Ketamine and MDMA treatment have been linked to changes in DNA methylation—a chemical mark that can influence how genes are read—in genes associated with neuroplasticity and immune processes. The findings come from a study examining blood and saliva samples taken from people treated for depression or post-traumatic stress disorder (PTSD).
DNA methylation is a chemical modification that can alter gene activity without changing the DNA sequence itself. Researchers often measure methylation in blood or saliva because those samples are easier to obtain than brain tissue, though changes in these tissues do not necessarily reflect what happens in the brain.
Ketamine and MDMA are being explored for mental health conditions and are sometimes described as psychoplastogens, drugs believed to promote neuroplasticity—the brain’s ability to form and reorganise connections. They operate through different mechanisms, and researchers do not yet fully understand how their effects might endure beyond treatment sessions.
Led by Moira G. Semple of Arizona State University, the researchers focused on about 2,900 genes that are especially active in the brain or involved in nerve-cell signalling, a strategy intended to be manageable in small samples rather than scanning the entire genome.
The ketamine group comprised 20 participants with moderate-to-severe depression, PTSD, or both. They received six infusions over two to three weeks, with blood samples taken before treatment and 10 days after it finished.
The MDMA group included 16 participants with severe PTSD taking part in a Phase 3 trial of MDMA-assisted therapy. They received three MDMA doses about four weeks apart alongside psychotherapy, with saliva collected before treatment and six to eight weeks after the final session. There was no non-drug control group in either analysis.
In each group, no individual methylation site changed enough to remain statistically significant after adjustment for the large number of sites tested. When results were pooled across sites within each gene, the researchers identified 405 genes with statistically significant methylation changes after ketamine and 346 after MDMA.
Across both treatments, the changes clustered in pathways related to neuroplasticity, such as the structure and organisation of synapses—the contact points between nerve cells. Some pathways tied to immune and stress-response signalling also emerged. Ketamine was linked to methylation changes in genes involved in glutamate signalling, while MDMA showed changes in genes including BDNF, which supports neuron growth and survival, and a dopamine transporter gene.
The overlap between the two treatments was modest at the level of individual genes: 47 genes changed in both groups, but only about a quarter altered in the same direction, and the magnitude of changes did not correlate. Overlap was greater when looking at broader biological pathways, and both treatments were associated with increased methylation of EFNA5, a gene previously linked to PTSD in large genetic studies.
Some patterns differed. Ketamine-associated changes were more strongly connected to synapse-related pathways, whereas MDMA-associated changes spanned a wider range of processes, including membrane transport and electrical signalling. The authors caution that these differences could reflect the distinct mechanisms of action, as well as study-specific factors such as the presence of psychotherapy with MDMA, the mix of diagnoses in the ketamine group, and the use of different sample types and collection times.
The authors summarised the shared pattern: “Across both compounds, altered loci [locations in the genome] converged on pathways related to neuroplasticity and neuroimmune regulation.” They emphasise that the findings indicate treatment-associated molecular changes, not necessarily that these changes explain therapeutic benefit.
Several limitations accompany the study. The participant groups were small, there was no non-treated comparison group, and the research did not determine whether methylation changes related to symptom improvement. Participants in the two groups were not directly compared within a single trial, and they differed in diagnosis, treatment context, and whether blood or saliva was tested.
The study could not show whether methylation changes affected gene activity, and ketamine participants were allowed to continue most of their medications. Factors such as smoking and ethnicity, both of which can influence methylation, were not included in the analysis. Two authors are employees of TruDiagnostic, a firm specialising in epigenetic testing, and nonprofits helped fund the MDMA analyses.
The study, “Brain-targeted epigenetic effects of two emerging psychoplastogens: ketamine & MDMA,” was authored by Moira G. Semple, Sarah E. Mennenga, Ryan Smith, Varun B. Dwaraka, Baruch Rael Cahn, Joseph Tafur, David M. Rabin, Berra Yazar-Klosinski and Candace R. Lewis.
