Future Treatments for Tobacco Dependence

Abstract

Scientific evidence supports that the combination of psychological counseling and pharmacological treatment is the most effective healthcare intervention to help smokers quit. Four types of medications have been shown to be safe and effective: nicotine replacement therapy (NRT), bupropion, varenicline, and cytisinicline. Nevertheless, based on the results of new studies, we can point out several opportunities for development clinical research in this field: (a) finding the most effective doses for cytisinicline, (b) finding the effectiveness and safety of cytisinicline in smokers with chronic disorders, (c) comparing the effectiveness and safety of cytisinicline at higher doses with varenicline at standard doses, (d) investigating the effectiveness and safety of varenicline and cytisinicline used at standard doses but in different pharmaceutical formulations, (e) comparing the effectiveness and safety of cytisinicline at higher doses with nicotine replacement combined treatment, (f) determining the effectiveness and safety of smoking cessation medications as a treatment for new tobacco and nicotine products users (electronic cigarettes and heated tobacco users), (g) to determine the effectiveness and safety of combining pharmacological treatment for smoking cessation with non-invasive brain stimulation, and (h) to optimize the efficacy and safety of smoking cessation medications based on nicotine metabolite ratio (NMR) and probably the most recent suggestion to determine the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists. All these aspects will be discussed in this paper.

Introduction

Pharmacological treatment for smoking cessation is one of the disciplines associated with the study of Smoking as a chronic and relapsing addictive disease that has had the most development in recent years.¹ Currently, there is sufficient scientific evidence to support the idea that the combination of psychological counseling and pharmacological treatment is the most effective healthcare intervention to help smokers quit, and that four types of drugs have been shown to be safe and effective: nicotine replacement therapy (NRT), bupropion, varenicline, and cytisinicline.2, 3, 4 The standard doses and duration of use for each of these drugs, as well as the efficacy and safety of their combined use, have been established by the results and conclusions of various meta-analyses and are incontrovertible.2, 5, 6, 7 However, there is still room for further investigation in several areas: (a) the effectiveness and safety of dose adjustments, (b) the suitability of the treatment to the individual characteristics of the smoker, (c) the comparison of the effectiveness and safety of different treatments used at varying doses and durations, (d) the effectiveness and safety of the drug when used with a new formulation, (e) the effectiveness and safety of some of these drugs in smokers with associated pathologies, and (f) the effectiveness and safety of these drugs for treating users of new forms of tobacco and nicotine consumption (e-cigarettes and heated tobacco). Studying all these aspects opens a wide window of opportunity for clinical research in the pharmacological treatment of smoking cessation. Clinical research is understood here as that which can be carried out by any healthcare professional in their daily clinical practice without requiring specific material resources or significant financial investment.

Throughout this article, different opportunities for clinical research in the pharmacological treatment of smoking will be presented, its neurophysiological bases will be discussed, the conclusions of the studies that explain the reasons for carrying out this type of clinical research will be shown, and the main objectives of these studies and the type of scientific methodology that could be used will be briefly stated.

In order to look for the scientific support of this paper we have performed a narrative review. This narrative review was conducted to synthesize emerging opportunities for clinical research in pharmacological and neuromodulatory treatments for tobacco dependence. We performed a structured search of the recent literature in three databases: PubMed, Embase and Cochrane Library PubMed, focusing on studies published in the past ten years that evaluated the efficacy, safety, mechanisms of action, or clinical applicability of varenicline, cytisinicline, nicotine replacement therapy, glucagon-like peptide-1 (GLP-1) receptor agonists, and non-invasive brain stimulation techniques for smoking cessation. Evidence from randomized controlled trials, observational studies, mechanistic research, and relevant systematic reviews was examined. Sources were selected based on methodological rigor and relevance to current or future clinical practice. The findings were integrated qualitatively to identify converging themes, knowledge gaps, and potential avenues for innovation in tobacco-dependence treatment.

