Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial

Lea J Mertens; Michael Koslowski; Felix Betzler; Manuela Brand; Ricarda Evens; Laura Kärtner; Andrea Jungaberle; Henrik Jungaberle; Tomislav Majić; Christian N Schmitz; Andreas Ströhle; Dennis Scharf; Moritz Spangemacher; Max Wolff; Zahra Assadi; Scharif Bahri; Lilith Becher; Luca V Färber; Niklas Kirchen; Eugenia Kulakova; Linda Kunz; Andy Meijer; Barbara Rohrmoser; Stefan Wellek; Moritz M Berger; Gerhard Gründer

doi:10.1001/jamapsychiatry.2026.0132

. 2026 Mar 18;83(5):448–460. doi: 10.1001/jamapsychiatry.2026.0132

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression

The EPISODE Randomized Clinical Trial

Lea J Mertens ^1,², Michael Koslowski ^3,⁴, Felix Betzler ^3,⁴, Manuela Brand ^1,², Ricarda Evens ^3,⁵, Laura Kärtner ^1,², Andrea Jungaberle ^3,^7,⁸, Henrik Jungaberle ^7,⁸, Tomislav Majić ^3,⁴, Christian N Schmitz ^1,^2,⁶, Andreas Ströhle ³, Dennis Scharf ^1,^2,⁶, Moritz Spangemacher ^1,^2,⁶, Max Wolff ^1,^2,^3,^7,⁸, Zahra Assadi ³, Scharif Bahri ³, Lilith Becher ³, Luca V Färber ^1,², Niklas Kirchen ^1,^2,⁶, Eugenia Kulakova ^3,⁴, Linda Kunz ^1,^2,⁶, Andy Meijer ³, Barbara Rohrmoser ^1,^2,⁶, Stefan Wellek ^2,⁹, Moritz M Berger ^2,⁹, Gerhard Gründer ^1,^2,^8,^✉

¹Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

²German Center for Mental Health, partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany

³Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany

⁴German Center for Mental Health, partner site Berlin-Potsdam, Berlin, Germany

⁵Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany

⁶Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

⁷MIND Foundation, Berlin, Germany

⁸OVID Health Systems GmbH, Berlin, Germany

⁹Core Facility of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

Accepted for Publication: January 11, 2026.

Published Online: March 18, 2026. doi:10.1001/jamapsychiatry.2026.0132

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Mertens LJ et al. JAMA Psychiatry.

^✉

Corresponding Author: Gerhard Gründer, Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159 Mannheim, Germany (gerhard.gruender@zi-mannheim.de).

Author Contributions: Ms Mertens and Dr Gründer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mertens, Koslowski, A. Jungaberle, H. Jungaberle, Majić, Stroehle, Wolff, Bahri, Wellek, Gründer.

Acquisition, analysis, or interpretation of data: Mertens, Koslowski, Betzler, Brand, Evens, Kärtner, A. Jungaberle, Majić, Schmitz, Stroehle, Scharf, Spangemacher, Wolff, Assadi, Bahri, Becher, Faerber, Kirchen, Kulakova, Kunz, Meijer, Rohrmoser, Wellek, Berger, Gründer.

Drafting of the manuscript: Mertens, Wolff, Wellek, Gründer.

Critical review of the manuscript for important intellectual content: Mertens, Koslowski, Betzler, Brand, Evens, Kärtner, A. Jungaberle, H. Jungaberle, Majić, Schmitz, Stroehle, Scharf, Spangemacher, Wolff, Assadi, Bahri, Becher, Faerber, Kirchen, Kulakova, Kunz, Meijer, Rohrmoser, Berger, Gründer.

Statistical analysis: Mertens, Schmitz, Wellek, Berger, Gründer.

Obtained funding: Mertens, H. Jungaberle, Stroehle, Wolff, Gründer.

Administrative, technical, or material support: Mertens, Koslowski, Betzler, Evens, Kärtner, H. Jungaberle, Majić, Stroehle, Scharf, Wolff, Bahri, Becher, Faerber, Kulakova, Meijer, Rohrmoser, Gründer.

Supervision: Mertens, Koslowski, Stroehle, Berger, Gründer.

Conflict of Interest Disclosures: Dr Betzler reported receiving personal fees from Takeda Pharmaceutical Company and Medice Arzneimittel Pütter GmbH & Co outside the submitted work. Ms Brand reported receiving board member fees from SÄPT Switzerland and mentorship fees from MIND Foundation outside the submitted work. Dr Evens reported receiving compensation for travel expenses from Beckley Psytech outside the submitted work. Dr A. Jungaberle reported receiving study support from Beckley Psytech and MindMed outside the submitted work and being a cofounder and/or shareholder of OVID Health Systems GmbH, OVID Clinic Berlin GmbH, OVID Beteiligungsgesellschaft mbH, OVID Tagesklinik GmbH & Co. KG, Metamorphosis Ecologica GmbH (Berlin, Germany), and MIND Foundation gGmbH (Berlin, Germany). Dr H. Jungaberle reported receiving nonfinancial support from the MIND Foundation gGmbH; being an employee of and a shareholder in OVID Clinic Berlin; and serving as chief executive officer of OVID Health Systems GmbH outside the submitted work. Dr Majić reported receiving travel expenses from Beckley Psytech. Dr Stroehle reported receiving teaching honoraria from the Zentrum für Psychotherapie of the Humboldt University Berlin (ZPHU/FAWP) and the Zentrum für Psychologische Psychotherapie Bremen. Dr Wolff reported being a shareholder in OVID Tagesklinik GmbH outside the submitted work. Mr Bahri reported receiving mentorship fees from the MIND Foundation gGmbH outside the submitted work. Ms Rohrmoser reported working in clinical studies for Eisai (Tokio, Japan), Acumen Pharmaceuticals (Newton, Massachusetts), Roche (Basel, Switzerland), Novo Nordisk (Bagsværd, Denmark), Beckley Psytech Limited (London, UK), MindMed (New York, New York), and Cybin (Tornoto, Ontario, Canada). Dr Gründer reported receiving grants from Beckley Psytech, Boehringer Ingelheim, and MindMed; personal fees from AbbVie, Beckley Psytech, Boehringer Ingelheim, Bristol Myers Squibb, Institute for Quality and Efficiency in Health Care, Johnson & Johnson, Lundbeck, MindMed, Otsuka, Roche, and ROVI; being owner of Mind and Brain Institute GmbH; and being a founder/shareholder of OVID Health Systems GmbH, OVID Clinic Berlin GmbH, OVID Beteiligungsgesellschaft mbH, OVID Tagesklinik GmbH & Co, and MIND Foundation gGmbH outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grant 01EN2006 A/B from the Federal Ministry of Education and Research (BMBF). Open access publication of the manuscript was supported by the German Center for Mental Health (DZPG).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the participants, without whom this research would not have been possible; the study teams at both study sites for their work in recruitment and data collection during the study; the entire teams at the Coordination Centre for Clinical Trials (KKS) Heidelberg and the Institute of Medical Biometry (IMBI) at Heidelberg University; the entire team at the Pharmacy of the University Mainz; and the Usona Institute, Madison, Wisconsin, for providing psilocybin. Beyond usual salary where applicable, no one received financial compensation for their contribution.

