Research on the safety risk of oral nicotine products and its prospects

Abstract

Oral nicotine products are a category of novel tobacco products that deliver nicotine through oral consumption. With increasing tobacco control measures worldwide and growing public health awareness, its safety risk has gained attention. However, the regulatory authorities still lack long-term data for oral nicotine products and limited data on additives, so the continued in-depth research is required in the future. By integrating data from chemical analyses, animal/cell studies, and human cohorts, this review first introduces the main commercially available oral nicotine products and their classifications, analyzes the potentially harmful substances and their concentrations, and then systematically elucidates the health effects of oral nicotine products (including on oral and cardiovascular systems) and their underlying mechanisms. Finally, based on relevant research, it proposes future directions for safety risk studies on oral nicotine products. In summary, this review offers consumers a clearer understanding of the safety risks of oral nicotine products, provides evidence to support their rational use, and delivers insights for companies and regulators to develop effective policies and reduce health risks.

Graphical abstract

Highlights

• •There are various classifications of oral nicotine products;
• •Oral nicotine products show less harmful components (e.g. TSNA) than tobacco;
• •Oral nicotine products still induce cardiovascular and oral mucosal effects;
• •Oral nicotine products can increase risk of pancreatic cancer, adverse pregnancy.

1. Introduction

With increasing global attention on smoking and health issues and the continuous strengthening of tobacco control measures, tobacco companies worldwide are actively expanding their presence in the novel tobacco product market [Pisinger and Mackay, 2019]. Among these, oral nicotine products are a category of novel tobacco products consumed through the oral cavity to deliver nicotine, including traditional oral tobacco, modern nicotine pouches, nicotine gum, and others [Hartmann-Boyce et al., 2025]. Unlike traditional cigarettes, these products do not generate smoke; instead, nicotine is absorbed through the oral mucosa into the bloodstream to produce physiological satisfaction [Felicione et al., 2026]. Their advantages include: (1) Convenience and suitability for use in various settings (e.g., on trains, airplanes, etc.), with no secondhand smoke to harm others or the public environment [Grandolfo et al., 2024]; (2) Diverse product options, as oral nicotine products come in various forms and flavors, catering to multifaceted consumer demands; (3) Currently, policies and regulations in many countries lack comprehensive oversight of oral nicotine products, such as in taxation and health warnings. These factors have contributed to the rapid expansion of the oral nicotine product market.

According to relevant data, the U.S. nicotine pouch market was estimated at $988.4 million in 2023 and is projected to grow at a compound annual growth rate (CAGR) of 33.6% from 2024 to 2030. Sales of nicotine pouches in the United States increased from 126 million units in the final five months of 2019 to 808 million units in the first three months of 2022, representing approximately a 6.4-fold increase (Majmundar et al., 2022). Over the longer term, sales rose more than 300-fold between 2016 and 2020, driven by rapid market expansion (Marynak et al., 2021). Given the rapid growth of oral nicotine products, tobacco companies worldwide have begun focusing on safety risk evaluations of these products [Travis et al., 2025; Long et al., 2023], such as analyzing harmful components in oral nicotine products and studying the pharmacokinetics of related constituents in the human body. The health-beneficial effects of oral nicotine products mainly apply to replacement of traditional cigarettes (as they contain relatively fewer harmful substances), but this does not mean that these products are completely harmless. Their use still poses safety risks in terms of cardiovascular, oral mucosa, reproductive, and pregnancy outcomes. So, it is important for providing consumers with rational data and theoretical guidance for using oral nicotine products.

This review takes oral nicotine products as the focal point, first outlining their classification and distinctions, then systematically summarizes the current research status on the safety of various types of oral nicotine products, including comparative analyses of harmful components. Furthermore, it elucidates the effects and underlying mechanisms of these products on various physiological systems based on both animal and human studies. Finally, potential strategies and methods to enhance the safety of oral nicotine products are proposed by relevant literature. Focusing on this emerging category of tobacco products, this review comprehensively presents the progress in safety risk evaluation research. It aims to help consumers better understand the characteristics of oral nicotine products while providing theoretical and data-driven support for tobacco companies to improve product safety.

2. Method for literature including

(i) Database and Retrieval Time: This study mainly uses PubMed and Web of Science as the main search databases, and includes relevant literature from the past decade to ensure the cutting-edge nature of the conclusions.

(ii) Search Terms: The main strategy is “(oral nicotine products” OR “tobacco products”)“ AND (“public health” OR “population studies” OR “safety risk assessment” OR “health risks”), and adjustments are made according to the grammar of each database. At the same time, the reference lists of the included literature are manually searched.

(iii) Inclusion/Exclusion Criteria: Inclusion: Peer-reviewed original studies (including in vivo, in vitro, and human epidemiological studies); in English or with English abstracts; the research content mainly includes animal, cell, and population studies on the safety risk of oral nicotine products. Exclusion: Studies without a control group; duplicate publications.

(iv) Screening Process: Two authors independently screen the titles/abstracts and the full papers. Disagreements are resolved through discussion or by a third author's decision.

3. Classification and characteristics of oral nicotine products

Oral nicotine products refer to products that are used by holding in the mouth, oral ingestion, or chewing, allowing nicotine to enter the bloodstream through the oral mucosa for absorption. Currently, the main types of oral nicotine products mainly include nicotine consumption demands (not as nicotine replacement therapy (NRT), that is, changes in the form of nicotine consumption), and on the other hand, they are regarded as a category of smoking cessation products (considered as NRT). The common classifications and basic information of currently available oral nicotine products are as follows, as shown in Fig. 1, oral nicotine products can be roughly classified into pouch type, dissolving type, gum based type and other type, and the Characteristics of different oral nicotine products can be seen in the Table 1.

