Brain-targeted epigenetic effects of two emerging psychoplastogens: ketamine & MDMA
Moira G. Semple, Sarah E. Mennenga, Ryan Smith, Varun B. Dwaraka, Baruch Rael Cahn, Joseph Tafur, David M. Rabin, Berra Yazar-Klosinski, Candace R. Lewis
Translational Psychiatry July 11, 2026 DOI: 10.1038/s41398-026-04191-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Clinical trial Peer reviewed |
|---|---|
| Sample size | 36 |
| Population | Clinical trial participants |
| Interventions | Ketamine MDMA |
| Topics | Ketamine MDMA Neuroplasticity Esketamine |
| Keywords | Epigenetics Dna methylation Schizophrenia object-oriented programming Dnam Drug Psychopharmacology Bioinformatics Hippocampal formation Clinical trial Mania Mood disorders |
| Key findings | Ketamine and MDMA induce peripheral DNA methylation changes that converge on neuroplasticity and neuroimmune pathways. |
Abstract
Psychoplastogen compounds such as ketamine and MDMA have shown therapeutic promise for mood and trauma-related disorders, yet the molecular mechanisms underlying their effects remain poorly understood. Here, we applied a Brain-Epigenome-Wide Association Study (BEWAS) targeting brain-relevant genes to examine DNA methylation changes following treatment. Pre- and post-treatment blood (ketamine, N = 20) and saliva (MDMA, N = 16) samples were collected from clinical trial participants. Treatment effects were assessed using repeated-measures linear mixed-effects models accounting for inter-individual baseline methylation differences, followed by gene- and network-level analyses. Ketamine and MDMA were associated with 405 and 346 significantly altered genes, respectively, alongside enrichment of 169 and 183 functional networks. Across both compounds, altered loci converged on pathways related to neuroplasticity and neuroimmune regulation. Together, these findings provide evidence that ketamine and MDMA induce peripheral epigenetic changes, highlighting their capacity to engage molecular pathways relevant to psychiatric health.