Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder
This randomised open-label study (n=24) found that two sessions with psilocybin (20 and 30mg/70kg) significantly improved depression scores for a population with major depressive disorder (MDD) up to 8 weeks later.
Authors
- Alan Davis
- Frederick Barrett
- Nathan Sepeda
Published
Abstract
Importance
Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.
Objective
To investigate the effect of psilocybin therapy in patients with MDD.
Design, Setting, and Participants
This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).
Interventions
Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.
Main Outcomes and Measures
The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).
Results
Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.2; 95% CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 3.0; 95% CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9-4.2; P < .001). In the overall sample, 17* participants (71%*) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).
Conclusions and Relevance
Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.
Research Summary of 'Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder'
Introduction
Major depressive disorder (MDD) is described as a leading global cause of disability with substantial personal and economic burden and limitations in current pharmacotherapies, including incomplete response, adverse effects, and adherence problems. Earlier research highlighted rapid but short-lived antidepressant effects of ketamine and preliminary evidence that one or two administrations of psilocybin, given with psychological support, produced antidepressant effects in patients with cancer-related distress and in small samples of treatment-resistant depression. Psilocybin was noted to act via serotonergic and possibly glutamatergic pathways and to have lower addiction liability and less long-term toxicity than ketamine, motivating further investigation in broader MDD samples. Davis and colleagues designed the present study to test whether psilocybin-assisted therapy reduces depressive symptoms in adults with moderate to severe MDD. The trial used a randomised, waiting list–controlled design to compare immediate administration of two psilocybin sessions (with psychological support) against an 8-week delayed treatment control, with clinician-blinded assessment of depression severity as the primary outcome.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Pro members can view the original manuscript directly in the browser.
Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
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). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder. JAMA Psychiatry, 78(5), 481. https://doi.org/10.1001/jamapsychiatry.2020.3285
References (24)
Papers cited by this study that are also in Blossom
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
Dutta, A., Mckie, S., Deakin, J. F. W. · Psychiatry Research (2014)
Fond, G., Loundou, A., Macgregor, A. et al. · Psychopharmacology (2014)
Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)
Nichols, D. E. · Pharmacological Reviews (2016)
Griffiths, R. R., Johnson, M. W. · Journal of Psychopharmacology (2016)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Goldberg, S. B., Pace, B. T., Nicholas, C. R. et al. · Psychiatry Research (2020)
Johnson, M. W., Griffiths, R. R., Hendricks, P. S. et al. · Neuropharmacology (2018)
Show all 24 referencesShow fewer