Fig. 1.

Classification and characteristics of oral nicotine products.

Table 1.

Characteristics of oral nicotine products.

Aspect	Pouch types: Nicotine pouches/traditional oral tobacco	Dissolving type/gum based type/ other type
Nicotine Content	High: Typically 3 mg - 25 mg per pouch, or even higher.	Low: Typically 2 mg or 4 mg per piece/lozenge, with clear upper limits.
Key Ingredients	Nicotine (or synthetic nicotine analogs), plant fibers, flavorings, pH adjusters (to enhance absorption).	Pharmaceutical nicotine, gum base, fillers, etc.
Typical Use	Placed between the gum and cheek (buccal/labial groove), no chewing, slow release.	Chewed or dissolved using specific techniques, absorbed through oral mucosa.
Regulatory Status	US: FDA-regulated. Products require authorization. Beware of “nicotine-free” products containing analogs like 6-methyl nicotine, which may have regulatory loopholes.	US: FDA-approved. Sold as over-the-counter (OTC) drugs with clear dosage and usage standards.

1. Pouch-type oral nicotine products: These mainly include traditional oral tobacco and modern nicotine pouches [Jordt and Jabba, 2024]. Traditional oral tobacco, also known as moist snuff, originated in Sweden and has a relatively high prevalence in Nordic regions. It is typically composed of small tobacco leaves, sodium carbonate, water, and additives, packaged in small pouches for use, with tobacco remaining the source of nicotine [Idris et al., 1998]. However, after consumption, traditional oral tobacco may leave stains and residual taste in the mouth, affecting aesthetics, leading to a gradual decline in its market share. Modern nicotine pouches primarily consist of nicotine salts, fillers, water, and additives packaged in small pouches, with nicotine content ranging from 2 to 20 mg per pouch. The nicotine source in these products is nicotine salts [Akhlaque et al., 2024]. Since they do not contain tobacco, nicotine pouches offer a more comfortable user experience and are more environmentally friendly. As a result, they have become the dominant product in the current oral nicotine market.

2. Dissolvable oral nicotine products: This category primarily includes nicotine lozenges and nicotine oral dissolving films (NODF). These products are composed of film-forming materials (such as hydroxypropyl methylcellulose), flavoring agents, and pH regulators, with a typical nicotine content of 1–4 mg per unit [Kheawfu et al., 2021]. Dissolvable oral nicotine products represent a novel form of NRT, primarily designed to assist smokers in quitting or reducing tobacco dependence. Their key features include rapid absorption and high discretion in use [Cilurzo et al., 2010].

3. Gum-based oral nicotine products: The most common example is nicotine gum, which mainly consists of a gum base, nicotine salts, and additives. These products typically contain 2–4 mg of nicotine per piece. Consumers absorb nicotine through chewing and buccal mucosa absorption. Characteristics include slower onset of action, mild oral irritation, and potential jaw fatigue or stomach discomfort with excessive chewing [Fernandes et al., 2021; Shiffman et al., 2020].

4. Other types of oral nicotine products: In addition to the aforementioned oral nicotine products, oral nicotine sprays [Perkins et al., 2019] are directly sprayed onto the buccal area or under the tongue, offering extremely rapid onset (1–2 min), precise dosing, and immediate relief of nicotine cravings. Other products such as stick-type oral nicotine products, nicotine syrups/drops, and nicotine micro-tablets have a relatively narrow consumer base, resulting in their low market share.

4. Pharmacokinetics of oral nicotine products

A key indicator for evaluating the sensory properties of oral nicotine products is the blood nicotine concentration curve following product use. Due to differences in formulation and manufacturing processes among various oral nicotine products, variations exist in their sensory effects (see Fig. 2A, it represents nicotine release curves of oral nicotine products, showing the rate of nicotine release, the curve represents the rate at which nicotine is transferred from the product to the medium (such as artificial saliva) after it undergoes pre-treatment in the simulated oral environment (at 37 °C, pH = 7, etc.)). For instance, nicotine oral dissolving films exhibit faster nicotine release rates but shorter duration, while nicotine pouches demonstrate moderate release rates and longer duration. Several research institutions have conducted analyses and monitoring of blood nicotine concentrations after the use of oral nicotine products to prevent potential toxic effects caused by nicotine overdose. Fiona Chapman et al. investigated two commercially available nicotine pouches (nicotine content: 6 mg/pouch and 10 mg/pouch) and Marlboro traditional cigarettes (nicotine content: 0.8 mg/stick). The study involved 24 participants, with blood samples collected at specific time points over eight hours after product use for nicotine concentration measurement. The results showed that traditional cigarettes produced higher peak blood nicotine concentrations than nicotine pouches (see Fig. 2B, it represents blood nicotine concentration profiles following the use of nicotine pouches versus traditional cigarettes by consumers). The time to peak concentration (T max) was approximately 8 min for traditional cigarettes, compared to about 25 min for nicotine pouches [Chapman et al., 2022; Lunell et al., 2020]. These data indicate that the route of nicotine administration significantly impacts blood nicotine concentration. Cigarettes enable the fastest absorption rate through the pulmonary mucosa, followed by nicotine pouches via the oral mucosa. In contrast, certain swallowed nicotine lozenges exhibit the slowest absorption rate through the intestinal tract, typically requiring 2–3 h to reach peak concentration [Lunell and Lunell, 2005; Digard et al., 2013]. Compared to traditional cigarettes, nicotine pouches demonstrate lower C max (maximum concentration) and slower absorption rates (see Fig. 2A, it represents nicotine release curves of oral nicotine products). The possibility of nicotine abuse is multi-factorial (pharmacokinetics, subjective effects, context, product design), oral nicotine products may change consumption behavior for current adult smokers compared to continued cigarette use, and it is necessary to establish a formal assessment of the potential for abuse of new products. This suggests that This pharmacokinetic profile also explains why oral nicotine products are often marketed as smoking cessation aids.