Opportunities for clinical research with nicotinic receptor agonist medications

The mesolimbic dopaminergic pathway consists of neurons located in the ventral tegmental area of the midbrain and their dendritic endings that connect with neurons in the nucleus accumbens.⁸ Acetylcholine receptors are present on the membranes of these neurons, and nicotine exerts its action more intensely and for a longer duration than acetylcholine itself.⁹ These receptors are composed of five polypeptide chains. Depending on the aminoacid sequence in each chain, there are several types: up to eight alpha chains (designated alpha 1 through alpha 7 and alpha 9 and alpha 10) and three beta chains (designated beta 2, beta 3, and beta 4). The most abundant nicotinic receptor is composed of three alpha 4 chains and two beta 2 chains.⁹ When nicotine acts on these receptors, it facilitates the release of dopamine in the neurons of the nucleus accumbens, leading to nicotine dependence in smokers.8, 9 When smokers are quitting, they do not inhale nicotine, and consequently, the nicotinic receptors on their neurons in the ventral tegmental area of the midbrain cannot be activated. This results in the absence of dopamine release in the nucleus accumbens, facilitating the development of withdrawal symptoms. The appearance of these symptoms is the main cause of relapse. Therefore, both full agonist medications (NRTs) and partial agonists (varencycline and cytisinicline) of the nicotinic receptor, by stimulating the receptor and triggering dopamine release in the nucleus accumbens, have proven effective in helping smokers quit.10, 11, 12

Clinical research studies pending with the partial agonists of nicotinic receptors: varenicline and cytisinicline

Analysis of the conclusions and results of various studies conducted with varenicline and cytisinicline indicates that further research is still needed to answer certain questions that remain unanswered in daily clinical practice. Table 1 shows the recommendations for the use of varenicline and cytisinicline at standard doses and durations.2, 3, 4, 5 However, the usual guidelines for using these medications can be modified to optimize their efficacy and safety. Some opportunities for clinical research in this regard are described below.

Table 1.

Recommendations for the use of nicotinic receptor agonists in smoking cessation.

Recommendation	Level of evidence	Quality of evidence	Grade of recommendation
Cytisinicline and varenicline have demonstrated superiority over placebo.	1b (cytisinicline), 1a (varenicline)	Moderate	Strong
Varenicline or cytisinicline may be more effective by increasing dose or duration.	2b	Low	Weak
Varenicline is effective in patients with psychiatric illness; efficacy increases with more intensive behavioral treatment.	2b	Low	Strong
Combinations of first-line smoking cessation medications are more effective than monotherapy, especially those including varenicline.	2a	Low	Strong

Clinical studies to identify the most effective and safe dose and duration of use for cytisinicline

The conclusions of the most recent studies conducted with cytisinicline have shown that: (a) cytisinicline at a dose of 3 mg every 8 h for 6 or 12 weeks is effective and safe for smoking cessation: 1 in 11 subjects using this dose for 6 weeks remained abstinent at the six-month follow-up, while in those using it for 12 weeks the ratio was 1 in 6; and (b) extending the treatment duration from 6 to 12 weeks did not result in a lower number of relapses at the 24-week follow-up in those subjects who had remained abstinent between the third and sixth weeks of treatment.13, 14, 15 On the other hand, a recent study conducted in routine clinical practice, in which a total of 337 smokers were treated with cytisinicline at standard doses for 25 days and followed up for one year showed that abstinence rates fell sharply and progressively over time, from 68% at the end of treatment to 48.7%, 40.9%, and 28.2% at the 3rd, 6th, and 12th months of follow-up, respectively. Furthermore, it was found that for each point of craving intensity, measured by the Single Rating of Craving Questionnaire, at the end of the pharmacological treatment, the chances of success at the 6th month were reduced by 13%.¹⁶ The results of these studies and recent meta-analyses suggest that the most advisable dosage for cytisinicline could be 3 mg every 8 h for 6 or 12 weeks, considering that in subjects with continuous abstinence between the third and sixth week of treatment, it would be sufficient to maintain it for only 6 weeks, and in those with occasional abstinence during that period, it would be advisable to extend it to 12 weeks.5, 13, 14, 15, 16

