The landscape of cocaine cytotoxicity and the role of sigma-1 receptor modulation and adulterant synergism.

Cocaine remains one of the most widely consumed illicit drugs globally, representing a significant public health challenge. While its acute reinforcing effects are mediated by the facilitation of dopaminergic and serotonergic neurotransmission, chronic exposure leads to pervasive neurobiological adaptations and systemic toxicity. Beyond its psychoactive properties, cocaine exerts multifaceted cytotoxic effects across several organ systems, including the brain, heart, and liver, primarily through the induction of oxidative stress, mitochondrial dysfunction, and the activation of apoptotic pathways. This review provides a comprehensive analysis of these cellular and molecular mechanisms and introduces novel evidence regarding the toxicological impact of seized cocaine. Original in vitro data demonstrate that the association of cocaine with common adulterants, levamisole, phenacetin, and caffeine, markedly exacerbates cytotoxicity through synergistic interactions. Furthermore, this review examines the pivotal role of the sigma-1 receptor (σ1R) in cocaine-induced toxicity, supported by molecular docking analyses that characterize specific interactions between the cocaine, adulterants, and conserved receptor residues. This receptor-mediated framework suggests a central mechanism contributing to the drug's combined toxic and reinforcing properties. Collectively, these findings integrate experimental, computational, and literature-based evidence to offer a broader mechanistic understanding of cocaine-induced toxicity and its modulation by adulterants, providing compelling evidence for the role of σ1R in these cytotoxic processes.