Fig. 2.

Classification of oral nicotine products. (A) Nicotine release curves of oral nicotine products, the curve represents the rate at which nicotine is transferred from the product to the medium (such as artificial saliva) after it undergoes pre-treatment in the simulated oral environment (at 37 °C, pH = 7, etc.); (B) blood nicotine concentration profiles following use of nicotine pouches (nicotine content: 6 mg/pouch and 10 mg/pouch) versus traditional cigarettes.

5. Current research status on the safety risk of oral nicotine products

Compared to traditional cigarettes and other tobacco products, oral nicotine products have simpler ingredient compositions and do not involve tobacco combustion processes, resulting in significantly reduced levels of harmful substances such as nitrosamines and aldehydes, but this does not mean that there are no harmful substances. However, with the growing consumer and expanding market size of oral nicotine products, tobacco companies and health regulatory agencies worldwide have conducted a series of safety risk evaluation studies on these products. This section will systematically review the composition and content of harmful substances in various types of oral nicotine products. Additionally, it will summarize the effects and underlying mechanisms of oral nicotine products on various physiological systems based on both animal and human studies.

5.1. Safety risks of traditional oral tobacco

5.1.1. Analysis of harmful components in traditional oral tobacco

Traditional oral tobacco represents the earliest category of oral nicotine products and is the only type that contains tobacco as an ingredient. Based on a series of literature reports and testing results, the harmful components in traditional oral tobacco can generally be categorized as follows:

(1) Tobacco-specific nitrosamines (TSNAs): The total content must not exceed 5 mg/kg of the product (by wet weight). Since oral tobacco contains tobacco, nitrosamines may be generated during processing. Studies indicate that some commercially available products contain relatively high levels of N-nitrosonornicotine (NNN, ranging from 500 to 600 ng/g) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, ranging from 150 to 200 ng/g), the FDA has set a limit standard for NNN in traditional oral tobacco is 1.0 μg/g (1 ppm). Trace amounts of N-nitrosoanatabine (NAT) and N-nitrosoanabasine (NAB) may also be detected, typically at concentrations below 5 ng/pouch [Hecht and Hatsukami, 2022; Lawler et al., 2020]. (2) Volatile carbonyl compounds: These may be produced during tobacco fermentation and remain as residues in oral tobacco. Testing results show that formaldehyde levels in traditional oral tobacco are approximately 1–3 ng/g, acetaldehyde levels range from 5 to 10 ng/g, and other aldehydes such as acrolein and crotonaldehyde are typically below 0.05 ng/g-significantly lower than in traditional cigarettes [Edwards et al., 2022]. (3) Heavy metals: In accordance with relevant regulation, the content of Cadmium≤0.5 mg/kg, Lead≤1.0 mg/kg, Arsenic≤0.25 mg/kg, Nickel≤2.25 mg/kg in traditional oral tobacco. The presence of heavy metals in oral tobacco is associated with soil absorption during tobacco cultivation or processing contamination. Testing reveals cadmium levels around 285 ng/g, lead levels approximately 1500 ng/g, arsenic levels below 20 ng/g, and nickel levels around 1400 ng/g. These findings suggest that heavy metal content should be a key focus in the safety risk evaluation of oral tobacco [Shafiq et al., 2024]. (4) Mycotoxins: Oral tobacco may become moldy during transportation or storage, potentially producing aflatoxins and ochratoxins. Under normal conditions, the levels of aflatoxins and ochratoxins in oral tobacco are below 0.01 ng/g [Back et al., 2023]. In addition to the above harmful substances, oral tobacco may also contain nitrosation byproducts such as N-nitrosodimethylamine (NDMA, <0.2 ng/mg) and polycyclic aromatic hydrocarbons (generally absent). Furthermore, the content of additives such as flavoring agents, moisturizers, and formulators has not yet been systematically reported. This is also a key area of focus for future studies. In summary, the levels of harmful substances in oral tobacco are closely related to raw material selection, processing methods, and storage conditions. These findings provide important data to support regulatory oversight of oral tobacco products.

