Psilocybin, From Ancestral Use to Therapeutic Potential: A Multidimensional Review of Its Pharmacological Basis and Current Perspectives.

OBJECTIVE: This review critically examines psilocybin, with particular emphasis on its pharmacokinetics and pharmacodynamics, including its serotonergic, neuroplastic, and anti-inflammatory mechanisms. It integrates historical context, preclinical and clinical evidence, and evaluates emerging therapeutic potential, safety, microdosing practices, and pharmacological interactions. METHODS: A literature search was conducted in PubMed and Google Scholar using the keywords "Psilocybin," "Psilocin," "Psychedelic therapy," "Psilocybe cubensis," and "Psychedelic microdosing," supplemented by manual searches of cross-references. All study types were included, from randomized trials to case reports. RESULTS: Psilocybin is metabolized into psilocin, which predominantly interacts with serotonin (5-hydroxytryptamine, 5-HT) receptors. These interactions contribute to enhanced synaptic plasticity, modulation of large-scale brain networks, and regulation of immune responses via microglial activity and suppression of pro-inflammatory cytokines. Preclinical and clinical evidence supports its efficacy in depression, anxiety, substance use disorders, neuropathic pain, epilepsy, and neuroinflammation. Psilocin also inhibits cytochrome P450 enzymes, raising concerns about drug interactions. Microdosing, though popular, remains inconclusive due to methodological limitations. CONCLUSIONS: Current findings suggest psilocybin offers sustained therapeutic effects and a favorable safety profile. However, uncertainties remain regarding long-term safety, individualized responses, and optimal dosing. Ethical and regulatory challenges require rigorous, standardized research for responsible clinical integration.