^✉

Corresponding author.

PMCID: PMC13000742 PMID: 41848690

This randomized clinical trial investigates the efficacy and safety of psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistance major depression.

Key Points

Question

What are the efficacy and safety of psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant major depression (TRD)?

Findings

In this randomized clinical trial including 144 adults with TRD, there were nonsignificant differences in the response rate on the Hamilton Rating Scale for Depression at 6 weeks (primary end point) for psilocybin, 25 mg; psilocybin, 5 mg; and nicotinamide. However, secondary outcomes showed clinically meaningful reductions in depressive symptoms for psilocybin, 25 mg vs comparators.

Meaning

Although the primary end point was negative, secondary outcomes suggest that psilocybin, 25 mg, with adjunct psychotherapy may exert clinically meaningful antidepressant effects in TRD.

Abstract

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.

Trial Registration

ClinicalTrials.gov Identifier: NCT04670081

Introduction

Major depressive disorder (MDD) affects approximately 280 million people worldwide and ranks second among causes of years lived with disability.^1,2 Treatment-resistant depression (TRD), commonly defined as failure to respond to 2 or more antidepressant treatments,^3,4 imposes a high individual and societal burden.^5,6 Innovative treatments for TRD are urgently needed.

Psilocybin, a partial serotonin 2A receptor agonist and classical psychedelic, accompanied by psychotherapy or psychological support, has shown promise for depression (MDD and TRD) in open-label⁷ and randomized clinical trials (RCTs) against waiting list,^8,9 (active) placebo,^10,11 low-dose psilocybin,¹² and escitalopram.¹³ A recent meta-analysis¹⁴ reported a pooled effect size of 0.66. Despite this potential, current evidence is constrained by methodological challenges, including small sample sizes, insufficient pharmacovigilance, functional unblinding, and expectancy effects.^15,16,17,18

This study evaluated the efficacy and safety of 1 high dose of psilocybin (25 mg) with adjunct psychotherapy in TRD, compared with low-dose psilocybin (5 mg) and active placebo (nicotinamide, 100 mg), both intended to aid blinding. Using a randomized parallel-group design with a second dosing after the primary end point, the study aimed to (1) reduce dropouts during the first treatment phase (until the primary end point), (2) reduce disappointment and symptom worsening in comparator groups if unblinding occurred, and (3) meet ethical obligations to offer active treatment to this vulnerable population. At the second dosing, psilocybin, 25 mg or 5 mg, was administered to examine the potential added benefit of a second 25-mg dose. Ensuring all participants received at least 1 dose of psilocybin, 25 mg, served both methodological and ethical purposes.

Methods

Study Design and Oversight

This phase 2b, triple-blind (investigator, participant, and rater blinded), active placebo-controlled, 4-arm, investigator-initiated RCT was sponsored by the Central Institute of Mental Health, Mannheim, Germany, and conducted at 2 German university hospitals from June 2021 to February 2024. The trial was approved by the Ethics Committees of the Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany, and the state of Berlin, and the Federal Institute for Drugs and Medical Devices. An independent data safety monitoring board continuously assessed the risk-benefit ratio. The study design and rationale have been published previously.¹⁵ The trial protocol and statistical analysis plan are available in Supplement 1 and Supplement 2, respectively. An overview of amendments to the protocol and statistical analysis plan (change log) is provided in eTable 4 in Supplement 3. A list of trial investigators is available in eTable 1 in Supplement 3. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

Participants

Adults aged 25 to 65 years with moderate to severe TRD, defined as a score of 17 or greater on the German Hamilton Rating Scale for Depression (HAMD17; range, 0-52, with higher scores indicating more severe symptoms) were eligible.¹⁹ Key inclusion and exclusion criteria are provided in eTable 2 in Supplement 3. TRD was defined as nonresponse to at least 2 adequate antidepressant treatments from different pharmacological classes in the current episode. Participants were required to discontinue ongoing psychotherapy and monoaminergic medication before dosing. A minimum abstinence of 2 weeks (fluoxetine, 5 weeks) was mandatory. Recruitment occurred via self-referral, referrals from treating clinicians, and public advertisements (website, media, flyers, word of mouth). Participant race was assessed at screening by an investigator and included Asian, Black, multiracial, and White.

Study Procedures

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.¹⁵ 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,^20,21 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 effects²² and psilocybin, 5 mg, as a nontherapeutic low-dose producing mild subjective effects.²³ 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 nicotinamide, 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).

Outcomes

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.²⁴ 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)²⁵ 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.²⁶

Safety Assessments

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 scale²⁷ for adverse effects and the Columbia-Suicide Severity Rating Scale (CSSRS).²⁸ 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.

Statistical Analysis

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 al¹⁵ and 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).^29,30

Results

Participants

A total of 3094 individuals contacted the trial centers, and 144 (mean [SD] age, 42.6 [10.8] years; 59 female [41.0%]; 85 male [59.0%]; 1 Asian [0.7%]; 2 multiracial [1.4%]; 141 White [98%]) were randomized (Figure 1 and Table 1). 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.

