Sweeteners in E-Cigarettes: A Minireview of Flavoring and Biological Action

Abstract

The use of sweeteners in e-cigarette liquids has become increasingly common, aiming to enhance the sensory appeal of vaping products. Compounds like aspartame, saccharin, and sucralose are added to provide a sweet taste without any calories, especially in flavored e-liquids popular among younger users. However, recent studies suggest that these additives may pose significant health risks when vaporized and inhaled. Sucralose, in particular, can break down into potentially harmful chlorinated by-products at high temperatures typical of vaping devices. Moreover, there is growing concern about the synergistic effects of sweeteners like sucralose, one sweetener with another and when combined with other e-liquid components. It has been observed that the presence of sucralose may amplify oxidative stress; genotoxicity, including mutations; and overall toxicity, along with environmental impact. This is not limited to nicotine- and smoke-related harm, as it may strengthen the toxic effect of the substances used in e-liquids that are not present in traditional cigarettes. The combined exposure to these heated compounds can intensify cytotoxicity, potentially increasing the risk of respiratory, cardiovascular, and neurological effects over time. While marketed as safer alternatives to tobacco, e-cigarettes containing sweeteners like sucralose may introduce new and poorly understood toxicological hazards that deserve urgent regulatory attention.

1. Introduction

The global rise in electronic cigarette use has reached alarming proportions, becoming what many public health experts now call a silent pandemic [1]. E-cigarettes have quickly become highly popular among both older and younger people [2,3] including teenagers, and this popularity has been based on a contradictory statement that they are an allegedly safe alternative to common cigarettes. This statement, accepted without full awareness of the risks e-cigarette components may pose [4,5], is at least partially wrong.

Smoking among teenagers had already been a problem during both the XX and XXI centuries [6,7,8]. Nevertheless, this problem persists, as students in the early years of secondary school are now among the frequent users of vaping devices [9,10], which indicates the decreasing age of smoking initiation in the ages of Z and alpha, and this is probably the most troubling factor of vaping use. This trend raises serious concerns given the vulnerability of adolescent neurological development and behavior transformation, leading to a high potential for long-term addiction and harm [11,12].

One of the main factors contributing to the popularity of e-cigarettes among youth is the wide variety of sweet, fruity, and candy-like smells and flavors, aimed to hide the bitter taste of nicotine and other smoking product flavors, while they face the conversation with parents and authority [13,14]. These are often made palatable and appealing through the addition of high-intensity sweeteners, including either natural (erythritol, perillartine, stevia, or neohesperidin) or synthetic (sucralose, saccharin, aspartame, neotame, advantame, and acesulfame potassium) sweeteners, creating the illusion of a somehow smoother and more attractive inhalation experience (Figure 1) [15,16]. Natural sweeteners based on polyphenolic and some terpenoid compounds may act as antioxidant and anti-inflammatory agents due to their chemical structure, providing, directly or indirectly, the chain termination of the radical process; other natural and synthetic sweeteners are much less biocompatible and toxic. Moreover, their interaction leads to a much more negative synergetic effect, which is still pending a thorough investigation [17,18,19,20].

The work [18], for example, mentions the toxic effect of different sweeteners, which may be manifested more expressively when the e-liquid is inhaled, as shown in [19,20].

While many of these sweeteners are approved for oral consumption at normal temperatures, their safety profile changes drastically when heated and inhaled [18,21,22] due to metabolic differences in digestive and respiratory systems. Unlike oral intake, inhalation can deliver these substances and/or their thermal degradation products, formed in the e-liquid or its aerosol, directly into the lungs, bypassing digestive metabolism and exposing delicate epithelial tissues to chemical degradation products [23,24]. Moreover, these compounds tend to provoke oxidative stress in epithelial cells, leading to direct [25,26] and indirect cytotoxic and genotoxic effects [27,28], which are still a lacuna to be fulfilled.

Among the most widely used sweeteners, sucralose, a chlorinated galactosucrose derivative, deserves special attention [29,30], being a chloroorganic compound, parent [31,32] to those already found in cigarette smoke [33,34]. Firstly, sucralose samples present in vapes may contain its industrial precursor, 6-acetylsucralose, which has proven to be genotoxic [35,36]. Moreover, when heated to the temperatures typical of vaping devices, sucralose can decompose into chlorinated compounds, including chloropropanols, dioxins, polychloroarenes, and 6-desoxychlorofrutctose, which may be even more harmful than the proper chloroorganic sweetener. Moreover, the enhanced use of these compounds in vapes may lead to environmental stress [37,38]. The review article [35] lists the effects of the environmental, oxidative, and genomic stress sucralose may pose. Aspartame, advantame, and neotame derivatives are also toxic at high temperatures, as they may yield methanol during their decomposition and hydrolysis [39,40,41,42]. The same concerns are also referent to saccharin. For this reason, the sweeteners’ biological behavior in e-cigarettes deserves special attention.

Moreover, unlike conventional cigarettes, which contain a relatively fixed mixture of tobacco-related compounds (which inclusively makes them more fool-proof than vapes), e-liquids are chemically diverse and often include non-typical substances absent from combustible tobacco [43,44,45]. Also, the proper nicotine derivatives and other N. tabacum and N. rustica alkaloids may be present in them in more water-soluble and, as a result, more biocompatible salt form, acting directly on brain nicotine receptors (Figure 2), provoking dopamine secretion and brain stimulation, leading an addicted user to continue smoking for hours.

The heating and aerosolization of these complex mixtures may produce unknown or poorly studied by-products [46,47], posing significant toxicological risks when inhaled chronically.

The detailed information concerning the chemical composition of e-cigarette liquids may be consulted in Appendix A of the present article and the references therein.

Despite growing evidence, regulation of sweeteners in e-cigarette products remains lax or entirely absent in many jurisdictions [48,49]. Even EFSA and US FDA regulate the sweeteners’ presence mostly in food but not in electronic liquids and vaping devices, which indicates the overall or nearly overall lack of attention to the problem. Manufacturers are often not required to disclose the full list of ingredients, which makes it difficult to determine the role of e-liquid component interactions in the general health of smokers and the environment around them. For this and other reasons, the long-term health effects of inhaling sweetened aerosols are still not well understood [50].

In this context, the present study aims to critically examine the role of sweeteners—particularly sucralose—in the formulation of e-liquids, their biological action in human and other organisms, and also their environmental fate. It explores the mechanisms of thermal degradation, potential for synergistic toxicity caused by the interaction between two sweeteners or between the sweeteners and the main e-liquid components, and the broader implications of chronic exposure to sweetened aerosols in the respiratory system.

2. Materials and Methods

Articles for this review were selected using a structured and transparent methodology. A comprehensive literature search was conducted across major scientific databases, including Web of Science, Scopus, and PubMed, using targeted keywords related to the use of sweeteners in e-liquids, their oral intake and inhalation metabolisms, environmental fate, ecotoxicity, genotoxicity, oxidative stress, and recycling.

Inclusion criteria focused on the relevance to the review topic, methodological rigor, and publication in peer-reviewed journals. To ensure a thorough and up-to-date overview of the field, additional references were identified through citation tracking. Following the initial screening of titles and abstracts, full-text articles were evaluated to confirm their relevance and quality. Non-peer-reviewed manuscripts, including preprints and short conference papers, were excluded until the peer-review, necessary to assure research quality, is finished.

This systematic approach ensured the inclusion of high-quality studies published during the last 20 years, providing valuable insights into the current advances and ongoing challenges in the use, flavoring, and biological activity of sweeteners in e-cigarettes.

3. E-Cigarette Sweetening Overview

Both natural and synthetic sweeteners may be used to sweeten e-cigarette liquid and aerosol. Nevertheless, little to no investigation of their influence in electronic cigarette general safety, general toxicity, and ecological impact has been carried out.

3.1. Natural Sweeteners

Natural sweeteners added to e-cigarettes are generally those based on monosaccharides and include erythritol, neohesperidine, xylitol, and sorbitol, among other substances [51,52,53,54,55,56,57,58,59,60]. Although they are generally considered safer than the synthetic sweeteners, described in Section 3.2, their presence in electronic cigarettes, where they are inhaled nasally or orally in the presence of non-nutrient substances and not taken by mouth, alters their metabolic path (inclusively by the indigenous microbiome), which is why the investigation of their metabolic and environmental fate becomes of high importance.

The work [51] describes the impact of e-cigarette aerosol on the indigenous oral microbiome. Both natural and synthetic components possess cytotoxic effects on either epithelial cells or both indigenous and exogenous microbiota, leading to periodontal diseases. Moreover, the aerosol metabolism by-products strongly depend on bacterial community composition and include ethyl-4-acethylthiobutyrate, which is a frequent erythritol metabolite. Also, a quorum-sensing regulated gene expression in oral biofilms has been confirmed.

In [52], e-cigarettes containing the natural sweetener xylitol and synthetic sweetener sucralose, alongside their metabolites in aerosol, were analyzed by GC–MS. The e-cigarettes of the Velo brand, commercialized in Pakistan, were found to possess significant concentrations of xylitol, up to 16 mg/pouch, which were higher than those of some standard flavoring compounds, making it the expressive feature of the Velo brand. Moreover, in some cases, the sweetener declared concentration did not correspond to the real one, which might lead to a misinterpretation of the security perception of the vaping liquids.

The work [53] mentions the natural sweetener perillartine, used mostly in Japan as a component of Puff Bar Grape e-cigarette aerosol, which is similar to ethyl maltol. Both of them were used as taste correctors and may augment the nicotine biological action in the organism. The authors alert US federal regulators to impose the restrictions regarding classical cigarettes to e-cigarettes in order to prevent the legislative lacuna.

The work [54] mentions the simultaneous use of maltol, ethyl maltol, and ethyl acetate in e-cigarettes, aimed to hide not only the real flavor of nicotine and related compounds but also their smell. In this case, the natural sweeteners are used alongside the natural odorants, but the aldehydes, formed during their partial thermal decompositions, may be highly toxic.

The work [55] mentions the use of mogroside V from S. grosvenorii, a sweetener first used in Chinese cuisine and traditional medicine, in e-cigarettes as a flavoring agent. Mogroside V has shown a relatively safe behavior, so technically, this could be a viable alternative to the synthetic sweeteners mentioned in Section 3.2 for use in e-cigarettes, as it is thermally stable up to 150 °C, whereas sucralose decomposes at 120 °C. Nevertheless, the difference in the metabolism of oral and inhaled mogroside has to be taken into account.

The patent [56] mentions the sweetener for e-cigarette liquids based on the natural polyphenolic sweetener neohesperidine dihydrochalcone and the synthetic sweetener neotame. Nevertheless, the use of the natural sweeteners alongside the synthetic ones may alter the metabolism of both in the human organism and also provoke the synergic toxic effect between the two. Moreover, the oxidative stress provoked by neotame will concur with the antioxidant effect of the polyphenolic natural sweetener, and their efficiency will depend on the concentrations of both. The data of the permitted concentration range of both of the sweeteners are still pending a thorough investigation.

Common sweeteners, including glucose, sugar, fructose, and sorbitol, are rarely used in electronic cigarettes due to their dehydratation to furfural derivatives, which have already been detected in e-cigarette aerosol [57,58], and the influence of nicotine and other N. tabacum and N. rustica alkaloids on sugar consumption and insulin secretion, leading to the appearance of diabetes type 1 and 2 and amino acid metabolism deviation [59,60]. For this reason, they cannot be used as a safe flavoring component in e-cigarettes. General data of the use of natural sweeteners in electronic cigarettes are shown in

Table 1. Natural sweeteners in e-liquids and their biological actions.

Natural Sweetener	Nature of Substance	Objections	Nature of the Study	CAS Number:	Reference
Erythritol, xylitol	Carbohydrate-derived polyol	Cytotoxicity, Partial dehydratation, Metabolism, dependent on gut microbiota	In vivo, in vitro	149-32-6, 87-99-0	[51]
Xylitol (in the presence of synthetic sucralose)	Carbohydrate-derived polyol (involving carbohydrate-derived chlorohydrin)	Sweetener concentration, non-correspondent to the declared, possible metabolic synergetic effect between natural and artificial sweetener, sucralose, and xylitol dehydratation and its products	In vitro	87-99-0, 56038-13-2	[52]
Perillartine, ethylmaltol	Oxyme of an unsaturated aldehyde, in the presence of an ether	Sweetener, used mostly in Japan. Possible substitution of sucralose and other artificial sweeteners. Hydroxylamine formed during metabolism in some people. Dehydratation of ethylmaltol	In vitro	30950-27-7, 4940-11-8	[53]
Maltol, ethylmaltol, ethylacetate	Carbohydrate-derived polyol and its ether in the presence of a common ester	Decomposition, yielding toxic aldehydes	In vivo	4940-11-8, 118-71-8, 141-78-6	[54]
Mogroside V	A trisaccharide derivative of a terpenoid compound	Thermal stability. Possible substitute of sucralose. Objections about metabolism of inhaled form	In vitro	88901-36-4	[55]
Neohesperidine dihydrochalcone (in the presence of neotame)	Polyphenolic compound (an aromatic amino acid derivative being involved)	Synergetic toxic effect of inhaled form. Concurrence between the antioxidant action of neohesperidine and the oxidative stress of neotame	In vitro	13241-33-3, 165450-17-9	[56]
Glucose	Carbohydrate	Glucose intake and insulin secretion, affected by Nicotiana alkaloids. Dehydratation products involved	In vivo	50-99-7	[57]
Sugar	Carbohydrate	Glucose intake and insulin secretion, affected by Nicotiana alkaloids. Dehydratation products involved	In vivo	57-50-1	[58]
Fructose	Carbohydrate	Dehydratation products include furfural derivatives and aldehydes, which may be toxic when inhaled	In vivo	57-48-7	[59]
Sorbitol	Carbohydrate-derived polyol	Dehydratation leading to toxic compounds in aerosol	In vivo	50-70-4	[60]

.

So, natural sweeteners are already used in e-cigarettes as an alternative or additive to the artificial sugar substitutes, although their use is still less common. Nevertheless, there is a difference in the metabolic paths of these substances

-

When heated;

-

When inhaled vs. taken orally;

-

In the presence of other substances.

The main factors influencing the biological action of the sweetened e-liquids are the solution composition, temperature, puff duration, and thermal stability of the sweetener used (see Appendix A and Appendix B). The temperature in vape aerosol on its way to the user’s respiratory tract may be enhanced by up to 145–150 °C; most of the synthetic and natural sweeteners partly degrade at that temperature, along with some of the other e-liquid components.

Substituted furfural and other toxic or conditionally toxic aldehyde derivatives are formed during vaping following degradation. For this reason, the development of regulatory norms concerning the use of sweeteners in e-cigarettes is necessary to prevent possible intoxication and stress [47,48].

In this case, the most efficient alternatives to artificial sweeteners are perillartine and mogroside V. As vaping temperature may rise up to 150 °C, at which most of the natural and certain synthetic sweeteners are partially degraded, these compounds have thermal stability advantages. Mogroside remains stable up to 150 °C, and perillartine melts at 102 °C without decomposition and may withstand higher temperatures up to 180°. For this reason, these compounds may be efficiently used in electronic cigarettes, being an efficient substitution for natural and synthetic sweeteners.

The compressed safety data of the sweeteners used in e-liquids are given in Appendix B.

3.2. Artificial Sweeteners

Artificial sweeteners are more common in electronic cigarettes than natural ones due to the presence of solvents in which the synthetic sugar substitutes are more soluble. Moreover, these substances generally have an intensively sweet taste, which hides the nicotine and N. tabacum alkaloids flavor and smell; however, their adsorption is enhanced, and their metabolism is modified. The artificial sweeteners most used in electronic cigarettes are aspartame, saccharin, acesulfame K, neotame (see [56] and Appendix B), and especially sucralose [52,61,62,63,64,65,66,67,68,69,70,71,72,73,74]. Among the sweeteners, sucralose is the most used in e-cigarettes, which is the reason why its addition to vaping products is revised in a separate subsection.

3.2.1. Sucralose in E-Cigarettes

The reason why sucralose is the most frequently used in electronic cigarettes is its expressively sweet taste without a bitter aftertaste. This perception difference between sucralose and other synthetic sweeteners is explained by its carbohydrate nature, as it is in fact a trichlorogalactosucrose, industrially obtained from sucrose [35,62] (Figure 3).

Nevertheless, despite the expressively sweet taste of sucralose, its biological action in e-liquids, and also the toxin release promoted by it, makes its inhalation in vapes not so sweet. The oxidative stress following ROS formation, adduct formation, clastogenesis, direct and indirect DNA alteration, possible glycation, and environmental impact of sucralose have been reviewed in [35] and references therein. The present study complements the review with an emphasis on e-cigarettes.

Nevertheless, the main disadvantage of sucralose is its thermal instability in vaping conditions. At temperatures over 119 °C, it releases water, hydrogen chloride, and chloroorganic compounds, which are even more toxic than sucralose, broadening the gamma of negative activities of sucralose-based e-liquids.

A study by Schlapack, focused on e-liquids [63], examined the thermal degradation of sucralose when used as a sweetener in vaping products. The authors highlighted that several sucralose dehydration products are either carcinogenic or genotoxic. The inhalation route of exposure may present different biological impacts compared to ingestion, raising concerns about the potential synergistic genotoxic effect between sucralose and its degradation products. This negative biological activity is not the unique sucralose impact in electronic liquids.

Hu et al. [64] found that sucralose presence enhances the toxicity of benzo(a)pyrene, a component of either traditional cigarette smoke or e-cigarettes, in mice by inhibiting PGP-mediated efflux, leading to compound accumulation, increased ROS, and greater direct and indirect mutagenesis. Additionally, alterations in renal tissue structure were observed, leading to grave kidney failures.

Duell et al. [65] investigated the impact of sucralose and its degradation products on the stability and safety of glycerol- and propyleneglycol-based e-liquids by ¹H NMR spectroscopy, IC, and GC–MS. The presence of sucralose and its degradation products in heated vaping liquids led to enhanced dehydratation and oxidation of solvents, leading to the enhancement of the concentrations of aldehydes and hemiacetal, confirmed by NMR spectroscopy. The harmful chloroorganic compounds, especially chlorohydrins, have also been detected. This leads to the conclusion that the sucralose in e-liquids, while it degrades, enhances the solvents’ thermal dehydratation rate. This has also been observed by Kerber [66].

Rosbrock et al. [67] analyzed the relation between the nature of vaping devices used for e-cigarette smoking, sucralose concentration, and taste perception of the aerosol. Four commercial vaping liquids without and with sucralose (1% w/v) using a cartridge and tank were analyzed. Sweetness and flavor intensity were more strongly felt when the cartridge was used, and olfaction was permitted, which leads to the conclusion that, in the case of a cartridge used as an aerosol outlet, the sucralose concentration becomes higher in the aerosol.

Recent 2024-dated research by Yan [68] with coauthors investigates the impact of sucralose and neotame on the metal precipitation from e-liquids, resulting in direct and indirect cyto- and genotoxic action. The propyleneglycol-based electronic liquids with 2% (w/w) and 5% neotame or sucralose were investigated by a CCK-8 assay. It was shown that 5% sucralose provoked the most intensive transition metal precipitation from the e-liquid, especially nickel, whereas neotame did not show such an impact. This effect was explained by chloride-ion formation during sucralose degradation (by HCl elimination and its interaction with metal), followed by metal part corrosion, metal ion release, and metal deposition on the container surface. Cytotoxicity tests showed reduced viability of SH-SY-56 cells at nearly 65% and Beas-2B cells at nearly 63%. As a conclusion, neotame is suggested as a safer alternative to sucralose. Nevertheless, the biological effect of neotame in e-liquids is not so safe, as described below (see Section 3.2.2. and Appendix A and Appendix B).

In [69], Moser et al. quantified by GC–MS/GC–FID and estimated the cytotoxic effects of sucralose degradation products. The most abundant of them is 3-chloropropane-1,2 diol, an extremely toxic compound, which is a precursor for glycerol synthesis from propylene (Figure 4).

3-chloropropane-1,2-diol was detected at concentrations up to 10 g/kg. Moreover, the metabolic activity of HUVEC/Tert2 cells was decreased significantly by e-liquid aerosol condensate. Therefore, the authors reinforce the recommendation against the use of sucralose in e-liquids. Nevertheless, the sucralose degradation route to 3-chloropropane-1,2 diol and then to glycerol might be efficiently used to eliminate sucralose from the environment via a circular economy approach.

El-Hellani et al. [70] mention sucralose as a component of menthol-flavored and nicotine-flavored electronic liquids and investigate the effect of sucralose on ROS generation, provoked by the components of vaping products. Sucralose increased ROS production, but this effect was manifested more intensively in the presence of nicotine base and not nicotinium cation.

Kim et al. [71] investigated the cariogenic potential of tooth surfaces exposed to the sweeteners in electronic cigarettes. It was seen that the contact of S. mutans with tooth enamel grew four times in the presence of sweetened e-liquid aerosol with sweeteners including sucralose, triacetin, ethylbutyrate, and hexylacetate. The percentage of enamel hardness loss for the control for them was also significant. Analogous results are also mentioned by Gaur in [72].

The work [73] by Maloney et al. investigates the comparison of the human abuse of unflavored and sucralose-sweetened electronic cigarettes. It has been shown that the addition of sucralose augmented e-cigarette human abuse potential (HAP) due to its more attractive taste. Moreover, the augmented adsorption of nicotine alkaloids in the presence of sucralose, cited earlier, may also contribute to this HAP increment.

In continuation of [66], the work [74] investigates the influence of common e-liquid flavorants and externally added nicotine to the formation of toxins in e-liquids. The statement of the enhanced toxic carbonyl compound formation in the presence of sucralose has been reinforced. Moreover, it has been detected that the presence of sucralose augments the aerosol aldehyde and ketone concentration due to either sucralose or filler decomposition (see also Appendix A and Appendix B).

The biological impact of sucralose added to e-liquids and their aerosols is shown in

Table 2. Marketing and biological aspects of use of sucralose in e-liquids (↑—increase, ↓—decrease).

Vaping Products	Biological Activity	Experiment Type	Reference
E-liquid (in the presence of neotame)	Sweetener concentration, non-correspondent to the declared, possible metabolic synergetic effect between natural and artificial sweetener, sucralose and xylitol dehydratation and its products, ↑ toxic carbonyl compounds	In vitro	[52]
E-liquid aerosol	↑ toxic chloroorganic degradation products	In vitro, in vivo	[63]
Benzo[a]pyrene exposure	↑ renal toxicity, PGP inhibition, ↑ ROS	In vivo	[64]
E-liquid and e-liquid aerosol	↑ sucralose degradation rate, ↑ solvents oxidation and dehydratation rate, ↑ toxic chloroorganic degradation products, ↑ toxic carbonyl compounds	In vitro	[65]
E-liquid	↑ sucralose degradation rate, ↑ solvents oxidation and dehydratation rate, ↑ toxic chloroorganic degradation products, ