Increased global integration in the brain after psilocybin therapy for depression
This fMRI study assessed the impact of psilocybin on brain function in two clinical trials of depression. In both trials, the antidepressant response to psilocybin was rapid and sustained, correlating with decreases in fMRI brain network modularity. Network cartography analyses indicated that serotonin (5-HT) 2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after a psilocybin treatment. Together, the findings from both studies point to global increases in brain network integration as an antidepressant mechanism in psilocybin therapy.
Authors
- Robin Carhart-Harris
- David Nutt
- Christopher Timmermann
Published
Abstract
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck’s depression inventory was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin arm’) or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) (‘escitalopram arm’). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.
Research Summary of 'Increased global integration in the brain after psilocybin therapy for depression'
Introduction
Depression is a common and costly disorder marked by cognitive inflexibility, negative bias and rigid self-referential thinking. Neuroimaging work has implicated abnormal functioning of higher-order intrinsic networks—including the default mode network (DMN), executive network (EN) and salience network (SN)—in these features, and the serotonin 2A (5-HT2A) receptor, the principal binding site for classic psychedelics such as psilocybin, is densely expressed across these transmodal cortical areas. Previous clinical trials have reported substantial antidepressant effects of psilocybin therapy, but the neural mechanisms that might underlie these effects remain incompletely understood. Daws and colleagues set out to test the hypothesis that psilocybin therapy produces a subacute, global decrease in functional brain modularity—interpreted as an increase in network integration or a broadening of the brain's functional state space—and that this change would relate to antidepressant outcomes. The paper analyses resting-state fMRI and clinical data from two trials: an open-label trial in treatment-resistant depression (TRD) with scans at baseline and 1 day after the higher psilocybin dose, and a double-blind Phase II randomized controlled trial (DB-RCT) comparing two high-dose psilocybin sessions plus placebo capsules versus very low-dose (1 mg) psilocybin plus escitalopram, with scans at baseline and 3 weeks after the second psilocybin dose. The investigators also examine network-specific cartography and dynamic flexibility metrics to identify which network changes accompany clinical improvement.
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
Create a free account to open full-text PDFs.
Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Daws, R. E., Timmermann, C., Giribaldi, B., Sexton, J. D., Wall, M. B., Erritzoe, D., Roseman, L., Nutt, D., & Carhart-Harris, R. (2022). Increased global integration in the brain after psilocybin therapy for depression. Nature Medicine, 28(4), 844-851. https://doi.org/10.1038/s41591-022-01744-z
References (19)
Papers cited by this study that are also in Blossom
Lyons, T., Carhart-Harris, R. L. · Frontiers in Psychology (2018)
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
Andersen, K. A. A., Carhart-Harris, R. L., Nutt, D. J. et al. · Acta Psychiatrica Scandinavica (2020)
Carhart-Harris, R. L., Roseman, L., Bolstridge, M. et al. · Scientific Reports (2017)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Nutt, D. J., Erritzoe, D., Carhart-Harris, R. L. · Cell (2020)
Carhart-Harris, R. L., Friston, K. J. · Pharmacological Reviews (2019)
Lord, L. D., Expert, P., Atasoy, S. et al. · NeuroImage (2019)
Luppi, A. I., Carhart-Harris, R. L., Roseman, L. et al. · NeuroImage (2021)
Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
Show all 19 referencesShow fewer
Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)
Pasquini, L., Palhano-Fontes, F., Araújo, D. B. · Journal of Psychopharmacology (2020)
Roseman, L., Haijen, E. C. H. M., Idialu-Ikato, K. et al. · Journal of Psychopharmacology (2019)
Watts, R., Day, C. M., Krzanowski, J. et al. · Journal of Humanistic Psychology (2017)
Murphy-Beiner, A., Soar, K. · Psychopharmacology (2020)
Zeifman, R. J., Wagner, A. C., Watts, R. et al. · Frontiers in Psychiatry (2020)
Carhart-Harris, R. L., Nutt, D. J. · Journal of Psychopharmacology (2017)
Carhart-Harris, R. L., Wagner, A. C., Agrawal, M. et al. · Journal of Psychopharmacology (2021)
Carhart-Harris, R. L., Roseman, L., Haijen, E. C. H. M. et al. · Journal of Psychopharmacology (2018)
Cited By (60)
Papers in Blossom that reference this study
Moreno, F. A., Allen, K. E., Wiegand, C. B. et al. · Journal of Psychopharmacology (2026)
Thuery, G., Crossen, F., Mc Loone, D. et al. · Therapeutic Advances in Psychopharmacology (2026)
Mallaroni, P., Singleton, P., Mason, N. L. et al. · Molecular Psychiatry (2026)
Martens, M. A. G., Cunha, B. G., Erritzoe, D. et al. · Translational Psychiatry (2025)
Pellegrini, L., Fineberg, N. A., O'Connor, S. et al. · Comprehensive Psychiatry (2025)
Egger, K., Meling, D., Polat, F. et al. · Imaging Neuroscience (2025)
Socoró-Garrigosa, M., Sanz Perl, Y., Kringelbach, M. L. et al. · Annals of the New York Academy of Sciences (2025)
Roseby, W., Kettner, H., Roseman, L. et al. · Frontiers in Psychology (2025)
Subramanian, S., Renau, R., Perry, D. et al. · Scientific Data (2025)
Wall, M. B., Demetriou, L., Giribaldi, B. et al. · American Journal of Psychiatry (2025)
Show all 60 papersShow fewer
Singleton, S. P., Timmermann, C., Luppi, A. I. et al. · Communications Biology (2025)
Ertl, N., Ashraf, I., Azizi, L. et al. · Biorxiv (2025)
Shinozuka, K., Jerotic, K., Mediano, P. A. M. et al. · Translational Psychiatry (2024)
Marwood, L., Croal, M., Mistry, S. et al. · Journal of Psychiatric Research (2024)
Lyons, T., Spriggs, M. J., Kerkelä, L. et al. · Biorxiv (2024)
Petridis, P. D., Grinband, J., Agin-Liebes, G. et al. · Nature Mental Health (2024)
Avram, M., Fortea, L., Wollner, L. et al. · Molecular Psychiatry (2024)
Murphy, R. J. · Psychopharmacology (2024)
Yaden, D. B., Goldy, S. P., Weiss, B. et al. · Nature Reviews Psychology (2024)
Caspani, G., Ruffell, S. G. D., Tsang, WF. et al. · Pharmacological Research (2024)
Nicol, G. E. · Nature (2024)
Bagdasarian, F. A., Hansen, H. D., Chen, J. et al. · ACS Chemical Neuroscience (2024)
Szigeti, B., Heifets, B. D. · Biological Psychiatry (2024)
Lewis, E. C., Jaeger, A., Girn, M. et al. · Journal of Psychopharmacology (2024)
Peill, J. M., Marguilho, M., Erritzoe, D. et al. · Journal of Psychopharmacology (2024)
Tolle, H. M., Farah, J. C., Mallaroni, P. et al. · Network Neuroscience (2024)
Weiss, B., Leor Roseman, •., Giribaldi, B. et al. · International Journal of Mental Health and Addiction (2024)
Copa, D., Erritzoe, D., Giribaldi, B. et al. · Journal of Affective Disorders (2024)
Vohryzek, J., Cabral, J., Lord, L. D. et al. · Brain Communications (2024)
Erritzoe, D., Timmermann, C., Godfrey, K. et al. · Nature Mental Health (2024)
De Filippo, R., Schmitz, D. · Neuroscience and Biobehavioral Reviews (2024)
Szigeti, B., Weiss, B., Rosas, F. E. et al. · Psychological Medicine (2024)
Allen, J., Dames, S., Foldi, C. J. et al. · Molecular Psychiatry (2024)
Mallaroni, P., Mason, N. L., Kloft, L. et al. · NeuroImage (2024)
Pizzi, S. D., Chiacchiaretta, P., Sestieri, C. et al. · NeuroImage (2023)
Cameron, L. P., Benetatos, J., Lewis, V. et al. · Journal of Neuroscience (2023)
Haikazian, S., Chen-Li, D., Johnson, D. et al. · Psychiatry Research (2023)
Mallaroni, P., Mason, N. L., Kloft, L. et al. · Frontiers in Neuroscience (2023)
Jaster, A. M., González-Maeso, J. · Molecular Psychiatry (2023)
Wall, M. B., Harding, R., Zafar, R. et al. · Molecular Psychiatry (2023)
Van Elk, M., Fried, E. I. · Therapeutic Advances in Psychopharmacology (2023)
Mortaheb, S., Fort, L. D., Mason, N. L. et al. · Biological Psychiatry (2023)
Tyagi, R., Saraf, T. S., Canal, C. E. · ACS Pharmacology and Translational Science (2023)
Pereira, L. · European Neuropsychopharmacology (2023)
Dinkelacker, J., Pop, I. · Journal of Clinical Psychiatry (2023)
Heifets, B. D., Olson, D. E. · Neuropsychopharmacology (2023)
Zafar, R., Siegel, M., Harding, R. et al. · Frontiers in Psychiatry (2023)
Weiss, B., Ginige, I., Shannon, L. et al. · Psychological Medicine (2023)
Girn, M., Rosas, F. E., Daws, R. E. et al. · Trends in Cognitive Sciences (2023)
Timmermann, C., Roseman, L., Haridas, S. et al. · PNAS (2023)
Carhart-Harris, R. L., Chandaria, S., Erritzoe, D. E. et al. · Neuropharmacology (2023)
Timmermann, C., Vollenweider, F. X. · Trends in Cognitive Sciences (2023)
DellaCrosse, M., Pleet, M. M., Morton, E. et al. · PLOS ONE (2022)
Ledwos, N., Rodas, J. D., Husain, M. I. et al. · Journal of Psychopharmacology (2022)
Kwan, A. C., Olson, D. E., Preller, K. H. et al. · Nature Medicine (2022)
Gattuso, J. J., Perkins, D., Ruffell, S. G. D. et al. · International Journal of Neuropsychopharmacology (2022)
Kopra, E., Cleare, A. J., Rucker, J. et al. · Journal of Affective Disorders (2022)
Bogenschutz, M. P., Ross, S., Bhatt, S. R. et al. · JAMA Psychiatry (2022)
Hipólito, I., Mago, J., Rosas, F. E. et al. · Psyarxiv (2022)
Doss, M. K., de Wit, H., Gallo, D. A. · Psyarxiv (2022)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.