Figure 1. — IMP indicates investigational medicinal product; SAE, severe adverse event.

^aThe 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.

^bPrescreening 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*.

^cPatients were randomized to 4 trial arms determining their dosing scheme for the first and second IMP dose from the beginning. Both trial centers randomized 72 participants in the trial.

^dMajor time deviations in visit scheduling were regarded as an intercurrent event impacting the interpretation of the clinical outcome of interest when the time deviation was more than 3 weeks. Two of those 3 participants still underwent the whole trial/received both IMP administrations.

^eWhile receiving treatment refers to the estimand strategy of while-on-treatment according to the ICH E9 harmonized guideline on statistical principles for clinical trials (ICH E9(R1)).

^fAll randomized patients are included in the safety analysis set. Of those 144 patients, 143 received at least 1 IMP administration (1 person in the arm receiving psilocybin, 25 mg, was excluded due to high blood pressure the morning of the first dose).

Table 1. Demographic and Clinical Characteristics at Trial Entry and Baseline by Treatment Group at Primary End Point^a.

Characteristic	Nicotinamide + psilocybin, 25 mg (n = 48)	Psilocybin, 5 mg + psilocybin, 25 mg (n = 48)	Psilocybin, 25 mg + psilocybin, 25 mg or 5 mg (n = 48)	Overall (N = 144)
Age, mean (SD), y	42.63 (10.86)	41.77 (11.25)	43.42 (10.55)	42.60 (10.83)
Age, median (range), y	40 (27-62)	39 (25-63)	44 (26-64)	41 (25-64)
Sex, No. (%)
Female	20 (42)	18 (38)	21 (44)	59 (41)
Male	28 (58)	30 (62)	27 (56)	85 (59)
Race, No. (%)
Asian	0	0	1 (2)	1 (0.7)
Black	0	0	0	0
Multiracial	0	1 (2)	1 (2)	2 (1.4)
White	48 (100)	47 (98)	46 (96)	141 (98)
Level of education, No. (%)
Lower than high school	3 (6)	3 (6)	1 (2)	7 (5)
High school	16 (33)	10 (21)	8 (17)	34 (24)
Professional degree	6 (13)	7 (15)	7 (15)	20 (14)
Graduate	10 (21)	11 (23)	11 (23)	32 (22)
Postgraduate	13 (27)	17 (35)	21 (44)	51 (35)
IQ (WST)^b
Mean (SD)	109.28 (9.06)	111.28 (8.37)	115.13 (9.01)	111.92 (9.09)
Median (range)	107 (95-139)	110 (90-129)	114 (93-133)	110 (90-139)
Body mass index^b^,^c
Mean (SD)	25.48 (4.62)	23.22 (3.07)	24.99 (4.61)	24.58 (4.26)
Median (range)	25.13 (17.99-34.58)	22.82 (17.63-31.41)	25.20 (17.93-38.53)	24.31 (17.63-38.53)
Psychedelic naive, No. (%)	41 (85)	41 (85)	46 (96)	128 (89)
Psychiatric history
Duration since first MDD diagnosis, y
Mean (SD)	13.45 (9.47)	14.32 (10.38)	13.79 (9.26)	13.86 (9.65)
Median (range)	10.59 (1.16-36.47)	12.30 (1.25-48.73)	12.52 (2.05-40.77)	12.05 (1.16-48.73)
No. of MDD episodes
Mean (SD)	6.03 (8.02)	5.21 (6.57)	7.39 (11.56)	6.25 (9.04)
Median (range)	3 (1-40)	3 (1-30)	3.5 (1-50)	3 (1-50)
No. of previous psychiatric hospitalizations
Mean (SD)	2.17 (2.70)	2.27 (2.10)	1.98 (1.88)	2.14 (2.24)
Median (range)	1 (0-16)	2 (0-8)	2 (0-8)	2 (0-16)
No. of previous antidepressant agents tried (lifetime)
Mean (SD)	5.38 (2.97)	6.04 (3.27)	4.88 (2.06)	5.43 (2.83)
Median (range)	5 (2-16)	5 (2-19)	4 (2-11)	5 (2-19)
No. of augmentative agents tried (lifetime)
Mean (SD)	1.25 (1.66)	0.92 (1.66)	1.31 (1.98)	1.16 (1.77)
Median (range)	1 (0-8)	0 (0-9)	1 (0-11)	1 (0-11)
Withdrawn from antidepressant medication at trial entry, No. (%)^d	17 (35)	21 (44)	25 (52)	63 (44)
Withdrawn from any psychotropic medication at trial entry, No. (%)^d	19 (40)	23 (48)	28 (58)	70 (49)
Any current psychiatric comorbidity, No. (%)^e	37 (77)	37 (77)	38 (79)	112 (78)
Depression severity at baseline
HAMD17 total score
Mean (SD)	22.06 (3.59)	22.40 (4.85)	21.83 (5.10)	22.10 (4.53)
Median (range)	22 (15-30)	21 (14-34)	21 (11-33)	21 (11-34)
Mild: 8-16, No. (%)^f	2 (4)	3 (6)	7 (15)	12 (8)
Moderate: 17-24, No. (%)	33 (69)	30 (63)	28 (58)	91 (63)
Severe: ≥25, No. (%)	13 (27)	15 (31)	13 (27)	41 (28)
BDI-II^g
Mean (SD)	33.60 (9.77)	33.33 (8.73)	32.60 (9.21)	33.18 (9.19)
Median (range)	32.5 (11-55)	32.5 (17-52)	34.0 (15-58)	33 (11-58)
Minimal to mild: 11-19, No. (%)	3 (6)	2 (4)	4 (8)	9 (6)
Moderate: 20-28, No. (%)	10 (21)	14 (29)	13 (27)	37 (26)
Severe: ≥29, No. (%)	35 (73)	32 (67)	31 (65)	98 (68)
CGI severity
Mean (SD)	5.98 (0.56)	5.83 (0.66)	6.06 (0.67)	5.96 (0.64)
Median (range)	6 (5-7)	6 (5-7)	6 (5-8)	6 (5-8)
Moderately, No. (%)	8 (17)	15 (31)	8 (17)	31 (22)
Markedly, No. (%)	33 (69)	26 (54)	30 (63)	89 (62)
Severely to extremely severe, No. (%)	7 (15)	7 (15)	10 (21)	24 (17)
GAF
Mean (SD)	50.65 (7.71)	51.38 (7.72)	50.75 (8.04)	50.92 (7.78)
Median (range)	55 (30-66)	55 (35-65)	55 (31-65)	55 (30-66)
Suicidality at trial entry (CSSRS) ^h
Suicidal ideation in the past 6 mo, No. (%)
Wish to be dead	37 (77)	35 (73)	33 (69)	105 (73)
Nonspecific active suicidal thoughts	21 (44)	20 (42)	20 (42)	61 (42)
Active suicidal ideation with any method without intent to act	15 (31)	10 (21)	13 (27)	38 (26)
Active suicidal ideation with some intent to act, without specific plan	2 (4)	1 (2)	2 (4)	5 (3)
Active suicidal ideation with specific plan and intent	0	1 (2)	2 (4)	3 (2)
Suicidal behaviors, No. (%)ⁱ
Suicidal behaviors (lifetime)	12 (25)	6 (13)	12 (25)	30 (21)
Suicidal behaviors (past year)	1 (2)	1 (2)	3 (6)	5 (3)

