation variability to obtain one single point and confidence interval estimate to address imputation uncertainty. Response and remission were analyzed with the use of a generalized linear mixed model, and sustained response was analyzed with the use of a logistic-regression model. A "composite strategy" estimand was applied, whereby participants who initiated a new antidepressant treatment or withdrew from the trial for reasons of lack of efficacy or adverse events were classified as not having a response, remission, or a sustained response at all visits after these events. To control the overall type I error rate, a hierarchical test procedure was applied across the primary and three key secondary efficacy end points. The 25-mg group and then the 10-mg group were sequentially examined for each end point before proceeding to the next end point. All testing was done at the two-sided 0.05 alpha level. Descriptive statistics were used to analyze safety data from all randomly assigned participants who received single-dose treatment (safety analysis set), including adverse events, concomitant medications, evaluation of vital signs, clinical laboratory tests, findings from 12-lead ECG, and suicidality assessments.
A total of 428 participants were screened, and 233 were enrolled, underwent randomization, and received psilocybin treatment (safety analy- 1641 Psilocybin for Treatment-Resistant Depression sis set) and had at least one postbaseline efficacy evaluation (modified intention-to-treat analysis set). A total of 79 participants were assigned to the 25-mg group, 75 to the 10-mg group, and 79 to the 1-mg group (Fig.). By week 12, a total of 5 participants (6%) in the 25-mg group, 9 (12%) in the 10-mg group, and 10 (13%) in the 1-mg group had withdrawn from the trial. The demographic and clinical characteristics of the participants at baseline were similar across the three groups (Table); the mean age was 39.8 years, 52% were female, and 92% were White. A total of 95% of the participants reported previous depressive episodes, with a mean of 6.9 lifetime depressive episodes, and 86% of the participants reported a duration of the current depressive episode of longer than 1 year. These characteristics were similar to what has been observed in population studies involving persons with treatment-resistant depression, and the representativeness of the trial population is shown in Table. Two thirds of the participants were receiving antidepressant treatment at screening. At baseline, depression was moderate (MADRS total score, 20 to 30) in 30% of the participants and severe (MADRS total score, ≥31) in 68% of the participants. Mean MADRS total scores at baseline were 31.9 in the 25-mg group, 33.0 in the 10-mg group, and 32.7 in the 1-mg group. A total of 6% of the participants had previous exposure to psilocybin. Before the week 3 primary end-point assessment, initiation of treatment for depression was reported by 4 participants (5%) in the 25-mg group, 9 (12%) in the 10-mg group, and 14 (18%) in the 1-mg group. After week 3 and up to week 12, the number of participants initiating a treatment for depression was 26 (33%) in the 25-mg group, 18 (24%) in the 10-mg group, and 16 (20%) in the 1-mg group. Randomly assigned participants received a single dose of a proprietary, synthetic formulation of psilocybin, which was administered together with psychological support.
The least-squares mean change from baseline to week 3 in the MADRS total score was -12.0 points in the 25-mg group, -7.9 in the 10-mg group, and -5.4 in the 1-mg group. The difference in the least-squares mean change between the 25-mg group and the 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; * Plus-minus values are means ±SD. Randomly assigned participants received a single dose of a proprietary, synthetic formulation of psilocybin, which was administered together with psychological support. Percentages may not total 100 because of rounding. MDD denotes major depressive disorder. † Race was reported by the participants. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Total scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) range from 0 to 60, with higher scores indicating greater severity of depression. Two participants in the 10-mg group and two participants in the 1-mg group had an MADRS total score of less than 20 at baseline. ¶ Total scores on the 17-item Hamilton Depression Rating Scale (HAM-D-17) range from 0 to 52, with higher scores indicating greater severity of depression. The † This nonsignificant P value terminated significance testing on the basis of the prespecified hierarchical test procedure, and all the subsequent secondary efficacy end points are considered to be not significantly different between the 25-mg group or 10-mg group and the 1-mg group. ‡ A response was defined as a decrease of at least 50% from baseline in the MADRS total score. § Remission was defined as an MADRS total score of 10 or less. ¶ A sustained response was defined as a week 3 response sustained through week 12.
