Nicotine addiction remains one of the most persistent and challenging forms of substance dependence worldwide. Despite decades of research and the availability of pharmacological and behavioural interventions, relapse rates remain alarmingly high, reflecting the complex interplay of neurobiological, psychological, and environmental factors that drive nicotine dependence (Benowitz, 2010; McLaughlin et al., 2015). Traditionally, nicotine addiction has been attributed to its pharmacological action on nicotinic acetylcholine receptors (nAChRs), particularly the α4β2 and α6-containing subtypes located in the mesolimbic dopamine pathway, which includes the ventral tegmental area (VTA) and nucleus accumbens (NAc). When nicotine binds to these receptors, it stimulates dopamine release, producing reinforcing and pleasurable effects that contribute to repeated use (Kim and Picciotto, 2023; Picciotto and Kenny, 2021). Over time, neuroadaptive changes such as nAChR upregulation and increased sensitivity of dopaminergic circuits lead to compulsive intake and dependence (Feduccia et al., 2012; Leong et al., 2018).

However, the pathophysiology of nicotine addiction extends beyond dopaminergic reinforcement. Cessation leads to withdrawal, characterized by reduced dopamine transmission, emotional dysregulation, anxiety, irritability, and anhedonia—all of which contribute significantly to relapse (Di Chiara, 2000; McLaughlin et al., 2015; Wills et al., 2022). The stress-response systems, particularly the CRF pathway and the hypothalamic-pituitary-adrenal (HPA) axis, become hyperactivated during withdrawal, further intensifying emotional disturbances and craving (Takayanagi and Onaka, 2021; Winter and Jurek, 2019). Additionally, environmental cues associated with past nicotine use can persistently trigger craving and relapse, even after prolonged abstinence (Perkins, 2009).

Given these complex, multidimensional mechanisms, recent research has shifted toward identifying alternative therapeutic targets that modulate the stress-related and emotional dimensions of nicotine dependence. One such promising candidate is oxytocin, a neuropeptide traditionally recognized for its role in childbirth, lactation, maternal behaviour, and social bonding (Ren et al., 2024). Oxytocin consists of nine amino acids and is synthesized primarily in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus (Ito et al., 2019). It exerts its physiological effects by binding to oxytocin receptors (OXTRs), which are widely distributed in brain regions relevant to addiction, such as the amygdala, hypothalamus, nucleus accumbens, and prefrontal cortex (Leong et al., 2018; Sundar et al., 2021).

In preclinical studies, oxytocin has demonstrated the ability to alleviate multiple facets of nicotine withdrawal. These include somatic symptoms such as tremors, gasping, writhes, and muscle spasms (Manbeck et al., 2014), as well as anxiety and cue-induced nicotine-seeking behaviours (Houghton et al., 2021; Miller et al., 2016). Although its effect on anhedonia remains limited, oxytocin's modulation of CRF activity and mesolimbic dopamine signalling suggests a dual mechanism in addressing both stress and reward (Winter and Jurek, 2019; Wronikowska-Denysiuk et al., 2023). Oxytocin also exerts neuroimmune effects by reducing microglial activation and inflammation (Shi et al., 2024). Further, its interactions with the gut-brain axis (Rodrigues et al., 2021; Wang et al., 2025) and regulation via sex hormones and OXTR gene methylation (McClure et al., 2020; Proskynitopoulos et al., 2024) contribute to individual variability in treatment outcomes.

Sex differences in nicotine intake and oxytocin responsiveness have been observed, with female rats exhibiting higher nicotine consumption (Flores et al., 2019). Clinical studies suggest that oxytocin may reduce craving in the presence of stress; however, inconsistent findings reflect challenges related to pharmacokinetics, optimal dosage, administration route, hormonal fluctuations, and epigenetic variability (Buisman-Pijlman et al., 2014; Mota-Rojas et al., 2023; Ren et al., 2017; Simpson et al., 2024; Van Hedger et al., 2020).

Among emerging neurotherapeutic candidates, oxytocin stands out due to its uniquely broad mechanism of action that simultaneously targets the stress, reward, and social–emotional systems implicated in nicotine dependence. Unlike established treatments such as varenicline and bupropion—which are effective but limited by issues such as neuropsychiatric side effects, modest long-term abstinence rates, reduced efficacy in individuals with high stress reactivity, and poor tolerability in some patients—oxytocin addresses key therapeutic gaps that current agents leave unresolved. Varenicline and bupropion primarily act through nicotinic receptor modulation or monoaminergic enhancement, yet they do not adequately mitigate withdrawal-related anxiety, affective disturbances, or cue-triggered craving, all of which remain major contributors to relapse. Although newer approaches such as nicotinic α7 receptor agonists show promise in improving cognition and alleviating certain withdrawal symptoms, these strategies remain narrowly focused on receptor-level modulation. In contrast, oxytocin's influence on CRF-mediated stress circuits, mesolimbic dopamine function, neuroimmune activity, and social–emotional processing provides a more integrative and multifaceted therapeutic profile. This broad mechanism offers a strong rationale for prioritising oxytocin as a distinctive and potentially more comprehensive candidate within the evolving landscape of nicotine cessation therapies.

In light of these findings, the present review aims to synthesize existing evidence on the neurobiology of nicotine addiction and withdrawal, and critically evaluate oxytocin's potential as a neurotherapeutic agent. We highlight both preclinical and clinical insights, address translational barriers, and propose future directions to support the development of personalized oxytocin-based interventions for nicotine dependence.