5.1.2. Animal and cell studies for evaluating the safety risks of traditional oral tobacco

Existing research reports indicate that the effects of traditional oral tobacco on various physiological systems can be categorized into animal studies and human studies. In animal and cell studies, common modeling methods involve dissolving oral tobacco samples in ultrapure water or DMSO to obtain corresponding extracts, which are then administered to cultured cells or rats via gavage, followed by sample collection and analysis. However, this modeling method cannot fully reflect the real usage scenarios, such as the absence of physiological processes like chewing and saliva release. Moreover, there is still some residue of the contents in the oral nicotine products that has not been used after the usage. Therefore, these aspects need to be taken into consideration in subsequent studies. According to the literature, oral tobacco exhibits significant effects on the cardiovascular and digestive systems. Cardiovascular system: Hardip Sandhu et al. isolated rat cerebral artery segments and cultured the tissues in vitro for 24 h. The researchers added 1 μL of oral tobacco extract to 1 mL of organoid culture medium and incubated for 24 h before analysis. The results demonstrated that oral tobacco primarily targets vasoconstrictive G protein-coupled receptors (GPCRs), subsequently activating mitogen-activated protein kinase (MAPK). The GPCR/MAPK signaling pathway mediates imbalances in vascular smooth muscle contraction, proliferation, and apoptosis, which are the key mechanisms underlying the development of cerebrovascular and cardiovascular diseases [Sandhu et al., 2011]. Digestive system: Studies have shown that exposure to oral tobacco can increase the expression of nicotine acetylcholine receptors (nAChRs) in oral mucosal cells by 1.5 to 2.5 times. Additionally, abnormal expression of cell proliferation markers and cell cycle proteins-such as Ki67, PCNA, p21, cyclin D1, and p53-has been observed. These findings suggest that nicotine in oral tobacco may act on nAChRs in oral mucosal cells, leading to aberrant cell proliferation [Arredondo et al., 2001]. The above conclusion is consistent with consumer perception. Most consumers perceive a burning sensation on the oral mucosa when using oral nicotine products. Therefore, the evaluation of the oral safety risk of oral nicotine products should be further investigated. Furthermore, in the basal cells of the forestomach, oral tobacco can activate proliferation and inhibit apoptosis through the PI3K/Akt/NF-κB signaling axis. Mabrouk et al. administered 1 mL of oral tobacco extract (8 mg/200 g body weight) to male and female rats via gavage for three months. Histopathological examination revealed that unexposed rats exhibited intact liver structure with no significant pathological changes, whereas exposed rats displayed infiltrating cell aggregation, venous congestion, hemorrhage, and edema, indicating liver injury [Abo-Zaid et al., 2025].

Beyond its effects on cellular proliferation and apoptosis, traditional oral tobacco can also impair organ function through oxidative activation/reductive inhibition mechanisms. In a study by Jonah Sydney Aprioku et al., using both adolescent and adult male rats as subjects, researchers found that oral tobacco contents significantly increased malondialdehyde (MDA) levels while decreasing glutathione (GSH) and superoxide dismutase (SOD) activity in testicular tissue, demonstrating oxidative activation coupled with reductive inhibition. Notably, the exposed adolescent rats showed approximately 90% reduction in both sperm motility and count, while adult rats exhibited 86.4% decrease in sperm motility and 47% reduction in sperm count. Interestingly, nicotine administration alone did not produce significant changes in male fertility parameters [Aprioku and Ugwu, 2015]. These findings suggest that oral tobacco (rather than nicotine alone) may impair male reproductive function through oxidative stress activation, though the specific causative agents require further investigation. Additional systematic research revealed that after two weeks of administration with low-dose (96 mg/kg/day) and high-dose (960 mg/kg/day) oral tobacco extracts (The above-mentioned exposure doses can basically cover the levels of daily use of oral nicotine products by humans, and can effectively infer the negative effects resulting from low-frequency and high-frequency use of oral nicotine products), rats displayed significantly reduced GSH content and glutathione peroxidase (GSH-Px) expression in liver, lung, and kidney tissues, accompanied by markedly increased lipid peroxide levels-indicating substantial impairment of antioxidant defense systems [Yu et al., 2019]. Collectively, these animal and cellular studies demonstrate that traditional oral tobacco primarily induces organ morphological changes and functional abnormalities through two key mechanisms: disrupting cellular proliferation/apoptosis balance in various organs, and compromising their antioxidant defense capabilities. However, a clearer distinction between effects attributable to nicotine versus non-nicotine constituents should be explained in the future.

5.1.3. Cohort study for evaluating the safety risks of traditional oral tobacco

At present, traditional oral tobacco, also known as mainly refer to the unique moist snuff developed and derived in Sweden, its safety has drawn widespread attention from consumers. This usage pattern of moist snuff is more suitable for the cold climate in Northern Europe (no need to light them). For hundreds of years, the consumption of chewing tobacco in Northern Europe has been closely associated with class symbols, religious requirements, etc. Therefore, it has gradually become the main traditional way of using tobacco in regions such as Sweden and Norway. As a result, population cohort studies evaluating the safety risk of chewing tobacco have also focused on Northern Europe. Based on a series of research reports, population cohort studies evaluating the safety risk of moist snuff mainly focus on diseases of the digestive system (such as the mouth and stomach), cardiovascular system (such as blood vessels and heart), nervous system (such as Parkinson's disease), respiratory system, etc., as well as the impact of oral nicotine products exposure during pregnancy on the development of offspring. Table 2 summarizes the relevant population cohort studies on the safety risk of moist snuff. Including the research subjects, sample size, research conclusions and other contents.

Table 2.

Population cohort study on the safety of moist snuff.

