Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial
Abstract
Background: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature. Methods: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo ( n = 19) followed by psilocybin (0.3 mg/kg) ( n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period. Results: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin ( d′ = 1.02–2.27) than after placebo ( d′ = 0.65–0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects. Conclusions: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.
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Other studies have not found associations between symptom improvement and mystical-type experiences.
“However, other studies have not found associations between symptom improvement and mystical-type experiences”
From Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response (2024) · cites this paper as Sloshower et al., 2023
Research on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized study and several RCTs.
“Research on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized study 72 and several RCTs. 26,31-33,60,73-77”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [72]
Two trials reported no significant difference in the antidepressant effect between psilocybin and escitalopram or placebo.
“Concerning the outcome, two trials reported no significant difference in the antidepressant effect between psilocybin and escitalopram 26 or placebo, 72”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [72]
There are clear limitations such as small sample sizes with lack of diversity among participants and potential selection biases.
“Concerning the recruitment phase, there are clear limitations such as small sample sizes 25,31-33,39,57,60,72-74,77-81 with lack of diversity among participants 32,33,39,57,60,72,75-79 and potential selection biases. 26,31,39,72-74,76”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [72]
Among all the studies conducted, five were pilot studies.
“Amongall the studies conducted, five were pilot studies. 25,31,39,72,80”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [72]
Some studies showed inconsistent application of correction for multiple testing, no consideration of confounding factors, lack of randomization, and relatively short-term follow-up periods generally between one and 6 months after one or two single active psilocybin treatments.
“In terms of methodology, some studies showed inconsistent application of correction for multiple testing, 26,74 no consideration of confounding factors, 57,78 lack of randomization, 72 and relatively short-term follow-up periods were often observed, 25,26,31-33,39,57,72-81 generally between one and 6 months after one or two single active psilocybin treatments.”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [72]
Blinding procedures were not consistently robust, and comparison with placebo or standard treatments was lacking in many studies.
“Blinding procedures were not consistently robust, 26,32,60,72-76 and comparison with placebo or standard treatments was lacking in many studies. 25,26,31-33,39,57,60,72,73,75-81”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [72]
Cites
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817 · cited 2× · see citing works
“, 2015); (3) current moderate to severe major depressive episode of at least 6 weeks duration prior to screening, defined by a score ⩾17 on the GRIDHamilton Depression Rating Scale (HAM-D)-17 (Hamilton, 1960; International Society for CNS Drug Development, 2003); and (4) failed at least one adequate antidepressant tri…”
BackgroundMethodThe MOS 36-ltem Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection
Ware, J. E., & Sherbourne, C. D. (1992) · Medical Care · doi:10.1097/00005650-199206000-00002 · Cited by 30,033 · see citing works
The assessment of anxiety states by rating
HAMILTON, M. (1959) · British Journal of Medical Psychology · doi:10.1111/j.2044-8341.1959.tb00467.x · Cited by 11,455 · see citing works
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., Markowitz, J. C., Ninan, P. T., Kornstein, S., Manber, R., et al. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01866-8 · Cited by 3,829 · see citing works
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116675513 · Cited by 2,201 · cited 3× · see citing works
“…in cancer patients with depression and anxiety demonstrated clinically meaningful and statistically significant decreases in clinician- and self-rated measures of both depression and anxiety acutely and at long-term followup (Agin-Liebes et al., 2020; Griffiths et al., 2016; Ross et al., 2016).”
