The serotonergic plant-hallucinogen 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 in the patient’s brain are not entirely understood. Here, we treated cortical neurons derived from human induced pluripotent stem cells with the psychoactive 5-HT2A receptor agonist psilocin (the active metabolite of psilocybin). We analyzed how exposure to psilocin affects 5-HT2A receptor localization, BDNF expression, neuronal morphology, synaptic markers and neuronal function. Upon exposure of human neurons to psilocin, we observed a decreased extracellular 5-HT2A receptor presentation. Psilocin further provoked an augmentation of BDNF abundance and an increased phosphorylation of the protein kinase Akt which is associated with cell survival and neuronal plasticity. In addition, psilocin provokes morphological and functional changes that start shortly after administration and become manifested over time. More specifically, we found neuronal complexity, to be significantly increased up to 2 days post exposure. We also found an increase in spontaneous excitatory postsynaptic current amplitudes 7 days after psilocin exposure. That was accompanied by an increase in presynaptic synapsin and postsynaptic PSD-95 density, indicating synapse formation or strengthening. These data suggest that 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.