In this triple‑blind, active placebo‑controlled randomised trial (n=144) of adults with treatment‑resistant depression, two 25 mg doses of psilocybin plus adjunct psychotherapy produced clinically meaningful reductions in depressive symptoms on exploratory secondary measures but did not significantly improve the pre‑second‑dose HAMD17 response rate versus nicotinamide.
Importance
Psilocybin shows promise in treating depression, although limitations of previous research warrant further research. Objective To investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD).
Design, Setting, and Participants
This was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active placebo-controlled randomized clinical trial. Participants were randomized to 4 groups in ratios 2:2:1:1, receiving 2 doses 6 weeks apart (week 0, week 6) as follows: (1) placebo (nicotinamide, 100 mg) then psilocybin, 25 mg; (2) psilocybin, 5 mg, then 25 mg; and (3) psilocybin, 25 mg, then 5 mg or psilocybin, 25 mg, twice embedded in psychotherapeutic sessions. Participants aged 25 to 65 years with TRD and withdrawn from antidepressant medication were recruited predominantly from 2 outpatient settings in Germany. Study data were analyzed from April 2024 to November 2025.
Interventions
Oral synthetic psilocybin, 25 mg; psilocybin, 5 mg; or nicotinamide, 100 mg administered with psychotherapeutic sessions. Main Outcomes and Measures The primary end point was treatment response (≥50% reduction on the Hamilton Rating Scale for Depression [HAMD17]) at week 6 before the second dose. Key secondary end points were response on the Beck Depression Inventory II (BDI-II) and mean change from baseline on the HAMD17 and BDI-II at week 6.
Results
A total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder.
Conclusion and Relevance
In this randomized clinical trial, psilocybin, 25 mg, with adjunct psychotherapy, was associated with a clinically meaningful reduction in depressive symptoms in individuals with TRD, although findings did not show a significant effect on the primary outcome. The treatment was well tolerated by most participants, although safety signals were observed. While overall this constituted an inconclusive trial, these results add to the existing evidence on the potential of psilocybin treatment for depression.
Major depressive disorder affects around 280 million people worldwide and is a leading cause of disability. Treatment-resistant depression, usually defined as failure to respond to at least two antidepressant treatments, carries a particularly high personal and societal burden, creating a clear need for new treatment options. Psilocybin, a classical psychedelic and partial serotonin 2A receptor agonist, has shown promise for depression when combined with psychotherapy or psychological support. Evidence from open-label studies and randomised trials suggests potential benefit, and a recent meta-analysis reported a pooled effect size of 0.66. However, the evidence base remains limited by small samples, weak blinding, expectancy effects and incomplete safety monitoring. This study tested the efficacy and safety of a single 25 mg dose of psilocybin with adjunct psychotherapy in treatment-resistant depression, compared with 5 mg psilocybin and 100 mg nicotinamide as an active placebo. The design also included a second dosing session after the primary endpoint to reduce drop-out, limit disappointment and symptom worsening in comparator groups if unblinding occurred, and ensure that all participants received at least one 25 mg psilocybin dose for both ethical and methodological reasons.
This was a two-centre, triple-blind, Phase IIb randomized clinical trial conducted in Germany testing oral synthetic psilocybin with adjunct psychotherapy in treatment-resistant depression (TRD). Adults aged 25 to 65 years with moderate to severe TRD (HAMD17 ≥17) who had failed at least two adequate antidepressant treatments from different pharmacological classes were eligible. Participants were required to discontinue ongoing psychotherapy and monoaminergic medication before dosing (minimum abstinence 2 weeks, 5 weeks for fluoxetine). Recruitment used self-referral, clinician referral and public advertisement. Randomization used centre-stratified permuted blocks and allocated participants in a 2:2:1:1 ratio to four dosing sequences: (1) nicotinamide 100 mg then psilocybin 25 mg, (2) psilocybin 5 mg then psilocybin 25 mg, (3a) psilocybin 25 mg then 5 mg, and (3b) psilocybin 25 mg twice. Nicotinamide and a 5-mg psilocybin dose were intended as comparators to support blinding. All personnel, therapists, raters and participants were blinded to allocation. Each participant was assigned two therapists (one female, one male) and received a structured psychotherapeutic programme comprising seven 2-hour preparatory/integration sessions (14 hours total) surrounding two dosing sessions (week 0 and week 6). Dosing sessions lasted 6–8 hours with an overnight stay; participants also attended eight in-person visits and received eight weekly safety calls. Assessments included clinician-rated HAMD17, self-report BDI-II, laboratory tests, ECG, neuropsychological testing and functional MRI. The primary outcome was treatment response