All these data open a wide avenue for clinical research. This avenue should be explored with a randomized study that verifies the efficacy and safety of implementing the conclusions presented above. It is worth noting that a study with a similar objective has already been initiated. This is the CITISILONG study, an open-label, randomized follow-up study in which a total of 400 smokers will be assigned to three different treatment groups with cytisinicline at standard doses for 25, 50, or 75 days. The objectives of the study are not only to analyze the effectiveness and safety of the three types of treatment but also to study the economic impact of each of the arms of the study.¹⁷

Studies analyzing the effectiveness and safety of cytisinicline use in smokers with other associated chronic diseases

The efficacy and safety of cytisinicline use in smokers without other associated chronic pathologies has been established in several clinical trials and meta-analyses.18, 19, 20 However, these studies were conducted in a population of smokers without other relevant chronic diseases. We still lack reliable clinical studies analyzing the effectiveness and safety of this medication in smokers with chronic cardiovascular diseases, acute coronary syndrome, relevant psychiatric disorders, or other chronic conditions (liver disease, kidney disease, etc.). There is only one open-label follow-up study in which a group of 79 smokers with acute coronary syndrome were treated with cytisinicline at standard doses and duration, compared to 38 smokers with the same condition who did not receive treatment. The study showed no significant differences in safety. However, it was an uncontrolled study with very short-term follow-up.²¹ Therefore, it would be necessary to initiate randomized clinical studies in smokers with these types of controlled chronic pathologies that would provide us with information on the effectiveness and safety of using this medication in these populations.

Studies comparing the effectiveness and safety of varenicline at standard doses and duration versus cytisinicline at a dose of 3 mg every 8 h for 6 or 12 weeks

Recently, two studies comparing the efficacy of cytisinicline versus varenicline have been published.22, 23 The first study was an open-label, randomized, non-inferiority clinical trial. In this trial, the drugs were used at standard doses and durations for each medication. The continuous abstinence rate at six months was 11.7% for the cytisinicline group and 13.3% for the varenicline group (RD −1.62% [97.5% CI: −5.02% to infinity]; p = 0.03 for non-inferiority). Therefore, this study could not demonstrate the non-inferiority of cytisinicline compared to varenicline. However, it should be noted that the study analyzes abstinence at six months (three months after completing varenicline treatment and five months after completing cytisinicline treatment). Therefore, the data found when comparing the abstinence rate at four weeks after starting treatment, that is, when cytisinicline treatment ended, is relevant, showing that, while this rate in the cytisinicline group was 42.5%, in the varenicline group it was 32.3% (RD 10.2% [95% CI: 5.2–15.1%] p < 0.001). This finding could reflect that, over the same treatment period, cytisinicline is as effective as varenicline. This suggestion was explored in another clinical trial in which a total of 679 subjects were randomized (1:1) to receive either varenicline at standard doses for 12 weeks or cytisinicline at standard doses for 25 days plus two 1.5 mg tablets daily for maintenance from day 26 until the completion of 12 weeks of treatment. The results showed that the abstinence rate at six months of follow-up was 12.1% for the cytisinicline group versus 7.9% for the varenicline group (risk difference 4.29%, 95% CI: −0.22 to 8.79; RR 1.55; 95% CI: 0.97–2.46). Sensitivity analyses confirmed that the result was robust; that is, cytisinicline was as effective as varenicline in helping people quit smoking at six months of follow-up.²³ The results of these studies highlight the need to open new lines of clinical research comparing the effectiveness and safety of varenicline at standard doses and durations against that of cytisinicline at a dose of 3 mg every 8 h for 6 or 12 weeks. Alternatively, once the results of the CITISILONG study are available, the effectiveness and safety of the most effective dose obtained in that study could be compared with the standard dose of varenicline.

Studies investigating the effectiveness and safety of varenicline and cytisinicline used at standard doses but in different pharmaceutical formulations

Tryptophan and tyrosine, being precursors of serotonin and dopamine, can help control some symptoms of withdrawal syndrome, primarily feelings of discouragement and depression.²⁴ Considering this data, a recent study developed a dry powder inhaler that administered the two aminoacids in particles 2–4 μm in size, so that it could be used as a drug to help control withdrawal symptoms.²⁵ The results showed that the plasma levels of aminoacids obtained via the intratracheal route were higher than those obtained via the oral or intravenous routes; furthermore, the pharmacokinetic parameters obtained via the intratracheal route were the most favorable compared to those obtained by either of the other two routes.²⁵

On the other hand, cytisinicline has recently appeared in a new pharmaceutical formulation as an oral solution.²⁶ The effectiveness, adherence, tolerability, and satisfaction produced by this new formulation are being analyzed in a clinical study.²⁷

These findings suggest that the use of partial nicotinic receptor agonists (cytisinicline and varanicline) in new pharmaceutical formulations could be investigated as a way to increase the therapeutic options for smoking cessation.

