Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons.
Malin Schmidt, Anne Hoffrichter, Mahnaz Davoudi, Sandra Horschitz, Thorsten Lau, Marcus W Meinhardt, Rainer Spanagel, Julia Ladewig, Georg Köhr, Philipp Koch
eLife March 27, 2026 Peer reviewed DOI: 10.7554/elife.104006 via PubMed
Summary
Exposure to psilocin, the active metabolite of psilocybin, enhances neuronal plasticity in human cortical neurons derived from induced pluripotent stem cells. Treatment increased BDNF levels and induced changes in gene expression that promote neuroplasticity. Morphologically, neurons exhibited greater complexity and higher levels of synaptic proteins, leading to increased excitability and synaptic network activity. These findings suggest that psilocin may be beneficial for neuropsychiatric disorders associated with synaptic dysfunction.
Study at a glance
| Population | human cortical neurons derived from induced pluripotent stem cells |
|---|---|
| Key finding | Psilocin exposure enhances neuronal plasticity by increasing BDNF abundance and promoting changes in gene expression, morphology, and synaptic function. |
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 gene expression, neuronal morphology, synaptic markers and neuronal function. Psilocin 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 induce a state of enhanced neuronal plasticity, which could explain why psilocin is beneficial in the treatment of neuropsychiatric disorders where synaptic dysfunctions are discussed.