<p>Rimonabant (SR141716A), an inverse agonist of the cannabinoid receptor type 1&#xa0;(CB₁), once approved for treating obesity and metabolic disorders, was withdrawn shortly after due to psychiatric and psychological adverse events (PPAEs), including depression and suicidality. Although its primary pharmacological mechanism of action is well-characterized, the molecular basis underlying these neuropsychiatric effects remains unclear. Here, we investigated the epigenetic impact of rimonabant exposure, both in vitro and ex vivo, at therapeutically relevant concentrations and doses, with a focus on histone modifications and DNA methylation. In SH-SY5Y human neuroblastoma cells, after 24 and 96&#xa0;h treatment with 0.01 and 1 µM rimonabant significantly increased global histone H3 and H4 acetylation by 2.7- and 1.4-fold, respectively, without altering global DNA methylation levels. The effects on histone acetylation were partially reversed by a CB₁ receptor agonist, indicating a role for CB₁ 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&#xa0;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.</p>