Clinical research pending for full nicotinic receptor agonists

Undoubtedly NRT is the most studied medication for smoking cessation.2, 3, 4 However, some aspects still need further analysis, which could be provided by clinical research studies. Only one study compares the efficacy and safety of cytisinicline versus NRT for smoking cessation.²⁸ However, this study has significant methodological limitations: NRT is used in various formulations, the comparison between the two medications is performed asynchronously, etc. Therefore, it would be relevant to conduct a randomized study comparing the effectiveness and safety of combined NRT (patches plus another rapid-release nicotine formulation) versus cytisinicline used at a dose of 3 mg every 8 h for 6 or 12 weeks. Furthermore, conducting a study with the same characteristics but using varenicline at standard doses instead of cytisinicline is another major study still pending. While it is true that comparing partial nicotinic receptor agonists with combined NRT can be complex to analyze, and that the results of such studies would always be difficult to interpret correctly, a study protocol comparing the effectiveness of cytisinicline versus combined NRT in smokers with previous relapses was recently published.²⁹ However, a study still awaiting completion that could provide clear and conclusive results would be a randomized comparison of two groups of smokers: one treated with tapering nicotine patches for 12 weeks and the other treated with cytisinicline at a dose of 3 mg every 8 h for 6 or 12 weeks.

Several formulations for rapid nicotine administration have been studied: gum, lozenges, nasal spray, oral spray, and inhaler. While all of them have similar pharmacokinetic and pharmacodynamic characteristics, nasal nicotine spray has consistently proven to be the route that most quickly achieves the highest levels.³⁰ However, the absorption and pharmacodynamic parameters that could be obtained by providing nicotine replacement therapy via a dry powder inhaler have never been studied.²⁵

Pending clinical research in the pharmacological treatment of users of new tobacco and nicotine products (e-cigarettes and heated tobacco)

Currently, this is the most open field of clinical research, and a significant number of studies should be conducted. There are no conclusive and reliable findings on the efficacy and safety of different medications when used to facilitate cessation of vaping or heated tobacco use. Table 2 summarizes the characteristics and results of the main studies conducted to determine the efficacy and safety of medications for cessation of vaping and heated tobacco use.31, 32, 33, 34, 35, 36, 37, 38, 39 Based on the data in this table, it can be concluded that the studies conducted are few and incomplete, with significant methodological limitations; consequently, their conclusions are weak and inconsistent for daily clinical practice.40, 41, 42 This suggests a significant opportunity for clinical research in this field. Table 3 describes a group of clinical research studies that could be carried out simply and without requiring the availability of significant material resources to increase knowledge in this field.

Table 2.

Studies on treatment of e-cigarette users and heated tobacco users.

