Epigenetic markers as predictors of neurotoxicity and abuse potential of psychotropic drugs: integration of epigenetic modifications in New Approach Methodologies.

Neurotoxicity and abuse potential are strongly associated with psychotropic drugs. Although animal models have been used for decades to investigate different forms of toxicity, including neurotoxicity and abuse potential, increasing efforts have been directed toward overcoming their inherent limitations. In this context, the development of New Approach Methodologies (NAMs), aimed at improving chemical safety assessment through more protective and physiologically relevant models, has emerged as a promising strategy to predict the neurotoxic potential of drugs while contributing to the replacement, reduction, and refinement of animal experimentation. Nevertheless, the number of NAMs capable of reliably and efficiently predicting neurotoxicity remains limited. Importantly, psychotropic drugs have been shown to induce epigenetic modifications (e.g., DNA methylation, histone modifications), which are frequently associated with neurotoxic adverse effects. The integration of these alterations into NAMs may therefore represent a major advance for academia, industry, and regulatory agencies in assessing the neurotoxic and abuse potential of such substances. Here, we review the latest evidence on the role of psychotropic drug-induced epigenetic modifications in neurotoxicity and abuse potential. Importantly, we further discuss how integrating these epigenetic alterations into NAMs could advance risk assessment of neurotoxic effects and abuse liability.