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Abbreviations: BDI-II, Beck Depression Inventory II; CGI, Clinical Global Impression; CSSRS, Columbia-Suicide Severity Rating Scale; GAF, Global Assessment of Functioning; HAMD17, Hamilton Depression Rating Scale; MDD, major depressive disorder; WST, Wortschatztest.

^{^a}

A second table on baseline characteristics split by 4 treatment groups (1-3b) is provided in eTable 6 in Supplement 3.

^{^b}

Based on observations from 141 participants (n = 46 in the psilocybin, 5 mg, group; n = 47 in the nicotinamide group).

^{^c}

Calculated as weight in kilograms divided by height in meters squared.

^{^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.

^{^h}

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.

Baseline demographic and clinical characteristics were comparable across groups (Table 1 and eTables 6 and 7 in Supplement 3). The mean (SD) duration since the first MDD episode was 13.9 (9.7) years, with 6.3 (9.0) lifetime episodes. Baseline depression severity was moderate on the HAMD17 (means, 21.83-22.40; overall mean [SD], 22.10 [4.53]) but severe on the BDI-II (means, 32.60-33.60; overall mean [SD], 33.18 [9.19]), with 98 participants (68%) scoring in the severe range on the BDI-II.

Efficacy

Efficacy results for the HAMD17 are presented for the while-receiving-treatment population (Table 2, Table 3, Figure 2, and eFigure 2 in Supplement 3). At week 6 (primary end point), treatment response did not differ significantly between groups; 8 of 47 (17.0%) after psilocybin, 25 mg, classified as responders; 6 of 48 (12.5%) after psilocybin, 5 mg, classified as responders; and 5 of 47 (10.6%) after nicotinamide classified as responders (psilocybin, 25 mg vs nicotinamide: adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19, derived from confirmatory testing; 1-sided α P = .03). Details on model fit are provided in eFigure 3 in Supplement 3. The Breslow-Day test revealed weak evidence for a difference between centers; notably, nicotinamide response at week 6 occurred only at 1 center (eTable 8 in Supplement 3). At week 1, response rates were higher after psilocybin, 25 mg (16 of 47 [34.0%]), compared with nicotinamide (3 of 47 [6.4%]) and psilocybin, 5 mg (5 of 48 [10.4%]); the odds ratio favoring psilocybin, 25 mg (vs nicotinamide) was 7.60 (95% CI, 2.29-34.75).

Table 2. Primary and Secondary Efficacy Results of the Hamilton Depression Rating Scale (HAMD17) and Beck Depression Inventory II (BDI-II) (While-Receiving-Treatment Population) Treatment Phase I^a.