Category	Study description
Studies using NRT (nicotine replacement therapy)	Several open, non-randomized follow-up studies with small sample sizes (Silver B et al.; Sikka G et al.; Sahr M et al.).
	A study found that the use of NRT was the most significant factor associated with quitting vaping (Bejarano G et al.).
	Meta-analysis including results from one study showing lack of efficacy of NRT in vapers: RR 2.57 (0.29–22.93) (Butler AR et al.).
	A randomized study showed that nicotine mouth spray reduced craving associated with vaping cessation (Danielsson T et al.).
	No studies have evaluated the efficacy or safety of NRT for cessation of heated tobacco use.
Studies using varenicline	A non-randomized cohort study of dual users treated with standard-dose varenicline showed higher abstinence rates among those who used the medication compared with those who did not: 12.5% vs. 1.6%, p = 0.007; RR 7.8 (1.7–34.5) (Hajek P et al.).
	A double-blind, placebo-controlled randomized clinical trial using standard-dose varenicline showed higher vaping cessation efficacy at 3 and 6 months: OR 2.67 (1.25–5.68) and OR 2.52 (1.14–5.58), respectively (Caponnetto P et al.).
	Meta-analysis including results from one study showing low efficacy of varenicline in vapers intending to quit: RR 2.00 (1.09–3.68) (Butler AR et al.).
	No studies have evaluated the efficacy of varenicline for cessation of heated tobacco use.
Studies using cytisinicline	One study showed efficacy of cytisinicline at 3 mg every 8 h for 12 weeks at end of treatment: OR 2.64 (1.06–7.10), p = .04; but not at 16-week follow-up: OR 2.00 (0.82–5.32), p = .15 (Rigotti NA et al.).
	No data exists on the efficacy or safety of cytisinicline for cessation of heated tobacco use.

Table 3.

Proposed clinical research studies for the treatment of vapers and/or heated tobacco users.

Study type	Objective	Intervention	Population	Duration
Randomized clinical trial	To assess the effectiveness and safety of NRT at standard dosing and timing	Nicotine replacement therapy (standard regimen)	Vapers and/or heated tobacco users	Standard duration
Randomized clinical trial	To assess the effectiveness and safety of cytisinicline	Cytisinicline 3 mg every 8 h	Vapers and/or heated tobacco users	12 weeks
Randomized clinical trial	To assess the effectiveness and safety of bupropion	Bupropion	Vapers and/or heated tobacco users	12 weeks
Randomized clinical trial	To assess the effectiveness and safety of NRT combinations	Several NRT combinations (see below)	Vapers and/or heated tobacco users	12 weeks

NRT combination proposals included in the last study:

• Nicotine patches for 12 weeks plus nicotine gum

• Nicotine patches for 12 weeks plus nicotine mouth spray

• Nicotine patches for 12 weeks plus nicotine lozenges

• Nicotine mouth spray with decreasing doses for 12 weeks

Clinical research to determine the effectiveness and safety of combining pharmacological treatment for smoking cessation with non-invasive brain stimulation

The neurophysiological basis supporting the use of non-invasive brain stimulation combined with pharmacological treatment as a procedure to increase the effectiveness of these medications in helping people quit account for the following reasons.

The insula is located within the brain below the Sylvian fissure. It is connected to the dorsolateral prefrontal cortex (DLPFC) via the uncinate and front-insular fasciculations. Neurons in the insula send axons to the nucleus accumbens located in the ventral tegmental area of the midbrain.⁴³ Activation of the left insula is associated with craving, while activation of the right insula is associated with long-term tobacco use. Higher scores on the FTND questionnaire are associated with greater activation of the right insula.43, 44

It has been shown that inactivation of the insula through various mechanisms leads to a reduction in craving in smokers and even to cessation of tobacco use.43, 44, 45, 46

Considering these findings, the hypothesis, which has been tested by some studies, is that repeated non-invasive stimulation of the DPFC of the brain could lead to temporary inactivation of the insula, and that this inactivation would lead to a reduction in craving and a decrease in the likelihood of relapse. A recent systematic review of the literature found the following: (a) all non-invasive brain stimulation techniques are safe and well-tolerated; (b) studies comparing these techniques against placebo show significant results for reducing the number of cigarettes smoked per day and craving; (c) there is a need for well-designed studies without methodological limitations; and (d) more studies are needed that combine the use of these techniques with approved smoking cessation medications.⁴⁷

A systematic review of the literature was recently published analyzing the efficacy of combining non-invasive brain stimulation with pharmacological treatment. The main conclusions of this review were the following: (a) the combination of the two active treatments may help to control craving during the first weeks of treatment better than with medication alone, (b) the use of the two active treatments may increase long-term efficacy and (c) the use of the combined treatment does not increase the occurrence of adverse events.⁴⁸

This data support a new window for clinical research in smoking cessation treatment through randomized controlled trials with a larger number of patients who are followed more closely and who use the most appropriate techniques for non-invasive brain stimulation. Furthermore, determining the efficacy and safety of this combined procedure in recalcitrant smokers, in whom craving is the main symptom of withdrawal leading to relapse, would be a highly relevant area of research.

