Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons

Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons Philipp Koch, Malin Schmidt, Anne Hoffrichter, Mahnaz Davoudi, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4242829/v3 This work is licensed under a CC BY 4.0 License Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Abstract Psilocybin is studied as innovative medication in anxiety, substance abuse and treatment-resistant depression. Animal studies show that psychedelics promote neuronal plasticity by strengthening synaptic responses and protein synthesis. However, the exact molecular and cellular changes induced by psilocybin in the human brain are not known. Here, we treated human cortical neurons derived from induced pluripotent stem cells with the 5-HT2A receptor agonist psilocin - the psychoactive metabolite of psilocybin. We analyzed how exposure to psilocin affects 5-HT2A receptor localization, gene expression, neuronal morphology, synaptic markers and neuronal function. Upon exposure of human neurons to psilocin, we observed a decrease of cell surface-located 5-HT2A receptors first in the axonal- followed by the somatodendritic-compartment. Psilocin further provoked a 5-HT2A-R-mediated augmentation of BDNF abundance. Transcriptomic profiling identified gene expression signatures priming neurons to neuroplasticity. On a morphological level, psilocin induced enhanced neuronal complexity and increased expression of synaptic proteins, in particular in the postsynaptic-compartment. Consistently, we observed an increased excitability and enhanced synaptic network activity in neurons treated with psilocin. In conclusion, exposure of human neurons to psilocin might induces a state of enhanced neuronal plasticity which could explain why psilocin is beneficial in the treatment of neuropsychiatric disorders where synaptic dysfunctions are discussed. Health sciences/Molecular medicine Biological sciences/Neuroscience Biological sciences/Stem cells Full Text Additional Declarations The authors declare potential competing interests as follows: Authors M.S. and P.K. are listed as inventors on a filed patent application related to the treatment of neurological diseases by modulating brain BDNF. All other authors declare no competing interest. Supplementary Files SchmidtetalRtRFigure.pdf Cite Share Download PDF Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4242829","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":311596107,"identity":"501c6861-28a8-48f2-9723-14d661a62b9e","order_by":0,"name":"Philipp 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