End points: treatment phase 1	Psilocybin, 25 mg	Psilocybin, 5 mg	Nicotinamide
HAMD17, No.	47 ^b	48 ^b	47 ^b
Primary end point
Response at week 6
No./total No. of participants (%)	8/47 (17.0)	6/48 (12.5)	5/47 (10.6)
Odds ratio vs nicotinamide (95% CI)	1.73 (0.53 to 6.23); P = .19^c	1.14 (0.31 to 4.29)	NA
Odds ratio vs 5 mg (95% CI)	1.52 (0.47 to 4.85); P = .24^d	NA	NA
Secondary end points
Response at week 1
No./total No. of participants (%)	16/47 (34.0)	5/48 (10.4)	3/47 (6.4)
Odds ratio vs nicotinamide (95% CI)	7.60 (2.29 to 34.75)	1.68 (0.39 to 8.63)	NA
Odds ratio vs 5 mg (95% CI)	4.51 (1.49 to 13.69)	NA	NA
Total score at week 6, mean (SD)	15.9 (6.58)	18.9 (7.04)	20.4 (6.01)
Change from baseline at week 6 (SD)	6.06 (7.93)	3.46 (5.82)	1.51 (5.36)
Estimated average change from baseline at week 6 (95% CI)		−3.68 (−4.66 to −2.70)
Estimated difference at week 6 vs nicotinamide (95% CI)	−4.60 (−7.01 to −2.18); P <.001^d	−1.50 (−3.91 to 0.90)	NA
Estimated difference at week 6 vs 5 mg (95% CI)	−3.09 (−5.50 to −0.69); P = .02^d	NA	NA
Total score at week 1, mean (SD)	14.8 (7.01)	18.6 (7.12)	19.7 (5.18)
Change from baseline at week 1, mean (SD)	7.15 (7.76)	3.81 (6.02)	2.30 (4.24)
Estimated average change from baseline at week 1 (95% CI)		−4.42 (−5.40 to −3.44)
Estimated difference at week 1 vs nicotinamide (95% CI)	−4.89 (−7.31 to −2.48)	−1.07 (−3.47 to 1.34)	NA
Estimated difference at week 1 vs 5 mg (95% CI)	−3.83 (−6.23 to −1.42)	NA	NA
Remission at week 1, No./total No. (%)	7/47 (14.9)	4/48 (8.3)	1/47 (2.1)
Remission at week 6, No./total No. (%)	5/47 (10.6)	0/48 (0)	1/47 (2.1)
BDI-II, No.	47 ^b	48 ^b	47 ^b
Response at week 6
No./total No. of participants (%)	11/47 (23.4)	3/48 (6.3)	5/47 (10.6)
Odds ratio vs nicotinamide (95% CI)	2.64 (0.87 to 9.05); P = .049^d	0.57 (0.11 to 2.48)	NA
Odds ratio vs 5 mg (95% CI)	4.61 (1.19 to 17.83); P = .01^d	NA	NA
Response at week 1
No./total No. of participants (%)	13/47 (27.7)	9/48 (18.8)	4/47 (8.5)
Odds ratio vs nicotinamide (95% CI)	4.29 (1.36 to 16.46)	2.49 (0.74 to 9.86)	NA
Odds ratio vs 5 mg (95% CI)	1.72 (0.65 to 4.58)	NA	NA
Response at day 1
No./total No. of participants (%)	18/47 (38.3)	11/48 (22.9)	5/47 (10.6)
Odds ratio vs nicotinamide (95% CI)	5.13 (1.76 to 17.47)	2.64 (0.85 to 9.31)	NA
Odds ratio vs 5 mg (95% CI)	1.94 (0.77 to 4.89)	NA	NA
Total score at week 6 (SD)	24.7 (11.3)	29.6 (11.4)	32.0 (11.6)
Change from baseline at week 6 (SD)	8.02 (12.2)	3.36 (8.02)	1.40 (9.66)
Estimated average change from baseline week 6 (95% CI)		−4.22 (−5.69 to −2.75)
Estimated difference at week 6 vs nicotinamide (95% CI)	−7.21 (−11.86 to −2.56); P <.001^d	−2.05 (−6.67 to 2.58)	NA
Estimated difference at week 6 vs 5 mg (95% CI)	−5.16 (−9.79 to −0.52); P = .007^d	NA	NA
Total score at week 1, mean (SD)	23.5 (12.6)	27.6 (12.7)	30.1 (11.9)
Change from baseline at week 1, mean (SD)	9.27 (10.9)	5.50 (9.75)	3.44 (9.16)
Estimated average change from baseline at week 1 (95% CI)		−6.10 (−7.59 to −4.62)
Estimated difference at week 1 vs nicotinamide (95% CI)	−6.92 (−11.61 to −2.23)	−2.36 (−7.01 to 2.30)	NA
Estimated difference at week 1 vs 5 mg (95% CI)	−4.56 (−9.23 to 0.11)	NA	NA
Total score at day 1, mean (SD)	21.2 (12.9)	24.7 (12.0)	27.4 (12.1)
Change from baseline at day 1, mean (SD)	11.6 (9.09)	8.64 (8.31)	6.09 (8.69)
Estimated average change from baseline at day 1 (95% CI)		−8.94 (−10.42 to −7.46)
Estimated difference at day 1 vs nicotinamide (95% CI)	−5.84 (−10.51 to −1.17)	−2.47 (−7.15 to 2.20)	NA
Estimated difference at day 1 vs 5 mg (95% CI)	−3.37 (−8.02 to 1.28)	NA	NA
Remission at day 1, No./total No. (%)	10/47 (21.3)	4/48 (8.3)	4/47 (8.5)
Remission at week 1, No./total No. (%)	6/47 (12.8)	6/48 (12.5)	2/47 (4.3)
Remission at week 6, No./total No. (%)	6/47 (12.8)	2/48 (4.2)	1/47 (2.1)
Missing on scale level at day 1, No. (%)	0	3 (6.3)	3 (6.4)
Missing on scale level at week 1, No. (%)	3 (6.4)	2 (4.2)	2 (4.3)
Missing on scale level at week 6, No. (%)	1 (2.1)	1 (2.1)	0

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Abbreviations: BDI-II, Beck Depression Inventory II; HAMD17, Hamilton Depression Rating Scale; NA, not applicable.

^{^a}

Response = minimum 50% reduction on the HAMD17/BDI-II total score; remission, HAMD17 total score <8; BDI-II total score <10. At day 1, week 1, and week 7 the BDI-II in its original form was adapted to assess the time frame since the dosing session, including today. Response was analyzed using logistic regression models with treatment (psilocybin, 25 mg vs psilocybin, 5 mg vs nicotinamide in phase 1), center, and baseline HAMD17/BDI-II as independent variables. Change from baseline was evaluated by 2 mixed-effects linear regression models with the HAMD17/BDI-II total score as outcomes respectively, including treatment (according to treatment phase), time (according to treatment phase), treatment × time interactions, and center as a covariate (fixed effects) and participant-specific intercepts (random effects). Estimated average change from baseline at the respective time point refers to the estimated change across treatment groups.

^{^b}

The No. refers to the number of observations for assessment of the end point at week 6 (while-receiving-treatment population).

^{^c}

Reported P value is derived from formal confirmatory testing at a 1-sided α level of .03.

^{^d}

Reported P values are nominal uncorrected P values at a 1-sided α level of .03.

Table 3. Secondary Efficacy Results of the Hamilton Depression Rating Scale (HAMD17) and Beck Depression Inventory II (BDI-II) (While-Receiving-Treatment Population) Treatment Phase II^a.