Total scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) range from 0 to 60, with higher scores indicating greater severity of depression. I bars represent standard errors. The New England Journal of Medicine Downloaded from nejm.org by Floris Wolswijk on November 3, 2022. For personal use only. No other uses without permission. P<0.001), and the difference between the 10-mg group and the 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18) (Tableand Fig.). The nonsignificant finding for the comparison between the 10-mg group and the 1-mg group terminated significance testing on the basis of the prespecified hierarchical test procedure, and all the subsequent key secondary efficacy end points are considered to be not significantly different between the 25-mg group or the 10-mg group and the 1-mg group. Additional analyses for the primary efficacy end point are shown in Figure. These alternative data-handling strategies and analysis models provided results that were consistent with the findings for the primary efficacy end point. The incidence of response at week 3 was 37% in the 25-mg group, 19% in the 10-mg group, and 18% in the 1-mg group (odds ratio in the 25-mg group vs. the 1-mg group, 2.9 [95% CI, 1.2 to 6.6]; odds ratio in the 10-mg group vs. the 1-mg group, 1.2 [95% CI, 0.5 to 3.0]) (Table). The incidence of remission at week 3 was 29% in the 25-mg group, 9% in the 10-mg group, and 8% in the 1-mg group (odds ratio in the 25-mg group vs. the 1-mg group, 4.8 [95% CI, 1.8 to 12.8]; odds ratio in the 10-mg group vs. the 1-mg group, 1.2 [95% CI, 0.4 to 3.9]). The incidence of sustained response at week 12 was 20% in the 25-mg group, 5% in the 10-mg group, and 10% in the 1-mg group (odds ratio in the 25-mg group vs. the 1-mg group, 2.2 [95% CI, 0.9 to 5.4]; odds ratio in the 10-mg group vs. the 1-mg group, 0.7 [95% CI, 0.2 to 2.0]). Because of the failure of hierarchical testing, no definite conclusions can be drawn from secondary end-point results. The confidence interval for the odds ratio for sustained response at week 12 for both the 25-mg dose and the 10-mg dose as compared with the 1-mg dose included 1. A post hoc analysis of the primary end point that included sex or the number of lifetime episodes of depression showed results similar to those for the primary analysis. The results from per-protocol analysis of the primary end point were also consistent with the modified intention-to-treat population (Fig.). Additional efficacy results are included in Tables S3 through S6 and Figuresand.
Adverse events occurred in 66 participants (84%) in the 25-mg group, 56 (75%) in the 10-mg group, and 57 (72%) in the 1-mg group. The most frequent adverse events reported in the 25-mg group with onset on the day of psilocybin administration (day 1) were headache (in 24% of the participants), nausea (in 22%), and dizziness and fatigue (in 6% each) (Table). Adverse events that were rated as severe on day 1 were reported by 4% of the participants in the 25-mg group, 8% of those in the 10-mg group, and 1% of those in the 1-mg group. Just one participant (in the 25-mg group) was treated with adjunctive medication (lorazepam for acute anxiety) on day 1. There were no serious adverse events reported on day 1. From day 2 up to week 3 (primary end-point assessment), severe adverse events were reported by 9% of the participants in the 25-mg group, 7% of those in the 10-mg group, and 1% of those in the 1-mg group. The serious adverse events in the 25-mg group were suicidal ideation (in two participants) and intentional self-injury (nonsuicidal self-injurious behavior) (in two participants) and in the 10-mg group were suicidal ideation (in two participants), intentional selfinjury (in one participant), and hospitalization (for severe depression, in one participant). No serious adverse events were reported from day 2 up to week 3 in the 1-mg group. After week 3 and up to week 12 (end of trial), severe adverse events were reported by 3% of the participants in the 25-mg group, 4% of those in the 10-mg group, and no participants in the 1-mg group. Serious adverse events in the 25-mg group were suicidal behavior (in three participants), codeine withdrawal syndrome (in one participant), and adjustment disorder with anxiety and depressed mood (in one participant); in the 10-mg group were intentional self-injury (in one participant), depression (in one participant), and suicidal ideation (in one participant); and in the 1-mg group were intentional self-injury (in one participant). Severe adverse events during the trial period according to MedDRA system organ class and preferred term are shown in Table. At the baseline visit, suicidal ideation (passive or active but with no intent or plan) was reported by 21 participants (27%) in the 25-mg group, 27 (36%) in the 10-mg group, and 19 (24%) in the 1-mg group. The number of participants who showed worsening of suicidal state from baseline to week 3 were 11 (14%) in the 25-mg group, 13 (17%) in the 10-mg group, and 7 (9%) in the 1-mg group (Table). Three participants in the 25-mg group reported suicidal behavior after week 3. All three had a history of suicidal behavior or nonsuicidal self-injury before the trial and did not have a treatment response at week 3. No clinically significant changes in vital signs, clinical laboratory tests, or 12-lead ECGs were observed during the trial (see the Supplementary Appendix).
