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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)

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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.

Comparable studies

Other non-randomized and open-label trials on MDMA, most cited first.

Study Year Design Participants
Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Adults with chronic, treatment-resistant PTSD 2013 Long-term follow-up of a completed trial n = 19
First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder. Patients with alcohol use disorder (AUD) following community alcohol detoxification 2021 Open-label safety and tolerability proof-of-concept study n = 14
MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial. Couples in which one partner was diagnosed with PTSD 2020 Pilot study n = 6
Culturally informed research design issues in a study for MDMA-assisted psychotherapy for posttraumatic stress disorder People of color with posttraumatic stress disorder 2019 Phase 2 open-label multisite study
The Consequences of 3,4-Methylenedioxymethamphetamine Induced CYP2D6 Inhibition in Humans Healthy male subjects 2008 Controlled clinical trial n = 15

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Ketamine MDMA Neuroplasticity Esketamine