End points: treatment phase 2	Psilocybin, 25 mg + psilocybin, 25 mg	Psilocybin, 25 mg + psilocybin, 5 mg	Psilocybin, 5 mg + psilocybin, 25 mg	Nicotinamide +psilocybin, 25 mg
HAMD17, No.	22 ^b	21 ^b	44 ^b	41 ^b
Total score at week 7 (SD)	15.1 (5.57)	14.0 (8.53)	13.5 (7.14)	14.2 (7.02)
Change from baseline at week 7 (SD)	7.26 (7.05)	7.33 (8.90)	8.84 (5.54)	7.38 (6.80)
Estimated average change from baseline at week 7 (95% CI)		−7.78 (−8.96 to −6.60)
Estimated difference at week 7 vs nicotinamide first (95% CI)	0.75 (−2.53 to 4.03)	−0.27 (−3.61 to 3.08)	−0.84 (−3.54 to 1.87)	NA
Total score at week 12, mean (SD)	14.5 (6.38)	13.2 (8.29)	14.6 (7.79)	15.6 (7.68)
Change from baseline at week 12, mean (SD)	7.68 (8.11)	8.10 (8.48)	7.70 (7.74)	6.07 (6.73)
Estimated average change from baseline at week 12 (95% CI)		−7.50 (−8.69 to −6.31)
Estimated difference at week 12 vs nicotinamide first (95% CI)	−1.12 (−4.44 to 2.20)	−2.34 (−5.69 to 1.02)	−1.01 (−3.73 to 1.71)	NA
Response at week 12
No./total No. of participants (%)	6/22 (27.3)	7/21 (33.3)	13/44 (29.5)	14/41 (34.1)
Odds ratio vs nicotinamide first (95% CI)	0.70 (0.21 to 2.16)	0.93 (0.29 to 2.84)	0.79 (0.31 to 2.01)	NA
Remission at week 12, No./total No. (%)	0/22 (0)	6/21 (28.6)	9/44 (20.5)	9/41 (22.0)
BDI-II, No.	22 ^b	22 ^b	46 ^b	41 ^b
Total score at week 7, mean (SD)	21.7 (10.1)	20.0 (14.2)	20.6 (12.4)	20.4 (13.5)
Change from baseline at week 7, mean (SD)	14.0 (12.7)	9.38 (14.2)	12.4 (10.1)	11.8 (13.0)
Estimated average change from baseline at week 7 (95% CI)		−11.92 (−13.84 to −10.01)
Estimate at week 7 vs nicotinamide first (95% CI)	0.15 (−6.04 to 6.35)	−0.93 (−7.19 to 5.34)	−0.81 (−5.89 to 4.28)	NA
Total score at week 12, mean (SD)	22.5 (11.3)	20.0 (13.6)	23.3 (13.6)	24.1 (15.0)
Change from baseline at week 12, mean (SD)	11.6 (10.6)	9.45 (14.6)	9.66 (11.2)	9.13 (12.8)
Estimated average change from baseline at week 12 (95% CI)		−10.53 (−12.48 to −8.58)
Estimated difference at week 12 vs nicotinamide first (95% CI)	−1.76 (−8.17 to 4.65)	−3.83 (−10.06 to 2.41)	−0.59 (−5.71 to 4.52)	NA
Response at week 12
No./total No. of participants (%)	4/22 (18.2)	7/22 (31.8)	16/46 (34.8)	13/41 (31.7)
Odds ratio vs nicotinamide first (95% CI)	0.48 (0.11 to 1.73)	0.80 (0.24 to 2.49)	1.09 (0.43 to 2.81)	NA
Remission at week 12, No./total No. (%)	2/22 (9.1)	4/22 (18.2)	9/46 (19.6)	10/41 (24.4)
Missings on scale level at week 12, No. (%)	3 (13.6)	0	2 (4.3)	2 (4.9)

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Abbreviations: BDI-II, Beck Depression Inventory II; HAMD17, Hamilton Depression Rating Scale; NA, not applicable.

^{^a}

Response = minimum 50% reduction on the HAMD17/BDI-II total score; remission, HAMD17 total score <8; BDI-II total score <10. At day 1, week 1, and week 7 the BDI-II in its original form was adapted to assess the time frame since the dosing session, including today. Response was analyzed using logistic regression models with treatment (4 treatment groups in phase 2), center, and baseline HAMD17/BDI-II as independent variables. Change from baseline was evaluated by 2 mixed-effects linear regression models with the HAMD17/BDI-II total score as outcomes respectively, including treatment (according to treatment phase), time (according to treatment phase), treatment × time interactions, and center as a covariate (fixed effects) and participant-specific intercepts (random effects). Estimated average change from baseline at the respective time point refers to the estimated change across treatment groups.

^{^b}

The No. refers to the number of observations for assessment of the secondary end point at week 12 (while-receiving-treatment population).

Figure 2. — Dosings occurred at week 0 (dose 1) and week 6 (dose 2) after assessment of the primary end point, indicated by the dashed vertical lines. Total scores on the HAMD17 range from 0 to 52 with higher scores indicating more severe depressive symptoms. Bars represent 95% CIs. At week 6, the left number refers to the number of participants at assessment of the primary end point, and the right number refers to the number of participants who received the second investigational medicinal product (IMP) administration. Provided model statistics are based on a mixed-effects linear regression model for treatment phase 1 with the HAMD17 total score as outcomes, including treatment (nicotinamide vs psilocybin, 5 mg vs 25 mg), time (baseline, week 1, week 6), treatment × time interactions, and center as a covariate (fixed effects) and participant-specific intercepts (random effects). Reported P values are nominal uncorrected P values at a 1-sided α level of .03.

^aIn 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).

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) (Figure 2 and Table 2). Hodges-Lehmann CIs did not indicate any relevant differences.

BDI-II results aligned with the HAMD17 (Table 2). 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) (Table 2 and 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 3). 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 3). 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 regardless 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.

Safety

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.

Discussion

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 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,¹² 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,^11,12 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,¹⁸ 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,^10,12 this study selected 6 weeks to align with conventional antidepressant trials.³ Closer end points typically yield larger effects. Whether this represents a rapid, genuine antidepressant effect or merely a postacute afterglow phenomenon remains debated.^31,32,33 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 interventions.

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,^7,15 likely contributing to the divergence between primary and key secondary 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 trials^9,11 and slightly smaller than in another large TRD RCT.¹² This may partly reflect that in Goodwin et al,¹² 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.^34,35 TRD is a dynamically developing condition,^3,36 and psilocybin, like other antidepressants, appears more effective in MDD than TRD (Raison/Usona Institute, unpublished data, 2023).^9,11,12 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.³³ Should confirmatory studies substantiate psilocybin’s efficacy, it could signal a paradigm shift in psychiatry away from chronic symptom management.