This phase 2 clinical trial showed the feasibility of psilocybin monotherapy for up to 12 weeks in patients with a treatment-resistant episode of major depression. The change from baseline to week 3 in the MADRS total score (primary end point) was significantly better with a 25-mg dose than with a 1-mg dose; there was not significant difference between the 10-mg dose and the 1-mg dose. In addition to headache, nausea, dizziness, and fatigue, some participants had suicidal ideation or self-injurious behavior, and the proportions of these participants were numerically higher in the 25-mg and 10-mg groups than in the 1-mg group. In view of the participants who showed worsening of suicidal state, suicidality demands clinical vigilance in future trials of psilocybin for depression. The incidences of response and remission at 3 weeks were generally in the same direction as the primary end-point results; however, the analyses of these end points were ordered in the prespecified hierarchical test procedure after the significance testing had terminated, and no definite conclusions can be drawn from these results. The confidence interval for the odds ratio for sustained response at week 12 for the 25-mggroup as compared with the 1-mg group included 1. The current trial was designed to address some limitations of previous pilot studies and trials, including limited power, short-duration crossover design, reliance on single-site recruitment of participants, and interpretation of treatment effects that may be confounded by intensive concurrent psychological therapy. The current trial had a primary end point at 3 weeks but observed participants over 12 weeks of follow-up in a parallel-group design, included a trial population in which more than 90% of the participants did not have previous exposure to psilocybin, and used remote raters who were unaware of the details of the trial and the trial-group assignments to determine the primary end-point measure (MADRS total score). The manualized, time-limited approach to preparation, support, and integration of the psychedelic experience ensured safety and is not a stand-alone psychotherapy. For participants in this trial, psilocybin therapy represented a third-, fourth-, or fifth-line treatment. The incidence of response at week 3 of 37% in the 25-mg group in our trial was numerically lower than that described for first-line treatment of major depressive disorder in several large trials of citalopram, 1 nefazodone, and escitalopram, sertraline, or venlafaxinebut was higher than the incidences of response reported in the STAR*D trial for second-line treatments and beyond. Pharmacokinetic research has shown dose-dependent increases in receptor occupancy and subjective effects of psilocybin across the dose range of 3 to 30 mg.These findings may explain the differences in efficacy between the groups in the current trial. Limitations of the current trial include the lack of an active comparator, the lack of an ethnically diverse participant sample, and the exclusion of persons judged to be at a clinically significant risk for suicide. The intensity of the acute subjective effect of the 25-mg and 10-mg doses, as compared with the 1-mg dose, reduces the effectiveness of the double-blind structure of the trial. We did not assess participants' ability to guess their dose assignment, and ensuring blinding is an inherent limitation of studies of drugs that produce psychedelic subjective effects. Whether other preparations of psilocybin than the proprietary one used in this trial would show the same effects cannot be determined. In this trial of psilocybin administered in a single session with psychological support, a 25-mg dose but not a 10-mg dose resulted in a significantly greater reduction (improvement) in MADRS total scores than a 1-mg dose at 3 weeks in participants with treatment-resistant depression but was associated with adverse events. Secondary end-point results generally supported the primary analysis with the exception of 12week sustained response, at which time point the observed numerical difference was not considered to be statistically significant. Longer and larger trials, including comparison with existing treatments for depression, are required to deter-
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Papers in Blossom that reference this study
Drange, S., Cohen, J., Johansen, S. S. et al. · Frontiers in Psychiatry (2026)
Moreno, F. A., Allen, K. E., Wiegand, C. B. et al. · Journal of Psychopharmacology (2026)
Gordon, A. R., Carrithers, B. M., Pagni, B. A. et al. · Research Square (2024)