Research subjects	Sample size/type	Research conclusions	References
Type 2 diabetes	Prospective cohort study: A total of 36,742 population samples from Sweden from 2009 to 2017 were selected, with an age range of 56 to 95 years old	The use of moist snuff is associated with an increased risk of type 2 diabetes, but the correlation is not significant. Compounds other than nicotine may be the material basis for the risk of type 2 diabetes caused by smoking (inconclusive)	[Titova et al., 2023]
Parkinson's disease	Prospective cohort study: Data from seven prospective cohort studies were collected, involving 348,601 men, and 1199 new cases of Parkinson's disease were identified	Men using moist snuff frequently exhibit a roughly 60% reduced Parkinson's disease risk relative to non-users (approximately 1% - 2%), showing a negative association with the disorder. (small decreased risk)	[Yang et al., 2017]
Stroke	Prospective cohort study: Eight Swedish prospective cohort studies were collected, involving 130,485 men who had never smoked	There is no significant association between the use of moist snuff and the overall risk of stroke or the risk of any subtype of stroke (no significant association)	[Hansson et al., 2014]
Oral cancer	Prospective cohort study: It contains information on smoking and cigarette use among 279,897 Swedish male construction workers from 1978 to 1992	using moist snuff has no obvious association with oral cancer or lung cancer, but is associated with an increased risk of pancreatic cancer (small increased risk)	[Rodu, 2007]
Periodontitis	Prospective cohort study: A total of 546 population studies were selected, and after qualification screening and conditional exclusion, 36 studies were included in the qualitative analysis	Using moist snuff can increase the risk of periodontal pocket depth exceeding 4 mm, gum recession and loss of attachments, and lead to poorer dental health (small increased risk)	[Solberg et al., 2025]
Respiratory system	Prospective cohort study: Swedish individuals aged between 16 and 75 were included There were 26,697 participants	Using moist snuff is associated with a higher prevalence of asthma, respiratory symptoms and snoring (small increased risk)	[Choudhary and Qudeer, 2019]
Diseases during pregnancy	Case control study: A total of 392 studies were included. After screening and elimination, 12 studies were selected for analysis	Using moist snuff during pregnancy is associated with preterm birth, stillbirth and small for gestational age infants. The incidence rate is 3.4% in the early stage exposure and 2.1% in the late stage exposure of pregnancy (small increased risk)	[Kreyberg et al., 2019]
Gastroesophageal reflux	Prospective cohort study: Based on the HUNT3 Health Study of residents in Norway from 2006 to 2009. The association between gastroesophageal reflux and moist snuff was evaluated.	Using moist snuff may increase the incidence of gastroesophageal reflux, and the incidence rate is also higher than that when traditional cigarettes are used (small increased risk)	[Lie et al., 2017]
Cardiovascular diseases	Prospective cohort study: Data from a cohort of 41,162 Swedish adults, aged 56 to 94, were used	After adjusting the habit of using tobacco products, using moist snuff was not associated with mortality from heart and valve diseases, abdominal aortic aneurysms or cardiovascular diseases. However, compared with non-smokers, the risk of stroke increases (inconclusive)	[Yuan et al., 2022]

Based on the above population studies, it can be observed that most of the research has focused on the Nordic region (such as Sweden, Norway, etc.), while there is relatively less research in other regions (such as Asia, etc.). This might be related to the fact that the traditional oral tobacco originated in the Nordic region, which was initiated by the royal family, initially as a symbol of status, and gradually became a national habit in Swedish daily life. Additionally, the Swedish government also provided support in terms of taxation, such as significantly reducing the tax rate of traditional snuff and increasing the tax rate of cigarettes, making consumers more inclined to prefer traditional oral tobacco [Sohlberg and Wennberg, 2020]. Therefore, the related research is relatively systematic. However, traditional oral tobacco has not yet been widely adopted in countries such as Asia and America (this is significantly associated with the nicotine tolerance and consumption habits of Asians). Thus, some conclusions from the population studies show regional differences (such as “using moist snuff has no obvious association with oral cancer or lung cancer, stroke”). Moreover, Sweden has set an upper limit of 20 mg per bag for the nicotine content of traditional oral tobacco, mainly to avoid health concerns due to abuse. However, there is a lack of cohort studies comparing the health effects of different strong types of traditional oral tobacco. Currently, there are no systematic reports on the health impacts of traditional oral tobacco on consumers of different age groups and genders. Considering that traditional oral tobacco is still favored by consumers in the Nordic region, it is urgent to conduct systematic research on these factors in the future.

5.2. Safety risks of nicotine pouches

5.2.1. Analysis of harmful components in nicotine pouches

Currently, commercially available nicotine pouches are primarily composed of nicotine salts, fillers, and additives (including flavors, pH adjusters, stabilizers, and sweeteners), The current content of these additives has not been systematically reported, and it is a crucial factor that cannot be ignored. Compared to traditional oral tobacco products, the main components of nicotine pouches differ significantly. Based on relevant literature, the harmful components in nicotine pouches mainly originate from their formulation and can be categorized as follows, the regulatory safety threshold for harmful components is basically the same as that of traditional oral tobacco: (1) Nicotine salts: Market research data indicate that the nicotine content of commercially available nicotine pouches typically ranges from 3 to 10 mg/pouch, with some products reaching 15–20 mg/pouch [Stepanov et al., 2012]. The World Health Organization (WHO) recommends that adults should not consume more than 1 mg of nicotine per kilogram of body weight per day, while the U.S. Food and Drug Administration (FDA) suggests an acceptable daily intake of 0.5 mg/kg. Additionally, given the method of use, nicotine in the pouches is highly likely to dissolve in saliva and be easily swallowed, thereby irritating the digestive tract and stomach, leading to physical discomfort. Therefore, strict control of nicotine content in pouches and daily usage is crucial. (2) Nitrosamines: Compared to traditional oral tobacco products, nicotine pouches contain significantly lower levels of nitrosamines because they do not use tobacco leaves as raw material. Testing results also show that the content of major nitrosamines, such as N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in nicotine pouches is below 10 ng/g [Mallock et al., 2024]. (3) Additives: Additives in nicotine pouches account for approximately 5%–15% of the composition. For example, pH adjusters (e.g., sodium carbonate, sodium bicarbonate) typically maintain the pH of nicotine pouches at around 8.5, making them alkaline. In contrast, the normal oral environment has a neutral pH of 6.5–7.0. The alkaline nature of nicotine pouches can disrupt oral homeostasis, leading to conditions such as dental calculus and periodontitis. Furthermore, the various flavors and sweeteners in nicotine pouches, though present in small quantities (usually <6%), lack sufficient safety risk evaluation studies. (4) Others: Nicotine pouches may also contain trace amounts of heavy metals such as cadmium and nickel, but their levels are generally below 10 ng/g. Similarly, carbonyl compounds like formaldehyde and acetaldehyde are present at concentrations of less than 1 ng/g, representing a significant reduction compared to traditional oral tobacco products.

