Epigenetic landscapes of classical psychedelics and ketamine: molecular mechanisms of long-lasting neuromodulation

Classic psychedelics such as lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), and mescaline induce lasting changes in neuroplasticity and behavior that extend far beyond their acute pharmacological effects. Emerging evidence highlights that these enduring therapeutic benefits in neuropsychiatric conditions may be significantly mediated through complex epigenetic reprogramming mechanisms, although direct causal evidence remains limited. This review synthesizes current knowledge on how classical psychedelics and the rapid-acting antidepressant ketamine (an NMDA receptor antagonist) influence epigenetic regulation at multiple molecular levels, encompassing DNA methylation and hydroxymethylation, histone post-translational modifications (acetylation, methylation, phosphorylation), nucleosome positioning and higher-order chromatin restructuring, non-coding RNA (ncRNA) dynamics, and RNA epitranscriptomic modifications. Moreover, psychedelics appear to alter metabolic and mitochondrial pathways, thereby modulating the availability and nuclear transport of key epigenetic cofactors, such as acetyl-CoA, S-adenosylmethionine (SAM), and α-ketoglutarate. By integrating these pathways, we propose a unified model wherein psychedelic-induced signaling cascades may intersect with metabolic and epigenetic networks, potentially contributing to persistent transcriptional alterations and enhanced synaptic connectivity. Understanding these intricate mechanisms provides crucial insights into how transient exposure to psychedelics translates into sustained therapeutic outcomes, informing the development of novel neuroepigenetic interventions in molecular psychiatry.