at week 6 (defined as ≥50% reduction from baseline in HAMD17), assessed one day before the second dose. Key secondary end points were BDI-II response and mean change from baseline on HAMD17 and BDI-II at week 6. Ratings were collected at baseline, day 1, week 1, week 6, week 7 and week 12. Safety assessments (vital signs, UKU, Columbia-Suicide Severity Rating Scale, open questioning, labs, ECG) were performed at each visit and during weekly calls; adverse events (AEs) were coded using MedDRA. The trial was powered to detect a 40% difference in HAMD17 response between psilocybin 25 mg and nicotinamide at week 6 (80% power), based on optimistic prior estimates. The primary efficacy analyses used a while-receiving-treatment population (randomized and treated participants with at least one postbaseline assessment before an intercurrent event). The primary binary outcome was analysed by logistic regression in a predefined fixed-order (sequential) testing procedure comparing psilocybin 25 mg vs nicotinamide and then vs 5 mg, adjusting for centre and baseline HAMD17. Continuous outcomes (HAMD17 and BDI-II scores) were analysed using mixed-effects linear regression models with treatment, time and treatment × time interactions, centre as a fixed effect and participant intercepts as random effects. Sensitivity analyses included a principal stratum approach. Analyses were conducted using R and SAS between April 2024 and November 2025. Of note, 143 participants received at least one investigational medicinal product and 142 were included in the primary efficacy analysis (psilocybin 25 mg n = 47; psilocybin 5 mg n = 48; nicotinamide n = 47).
eFigure 1 in Supplement 3 provides an overview of trial procedures; details on adjunct psychotherapy are presented in the eMethods 1 in Supplement 3 and the published design.All participants provided written informed consent and were fully informed about study design, treatment arms, and randomization probabilities. After screening, patients were assigned to 2 therapists (1 female, 1 male) in accordance with guidelines for psychedelic research,and randomized (2:2:1:1) to the following: (1) nicotinamide, 100 mg, then psilocybin, 25 mg; (2) psilocybin, 5 mg, then psilocybin, 25 mg; and (3a) psilocybin, 25 mg, then 5 mg, or (3b) psilocybin, 25 mg, twice. Nicotinamide (the amide of niacin) and psilocybin, 5 mg, were selected as comparators to support blinding. Niacin has been proposed as an active placebo due to acute physiological effectsand psilocybin, 5 mg, as a nontherapeutic low-dose producing mild subjective effects.Because niacin is not approved in the European Union, nicotinamide was used; it is expected to produce fewer acute effects, functioning largely as an inert placebo. Randomization used center-stratified permuted blocks via an online tool managed independently. Each center contributed 50% of participants. All personnel (including therapists and raters) and patients remained blinded to allocation until trial completion. Baseline assessments were conducted 1 week before the first investigational medicinal product (IMP) administration. Participants then received psilocybin, 25 mg; psilocybin, 5 mg; or nico-tinamide, 100 mg (treatment phase 1), followed 6 weeks later by a second dosing session (after assessment of the primary end point) with 25 mg or 5 mg of psilocybin (treatment phase 2). Both dosing sessions (6-8 hours plus overnight stay) were embedded in a structured psychotherapeutic program comprising 7 2-hour preparatory and integration sessions (14 hours total) (eFigure 1 and eMethods 1 in Supplement 3). Overall, participants completed 8 in-person visits and 8 weekly therapist safety calls. Assessments included self-report and clinician-rated scales, laboratory assessments, a neuropsychological battery, and functional magnetic resonance imaging scans (eTable 3 in Supplement 3).
The primary end point was treatment response, defined as 50% or greater reduction in HAMD17 score, 6 weeks after the first dose (1 day before the second dose). We hypothesized that the group receiving 25 mg would show a higher response rate than those receiving nicotinamide and 5 mg of psilocybin, tested sequentially in a fixed-order procedure, wherein the 25-mg vs 5-mg comparison was contingent on demonstrating superiority over nicotinamide. The German GRID-HAMD17 was administered at baseline, week 1, week 6, week 7, and week 12 by trained, blinded raters.Ratings were conducted by local investigators not involved in therapy, and sharing dosing-session information with raters was discouraged to maintain blinding. Key secondary end points were (1) HAMD17 change from baseline at week 6 and (2) Beck Depression Inventory II (BDI-II; range, 0-66, with higher scores indicating greater severity)change from baseline and response (≥50% reduction) at week 6. Further secondary end points included (1) HAMD17 change from baseline and response (≥50% reduction) at week 1 and week 12, (2) BDI-II change from baseline and response (≥50% reduction) at day 1, week 1, and week 12, and (3) remission rate (HAMD17 <8; BDI-II <10) at week 1, week 6, and week 12. Clinically relevant changes are commonly defined as 3 to 5 points on the HAMD17 and 3 to 6 points on the BDI-II.