Strengths and Limitations

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,³⁷ 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,^13,14,38 despite concurrent psychotherapy. Besides unblinding, TRD-specific sample characteristics may also account for the low placebo response. These findings underscore the difficulty of maintaining double-blinding in psychedelic RCTs.³⁹ Yet expectancy, placebo, and nocebo effects remain central to all antidepressant interventions.^40,41

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 (Table 1 and 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, well-powered designs with active comparators, longer durations, individualized dosing, central independent raters, multiple centers, and adherence ratings within standardized psychotherapy protocols.

Conclusions

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.

Supplement 1.

Trial Protocol.

jamapsychiatry-e260132-s001.pdf^{(1.4MB, pdf)}

Supplement 2.

Statistical Analysis Plan.

jamapsychiatry-e260132-s002.pdf^{(285.4KB, pdf)}

Supplement 3.

eTable 1. List of Investigators per Study Site

eMethods 1. Study Design and Procedures

eTable 2. Overview of the Key Inclusion and Exclusion Criteria

eFigure 1. Study Timeline and Procedures

eTable 3. Selected Overview of Assessments

eMethods 2. Statistical Analysis

eTable 4. Protocol and Statistical Analysis Plan Change Log

eTable 5. Overview of Premature Study Terminations

eTable 6. Demographic and Clinical Characteristics at Trial Entry and Baseline by Treatment Group

eTable 7. Additional Patient Characteristics at Trial Entry by Treatment Group

eFigure 2. Absolute HAMD17 Total Scores at Baseline and Week 6 Comparing 25 mg Psilocybin With Nicotinamide and 5 mg Psilocybin

eFigure 3. Model Fit (Binned Calibration Plot) of the Logistic Regression Model of the Primary End Point

eTable 8. HAMD17 Response Rates by Treatment Group and Center Until Week 6

eTable 9. Sensitivity Analysis: Primary and Secondary Efficacy Results on the HAMD17

eFigure 4. Mean Change From Baseline on the BDI-II Total Score

eFigure 5. Absolute BDI-II Total Scores at Baseline and Week 6 Comparing 25 mg Psilocybin With Nicotinamide and 5 mg Psilocybin

eTable 10. Exploratory Efficacy Analyses of the GAF and CGI Scales Over the Study Period

eTable 11. Change From Baseline on the HAMD17 at Week 6 by Sex and Treatment Group (Dose 1)

eTable 12. Change from Baseline on the HAMD17 at Week 6 by Antidepressant Withdrawal Status and Treatment Group (Dose 1)

eTable 13. Change from Baseline on the HAMD17 at Week 6 by Baseline Severity on the HAMD17 and Treatment Group (Dose 1)

eTable 14. Descriptive HAMD17 Outcomes at Week 6 by Lifetime Psychedelic Experience and Treatment Group (Dose 1)

eResults 1. Safety Results

eTable 15. Incidence of Adverse Events Reported on the Dosing Days, Day 1 to Day 7 and After Day 7 Up to Week 6 After Each Investigational Medicinal Product (IMP) Administration (Safety Population)

eTable 16. Incidence of Severe Adverse Events Reported on the Dosing Days, Day 1 to Day 7, and After Day 7 Up to Week 6 After Each IMP Administration (Safety Population)

eTable 17. Incidence of Adverse Events Reported on the Dosing Days, Day 1 to Day 7, and After Day 7 Up to Week 6 After Each IMP Administration Using the Raw MedDRA System Preferred Terms (Safety Population)

eTable 18. Overview of Suicidal and Nonsuicidal Self-Injurious Behaviors By Treatment Group

eTable 19. CSSRS Suicidal Ideation Shift Analysis: Shift to Worst Postbaseline Scores Until Week 6

eTable 20. CSSRS Suicidal Ideation Shift Analysis: Shift to Worst Postbaseline Scores From Dose 2 Until Week 12

eTable 21. Dose 1—Patients’ Assumed Treatment Allocations and Certainty Ratings

eTable 22. Descriptive HAMD17 Outcomes at Week 6 by Functional Unblinding Status and Treatment Group (Dose 1)

eTable 23. Dose 1—Therapists’ Assumed Treatment Allocations and Certainty Ratings

eFigure 6. Total Emotional Breakthrough Inventory (EBI) Scores by IMP Doses at Dose 1 and 2

eResults 2. Additional Therapeutic Support

eTable 24. Background Information on the Population Affected by Treatment-Resistant Depression

eReferences.

jamapsychiatry-e260132-s003.pdf^{(1.7MB, pdf)}

Supplement 4.

Data Sharing Statement.

