Therapeutically relevant rimonabant exposure drives epigenetic remodeling in neuronal cells and rat brain tissue

in the observed epigenetic modulation. Rimonabant also decreased histone deacetylases (HDAC) activity and reduced the levels of H3K4me3 and H3K27me3, marks that have been previously identified in psychiatric perturbations. Moreover, 4-week oral administration of 3 or 15 mg/kg rimonabant to rats produced region- and dose-specific alterations in H3K4me3, H3K27me3, H3K9ac, and 5-methylcytosine levels across the prefrontal cortex, hippocampus, and nucleus accumbens, in line with epigenetic profiles characteristic of depression, anxiety, and schizophrenia. Collectively, these findings demonstrate that rimonabant disrupts key epigenetic regulatory mechanisms in the brain and support the hypothesis that epigenetic dysregulation contributes to its psychiatric liabilities. This work strengthens the value of incorporating epigenetic endpoints into neuropharmacological safety assessments.