Clinical research to optimize the efficacy and safety of smoking cessation medications based on nicotine metabolite ratio (NMR)

Nicotine metabolite ratio is a parameter used to determine the rate at which nicotine is metabolized. This drug is metabolized by the enzyme P450 2A6. The activity of this enzyme is genetically regulated, such that higher enzyme activity (determined by NMR values) is associated with greater nicotine dependence and lower efficacy of smoking cessation medications; while lower enzyme activity is associated with lower dependence and greater efficacy of smoking cessation drugs.49, 50 Consequently, tailoring the pharmacological treatment for smoking cessation to the level of enzyme activity can optimize its efficacy and safety. A systematic review and meta-analysis of various clinical trials evaluating the efficacy and safety of smoking cessation medications based on NMR values was recently conducted.⁵¹ The main clinical practice conclusions of this meta-analysis show that pharmacological treatment effectiveness varies meaningfully according to nicotine-metabolizing phenotype. Fast metabolizers show substantially reduced treatment benefit, with an overall ∼19% lower effectiveness compared with slow metabolizers. Consistently, nicotine replacement therapy is less effective in fast metabolizers, whereas slow metabolizers experience greater benefit (RR 0.70 [0.58–0.83]). In contrast, varenicline performs similarly across metabolic groups (RR 1.04 [0.75–1.44]) and is notably more effective than NRT among fast metabolizers (RR 1.40 [1.02–1.91]). These findings support a treatment-matching approach, as aligning therapy with metabolic profile appears to enhance adherence and reduce adverse effects (Table 4).⁵¹

Table 4.

Practical conclusions on the use of NMR for optimizing pharmacological treatment in smokers.

Conclusion	Description
Reduced effectiveness in fast metabolizers	Pharmacological treatments in fast nicotine metabolizers show approximately 19% lower effectiveness compared with slow metabolizers.
NRT effectiveness varies by metabolism rate	Nicotine replacement therapy (NRT) is more effective in slow metabolizers than in fast metabolizers (RR: 0.70 [0.58–0.83]).
Varenicline effectiveness and comparison with NRT	Varenicline shows similar effectiveness in both fast and slow metabolizers (RR: 1.04 [0.75–1.44]), but in fast metabolizers it is more effective than NRT (RR: 1.40 [1.02–1.91]).
Treatment matching improves adherence and tolerability	Aligning the pharmacological treatment with the patient's metabolic profile increases adherence and reduces the occurrence of adverse effects.

Following the findings of this meta-analysis, a number of clinical research studies can be conducted in this field. Among these studies, the following stand out: (a) a randomized clinical trial assessing the impact of NMR determination on the effectiveness, safety, and cost of different smoking cessation medications; (b) randomized clinical trials evaluating the effectiveness and safety of the medications used according to the meta-analysis findings. Specifically: the use of NRT in slow metabolizers, the use of varenicline in rapid metabolizers, and the use of cytisinicline at a dose of 3 mg every 8 h for 6–12 weeks in rapid metabolizers and at standard doses in slow metabolizers.

Clinical research to determine the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists

The habenula is a brain structure located in the diencephalon. It is divided into two parts: the medial habenula and the lateral habenula. In the medial part, neuronal cell bodies send axons to the interpeduncular nucleus. This is another brain structure located in the midbrain between the two cerebral peduncles. This constitutes the medial habenula-interpeduncular nucleus circuit.⁵² GABAergic nicotinic receptors are located in this circuit. When stimulated by nicotine, GABA is released, which stimulates neurons in the interpeduncular nucleus, leading the subject to develop an aversion to nicotine intake.⁵³ Thus, nicotine intake is understood to be regulated by two circuits: the mesolimbic dopaminergic circuit (which controls the reward associated with nicotine consumption) and the medial habenula-interpeduncular nucleus circuit (which controls aversion to nicotine consumption).

