Epigenetic landscapes of classical psychedelics and ketamine: molecular mechanisms of long-lasting neuromodulation
Molecular Psychiatry July 10, 2026 DOI: 10.1038/s41380-026-03744-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Key findings | Classic psychedelics and ketamine may induce lasting therapeutic effects through complex epigenetic reprogramming mechanisms, including DNA methylation, histone modifications, and metabolic pathway interactions, though direct causal evidence remains limited. |
Abstract
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.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cites 22
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
and 17 more in the library