From the aforementioned databases, 100 studies were retrieved from the search. After the removal of 52 duplicates, 48 studies underwent screening of their titles and abstracts. A total of 12 studies underwent full-text review and were screened based on the eligibility criteria. Subsequently, four studies were removed due to wrong outcomes (n = 2) and wrong study interventions (n = 2) (Fig. 1). Eight studies were included in this review; their results and experimental design are presented in Table 4.

Herein, we also assessed animal studies to complement the clinical research findings. It was noted that some of these studies did not adequately address certain critical aspects, not all studies clearly indicated random selection methods, and some did not specify how animals were chosen for outcome assessment. Specifically, two studies were found to have gaps in addressing blinding of caregivers/investigators and random selection for outcome assessment. All publications exhibited a low risk of bias across various domains (Tables 2, 3).

The included clinical studies consistently reported whether blinding was maintained for researchers and participants and whether allocation to experimental groups was randomized. None of the included human studies was found to have a high risk of bias (Table 3).

A total of five preclinical studies were identified evaluating the effect of GLP-1RA monotherapy on animal models of NUD. Rodents were allowed self-administered nicotine, forming nicotine-seeking and withdrawal habits [20, 21]. Herman et al. and Egecioglu et al. reported that liraglutide and exendin-4, respectively, attenuated self-administration and reinstatement in these rodents, while repeated administration of GLP-1RAs reduced the occurrence of withdrawal-induced hyperphagia and post-smoking cessation weight gain [20, 21]. Herman et al. found that during subsequent reinstatement sessions, total lever responses releasing nicotine were significantly lower in rats treated with liraglutide compared to the vehicle-treated controls [F(1, 24) = 60.86, p < 0.0001] [20]. Egecioglu et al. further reported that exendin-4 attenuated nicotine-induced dopamine release [21].

Additionally, Egecioglu et al. examined the impact of exendin-4 on nicotine-induced conditioned place preference, a behavioural paradigm that proxies drug reward properties [21]. Mice showed a significant preference for the nicotine-paired compartment, which was reversed by exendin-4 administration (p ≤ 0.05) [21].

The capability of GLP-1RAs to cross the blood–brain barrier suggests that the physiological role of these agents may extend beyond that of glucose homeostasis and food intake as a potential pharmacotherapy for NUD [21]. A separate study using murine models reported that 79% of GLP-1 neurons in the NTS were activated by nicotine exposure, which further reduced nicotine consumption [22]. The aforementioned findings were reported to be subserved by the medial habenula-interpeduncular nucleus (MHb-IPN) [22]. The MHb-IPN circuit has downstream targets that promote nicotine aversion, prompted by GLP-1 release from NTS terminals that stimulate habenular terminals, although such targets are currently unknown [22]. Additionally, mice treated with exendin-4 under a fixed ratio schedule of reinforcement exhibited a consistent inhibitory effect on nicotine consumption compared to the control [22].

Similarly, Falk et al. demonstrated attenuation of nicotine-induced dopamine release by liraglutide administration  [23]. The combination of nicotine and liraglutide increased neuronal activity in several brain regions involved in body weight regulation [23]. The combination administration synergistically increased c-Fos expression in the ventral tegmental area and nucleus accumbens [23].

Among patients with a high susceptibility for post-nicotine cessation weight gain, as well as risk for psychotropic-drug related weight gain, GLP-1RAs represent a viable option [24]. We identified one behavioural animal study that evaluated the association between metabolic change and nicotine consumption. Shankar et al. investigated the impact of nicotine on feeding behaviour and associated hormonal changes [25]. Post hoc analysis indicated significant increases in food intake for nicotine, while GLP-1 coupled administration did not significantly alter food intake [25].

Clinical data evaluating the efficacy of GLP-1RAs for NUD and nicotine use is preliminary (Table 4). The search identified three clinical studies with a total of 594 participants.

Yammine et al. evaluated craving and post-nicotine cessation body weight in smoking persons with prediabetes or obesity (n = 84) who were adjunctively assigned to placebo or extended-release exenatide in combination with NRT or no medication [26]. After six weeks of intervention, exenatide increased the incidence of smoking abstinence by 19.5%, demonstrating higher posterior probability compared to placebo (PP = 96.5%) [26]. The Questionnaire of Smoking Urges (QSU), which measures craving for nicotine revealed significantly lower urges to smoke in persons assigned to exenatide when compared to placebo [26]. Notably, there was a substantial difference in post-nicotine cessation body weight between the two groups, wherein the experimental group weighed 5.6 pounds less than placebo-treated participants at study endpoint [26].

A separate study enrolled 255 participants with moderate nicotine dependence and investigated whether adjunctive dulaglutide would aid in smoking cessation [27]. Participants were randomly assigned to either placebo or dulaglutide in combination with varenicline and behavioural counselling as part of a 12-week intervention period, with follow-up visits at weeks 24 and 52 [27]. The primary outcome, self-reported and biochemically confirmed abstinence at week 12, revealed no significant difference between the dulaglutide and placebo groups, with 63% and 65% abstinence rates, respectively [27]. Notwithstanding the non-significant difference between groups, participants assigned to dulaglutide exhibited lower post-nicotine cessation weight gain at the 12-week mark (− 1.0 kg) than the placebo group (+ 1.9 kg) [27].

The long-term effect of GLP-1RAs on nicotine abstinence, as well as rates of return-to-smoking behaviour, has also been preliminarily evaluated. Luthi et al. conducted a 12-month follow-up study that included participants who underwent a smoking cessation intervention program with dulaglutide or placebo in combination with standard care [28]. At week 52, prolonged abstinence rates were 29% and 27% for dulaglutide and placebo, respectively [28]. Collectively, findings suggest that GLP-1RAs may actively mitigate smoking cessation success, long-term abstinence, and post-nicotine cessation weight gain with overall good acceptability  [20,21,22,23,24,25,26,27,28].