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