Brain-targeted epigenetic effects of two emerging psychoplastogens: ketamine & MDMA

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.