The global rise in addictive drug use has become a major public health concern, increasingly linked to the development of depression-a psychiatric disorder affecting over 300 million people worldwide. Emerging evidence indicates that chronic exposure to addictive substances can induce or exacerbate depressive symptoms through reward circuitry alterations, neuroinflammation, altered hypothalamic pituitary adrenal axis function, and mitochondrial dysfunction, thereby establishing a neurobiological milieu that favors drug induced depressive states. This review summarizes how epigenetic mechanisms, such as DNA methylation, histone modifications, non-coding RNAs and RNA modifications, convey the enduring effects of addictive drugs on gene expression related to mood regulation, stress response, and neural plasticity, offering potential biomarkers for early detection and individualized treatment. We further outline major technical constraints and unresolved mechanistic issues and highlight emerging approaches such as cell type resolved epigenomic mapping and locus specific epigenome editing that may enable more causal and translational insights. By integrating neurobiological and epigenetic perspectives, this review offers a clearer framework for understanding addiction and depression comorbidity and points to promising therapeutic opportunities. This Review article explores shared epigenetic mechanisms linking addictive drug use and depression, highlighting DNA methylation, histone modifications and non-coding RNAs as key contributors to their comorbidity.
Zhang et al. (Sat,) studied this question.