jamapsychiatry-e260132-s004.pdf^{(16.3KB, pdf)}

References

1.Vizhub Health Data . Evaluation IfHM—Global Health Data Exchange (GHDx). Accessed October 12, 2024.
2.Ferrari AJ, Santomauro DF, Aali A, et al. ; GBD 2021 Diseases and Injuries Collaborators . Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10440):2133-2161. doi: 10.1016/S0140-6736(24)00757-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.European Medicines Agency (EMA) . Guideline on clinical investigation of medicinal products in the treatment of depression—revision 2. Accessed December 18, 2024. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-depression-revision-2_en.pdf
4.US Food and Drug Administration (FDA) . Major depressive disorder: developing drugs for treatment—guidance for industry (revision 1). Accessed December 18, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/major-depressive-disorder-developing-drugs-treatment
5.Lundberg J, Cars T, Lööv SÅ, et al. Association of treatment-resistant depression with patient outcomes and health care resource utilization in a population-wide study. JAMA Psychiatry. 2023;80(2):167-175. doi: 10.1001/jamapsychiatry.2022.3860 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry. 2019;19(1):247. doi: 10.1186/s12888-019-2222-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619-627. doi: 10.1016/S2215-0366(16)30065-7 [DOI] [PubMed] [Google Scholar]
8.Rosenblat JD, Meshkat S, Doyle Z, et al. Psilocybin-assisted psychotherapy for treatment resistant depression: a randomized clinical trial evaluating repeated doses of psilocybin. Med. 2024;5(3):190-200.e5. doi: 10.1016/j.medj.2024.01.005 [DOI] [PubMed] [Google Scholar]
9.Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.von Rotz R, Schindowski EM, Jungwirth J, et al. Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomized clinical trial. EClinicalMedicine. 2022;56:101809. doi: 10.1016/j.eclinm.2022.101809 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Raison CL, Sanacora G, Woolley J, et al. Single-dose psilocybin treatment for major depressive disorder: a randomized clinical trial. JAMA. 2023;330(9):843-853. doi: 10.1001/jama.2023.14530 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-1648. doi: 10.1056/NEJMoa2206443 [DOI] [PubMed] [Google Scholar]
13.Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin vs escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411. doi: 10.1056/NEJMoa2032994 [DOI] [PubMed] [Google Scholar]
14.Metaxa AM, Clarke M. Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis. BMJ. 2024;385:e078084. doi: 10.1136/bmj-2023-078084 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Mertens LJ, Koslowski M, Betzler F, et al. Methodological challenges in psychedelic drug trials: Efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE)—rationale and study design. Neurosci Appl. 2022;1:100104. doi: 10.1016/j.nsa.2022.100104 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Gründer G, Mertens L. Psilocybin for depression. N Engl J Med. 2021;385(9):863. doi: 10.1056/NEJMc2108082 [DOI] [PubMed] [Google Scholar]
17.Aday JS, Heifets BD, Pratscher SD, Bradley E, Rosen R, Woolley JD. Great expectations: recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology (Berl). 2022;239(6):1989-2010. doi: 10.1007/s00213-022-06123-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Hinkle JT, Graziosi M, Nayak SM, Yaden DB. Adverse events in studies of classic psychedelics: a systematic review and meta-analysis. JAMA Psychiatry. 2024;81(12):1225-1235. doi: 10.1001/jamapsychiatry.2024.2546 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56-62. doi: 10.1136/jnnp.23.1.56 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Garcia-Romeu A, Richards WA. Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions. Int Rev Psychiatry. 2018;30(4):291-316. doi: 10.1080/09540261.2018.1486289 [DOI] [PubMed] [Google Scholar]
21.Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-620. doi: 10.1177/0269881108093587 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165-1180. doi: 10.1177/0269881116675512 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl). 2011;218(4):649-665. doi: 10.1007/s00213-011-2358-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Schmitt A, Kulzer B, Hermanns N. German Version of the GRID Hamilton Rating Scale for Depression (GRID-HAMD). Forschungsinstitut der Diabetes-Akademie Bad Mergentheim (FIDAM); 2012. [Google Scholar]
25.Beck AT, Steer RA, Carbin MG. Psychometric properties of the Beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77-100. doi: 10.1016/0272-7358(88)90050-5 [DOI] [Google Scholar]
26.Hengartner MP, Plöderl M. Estimates of the minimal important difference to evaluate the clinical significance of antidepressants in the acute treatment of moderate-to-severe depression. BMJ Evid Based Med. 2022;27(2):69-73. doi: 10.1136/bmjebm-2020-111600 [DOI] [PubMed] [Google Scholar]
27.Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100. doi: 10.1111/j.1600-0447.1987.tb10566.x [DOI] [PubMed] [Google Scholar]
28.Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 3 multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.SAS Institute . SAS/STAT 9.4 support, version 9.4. Accessed April 15, 2024. https://support.sas.com/en/software/sas-stat-support.html
30.R Project . The R project for statistical computing, version 4.4. Accessed April 15, 2024. https://www.R-project.org/
31.Gründer G, Brand M, Mertens LJ, et al. Treatment with psychedelics is psychotherapy: beyond reductionism. Lancet Psychiatry. 2024;11(3):231-236. doi: 10.1016/S2215-0366(23)00363-2 [DOI] [PubMed] [Google Scholar]
32.Evens R, Schmidt ME, Majić T, Schmidt TT. The psychedelic afterglow phenomenon: a systematic review of subacute effects of classic serotonergic psychedelics. Ther Adv Psychopharmacol. 2023;13:20451253231172254. doi: 10.1177/20451253231172254 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Spangemacher M, Mertens LJ, Färber LV, Jungaberle A, Jungaberle H, Gründer G. Psilocybin as a disease-modifying drug—a salutogenic approach in psychiatry. Dtsch Arztebl Int. 2024;121(26):868-874. doi: 10.3238/arztebl.m2024.0224 [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Newton-Howes G, Tyrer P, Johnson T, et al. Influence of personality on the outcome of treatment in depression: systematic review and meta-analysis. J Pers Disord. 2014;28(4):577-593. doi: 10.1521/pedi_2013_27_070 [DOI] [PubMed] [Google Scholar]
35.Schramm E, Klein DN, Elsaesser M, Furukawa TA, Domschke K. Review of dysthymia and persistent depressive disorder: history, correlates, and clinical implications. Lancet Psychiatry. 2020;7(9):801-812. doi: 10.1016/S2215-0366(20)30099-7 [DOI] [PubMed] [Google Scholar]
36.Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. doi: 10.1176/ajp.2006.163.11.1905 [DOI] [PubMed] [Google Scholar]
37.Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry. 2022;79(10):953-962. doi: 10.1001/jamapsychiatry.2022.2096 [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Llorca PM, Azorin JM, Despiegel N, Verpillat P. Efficacy of escitalopram in patients with severe depression: a pooled analysis. Int J Clin Pract. 2005;59(3):268-275. doi: 10.1111/j.1742-1241.2005.00440.x [DOI] [PubMed] [Google Scholar]
39.Muthukumaraswamy SD, Forsyth A, Lumley T. Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Rev Clin Pharmacol. 2021;14(9):1133-1152. doi: 10.1080/17512433.2021.1933434 [DOI] [PubMed] [Google Scholar]
40.Mora MS, Nestoriuc Y, Rief W. Lessons learned from placebo groups in antidepressant trials. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1879-1888. doi: 10.1098/rstb.2010.0394 [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Hieronymus F, López E, Werin Sjögren H, Lundberg J. Control group outcomes in trials of psilocybin, SSRIs, or esketamine for depression: a meta-analysis. JAMA Netw Open. 2025;8(7):e2524119-e2524119. doi: 10.1001/jamanetworkopen.2025.24119 [DOI] [PMC free article] [PubMed] [Google Scholar]

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