Oxytocin as a neurotherapeutic target for nicotine withdrawal and craving modulation.

Nicotine addiction is a chronic relapsing disorder driven by neuroadaptive changes in reward, stress, and emotional regulation systems. Withdrawal symptoms, including anxiety, irritability, cravings, and anhedonia, significantly hinder smoking cessation efforts. Despite current treatment options such as nicotine replacement therapy, relapse rates remain high. Traditionally, nicotine's reinforcing properties have been attributed to its action on nicotinic acetylcholine receptors (nAChRs) within the mesolimbic dopamine system, particularly the ventral tegmental area (VTA) and nucleus accumbens (NAc). However, growing evidence shows nicotine dependence involves systems beyond classical dopaminergic pathways, including stress-response mechanisms, neuroimmune activation, and neuroendocrine modulation. Withdrawal triggers corticotropin-releasing factor (CRF) dysregulation, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, mood disturbances, and persistent cue-induced cravings. Oxytocin, a neuropeptide involved in social bonding and stress modulation, has emerged as a promising therapeutic candidate capable of modulating these complex mechanisms. Preclinical studies demonstrate oxytocin's ability to alleviate withdrawal-induced anxiety, reduce somatic symptoms, suppress cue-induced nicotine seeking, and modulate reward-related brain circuits. Additionally, oxytocin exerts anti-inflammatory effects by attenuating neuroimmune responses and reducing microglial activation. While its efficacy in reversing anhedonia remains limited, oxytocin may also influence gut-brain signalling pathways. Epigenetic studies reveal sex-specific differences in oxytocin receptor (OXTR) gene methylation and hormonal influences during nicotine withdrawal, suggesting a role for personalized approaches. Clinical trials yield inconsistent findings, showing potential in reducing craving intensity but variability in relapse prevention outcomes. This review critically examines oxytocin's role in nicotine addiction, underlying neurobiological mechanisms, and translational challenges, emphasizing the need for biomarker-guided, large-scale trials to validate its therapeutic utility.