Studerus, E., Kometer, M., Hasler, F. et al. · Journal of Psychopharmacology (2010)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Griffiths, R. R., Johnson, M. W., Richards, W. A. et al. · Psychopharmacology (2011)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Johnson, M. W., Garcia-Romeu, A., Griffiths, R. R. · The American Journal of Drug and Alcohol Abuse (2016)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Garcia-Romeu, A., Griffiths, R. R., Johnson, M. W. · Current Drug Abuse Reviews (2015)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Griffiths, R. R., Johnson, M. W., Richards, W. A. et al. · Journal of Psychopharmacology (2017)
Davis, A. K., Barrett, F. S., Griffiths, R. R. · Journal of Contextual Behavioral Science (2020)
Garcia-Romeu, A., Davis, A. K., Fire Erowid et al. · Journal of Psychopharmacology (2019)
Garcia-Romeu, A., Davis, A. K., Griffiths, R. R. et al. · Frontiers in Psychiatry (2020)
Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)
Cited By (135)
Papers in Blossom that reference this study
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · Journal of Affective Disorders (2026)
Jungwirth, J., Westenhöfer, S., Aicher, H. et al. · Preprints (2025)
Ellis, S., Bostian, C., Donnelly, A. et al. · Journal of Affective Disorders (2025)
Agrawal, R., Gillie, D., Mungenast, A. et al. · ACS Chemical Neuroscience (2025)
Knock, E., Siefried, K. J., Gill Bedi, |. et al. · Addiction (2025)
Mu, F., Zaczek, H., Becker, A. M. et al. · Med (2025)
Ross, M. L., Iyer, R., Williams, M. L. et al. · General Hospital Psychiatry (2025)
Williams, Z. J., Barnett, H., Szigeti, B. · OSF Preprints (2025)
Peck, S. K., Knatz Peck, S., Brewerton, T. D. et al. · Journal of Eating Disorders (2025)
Wall, M. B., Demetriou, L., Giribaldi, B. et al. · American Journal of Psychiatry (2025)
Show all 135 papersShow fewer
Harding, R., Singer, N., Wall, M. B. et al. · Molecular Psychiatry (2025)
Zhou, K., De Wied, D., Carhart-Harris, R. L. et al. · PNAS (2025)
Shao, L-X,, Tan, D., Liao, C., Davoudian, P. A. et al. · Nature Communications (2025)
Chisamore, N., Kaczmarek, E. S., Doyle, Z. et al. · Canadian Journal of Psychiatry (2025)
Kugel, J., Laukkonen, R., Yaden, D. B. et al. · Neuroscience and Biobehavioral Reviews (2025)
Meshkat, S., Kaczmarek, E., Doyle, Z. et al. · Psychedelic Medicine (2025)
Zeifman, R. J., Spriggs, M. J., Kettner, H. et al. · Scientific Reports (2025)
Silva, F., Butlen-Ducuing, F., Guizzaro, L. et al. · Neuroscience Applied (2025)
Ellis, S., Bostian, C., Feng, W. et al. · Journal of Affective Disorders (2025)
Jungwirth, J., Von Rotz, R., Dziobek, I. et al. · Molecular Psychiatry (2024)
Swanson, L. R., Jungers, S., Varghese, R. et al. · Journal of Vision (2024)
Erritzoe, D., Barba, T., Greenway, K. T. et al. · EClinicalMedicine (2024)
Salvetti, G., Saccenti, D., Moro, A. S. et al. · Brain Sciences (2024)
Casanova, A. F., Ort, A., Smallridge, J. W. et al. · iScience (2024)
Sloshower, J. A., Zeifman, R. J., Guss, J. et al. · Scientific Reports (2024)
Meling, D., Ehrenkra, R., Nayak, S. et al. · Psychoactives (2024)
Berit, S., Meling, D., Hirsch-Hoffmann, M. et al. · Scientific Reports (2024)
Levin, A. W., Lancelotta, R., Sepeda, N. D. et al. · PLOS ONE (2024)
Rosenblat, J. D., Meshkat, S., Doyle, Z. et al. · Med (2024)
Aday, J. S., Bloesch, E. K., Davis, A. K. et al. · Journal of Humanistic Psychology (2024)
Timmermann, C., Zeifman, R. J., Erritzoe, D. et al. · Scientific Reports (2024)
Sandbrink, J. D., Johnson, K., Gill, M. et al. · AJOB Neuroscience (2024)
Solaja, I., Haldane, K., Mason, N. et al. · Neuroscience and Biobehavioral Reviews (2024)
Agrawal, M., Richards, B. D., Richards, W. A. et al. · Cancer (2023)
Marseille, E., Stauffer, C., Agrawal, M. et al. · Frontiers in Psychiatry (2023)
Kvam, T-M., Uthaug, M. V., Andersen, K. A. A. et al. · Frontiers in Psychiatry (2023)
Ekins, T. G., Brooks, I., Kailasa, S. et al. · Biorxiv (2023)
Haikazian, S., Chen-Li, D., Johnson, D. et al. · Psychiatry Research (2023)
Nayak, S., Jackson, H., Sepeda, N. D. et al. · Frontiers in Psychiatry (2023)
