Ketamine and MDMA treatment were associated with changes in DNA methylation, a chemical modification that can influence gene activity, at genes linked to neuroplasticity and immune processes, according to a study published in Translational Psychiatry. The changes were measured in blood and saliva samples from people treated for depression or post-traumatic stress disorder.

DNA methylation is a chemical mark that can influence how easily a cell reads certain genes. It does not alter the DNA code itself. Researchers often measure methylation in blood or saliva because those samples are easier to collect than brain tissue. However, a change in blood or saliva does not necessarily mean the same change has occurred in the brain.

Ketamine and MDMA are being studied for mental health conditions, including depression and post-traumatic stress disorder (PTSD). Both are sometimes called psychoplastogens, compounds thought to promote neuroplasticity, the brain’s ability to form and reorganize connections. They act through different mechanisms, and researchers do not yet fully understand how their effects may last beyond the treatment sessions.

Led by Moira G. Semple of Arizona State University, the researchers investigated whether either treatment was associated with methylation changes in genes considered relevant to brain health. Rather than examining the entire genome, they focused on about 2,900 genes that are particularly active in the brain or involved in signaling between nerve cells, an approach intended to make the analysis more manageable in small samples.

The researchers analyzed samples from two separate studies. The ketamine group included 20 people (average age about 40; 15 women) with moderate-to-severe depression, PTSD, or both. They received six ketamine infusions over two to three weeks, with blood samples collected before treatment and 10 days after it ended.

The MDMA group included 16 people (average age about 43; seven women) with severe PTSD who took part in a Phase 3 clinical 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. Neither analysis included a comparison group that did not receive the drug.

In each group, no individual methylation site changed enough to remain statistically significant after correcting for the large number of sites tested. When the researchers combined results across all the sites within each gene, they identified 405 genes with statistically significant methylation changes after ketamine and 346 after MDMA.

In both groups, the changes clustered in biological pathways related to neuroplasticity, such as the structure and organization of synapses, the points where nerve cells communicate. Some pathways related to immune and stress-response signaling also emerged. Ketamine was associated with changes in genes involved in glutamate signaling, while MDMA was associated with changes in genes such as BDNF, which supports the growth and survival of nerve cells, and a dopamine transporter gene.

The two treatments overlapped only partly at the level of individual genes. Forty-seven genes changed in both groups, but only about a quarter changed in the same direction, and the sizes of the changes were not correlated. The overlap was greater at the level of broader biological pathways, and both treatments were associated with increased methylation of EFNA5, a gene that has been linked to PTSD in large genetic studies.

Some of the patterns also differed. Ketamine changes were more strongly linked to synapse-related pathways, while MDMA changes were associated with a wider range of processes, including the movement of substances across cell membranes and electrical signaling. The authors noted that these differences could reflect the treatments’ distinct effects, but could also be due to differences between the studies, such as the use of psychotherapy with MDMA, the mix of diagnoses in the ketamine group, and the different sample types and collection times.

The authors summarized the shared pattern: “Across both compounds, altered loci [locations in the genome] converged on pathways related to neuroplasticity and neuroimmune regulation.” This is evidence of treatment-associated molecular changes, not proof that these changes explain why either treatment may help patients.

Some limitations should be noted. The groups were small, neither included a comparison group, and the study did not examine whether the methylation changes were related to symptom improvement. The ketamine and MDMA participants were not compared within one trial and differed in diagnosis, treatment context, and whether blood or saliva was tested.

The study also could not show whether the methylation changes affected gene activity, and participants receiving ketamine were allowed to continue most of their medications. Smoking and ethnicity, both of which can affect methylation, were not included in the analysis. Two of the authors are employees of TruDiagnostic, an epigenetic testing company, and nonprofits led by two other authors 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.