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 Peer reviewed DOI: 10.1038/s41398-026-04191-3 via OpenAlex
Summary
Ketamine and MDMA, compounds known as psychoplastogens, show therapeutic potential for mood and trauma disorders. This study examined DNA methylation changes in blood and saliva samples from clinical trial participants before and after treatment. Ketamine (20 participants) and MDMA (16 participants) were associated with 405 and 346 significantly altered genes, respectively, along with enrichment of 169 and 183 functional networks. The altered loci converged on pathways related to neuroplasticity and neuroimmune regulation, indicating that these compounds induce peripheral epigenetic changes that engage molecular pathways relevant to psychiatric health.
Study at a glance
| Design | clinical trial |
|---|---|
| Sample size | 36 |
| Population | clinical trial participants |
| Key finding | Ketamine and MDMA induce peripheral epigenetic changes that converge on pathways related to neuroplasticity and neuroimmune regulation. |
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.