Xin, Y., Armstrong, S. B., Averill, L. A. et al. · Psychology of Consciousness Theory Research and Practice (2023)
Jones, G. M., Nock, M. K. · Frontiers in Psychiatry (2023)
Abrams, S. K., Rabinovitch, B. S., Zafar, R. et al. · Neurotherapeutics (2023)
Pereira, L. · European Neuropsychopharmacology (2023)
Boehnke, K. F., Cox, K., Weston, C. et al. · Frontiers in Psychiatry (2023)
Zeifman, R. J., Wagner, A. C., Monson, C. M. et al. · Journal of Affective Disorders (2023)
Glynos, N., Kruger, D. J., Kolbman, N. et al. · Journal of Psychoactive Drugs (2023)
Heifets, B. D., Olson, D. E. · Neuropsychopharmacology (2023)
Noorani, T. N., Bedi, G., Muthukumaraswamy, S. · Psychological Medicine (2023)
Low, F., Earleywine, M. · Journal of Psychoactive Drugs (2023)
Reckweg, J., van Leeuwen, C., Theunissen, E. L. et al. · Frontiers in Psychiatry (2023)
Mallaroni, P., Mason, N. L., Reckweg, J. T. et al. · Clinical Pharmacology and Therapeutics (2023)
Pleet, M. M., White, J., Zamaria, J. A. et al. · Psychedelic Medicine (2023)
Boehnke, K. F., Kruger, D. J., Lucas, P. · International Journal of Mental Health and Addiction (2023)
Thal, S. B., Wieberneit, M., Sharbanee, J. M. et al. · Journal of Humanistic Psychology (2023)
Kangaslampi, S. · Journal of Psychedelic Studies (2023)
Weiss, B., Sleep, C., Miller, J. D. et al. · Journal of Personality Disorders (2023)
Kinderlehrer, D. A. · International Medical Case Reports Journal (2023)
Jones, G. M., Lipson, J., Wang, E. · Scientific Reports (2023)
Mathai, D. S., Nayak, S., Yaden, D. B. et al. · Psychopharmacology (2023)
Moreton, S. G., Arena, A. F., Foy, Y. et al. · Death Studies (2023)
Armstrong, S. B., Xin, Y., Sepeda, N. D. et al. · Military Medicine (2023)
Burmester, D., Madsen, M. K., Szabo, A. et al. · Comprehensive Psychoneuroendocrinology (2023)
Cameron, L. P., Patel, S. D., Vargas, M. V. et al. · ACS Chemical Neuroscience (2023)
Gray, J. C., Murphy, M., Carter, S. E. et al. · Military Medicine (2022)
DellaCrosse, M., Pleet, M. M., Morton, E. et al. · PLOS ONE (2022)
Bohn, A., Kiggen, M. H. H., Uthaug, M. V. et al. · International Journal for the Psychology of Religion (2022)
Olsen, A. S., Ozenne, B., Madsen, M. K. et al. · NeuroImage (2022)
Devenot, N., Seale-Feldman, A., Smith, E. et al. · Kennedy Institute of Ethics Journal (2022)
MacCallum, C. A., Pistawka, C. A., Deol, J. K. et al. · Frontiers in Psychiatry (2022)
Ortiz Bernal, A. M., Raison, C. L., Lancelotta, R. et al. · Frontiers in Psychiatry (2022)
de la Salle, S., Gran-Ruaz, S., Davis, A. K. et al. · Canadian Psychology (2022)
Kopra, E., Cleare, A. J., Rucker, J. et al. · Journal of Affective Disorders (2022)
Madsen, M. K., Ozenne, B., Armand, S. et al. · Frontiers in Psychology (2022)
Ornelas, I. M., Cini, F. A., Wießner, I. et al. · Experimental Neurology (2022)
Luoma, J. B., Pilecki, B., Davis, A. K. et al. · Drugs Education Prevention and Policy (2022)
Glynos, N., Fields, C. W., Barron, J. et al. · Journal of Psychoactive Drugs (2022)
van Elk, M., Yaden, D. B. · Neuroscience and Biobehavioral Reviews (2022)
Luppi, A. I., Hansen, J. Y., Adapa, R. et al. · Biorxiv (2022)
Nayak, S., Singh, M., Yaden, D. B. et al. · Journal of Psychopharmacology (2022)
Johnson, M. W. · Current Topics in Behavioral Neurosciences (2022)
Cavarra, M., Falzone, A., Ramaekers, J. G. et al. · Frontiers in Psychology (2022)
Belser, A. B. · Frontiers in Psychology (2022)
Argento, E., Goldenberg, S., Deering, K. et al. · Drug and Alcohol Dependence (2022)
Johnson, S., Letheby, C. · Journal of Psychedelic Studies (2022)
Doss, M. K., Samaha, J., Barrett, F. S. et al. · Biorxiv (2022)
Yaden, D. B., Earp, D., Graziosi, M. et al. · Frontiers in Psychology (2022)
McCulloch, D. E-W., Knudsen, G. M., Barrett, F. S. et al. · Neuroscience and Biobehavioral Reviews (2022)