It is worth noting that receptors for glucagon-like peptide-1 have been described in both circuits. Furthermore, several studies have found that the use of GLP-1 receptor agonists reduces nicotine intake, cravings, and weight gain associated with smoking cessation.54, 55, 56

Considering these findings, several randomized clinical trials have been conducted to determine the efficacy and safety of various GLP-1 receptor agonists to help smokers quit. All of these studies were included in a recent systematic literature review and meta-analysis presented at the American Psychiatric Association meeting in May 2025. Three clinical trials involving 410 smokers were reviewed. Three combinations were tested in each trial: exanatide, nicotine patches, and placebo; exanatide, cognitive behavioral therapy, and placebo; and dulaglutide, varenicline, and placebo.⁵⁷ The efficacy results showed that: (a) no significant differences were found between active treatment and placebo: OR: 1.22 (0.71–2.10); p = 0.46. However, weight gain was reduced with the active treatments: OR: 2.59 kg (−3.70–0.10; −1.48). p < 0.00001. The safety results showed no significant differences for psychiatric disorders, although a greater number of digestive symptoms were demonstrated in those using active treatment.⁵⁷

However, data from the most recent publication show the results of a narrative literature review and a meta-analysis.⁵⁸ The narrative review found twelve studies (eight human and four preclinical). Preclinical studies demonstrated consistent attenuation of nicotine-seeking behavior and mesolimbic dopaminergic signaling via GLP-1 receptor agonism. Among human studies, exenatide showed the most robust efficacy in enhancing abstinence and reducing craving and weight gain. Dulaglutide did not improve abstinence, though it conferred metabolic benefits. Semaglutide showed indirect behavioral benefits in real-world observational data. Adverse events were predominantly mild gastrointestinal symptoms.⁵⁸ The results of the meta-analysis performed on clinical trials showed no significant differences for abstinence. The pooled odds ratio was 1.16 (95% CI 0.76–1.79; p = 0.49).⁵⁸

This data suggests that the use of GLP-1 receptor agonist medications may be promising therapeutical options for smoking cessation. Clinical research on this field is warranted.

Limitations

This paper is a narrative review, and several methodological limitations must be acknowledged. Because narrative reviews do not follow a standardized or reproducible search strategy, selection bias cannot be fully avoided, and the evidence base may be incompletely represented. Subjective interpretation by the authors is also possible, given the absence of predefined inclusion criteria and formal quality appraisal. Consequently, the conclusions of this review should be interpreted with caution. Nevertheless, this narrative synthesis offers a valuable conceptual overview of emerging opportunities for clinical research on the pharmacological treatment of tobacco use.

Ethical considerations

This literature review did not involve the collection of new data from human participants or animals. All information analyzed was obtained from previously published studies. Ethical approval and informed consent were therefore not required. Nevertheless, the review was conducted following principles of academic integrity, transparency, and respect for intellectual property.

Artificial intelligence involvement

The paper has been produced without involvement of AI.

Informed consent

This article is a literature review and does not involve original data collection from human participants. Therefore, informed consent was not required.

Funding

The authors declare that they have not received any funding for this study.

Authors’ contributions

CAJ-R wrote the first manuscript and it was sent to the rest of the authors. The contributions of these authors were discussed, approved and added to the paper.

Conflicts of interest

CAJ-R has received honoraria for presentations, participation in clinical studies and consultancy from: Adamed, Aflofarm, Bial, Chiesi, GSK, Gebro Pharma, Kenvue, Neuraxpharm and Pfizer.

JIG-O has received honoraria for lecturing, scientific advice, participation in clinical studies or writing for publications for the following (alphabetical order): Aflofarm, Adamed, Boehringer, Esteve, Neuroxpharm and Pfizer.

CRC has received honoraria for speaking engagements, sponsored courses, and participation in clinical studies from Adamed, Aflofarm, GSK, Menarini, Mundipharma, Chiesi, Novartis, J&J, Pfizer, and Teva.

JAR reports grants and personal fees from Aflofarm, Adamed, GSK, grants, personal fees and non-financial support from Pfizer, Novartis AG, Menarini, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial from Astra-Zeneca, Grants and personal fees from, Gebro Pharma, personal fees from Sanofi-Regeneron, outside the submitted work.

The other authors declare that they have no conflict of interest with respect to this document.