Serotonergic psychedelics like psilocybin and LSD activate serotonin 5-HT2A receptors in cortical brain regions, altering perception, cognition, and emotions. Their ability to promote neuroplasticity—forming new neural connections and rewiring networks—is thought to underlie therapeutic potential for depression, anxiety, and substance use disorders. These compounds also interact with other serotonin receptor subtypes (5-HT1A, 5-HT2C) and neurotrophin receptors, adding complexity to their effects. Research is exploring nonhallucinogenic derivatives that retain therapeutic benefits without intense psychedelic experiences, potentially reducing adverse reactions. The review also discusses psychedelics as substrates for post-translational protein modification as part of their mechanism.
Psilocybin, a psychedelic tryptamine, shows promise for treating conditions like treatment-resistant depression and PTSD by rapidly improving depression scores. Its primary mechanism involves activating the serotonin 2A receptor, but downstream therapeutic effects remain unclear. This study analyzed dose- and sex-dependent transcriptional changes in mouse forebrains at 8 hours, 24 hours, and 7 days after a single low (0.25 mg/kg) or high (1 mg/kg) dose. Females showed faster transcriptional changes and attenuation at low doses compared to males, and more robust responses to high doses at early timepoints. Low-dose effects persisted at 7 days, outlasting high-dose changes, and involved pathways related to neuronal differentiation and neurogenesis. These sexually divergent and temporal molecular effects should inform treatment strategies and timing with cognitive behavioral therapy.