Gill, H., Puramat, P., Patel, P. et al. · Psychiatry Research (2022)
Murphy, R., Murphy-Beiner, A., Kettner, H. et al. · Frontiers in Pharmacology (2022)
Pots, W., Chakhssi, F. · Frontiers in Psychology (2022)
Raison, C. L., Jain, R., Jain, S. et al. · Frontiers in Psychiatry (2022)
McCulloch, D. E-W., Madsen, M. K., Jensen, P. S. et al. · Frontiers in Pharmacology (2022)
Sarparast, A., Thomas, K., Malcolm, B. et al. · Psychopharmacology (2022)
Maia, L. O., Massarentti, C. M., Tófoli, L.F. · Psychopharmacology (2022)
Yu, C. L., Liang, C. S., Yang, F. et al. · Journal of Clinical Medicine (2022)
Argento, E., Socias, M. E., Hayashi, K. et al. · International Journal of Drug Policy (2022)
Markopoulos, A., Inserra, A., De Gregorio, D. et al. · Frontiers in Pharmacology (2022)
Müller, F., Holze, F., Becker, A. M. et al. · Psychopharmacology (2022)
Olson, D. E. · Biochemistry (2022)
Barrett, F. S., Zhou, Y., Carbonaro, T. M. et al. · Frontiers in Neuroergonomics (2022)
Glynos, N. G., Pierce, J., Davis, A. K. et al. · Journal of Psychoactive Drugs (2022)
Simonsson, O., Goldberg, S. B. · Journal of Psychoactive Drugs (2022)
Mertens, L. J., Koslowski, M., Betzler, F. et al. · Neuroscience Applied (2022)
Dursun, S. M., Kelly, J. R., Gillan, C. M. et al. · Frontiers in Psychiatry (2021)
Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)
Rucker, J., Jafari, H., Mantingh, T. et al. · BMJ Open (2021)
Page, L., Rehman, A., Syed, H. et al. · Frontiers in Psychiatry (2021)
Nygart, V., Pommerencke, L. M., Carhart-Harris, R. L. et al. · Frontiers in Psychology (2021)
Strumila, R., Guillaume, S. · Pharmaceuticals (2021)
Doss, M. K., Považan, M., Rosenberg, M. D. et al. · Translational Psychiatry (2021)
van Oorsouw, K., Uthaug, M. V., Mason, N. L. et al. · Journal of Psychedelic Studies (2021)
Matzopoulos, R., Morlock, A., Morlock, R. et al. · MedRvix (2021)
Brennan, W., Jackson, M. A., MacLean, K. A. · Journal of Humanistic Psychology (2021)
Davis, A. K., Agin-Liebes, G. I., España, M. et al. · Journal of Psychoactive Drugs (2021)
Davis, A. K., Xin, Y., Sepeda, N. D. et al. · Chronic Stress (2021)
Khan, S. I., Carter, G. T., Aggarwal, S. K. et al. · Frontiers in Neuroscience (2021)
Kočárová, C., Horacek, J., Carhart-Harris, R. L. · Frontiers in Psychiatry (2021)
Mayer, C. E., LeBaron, V. T., Acquaviva, K. D. · Journal of Psychoactive Drugs (2021)
Ballentine, G., Friedman, S. F., Bzdok, D. · Science Advances (2021)
Savino, A., Nichols, C. D. · Biorxiv (2021)
Corrigan, K., Haran, M., Mccandliss, C. et al. · Irish Journal of Medical Science (2021)
Rodrigues, L. S., Rossi, G. N., Rocha, J. M. et al. · European Archives of Psychiatry and Clinical Neuroscience (2021)
Carhart-Harris, R. L., Wagner, A. C., Agrawal, M. et al. · Journal of Psychopharmacology (2021)
Hesselgrave, N., Troppoli, T. A., Wulff, A. B. et al. · PNAS (2021)
Olson, D. E. · ACS Pharmacology and Translational Science (2021)
Weiss, B., Miller, J. D., Carter, N. T. et al. · Scientific Reports (2021)
Dos Santos, R. G., Hallak, J. E., Baker, G. et al. · Journal of Psychopharmacology (2021)
Simonsson, O., Sexton, J. D., Hendricks, P. S. · Journal of Psychopharmacology (2021)
Aday, J. S., Davis, A. K., Mitzkovitz, C. M. et al. · ACS Pharmacology and Translational Science (2021)
Garcia-Romeu, A., Barrett, F. S., Carbonaro, T. M. et al. · Journal of Psychopharmacology (2021)
Thomas, C. W., Blanco-Duque, C., Breant, B. et al. · Translational Psychiatry (2021)
McCulloch, D. E-W., Madsen, M. K., Stenbæk, D. S. et al. · Journal of Psychopharmacology (2021)
Kaertner, L. S., Steinborn, M. B., Kettner, H. et al. · Scientific Reports (2021)
Williams, T. M., Davis, A. K., Xin, Y. et al. · Drugs Education Prevention and Policy (2020)
Nichols, D. E., Walter, H. · Pharmacopsychiatry (2020)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.