5.2.2. Animal and cell studies for evaluating the safety risks of nicotine pouches

In addition, research on the co-exposure of nicotine pouches with other tobacco constituents is also a key focus. For example, nitrosamines are a class of carcinogens found in traditional cigarettes. In studies using hamsters as subjects, when nicotine (6%) or N-nitrosonornicotine (NNN, 0.01%) was applied separately to the cheek pouches, histopathological changes-including moderate hyperplasia and hyperkeratosis were observed in the cheek pouches and forestomach [East et al., 2021], though the degree of damage was relatively mild. However, when co-treated with nicotine (6%) and NNN (0.01%), squamous cell papillomas were clearly observed, and the frequency of forestomach hyperplasia with hyperkeratosis was higher than with NNN or nicotine exposure alone. These findings indirectly suggest that if nicotine pouches are used concurrently with traditional cigarettes, they may exacerbate the carcinogenic effects of nitrosamines in cigarette smoke. This provides valuable data to support the rational use of tobacco products by consumers [Chen et al., 1994]. Furthermore, evidence suggests that male and female mice exhibit sex-specific differences in their responses to nicotine pouches. Ann Marie Centner et al. investigated the effects of tobacco product exposure (including nicotine pouches) on vascular endothelium, plaque formation, and inflammatory responses in male and female mice [Centner et al., 2025]. The results showed that tobacco products upregulated levels of total cholesterol (THC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in male mice, whereas in female mice, only LDL and IL1A levels were elevated. Additionally, male mice exhibited more severe vascular endothelial damage, while female mice showed an increased number of vascular plaques. These pathological changes may be associated with elevated senescence-associated GLB1/β-galactosidase (SA-GLB1) and interleukin 17 A (IL17A). Thus, ae shown in Fig. 3, the toxic effects of nicotine pouches are multifaceted, depending not only on their own constituents but also on co-exposed substances, different signaling pathways are involved in this process. However, there is limited research on the effects of nicotine pouch constituents on reproductive function, endocrine function, and cardiovascular function at the cellular and animal levels, necessitating further systematic exploration.

Fig. 3.

Effects of nicotine pouches exposure on cells and their mechanisms.

5.2.3. Cohort study for evaluating the safety risks of nicotine pouches

The growing popularity of nicotine pouches has prompted extensive research into their safety in human populations. The nicotine in these pouches comes from two primary sources: synthetic nicotine (often referred to as tobacco-free nicotine pouches, TFN) and tobacco-derived nicotine (TDN). In 2023, Meghan E. Morean et al. conducted an online Qualtrics survey involving 630 young adults (aged 18–25), assessing risk perceptions, usage frequency, and other factors related to TFN and TDN pouches. The results showed that participants generally perceived TFN as safer than TDN and used it more frequently. Moreover, this risk perception was significantly correlated with usage frequency but showed no clear association with flavor or smoothness of the pouches, suggesting that consumers prioritize safety when choosing nicotine pouches. To further validate these findings, the same research team surveyed 609 young adults later that year. The participants were categorized into three groups: non-susceptible to nicotine pouches (66.2%), susceptible to nicotine pouches (23.5%), or past users of nicotine pouches (10.3%). Logistic regression analysis revealed that participants with a history of nicotine pouch use were more likely to continue using them compared to non-susceptible or susceptible individuals. Additionally, awareness and risk perception of nicotine pouches were significantly correlated with their usage. This cohort study further supported the earlier conclusions [Morean et al., 2023a, Morean et al., 2023b]. Taken together, these cohort studies indicate that safety risk concerns can partly influence consumer preferences regarding nicotine pouches. This underscores the need for regulatory agencies to pay closer attention to safety risk evaluations of these products.

Furthermore, comprehensive cohort studies have reported that the use of nicotine pouches can lead to an increase in heart rate, exhibiting a certain dose-dependent relationship, the increased heart rate will increase the burden on the heart, raise the oxygen consumption of the myocardium, damage the inner walls of blood vessels, accelerate arteriosclerosis, and thereby increase the incidence of various cardiovascular diseases. As the oral cavity serves as the primary site of nicotine pouch use, substances such as nicotine and pH adjusters in the pouches can negatively impact oral mucosal cells, potentially inducing periodontal disease and related conditions. Sintija Miluna et al. conducted oral mucosal examinations on 76 participants and categorized them into four groups—nicotine pouch users, e-cigarette users, traditional cigarette smokers, and a control group-based on questionnaire responses. Saliva samples were collected to analyze relevant biomarkers. The results revealed varying degrees of white granular lesions and hyperplastic changes in the oral mucosa (specifically in the area where the nicotine pouch was placed) among nicotine pouch users, with the severity positively correlated with the duration and frequency of use. Analysis of inflammatory markers in saliva showed no significant association between mucosal changes and levels of interleukin-1 (IL-1), IL-8, tumor necrosis factor-α (TNF-α), or leucine-rich alpha-2-glycoprotein- (1LRG1) (P > 0.05). However, IL-6 levels exhibited a statistically significant correlation with oral mucosal changes (P < 0.05). Additionally, elevated levels of these inflammatory factors in saliva were significantly linked to nicotine pouch use (P < 0.05). These findings suggest that nicotine pouch use may exacerbate inflammatory responses in the oral cavity, further contributing to mucosal lesions [Kent et al., 2025]. Moreover, when peripheral blood mononuclear cells (PBMCs) from volunteers were exposed to an extract of nicotine pouch contents (0.025 g/mL), a significant increase in pro-inflammatory cytokines—including IL-1β, IL-6, IL-18, TNF-α, and MIP-1α—was observed in the supernatant culture medium [Travis et al., 2025].

This review summarizes relevant cohort studies on the safety risk evaluation of nicotine pouches (Table 3), with research primarily focused on the oral cavity and cardiovascular system. Considering the composition of nicotine pouches-including nicotine salts, microcrystalline cellulose, and various additives-previous studies have demonstrated that nicotine exhibits multi-organ toxic effects (e.g., on hepatic glucose and lipid metabolism, gonadal reproductive function, adrenal steroid hormone synthesis, and renal glomerular filtration). However, there is limited evidence regarding the health impacts of additives such as microcrystalline cellulose, flavorings, and fragrances, particularly concerning their concentrations and dosage levels. Therefore, future human studies on the safety risk evaluation of nicotine pouches should expand their scope to more systematically elucidate the health effects on consumers. Additionally, close attention should be paid to the potential adverse effects of the concentration and content of each component in nicotine pouches. On one hand, this will provide manufacturers with safer formulation recommendations; on the other hand, it will assist regulatory agencies in establishing more reasonable and effective safety risk evaluation standards for nicotine pouches.

Table 3.

Population cohort study on the safety of nicotine pouches.

Research subjects	Sample size	Research conclusions	References
Nicotine pouches consumption habits	Prospective cohort study: The consumption of nicotine pouches in Sweden and Denmark market was surveyed and statistically analyzed	The average daily consumption in Sweden and Denmark is 8.4 and 8 pouches respectively. The conclusion of the Dutch survey is that 42% of users consume less than 5 pouches per day, and 8.3% more than 20 pouches per day (inconclusive)	[Robichaud et al., 2020]
Nicotine release kinetics	Case control study: A total of 39 subjects were screened, among whom only 18 were included in the study	Compared with traditional cigarettes, the use of nicotine pouches can shorten the time for blood nicotine concentration to peak (small increased risk)	[Lunell et al., 2020]
Acute toxic effects of nicotine pouches	Case study (one person): A 21-year-old man took 15 nicotine pouches (10.9 mg per bag) within 12 h.	Acute poisoning reactions are manifested as elevated blood pressure and heart rate, rapid breathing, decreased body temperature, dilated pupils, and a significant increase in serum creatinine levels (small increased risk)	[Miluna et al., 2022]
Lesions of the oral mucosa	Prospective cohort study: A total of 60 participants were involved, including 21 females and 39 males, with an average age of 31	After long-term use of nicotine pouches, gum depression was observed, and oral white mucosal lesions were also observed (small increased risk)	[Alizadehgharib et al., 2022]
Nicotine pouches dependence	Case control study: A total of 39 participants quit smoking for 24 h before participating in the survey	The data from the fagstrom test for nicotine dependence and the syndrome scale indicated that flavored nicotine pouches were more attractive to the subjects (small increased risk)	[Rangel-Gomez et al., 2019]
Nicotine pouches additive	Cross-sectional study: The study covered 48 types of nicotine pouches and their contents available on the market	A total of 180 chemical substance components were detected, among which each pouch contained an average of 17 chemical components, with a maximum of 32 and a minimum of 2 (small increased risk)	[Mallock-Ohnesorg et al., 2023]
Cardiovascular effects of nicotine pouches	Prospective cohort study: Fifteen daily smokers were recruited and used nicotine pouches of different doses	It can be found that after using nicotine pouches, the heart rate of smokers increases in a dose-dependent manner (about 15–30 beats per minute), and the atherosclerotic parameters also increase (small increased risk)	[Mallock-Ohnesorg et al., 2024]
Lipid effect of nicotine pouches	Prospective cohort study: Twenty-five nicotine pouches users and non-nicotine pouches users were included	The levels of blood cholesterol and triglycerides in users of nicotine pouches are significantly elevated, while the level of high-density lipoprotein is significantly decreased (small increased risk)	[Rao and Subash, 2013]
Weight effect of nicotine pouches	Prospective cohort study: A total of 72 female smokers were included, among whom 17 had quit smoking	After quitting smoking, the weight gain of women is more significant than that of men (4 kg within 2 weeks), and it is related to the changes in the levels of IGF1, leptin, etc. in the blood (no significant association)	[Moffatt et al., 2000]
Glycemic effect of nicotine pouches	Prospective cohort study: Seven male and seven female subjects were recruited and used nicotine pouches and wine simultaneously	It can be found that the HPA axis of the subjects is activated, the GC level in the blood is elevated, and the blood glucose is somewhat reduced (no significant association)	[Ismail et al., 2022]