BackgroundResultRoss, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., et al. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116675512 · Cited by 1,698 · see citing works
Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0457-5 · Cited by 1,684 · see citing works
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M. J., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J. A., Forbes, B., Feilding, A., et al. (2016) · The Lancet Psychiatry · doi:10.1016/s2215-0366(16)30065-7 · Cited by 1,540 · see citing works
Trial of Psilocybin versus Escitalopram for Depression
Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2032994 · Cited by 1,391 · see citing works
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial
Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.3285 · Cited by 1,301 · see citing works
Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer
Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.116 · Cited by 1,206 · see citing works
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A., Vogel, H., & Hell, D. (1998) · NeuroReport · doi:10.1097/00001756-199812010-00024 · Cited by 1,018 · see citing works
Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects
Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., McCann, U., & Jesse, R. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2358-5 · Cited by 932 · see citing works
MacLean, K. A., Johnson, M. W., & Griffiths, R. R. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111420188 · Cited by 895 · see citing works
Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00974 · Cited by 808 · see citing works
Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin
Barrett, F. S., Johnson, M. W., & Griffiths, R. R. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115609019 · Cited by 637 · see citing works
Madsen, M. K., Fisher, P. M., Burmester, D., Dyssegaard, A., Stenbæk, D. S., Kristiansen, S., Johansen, S. S., Lehel, S., Linnet, K., Svarer, C., et al. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0324-9 · Cited by 517 · see citing works
Gukasyan, N., Davis, A. K., Barrett, F. S., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., & Griffiths, R. R. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811211073759 · Cited by 425 · see citing works
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J.-M. S., Johnson, M. W., & Griffiths, R. R. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116678781 · Cited by 366 · cited 5× · see citing works
“After drug effects had subsided on each dosing day, participants completed the Mystical Experience Questionnaire-30 (MEQ-30) (Barrett et al., 2015) and the Challenging Experience Questionnaire (CEQ) (Barrett et al., 2016) to retrospectively rate peak acute drug effects.”
BackgroundMethodInfluentialAgin-Liebes, G. I., Malone, T., Yalch, M. M., Mennenga, S. E., Ponté, K. L., Guss, J., Bossis, A. P., Grigsby, J., Fischer, S., & Ross, S. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881119897615 · Cited by 360 · see citing works
Blinding and expectancy confounds in psychedelic randomized controlled trials
Muthukumaraswamy, S. D., Forsyth, A., & Lumley, T. (2021) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2021.1933434 · Cited by 324 · see citing works
The GRID-HAMD: standardization of the Hamilton Depression Rating Scale
Williams, J. B. W., Kobak, K. A., Bech, P., Engelhardt, N., Evans, K., Lipsitz, J., Olin, J., Pearson, J., & Kalali, A. (2008) · International Clinical Psychopharmacology · doi:10.1097/yic.0b013e3282f948f5 · Cited by 295 · see citing works
Inclusion of people of color in psychedelic-assisted psychotherapy: a review of the literature.
Michaels, T. I., Purdon, J., Collins, A., & Williams, M. T. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1824-6 · Cited by 265 · see citing works
Aday, J. S., Heifets, B. D., Pratscher, S. D., Bradley, E., Rosen, R., & Woolley, J. D. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06123-7 · Cited by 237 · see citing works
Clinical applications of hallucinogens: a review
Garcia-Romeu, A., Kersgaard, B., & Addy, P. H. (2016) · Experimental and Clinical Psychopharmacology · doi:10.1037/pha0000084 · Cited by 201 · see citing works
Dakwar, E., Nunes, E. V., Hart, C. L., Foltin, R. W., Mathew, S. J., Carpenter, K. M., Choi, C. J. “., Basaraba, C. N., Pavlicova, M., & Levin, F. R. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.18101123 · Cited by 186 · see citing works
Dakwar, E., Levin, F., Hart, C. L., Basaraba, C., Choi, J., Pavlicova, M., & Nunes, E. V. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19070684 · Cited by 183 · see citing works
Sloshower, J., Guss, J., Krause, R., Wallace, R. M., Williams, M. T., Reed, S., & Skinta, M. D. (2020) · Journal of Contextual Behavioral Science · doi:10.1016/j.jcbs.2019.11.002 · Cited by 171 · see citing works
Self-citationD’Souza, D. C., Syed, S. A., Flynn, L. T., Safi-Aghdam, H., Cozzi, N. V., & Ranganathan, M. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01344-y · Cited by 162 · see citing works
Self-citationGukasyan, N., & Nayak, S. M. (2021) · Transcultural Psychiatry · doi:10.1177/1363461520983684 · Cited by 153 · see citing works
Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin
Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H., Luddy, C., Flynn, L. T., Lindsey, H. M., Pittman, B. P., Cozzi, N. V., & D’Souza, D. C. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00962-y · Cited by 139 · see citing works
Self-citationSerotonin toxicity of serotonergic psychedelics
Malcolm, B., & Thomas, K. (2022) · Psychopharmacology · doi:10.1007/s00213-021-05876-x · Cited by 138 · see citing works
Expectancy in placebo-controlled trials of psychedelics: if so, so what?
