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. 2025 Mar 1:372:523-532.
doi: 10.1016/j.jad.2024.12.061. Epub 2024 Dec 18.

The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression

Guy M Goodwin  1 , Scott T Aaronson  2 , Oscar Alvarez  3 , Robin Carhart-Harris  4 , Jamie Chai-Rees  5 , Megan Croal  5 , Charles DeBattista  6 , Boadie W Dunlop  7 , David Feifel  8 , David J Hellerstein  9 , Muhammad I Husain  10 , John R Kelly  11 , Namik Kirlic  12 , Rasmus W Licht  13 , Lindsey Marwood  5 , Thomas D Meyer  14 , Sunil Mistry  5 , Ania Nowakowska  5 , Tomáš Páleníček  15 , Dimitris Repantis  16 , Robert A Schoevers  17 , Hollie Simmons  5 , Metten Somers  18 , Emma Teoh  5 , Joyce Tsai  12 , Mourad Wahba  19 , Sam Williams  5 , Allan H Young  20 , Matthew B Young  12 , Sidney Zisook  21 , Ekaterina Malievskaia  5
Affiliations

The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression

Guy M Goodwin et al. J Affect Disord. .

Erratum in

Abstract

Objective: To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression.

Methods: For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support. The resulting psychedelic experience (Five-Dimensional Altered States of Consciousness questionnaire [5D-ASC] and Emotional Breakthrough Inventory [EBI]) were measured. These proximal variables and outcome 3 weeks post-administration (change in Montgomery-Åsberg Depression Rating Scale [MADRS]) were explored using correlation analysis.

Results: The mean intensity of psychedelic effects was dose-related, but distributions of scores for different doses overlapped considerably. Depression response correlated with select aspects of the psychedelic experience overall and for individual doses. At the 25 mg dose, 5D-ASC dimensions Oceanic Boundlessness (Pearson correlation coefficient r = -0.508) and Visual Restructuralization (r = -0.516), and EBI (r = -0·637) were the variables with the strongest correlation to the Week 3 change from Baseline in MADRS score.

Limitations: The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples.

Conclusions: The intensity of psychedelic experience overlaps widely across doses and mitigates the risk of unblinding to dose. Correlations between psychedelic experience and outcome suggest specificity in psilocybin's mechanism of action. Quality and intensity of psychedelic experience may be a measure of pharmacodynamic effect and reveal an effective dose response phenomenon for single oral doses.

Keywords: Dose-response; Psilocybin; Psychedelic; Psychedelic experience; Randomized-control trial; Treatment-resistant depression.

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Conflict of interest statement

Declaration of competing interest GMG, JC-R, MC, NK, LM, SM, AN, HS, ET, JT, SW, MBY, and EM are current or past employees of subsidiaries of Compass Pathways plc and own shares, share options, and/or restricted share units in Compass Pathways plc. GMG has consulted for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, EVApharm, H Lundbeck A/S, Janssen Global Services, Novartis, Ocean Neurosciences, Servier, Takeda and WebMD. CD, BWD, DF, MIH, DJH, TDM, and SZ have received grant funding from Compass Pathfinder. STA, OA, CD, BWD, DF, DJH, MIH, JRK, RWL, TDM, TP, DR, RAS, MS, MW, AHY, and SZ were site investigators or sub-investigators for Compass Pathfinder during the clinical trial and/or ongoing clinical trials by the Sponsor, and received funding to conduct the study. STA has consulted for Compass Pathfinder, Genomind, Janssen Global Services, LivaNova, Neuronetics, and Sage Therapeutics. RC-H is a scientific advisor to Usona Institute, Maya Health, Osmind, Entheos Labs, TRYP therapeutics, Otsuka, and Journey Collab. JC-R holds shares in GSK, Haleon, ABVC Biopharma, and Avalo Therapeutics. CD has consulted for AbbVie and Corcept Therapeutics. CD has received grant funding from Beckley Psytech, Relmada Therapeutics, and Sage Therapeutics. BWD has received research support from Boehringer Ingelheim, NIMH, and the Usona Institute, and has served as a consultant for Biohaven, Cerebral Therapeutics, Myriad Neuroscience, and Otsuka. DF has received grant funding from MindMed, Neurolief, Perception Neuroscience, Compass Pathfinder, and Relmada Therapeutics. DF holds a patent for psychedelic drug treatment of neuropsychiatric disorders and cerebral palsy. DJH has consulted for Reset Pharmaceuticals. DJH has received grant funding from Assurex, Intra-Cellular Therapies, Marinus Pharmaceuticals, Compass Pathfinder, Relmada Pharmaceuticals, and Beckley Foundation. MIH owns shares in Mindset Pharma, has received consultancy fees from Psyched Therapeutics, Wake Network Inc. and has led contracted research for Neurocentrx and Compass Pathfinder. JRK has consulted for Clerkenwell Health and has received grant funding from the Health Research Board (ILP-POR-2022-030). NK has received grant funding from the National Institute for General Medical Sciences and the William K. Warren Foundation and has consulted for BehaVR. RWL has participated in speaking engagements for H Lundbeck A/S, Janssen Global Services, and Teva Pharmaceuticals. TP has consulted for Atai Life Sciences, CB21 Pharma, and GH Research. TP was/is a principal investigator at Ketabon GmbH, MAPS Europe BV and GH Research of the Czech sites at National Institute of Mental Health (Czech Republic) and Psyon clinic. TP is a founder and former fiduciary officer at the PSYRES Foundation, Psyon clinic, and the Society for the Promotion of Neuroscience Research. DR is honorary board chair of the nonprofit organization MAPS Deutschland. RAS has consulted for Clexio Biosciences and GH Research and has received grant funding from Janssen Pharmaceuticals. SZ and MW have participated in speaking engagements for Compass Pathfinder and Janssen Pharmaceuticals. ET receives studentship funding from the Medical Research Council. AHY is employed by King's College London; Honorary Consultant South London and Maudsley NHS Foundation Trust (NHS UK). AHY is editor of Journal of Psychopharmacology and Deputy Editor for BJPsych Open. AHY participated in paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: AstraZenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Compass Pathfinder, Sage, Novartis, Neurocentrx. AHY was principal investigator in the Restore-Life VNS registry study funded by LivaNova, ESKETINTRD3004 funded by Janssen Research & Development, LLC, and “The Effects of Psilocybin on Cognitive Function in Healthy Participants”. AHY is principal investigator for Novartis MDD study MIJ821A12201 and additional studies for Compass Pathfinder. AHY has received grant funding from NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK); and Janssen (UK) EU Horizon 2020. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

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