5.3. Safety risks of other oral nicotine products

In addition to traditional oral tobacco and novel nicotine pouches, oral nicotine products also include nicotine gum, nicotine lozenges, and nicotine oral films. These products were primarily developed as smoke-free tobacco alternatives to cigarettes and are considered an effective harm reduction strategy. They also serve as “NRT” to aid smoking cessation. Michael Kotlyar et al. investigated the pharmacokinetics of such nicotine lozenges and compared them with nicotine pouches (both containing 4 mg nicotine) [Kotlyar et al., 2007]. The study enrolled 10 participants who were randomly assigned to use the products in a controlled setting for 30 min per session, totaling five sessions. Blood nicotine levels and withdrawal symptoms were analyzed. The results showed that nicotine pouches and lozenges produced similar peak plasma nicotine concentrations (approximately 8.5 ng/mL), whereas nicotine gum yielded a significantly lower peak concentration (∼4.4 ng/mL). All three products exhibited comparable plasma nicotine half-lives, ranging from 2.7 to 3 h. Further safety risk assessments revealed that participants experienced adverse effects such as nausea, dizziness, and throat irritation with all three products, with potential long-term negative impacts on oral mucosa and the gastrointestinal system [Azzopardi et al., 2022]. Another study examined cardiovascular risk parameters in volunteers using nicotine lozenges versus a placebo. Compared to the placebo, nicotine lozenge use led to: Increased systolic and diastolic blood pressure (123 ± 2 vs. 118 ± 3 mmHg; 63 ± 1 vs. 69 ± 2 mmHg); Elevated mean arterial pressure (82 ± 2 vs. 87 ± 1 mmHg); Higher heart rate (64 ± 2 vs. 71 ± 3 bpm); Increased blood oxygen saturation (97.1 ± 0.3% vs. 98.2 ± 0.3%); Significant rise in muscle sympathetic nerve activity (MSNA) (28 ± 3 vs. 32 ± 3 bursts/min) [Najem et al., 2006]. These findings collectively indicate that NRT products such as nicotine lozenges and oral films can activate peripheral sympathetic nerve activity, potentially increasing cardiovascular risk.

6. Conclusions and prospects

The original purpose of oral nicotine products was to help tobacco users quit smoking. However, driven by increasing global health awareness, regulatory restrictions on traditional cigarette consumption, and the diversified flavors and convenience of oral nicotine products, these novel tobacco products have gained widespread popularity in international markets. They are increasingly favored by consumers, with their sales share among tobacco products rising annually, which also brings potential health risks. Currently, the number of teenagers using oral nicotine products has doubled between 2023 and 2024. Different flavored products continue to attract teenagers, which has a negative impact on brain development. At the same time, for those who have not completely quit traditional cigarettes, the dual exposure effect of occasionally using oral nicotine products seems to potentially induce higher cardiovascular risks. Additionally, nicotine is known to affect insulin sensitivity and the reproductive system (such as placental blood flow). Given the high absorption efficiency of these products, it is necessary to assess the long-term effects on diabetes risk and pregnancy outcomes (such as low birth weight), all of which require attention. In summary, various products can be classified as extremely high risk (traditional cigarettes), high risk (dual exposure), medium risk (high-dose oral nicotine products), and low to medium risk (low-dose oral nicotine products). Systematically understanding different types of tobacco products can help provide guidance and recommendations for consumer health.

As Fig. 4 shows, this review systematically summarizes the fundamental characteristics and usage patterns of various oral nicotine products. Based on existing literature, it analyzes the pharmacokinetics (including peak blood nicotine concentration, half-life, and time to peak concentration) following the use of these products. Furthermore, it examines potentially harmful substances in the formulations of different oral nicotine products and preliminarily elucidates their negative effects on the oral cavity and cardiovascular system, along with the underlying mechanisms, through animal and cellular studies. Additionally, it consolidates human studies to confirm the adverse health impacts of oral nicotine product usage. Current safety risk evaluations of oral nicotine products remain insufficient in several aspects: (1) Multi-organ and multi-system risk assessment: Comprehensive studies should be conducted using various cell lines or organoids to evaluate the effects of oral nicotine products on glucose and lipid metabolism, sexual function, endocrine function, and other systemic impacts. Multi-omics technologies should be employed to explore the associated mechanisms. (2) Inadequate research on product formulations: These products contain additives such as flavorings, humectants, and preservatives. The potential health effects of their concentrations and dosage levels remain unclear, and optimal additive thresholds have yet to be determined. (3) Lack of safety risk evaluations for combined use with other tobacco products: Since oral nicotine products are designed for smoking cessation, some consumers may use them alongside traditional cigarettes, leading to dual or multiple exposures. The health implications of such combined usage patterns remain unreported. In summary, this review outlines the current status and future directions for the safety risk evaluation of oral nicotine products. On one hand, it helps consumers systematically understand the health risks of these products and promotes rational usage. On the other hand, it provides regulatory agencies with insights to implement more effective and reasonable controls on the sale of oral nicotine products.

Fig. 4.

Conclusions and prospects. This figure summarizes the classification, influencing factors of consumption, dynamic characteristics, target sites and remaining questions concerning oral nicotine products, helping readers better understand such products.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.