Butler, M., Jelen, L., & Rucker, J. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06221-6 · Cited by 100 · cited 2× · see citing works
“A number of recent papers have discussed the challenges to isolating individual components of this complex package in controlled trials (Aday et al., 2022; Butler et al., 2022; Gukasyan and Nayak, 2021).”
Schenberg, E. E. (2021) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2021.1951473 · Cited by 41 · see citing works
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Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis
Hinkle, J. T., Graziosi, M., Nayak, S. M., & Yaden, D. B. (2024) · JAMA psychiatry · doi:10.1001/jamapsychiatry.2024.2546 · Cited by 156 · see citing works
History repeating: guidelines to address common problems in psychedelic science
van Elk, M., & Fried, E. I. (2023) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253231198466 · Cited by 137 · see citing works
Sloshower, J., Zeifman, R. J., Guss, J., Krause, R., Safi-Aghdam, H., Pathania, S., Pittman, B., & D’Souza, D. C. (2024) · Scientific Reports · doi:10.1038/s41598-024-58318-x · Cited by 65 · see citing works
“For safety data along with other clinical and subjective measures collected, see 11 .”
BackgroundMethodInfluentialBreeksema, J. J., Niemeijer, A., Krediet, E., Karsten, T., Kamphuis, J., Vermetten, E., van den Brink, W., & Schoevers, R. (2024) · Scientific Reports · doi:10.1038/s41598-024-53188-9 · Cited by 58 · see citing works
Calder, A. E., Rausch, B., Liechti, M. E., Holze, F., & Hasler, G. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241278873 · Cited by 20 · see citing works
“However, other studies have not found associations between symptom improvement and mystical-type experiences (Agin-Liebes et al., 2020; Gukasyan et al., 2022; Sloshower et al., 2023).”
BackgroundAssessing potential of psilocybin for depressive disorders
Kozak, Z., Johnson, M. W., & Aaronson, S. T. (2023) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2273493 · Cited by 11 · see citing works
Scala, M., Fabbri, C., Fusar-Poli, P., Di Lorenzo, G., Ferrara, M., Amerio, A., Fusar-Poli, L., Pichiecchio, A., Asteggiano, C., Menchetti, M., et al. (2024) · CNS Spectrums · doi:10.1017/s1092852924002268 · Cited by 9 · see citing works
Serotonergic psychedelics for depression: A comprehensive overview
Wingert, A. M., Agnorelli, C., Peill, J., Reed, S., Nutt, D. J., & Erritzoe, D. (2025) · International Review of Neurobiology · doi:10.1016/bs.irn.2025.04.009 · Cited by 2 · see citing works
- Authors
- Sloshower, J., Skosnik, P. D., Safi-Aghdam, H., Pathania, S., Syed, S., Pittman, B., & D’Souza, D. C.
- Affiliations
- Yale University (US)
- VA Connecticut Healthcare System (US)
- Corresponding author
- D’Souza, Deepak Cyril
- ORCID
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2023-03-20
- Volume
- 37
- Issue
- 7
- Pages
- 698-706
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- OpenAlex
- W4327895864
- Cited by
- 165
- References
- 34
- Citations by year
- 2026: 39 · 2025: 48 · 2024: 60 · 2023: 18
- FWCI
- 47.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heffter Research Institute
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Keywords
- psilocybin, major depressive disorder, psychedelic-assisted psychotherapy, antidepressant effects, placebo effect, expectancy effects, mystical experience, anxiety, quality of life, blinding
- MeSH terms
- Antidepressive Agents, Major Depressive Disorder, Hallucinogens, Humans, Psilocybin, Quality of Life
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