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Papers cited by this study that are also in Blossom
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Rosenblat, J. D., Meshkat, S., Doyle, Z. et al. · Med (2024)
Schindowski, E. M., Jungwirth, J., Schuldt, A. et al. · EClinicalMedicine (2023)
Raison, C. L., Sanacora, G., Woolley, J. D. et al. · JAMA (2023)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Mertens, L. J., Koslowski, M., Betzler, F. et al. · Neuroscience Applied (2022)
Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)
Hinkle, J. T., Graziosi, M., Nayak, S. et al. · JAMA Psychiatry (2024)
Richards, W. A., Garcia-Romeu, A. · International Review of Psychiatry (2018)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Griffiths, R. R., Johnson, M. W., Richards, W. A. et al. · Psychopharmacology (2011)
Gründer, G., Brand, M., Mertens, L. J. et al. · Lancet Psychiatry (2024)
Sample and analysis populations: A total of 144 participants were randomized and 143 received at least one dose; 142 were included in the primary efficacy analysis with group sizes of 47 (psilocybin 25 mg), 48 (psilocybin 5 mg) and 47 (nicotinamide). By week 12, 10 participants had reinitiated antidepressant medication and 4 withdrew for lack of efficacy or need for additional interventions. Primary outcome (binary HAMD17 response at week 6): The predefined hierarchical comparison of psilocybin 25 mg versus nicotinamide for the primary binary end point did not reach statistical significance. Reported response rates at week 6 were 17% for psilocybin 25 mg, 13% for psilocybin 5 mg and 11% for nicotinamide; the adjusted odds ratio for psilocybin 25 mg versus nicotinamide reported in the paper was non-significant, and because the first hierarchical comparison was nonsignificant, further formal testing in the sequential procedure was not performed. Continuous outcomes and key secondary measures: Mixed-effects models for continuous HAMD17 scores provided evidence of symptom reduction with psilocybin 25 mg. At week 6 the estimated mean difference in HAMD17 change from baseline for psilocybin 25 mg versus nicotinamide was −4.60 (95% CI −7.01 to −2.18; P < .001); an even larger difference was seen at week 1 (−4.89; 95% CI −7.31 to −2.48). Comparisons of psilocybin 25 mg versus 5 mg also favoured 25 mg at week 1 (−3.38; 95% CI −6.23 to −1.42) and at week 6 (−3.09; 95% CI −5.50 to −0.69; P = .02). BDI‑II results were consistent with the HAMD17 findings: a strong effect of psilocybin 25 mg versus nicotinamide was observed 1 day after treatment (estimated mean difference −5.84; 95% CI −10.51 to −1.17) that persisted to week 6 (−7.21; 95% CI −11.86 to −2.56; P < .001). At week 6 BDI-II response (≥50% reduction) occurred in 11 of 47 (23.4%) participants receiving psilocybin 25 mg versus 5 of 47 (10.6%) in the nicotinamide arm and 3 of 48 (6.3%) in the 5-mg arm; nominal odds ratios for BDI-II response were reported (psilocybin 25 mg vs nicotinamide OR 2.64; 95% CI 0.87–9.05; P = .049; psilocybin 25 mg vs 5 mg OR 4.61; 95% CI 1.19–17.83; P = .01), but these were exploratory given the predefined testing sequence. Treatment phase 2 (after the second dose) showed no between-group differences in HAMD17 or BDI-II response rates; all groups demonstrated clinically relevant within-participant improvements by week 12. The pooled estimated mean change from baseline at week 12 across groups was −7.50 (95% CI −8.69 to −6.31) on HAMD17 and −10.53 (95% CI −12.48 to −8.58) on BDI-II, corresponding to substantial symptom reduction across arms when most participants had received at least one 25-mg dose. Post hoc subgroup analyses suggested smaller HAMD17 decreases after psilocybin 25 mg in females, similar effects regardless of antidepressant-withdrawal status, and larger reductions in those with more severe baseline depression. Functional unblinding assessments indicated many participants correctly identified the high-dose psilocybin condition. Safety: Across 280 investigational product administrations (143 individuals), adverse events were common and primarily acute on dosing days. The paper reports AEs in 160 cases (100%) after psilocybin 25 mg, 66 cases (92%) after psilocybin 5 mg and 34 cases (71%) after nicotinamide; most AEs occurred on dosing days. Perceptual and experience-related AEs after psilocybin 25 mg included pseudohallucination (21%), paresthesias/dysesthesias (14%), synesthesia (13%), paranoia (3.8%) and rare occurrences of hallucination, thought disorder or brief psychosis-like states; these events were transient and resolved the same day. Suicidal ideation on dosing day (day 0) was reported in 6 participants (4%) after psilocybin 25 mg, 1 participant (1%) after psilocybin 5 mg and 1 participant (2%) after nicotinamide. Severe AEs on dosing days were more frequent after psilocybin 25 mg (44 of 160 cases, 28%) than after comparators; from day 1 onwards severe AEs were rare. There were four serious adverse events in total, two of which were judged related to psilocybin 25 mg, including one case of hallucinogen persisting perception disorder with broader psychological destabilisation. Suicidal and nonsuicidal self-injurious behaviours were infrequent and worsening of suicidal ideation from baseline was reported as comparable across treatment arms.
The authors interpret the trial as inconclusive: although the primary binary endpoint (≥50% HAMD17 reduction at week 6) did not show a statistically significant benefit of psilocybin 25 mg versus nicotinamide, continuous measures of depressive symptoms (HAMD17 and BDI-II change from baseline) provided evidence of clinically meaningful reductions with psilocybin 25 mg at week 6. They highlight a divergence between the null primary outcome and positive key secondary continuous outcomes, calling for cautious interpretation. The investigators note that antidepressant effects peaked early (around 1 week) with higher response at week 1 for the 25-mg dose, and that no additional between-group benefit was observed after the second dose; by week 12, when most participants had received high-dose psilocybin at least once, symptom reductions were substantial across groups. The authors discuss possible explanations for the low primary response rates and divergence from prior trials: overestimation of treatment effects in power calculations (no prespecified minimum important difference), the chronic and comorbid nature of the TRD sample (including personality disorder traits), strict medication-free status compared with some prior studies, potential effects of expectancy and functional unblinding, and the choice of a 6-week primary time point (whereas prior studies often used earlier endpoints). They also note that the HAMD17 may emphasise somatic symptoms and be less sensitive to psilocybin’s emotional and cognitive effects. On safety, the authors report most AEs were mild to moderate and occurred acutely on dosing days, but they emphasise safety signals including increased suicidal ideation on dosing days after 25 mg and one instance of persisting perceptual disturbance. They attribute higher AE rates than earlier reports at least partly to more systematic and sensitive AE assessment capturing perceptual and emotional changes associated with psychedelic experiences. The authors argue these findings highlight the need for standardised risk monitoring and pharmacovigilance and reinforce that psilocybin should be administered within a psychotherapeutic framework. Key limitations acknowledged by the authors include functional unblinding (most participants correctly identified the high-dose condition), an unexplained small centre effect, overestimation of effect size in the power calculation (no predefined MID), a socioeconomically and ethnically homogeneous sample limiting generalisability, exclusion of participants at high suicide risk, lack of follow-up beyond 12 weeks, possible early underreporting of acute AEs, and missing adherence and therapy-quality ratings. They suggest future confirmatory studies should prespecify a minimum important difference and be adequately powered, include central independent raters, longer follow-up, multiple centres, adherence measures within standardised psychotherapy protocols and further exploration of dosing regimens and psychotherapeutic strategies to prolong effect duration. The authors position their results amid prior research by noting that while the trial did not meet its primary endpoint, the continuous-outcome findings and rapid early antidepressant effects align with previous signals of psilocybin efficacy; nonetheless, the divergence between endpoints and the safety observations mean the findings should be seen as hypothesis generating and warrant replication in larger, well powered trials.
The authors conclude that in this randomized trial in patients with treatment-resistant depression, psilocybin 25 mg with adjunct psychotherapy did not increase HAMD17-defined response rates at week 6 (primary end point) but did produce greater reductions in depressive symptoms on continuous measures at week 6 (key secondary end point). Because primary and key secondary outcomes diverged, the overall findings are inconclusive and require cautious interpretation. No clear additional benefit of a second 25-mg administration was observed within the study timeframe; by week 12 mean symptom reductions were substantial across groups after most participants had received at least one high dose. Psilocybin was generally tolerated but associated with acute adverse events and safety signals, including suicidal ideation on dosing days and one case of persisting perceptual disturbance. The authors state that larger, adequately powered confirmatory trials with longer follow-up are needed to clarify efficacy, durability and mechanisms of action.
Safety assessments were conducted at each in-person visit and during weekly phone calls through week 12. They included open questioning, clinical observation, vital signs, 12-lead electrocardiogram, laboratory tests, and ratings of the Udvalg for Kliniske Undersøgelser (UKU) rating scalefor adverse effects and the Columbia-Suicide Severity Rating Scale (CSSRS).Adverse events (AEs) were collected from first IMP administration until week 12, and thus, all AEs were treatment emergent. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) system, version 27.0, by the Coordination Centre for Clinical Trials (KKS) Heidelberg together with study leads (G.G., L.J.M.). In select cases, MedDRA terms were adapted for harmonization or to better represent the original AE terms when no adequate term was available.
The study was powered (80%) to detect a 40% difference in HAMD17 response between psilocybin, 25 mg, and nicotinamide at week 6, assuming response rates of 50%, 20%, and 10% for psilocybin, 25 mg; psilocybin, 5 mg; and nicotinamide, respectively. Details are provided in the study by Mertens et aland Supplement 1. A while-on-treatment strategy (hereafter referred to as while receiving treatment) was used for the main efficacy analyses, including all randomized and treated participants with at least 1 postbaseline assessment before an intercurrent event. Sensitivity analyses used a principal stratum approach (eTable 9 in Supplement 3). Per design, analyses for treatment phase 1 (to week 6) modeled treatment as a 3-level factor (psilocybin, 25 mg; psilocybin, 5 mg; nicotinamide), treatment phase 2 (week 6-12) included a 4-level factor (groups 1-3b). The primary end point (≥50% HAMD17 reduction at week 6) was analyzed using logistic regression comparing psilocybin, 25 mg vs nicotinamide and psilocybin, 25 mg vs 5 mg in a predefined fixed-order procedure, including center and baseline HAMD17 as covariates. Secondary response endpoints were analyzed analogously. HAMD17 and BDI-II change from baseline were evaluated by mixed-effects linear regression models for both treatment phases with the HAMD17/BDI-II total scores as outcomes respectively, including treatment, time, treatment × time interactions, and center as a covariate (fixed effects) and participant-specific intercepts (random effects). We assumed normally distributed random effects with zero mean and a variance to be estimated, uncorrelated with fixed effects. Confirmatory tests were conducted sequentially, as per the predefined fixed-order procedure, at a 1-sided significance level of α = .03, reflecting directed hypotheses of superiority. Tests referring to secondary end points are reported by nominal uncorrected P values for exploratory purposes (eMethods 2 in Supplement 3). Further analyses are outlined in eMethods 2 in Supplement 3. Descriptive statistics summarized baseline characteristics and safety outcomes in all randomized participants (safety population). AE incidence was evaluated per study period: dosing days after IMP administration (day 0), days 1 to 7, and days 8 to 42 after each dose. Statistical analyses were performed from April 2024 to November 2025 using R, version 4.4 (R Project for Statistical Computing), and SAS, version 9.4 (SAS Institute).and Table). A total of 143 participants received at least 1 IMP administration, and 137 completed the 6-week primary end point compliantly, with comparable discontinuation rates across groups; 142 participants were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Premature terminations are summarized in eTable 5 in Supplement 3. By week 12, 10 participants (7%) had reinitiated antidepressant medication, and 4 (3%) withdrew due to lack of efficacy and/or need for additional interventions. The number of initial contacts is the total number of people expressing interest at both trial centers. Because recruitment was conducted autonomously at both trial centers without exchange of personal information between centers, people who contacted both trial centers are potentially counted twice. b Prescreening consisted of a multistep process, starting with (1) an initial email contact, through which first relevant data on the inclusion and exclusion criteria were collected and (2) a prescreening call via video or phone. Individuals who did not report back after initial contact or were only prescreened in terms of data provided via email are counted as prescreened.
Efficacy results for the HAMD17 are presented for the whilereceiving-treatment population ( Active suicidal ideation with some intent to act, without specific plan Active suicidal ideation with specific plan and intent d Withdrawal from antidepressant or all psychoactive medication at trial entry was counted as yes if patients withdrew from their medication after providing informed consent or within 4 weeks prior but within the prescreening/ screening process. e Details on the psychiatric comorbidities are provided in eTable 7 in Supplement 3. f In line with the inclusion/exclusion criteria, no patient had HAMD17 scores in the mild range at trial entry (HAMD17 total score range at screening: 17-32). g Four patients had missing values on the BDI-II at baseline. Those missing values were imputed with the BDI-II scores from visit 2 (1 day before dose 1), see the statistical analysis plan in Supplement 2 for details.The CSSRS assessment at trial entry is provided here as it provides a better impression of the disease severity through assessment of the current and recent degree of suicidality (with reference to the past 6 to 12 months before trial entry) as well as the lifetime history of suicidality. CSSRS values of the baseline assessment (assessing the period since screening) are provided in the text and reported with respect to the post-baseline changes. i Included suicidal behaviors are preparatory actions, aborted and interrupted suicide attempts, and actual suicide attempts. The HAMD17 linear mixed model for treatment phase 1 revealed evidence for an effect of psilocybin, 25 mg vs nicotinamide at week 6 (estimated mean difference, -4.60; 95% CI, -7.01 to -2.18; P <.001), with an even stronger effect at week 1 (-4.89; 95% CI, -7.31 to -2.48). For psilocybin, 25 mg vs 5 mg, effects were strong at week 1 (-3.38; 95% CI, -6.23 to -1.42) and at week 6 (-3.09; 95% CI, -5.50 to -0.69; P = .02) (Figureand Table). Hodges-Lehmann CIs did not indicate any relevant differences. BDI-II results aligned with the HAMD17 (Table). At week 6, response was more frequent after psilocybin, 25 mg (11 of 47 [23.4%]) vs nicotinamide (5 of 47 [10.6%]) and psilocybin, 5 mg (3 of 48 [6.3%]), but the effects showed weak evidence for a difference between groups (psilocybin, 25 mg vs nicotinamide: OR, 2.64; 95% CI, 0.87-9.05; P = .049; psilocybin, 25 mg vs 5 mg: OR, 4.61; 95% CI, 1.19-17.83; P = .01). Results of the BDI-II linear mixed regression for treatment phase 1 showed a strong effect of psilocybin, 25 mg vs nicotinamide 1 day after treatment (estimated mean difference, -5.84; 95% CI, -10.51 to -1.17) that lasted until week 6 (-7.21; 95% CI, -11.86 to -2.56; P <.001). The comparison of psilocybin, 25 mg vs 5 mg revealed differences at week 6 (-5.16; 95% CI, -9.79 to -0.52; P = .007) (Tableand eFigures 4 and 5 in Supplement 3). After the second dose (week 12), no group differences were observed in HAMD17 or BDI-II response rates. The HAMD17/ BDI-II linear mixed models for treatment phase 2 showed no group differences but large within-participant effects across groups (Table). At week 12, the estimated average change from baseline across groups was -7.50 (95% CI, -8.69 to -6.31) on the HAMD17 and -10.53 (95% CI, -12.48 to -8.58) on the BDI-II, indicating clinically relevant improvements in all groups (Table). Of note, all results of treatment phase 2 are hypothesis generating, not confirmatory. Results of additional efficacy parameters are provided in eTable 10 in Supplement 3. Post hoc subgroup analyses of HAMD17 change to week 6 showed (1) smaller decreases after psilocybin, 25 mg, in females (eTable 11 in Supplement 3), (2) similar effects regard-less of antidepressant-withdrawal status (eTable 12 in Supplement 3), and (3) greater reductions among patients with severe baseline depression (eTable 13 in Supplement 3). Functional unblinding results for participants and therapists are reported in eTables 21 and 23 in Supplement 3, respectively. Additional descriptive subgroup analyses of HAMD17 change to week 6 and response rates, stratified by functional unblinding status and prior lifetime psychedelic experience, are provided in eTables 22 and 14 in Supplement 3, respectively.
In total, 143 individuals received 280 IMP administrations. AEs occurred in 160 cases (100%) after psilocybin, 25 mg; in 66 cases (92%) after psilocybin, 5 mg; and 34 cases (71%) after nicotinamide (eTable 15 in Supplement 3). Most AEs occurred acutely on dosing days (day 0). AEs related to altered reality perception included pseudohallucination (33 [21%]), paresthesias/dysesthesias (23 [14%]), synesthesia (20 [13%]), paranoia (6 [3.8%]), thought disorder (3 [1.9%]), hallucination (3 [1.9%]), a brief psychosislike state (1 [0.6%]), delusion (1 [0.6%]), déjà vu (1 [0.6%]), and self-disorder (2 [1.3%]) after psilocybin, 25 mg; all were transient and recovered the same day. Suicidal ideation was reported in 1 participant (2%) after nicotinamide, 1 participant (1%) after psilocybin, 5 mg, and 6 participants (4%) after psilocybin, 25 mg, on day 0. From days 8 to 42, AE frequencies were similar across IMPs. Severe AEs occurred in 44 of 160 cases (28%) after psilocybin, 25 mg; in 3 of 72 cases (4%) after psilocybin, 5 mg; and in 4 of 48 cases (8%) after nicotinamide on day 0; they were rare from day 1 onwards (details in eTable 16 in Supplement 3). AEs using the raw MedDRA preferred terms appear in eTable 17 in Supplement 3. There were 4 SAEs, 2 considered related to psilocybin, 25 mg (eResults 1 in Supplement 3). Suicidal and nonsuicidal self-injurious behaviors were infrequent across groups (eTable 18 in Supplement 3). Worsening of suicidal ideation from baseline was comparable across all treatment arms (eTables 19 and 20 in Supplement 3). One case of suicidal preparatory behavior occurred after nicotinamide (week 3), and 2 after psilocybin, 25 mg (weeks 7 and 12); all affected participants had histories of active suicidal ideation and behavior.
This 2-center, triple-blind, phase 2b RCT, although negative on the primary outcome, provides important evidence for the feasibility, safety, and potential efficacy of psilocybin, 25 mg, with adjunct psychotherapy for TRD. Although psilocybin, 25 mg, was not significantly superior to nicotinamide for the primary outcome (response at week 6: psilocybin, 25 mg = 17%; psilocybin, 5 mg = 13%; nicotinamide = 11%), the key secondary end point-HAMD17 change from baseline to week 6-revealed differences for psilocybin, 25 mg vs nicotinamide and vs psilocybin, 5 mg, providing evidence for efficacy. This divergence between primary and key secondary outcomes warrants cautious interpretation. Hypothesis-generating secondary outcomes indicated that antidepressant effects peaked after 1 week, when response was markedly higher with psilocybin, 25 mg (34.0%), than with comparators (6.4% and 10.4%). After the second dose, when all participants had received psilocybin, 25 mg, at least once, no group differences were observed, but the mean HAMD17 change from baseline at week 12 (-7.5 points; 31% responders) suggests a sustained antidepressant effect without added benefit from a second 25-mg Change from baseline at week 12, mean (SD) dose. As the study was not powered to detect between-group effects in the second treatment phase, these findings remain exploratory. Results of the BDI-II were in line with those of HAMD17. Post hoc subgroup analyses suggest no influence of antidepressant withdrawal (eTable 12 in Supplement 3) and indicated stronger efficacy in males (eTable 11 in Supplement 3) and in individuals with more severe depression (eTable 13 in Supplement 3). Psilocybin was generally well tolerated, with most AEs mild to moderate and occurring acutely on dosing days, although safety signals were observed. Consistent with Goodwin et al,suicidal ideation was slightly more frequent on dosing days after psilocybin, 25 mg (4%), than in comparator conditions (1%-2%). SAEs or severe AEs were rare. One participant developed hallucinogen persisting perception disorder with broader psychological destabilization (eResults 1 in Supplement 3). Overall, AE rates after psilocybin, 25 mg, were higher than in prior studies,likely reflecting more systematic AE assessment that captured perceptual and emotional changes typical of psychedelic experiences, regardless of expectedness or therapeutic value. As inadequate AE assessment has been a key limitation of earlier trials,this study adds relevant safety data but highlights the need for more standardized risk monitoring and pharmacovigilance tools. The safety profile, together with additional support needs in some patients (eResults 2 in Supplement 3), underscores the importance of administering psilocybin within a psychotherapeutic framework. Higher response rates at week 12 (27%-34%) compared with week 6 (17% for psilocybin, 25 mg) may further suggest benefits of continued therapeutic engagement. In this study, the antidepressant effect of psilocybin, 25 mg, peaked shortly after administration. Although most prior studies assessed primary end points 2 or 3 weeks after doses,this study selected 6 weeks to align with conventional antidepressant trials.Closer end points typically yield larger effects. Whether this represents a rapid, genuine antidepressant effect or merely a postacute afterglow phenomenon remains debated.The observed association between the psychotherapeutic quality of the acute experience (Emotional Breakthrough Inventory score) and depression outcomes supports a mechanistic role of the psychedelic experience (eFigure 6 in Supplement 3). Future studies should examine strategies to prolong antidepressant effects, such as optimized dosing regimens or psychotherapeutic inter ventions. The primary end point (binary response) was chosen for its clinical relevance but was affected by overestimation of the expected treatment effect in power calculation. This calculation was not based on a prespecified minimum important difference (MID)-an omission for a phase 2b trial-but on large effect sizes from the first open-label TRD trial,likely contributing to the divergence between primary and key second- In the nicotinamide group, in total 44 participants received a second IMP administration, 2 with major time deviations as an intercurrent event (and, therefore, not included in the while-receiving-treatment population for the second treatment phase). ary end points at week 6. The key secondary end point nevertheless demonstrated a strong and clinically meaningful effect of psilocybin, 25 mg, although smaller than in other MDD trialsand slightly smaller than in another large TRD RCT.This may partly reflect that in Goodwin et al,17% of participants in the arm receiving psilocybin, 25 mg, had resumed antidepressants by week 6, whereas all participants here remained medication free. The relatively low response rates likely also reflect the clinical representativeness of our TRD sample (eTable 24 in Supplement 3), with many chronically ill patients and frequent psychiatric comorbidities, particularly personality disorders or accentuated traits (eTable 7 in Supplement 3), known to worsen prognosis.TRD is a dynamically developing condition,and psilocybin, like other antidepressants, appears more effective in MDD than TRD (Raison/ Usona Institute, unpublished data, 2023).Future research should clarify whether psilocybin might be particularly beneficial in earlier, less chronic depression, when patients may better utilize rapid symptom relief and therapeutic insights. The expectation of a second dose and longer therapeutic engagement may also have influenced week-6 outcomes. Lastly, the HAMD17, emphasizing somatic symptoms, might be less sensitive to psilocybin's emotional and cognitive effects. Unlike conventional symptom-focused pharmacotherapies requiring daily dosing, psilocybin and other psychedelics, with adjunct psychotherapy, have been proposed to exert salutogenic, potentially disease-modifying effects, that may target core etiological mechanisms of depression.Should confirmatory studies substantiate psilocybin's efficacy, it could signal a paradigm shift in psychiatry away from chronic symptom management.
This study has several strengths. Assessment of blinding integrity, rarely reported in psychedelic and antidepressant trials, represents a key strength of this study. The prospect of receiving at least 1 high-dose psilocybin (25 mg) likely reduced dropouts and enhanced adherence in comparator arms. Although the 3-arm design and inclusion of a low-dose psilocybin control increased uncertainty when compared with prior functional unblinding results,most participants (86%) correctly identified psilocybin, 25 mg. Hence, the present design did not prevent functional unblinding sufficiently, nor did it compensate for reduced placebo effects in comparator arms: response to nicotinamide at 6 weeks was markedly lower than typical placebo response rates,despite concurrent psychotherapy. Besides unblinding, TRD-specific sample characteristics may also account for the low placebo response. These findings underscore the difficulty of maintaining doubleblinding in psychedelic RCTs.Yet expectancy, placebo, and nocebo effects remain central to all antidepressant interventions.Key trial limitations include functional unblinding, an unexplained (small) center effect, and overestimation of the treatment effect in power calculation, which likely reduced power to detect a difference on the primary end point. Future studies should prespecify an MID and power accordingly. Although change thresholds of 3 to 5 HAMD17 points and 3 to 6 BDI-II points are commonly cited as clinically meaningful, the appropriate MID depends on the population (MDD vs TRD), treatment regimen, and comparator. Functional unblinding was assessed in patients and therapists (eTables 21 and 23 in Supplement 3), but not in raters, and neither were patients' expectations. Relatedly, the extent to which expectancy effects may have contributed to observed between-group differences on outcomes cannot be determined; the present results, however, suggest that functional unblinding of dose 1 played a negligible role in depression outcomes at week 6 (eTable 22 in Supplement 3). Although the sample was clinically representative (Tableand eTables 6, 7, and 24 in Supplement 3), it was socioeconomically and ethnically homogenous, and self-selection bias may limit generalizability. Further limitations include absence of follow-up beyond 12 weeks, exclusion of participants at high suicide risk or with very low functioning, potential underreporting of acute AEs in the beginning, and missing adherence and therapy quality ratings (eg, therapeutic alliance, patient satisfaction). Future studies may benefit from employment of innovative, wellpowered designs with active comparators, longer durations, individualized dosing, central independent raters, multiple centers, and adherence ratings within standardized psychotherapy protocols.
In this RCT in patients with TRD, psilocybin, 25 mg, with psychotherapy did not increase response rates (primary end point) but produced greater reductions in depressive symptoms at week 6 (key secondary end point). Although results suggest potential efficacy, the divergence between primary and secondary outcomes renders the findings inconclusive and calls for cautious interpretation and replication. Within the study time frame, no additional benefit was observed from a second psilocybin, 25 mg, administration; by week 12, after all participants had received psilocybin, 25 mg, mean symptom reductions were substantial across groups. Psilocybin was generally well tolerated but associated with acute AEs and safety signals, including suicidal ideation on dosing days and one case of persisting perceptual disturbance. These findings highlight the potential of psilocybin with adjunct psychotherapy for depression, including TRD, while emphasizing the need for larger, adequately powered confirmatory trials with long-term follow-up to clarify durability and mechanisms of action.
Hieronymus, F., López, E., Sjögren, H. W. et al. · JAMA Network Open (2025)