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Increased global integration in the brain after psilocybin therapy for depression

Nature Medicine volume 28, pages 844–851 (2022)Cite this article

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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.

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Fig. 1: Trial design schematics.
Fig. 2: Recruitment flow diagrams.
Fig. 3: Beck depression inventory scores.
Fig. 4: Responses of patients with TRD to psilocybin therapy relate to increases in brain network integration.
Fig. 5: Increased global brain network integration correlates with treatment response following psilocybin, but not following escitalopram.

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Data availability

All requests for raw and analyzed data and materials are promptly reviewed by R.C.H. and D.J.N., chief investigator and principal investigator, respectively, on the original work. Patient-related data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality. Source data are provided with this paper.

Code availability

All analyses and data visualizations were conducted in MATLAB R2020a. Codes for generating each data figure are available at https://github.com/rdaws/psilodep.

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Acknowledgements

R.E.D. was supported by an Engineering and Physical Sciences Research Council PhD scholarship at the Imperial College London Centre for Neurotechnology (EP/L016737/1). The research was carried out at the National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility. The open-label trial was funded by a Medical Research Council clinical development scheme grant (MR/J00460X/1). The DB-RCT was funded by a private donation from the Alexander Mosley Charitable Trust, supplemented by Founders of Imperial College London’s Centre for Psychedelic Research.

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Authors and Affiliations

  1. The Computational, Cognitive and Clinical Neuroimaging Laboratory (C3NL), Imperial College London, London, UK

    Richard E. Daws & Christopher Timmermann

  2. Centre for Neuroimaging Sciences, Kings College London, London, UK

    Richard E. Daws

  3. Centre for Psychedelic Research, Division of Academic Psychiatry, Imperial College London, London, UK

    Christopher Timmermann, Bruna Giribaldi, James D. Sexton, David Erritzoe, Leor Roseman, David Nutt & Robin Carhart-Harris

  4. Invicro London, Hammersmith Hospital, London, UK

    Matthew B. Wall

  5. Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK

    Matthew B. Wall

  6. Clinical Psychopharmacology Unit, University College London, London, UK

    Matthew B. Wall

  7. Psychedelics Division, Neuroscape, Department of Neurology, University of California, San Francisco, CA, USA

    Robin Carhart-Harris

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Contributions

This study was designed and planned by R.C.-H. and D.N. and conducted by B.G., M.B.W., D.E. and L.R. The specific analysis was designed by R.E.D. and C.T. The analysis was conducted and visualized by R.E.D. The manuscript was drafted by R.E.D., C.T. and R.C.-H. All authors contributed to the interpretation of the study results and revised and approved the manuscript for intellectual content. The corresponding author (R.E.D.) attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Corresponding author

Correspondence to Richard E. Daws.

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Competing interests

R.C.H. reports receiving consulting fees from Entheon Biomedical and Beckley Psytech; B.G. received consulting fees from SmallPharma; D.E. received consulting fees from Field Trip and Mydecine; D.N. received consulting fees from Algernon and H. Lundbeck and Beckley Psytech, advisory board fees from COMPASS Pathways and lecture fees from Takeda and Otsuka and Janssen plus owns stock in Alcarelle, Awakn and Psyched Wellness. The other authors declare no competing interests.

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Nature Medicine thanks David Hellerstein, Jared Van Snellenberg and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–4 and Tables 1 and 2.

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Supplementary Data 1

Data plotted in Supplementary Fig. 1.

Supplementary Data 2

Data plotted in Supplementary Fig. 2.

Supplementary Data 3

Data plotted in Supplementary Fig. 3.

Supplementary Data 4

Data plotted in Supplementary Fig. 4.

Source data

Source Data Fig. 3

BDI scores (one tab per trial).

Source Data Fig. 4

Modularity (Q) baseline and post-treatment, BDI and DMN, EN and SN integration scores (open-label trial).

Source Data Fig. 5

Modularity (Q) baseline and post-treatment, BDI and 7 × 7 network correlation coefficients and P values for each arm (DB-RCT).

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Daws, R.E., Timmermann, C., Giribaldi, B. et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med 28, 844–851 (2022). https://doi.org/10.1038/s41591-022-01744-z

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