Psilocybin desynchronizes brain networks

The relationship between the acute effects of psychedelics and their persisting neurobiological and psychological effects is poorly understood. Here, we tracked brain changes with longitudinal precision functional mapping in healthy adults before, during, and for up to 3 weeks after oral psilocybin and methylphenidate (17 MRI visits per participant) and again 6+ months later. Psilocybin disrupted connectivity across cortical networks and subcortical structures, producing more than 3-fold greater acute changes in functional networks than methylphenidate. These changes were driven by desynchronization of brain activity across spatial scales (area, network, whole brain). Psilocybin-driven desynchronization was observed across association cortex but strongest in the default mode network (DMN), which is connected to the anterior hippocampus and thought to create our sense of self. Performing a perceptual task reduced psilocybin-induced network changes, suggesting a neurobiological basis for grounding , connecting with physical reality during psychedelic therapy. The acute brain effects of psilocybin are consistent with distortions of space-time and the self. Psilocybin induced persistent decrease in functional connectivity between the anterior hippocampus and cortex (and DMN in particular), lasting for weeks but normalizing after 6 months. Persistent suppression of hippocampal-DMN connectivity represents a candidate neuroanatomical and mechanistic correlate for pro-plasticity and anti-depressant effects of psilocybin. ### Competing Interest Statement Author JSS is an employee of Sumitomo Pharma America and has received consulting fees from Forbes Manhattan. Author GEN has received research support from Usona Institute (drug only). She has served as a paid consultant for IngenioRx, Alkermes, Inc., Sunovion Pharmaceuticals, Inc., and Novartis Pharmaceuticals Corp. NUFD is a co-founder of Turing Medical Inc, has financial interest, and may benefit financially if the company is successful in marketing FIRMM motion monitoring software products. NUFD may receive royalty income based on FIRMM technology developed at Washington University School of Medicine and licensed to Turing Medical Inc. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine. The other authors declare no competing interests. All authors report no financial interest in psychedelics companies. ### Clinical Trial NCT04501653 ### Funding Statement This work was supported by grant GF0010787 from the Taylor Family Institute Fund for Innovative Psychiatric Research (JSS), grant R25 MH112473 from the National Institute of Mental Health (Dr Siegel, Subramanian, Bender, Horan, Nicol), grant UL1 TR002345 (Institute of Clinical and Translational Science Award 5157) from the National Center for Advancing Translational Sciences (JSS), and grant T32DA007261 from the National Institute on Drug Abuse, McDonnell Center for Systems Neuroscience Award 202002165 (JSS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki and procedures established by the Washington University in Saint Louis Institutional Review Board. All participants were compensated for their time. All aspects of this study were approved by the Washington University School of Medicine (WUSM) Internal Review Board, the Washington University Human Research Protection Office (WU HRPO), the Federal Drug Administration (IND: 202002165) and the Missouri Drug Enforcement Agency (DEA) under a federal DEA schedule 1 research license and registered with clinicaltrials.gov ([NCT04501653][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes De-identified data are available upon request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04501653&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F24%2F2023.08.22.23294131.atom