Mechanisms of neuroplasticity induced by permeable serotonergics
September 27, 2025 A. N. Fedorov
Serotonergic psychedelics like psilocybin, DMT, LSD, and mescaline can reduce depression and anxiety after just one or two doses, with benefits lasting weeks to months, suggesting lasting biological change rather than temporary drug action. In cultured neurons, these compounds increase dendritic growth and synapse formation, requiring intracellular permeability. In cortical circuits, they boost glutamate and AMPA signaling, activate plasticity-related genes, and support extinction learning. Across species, these changes correspond to antidepressant and anxiolytic effects that may not require hallucinations. The author proposes a permeability-plus mechanism: cell-permeable psychedelics engage intracellular 5-HT2A receptors, triggering gene expression, BDNF-TrkB signaling, and cortical glutamate activity that together produce durable neuroplasticity.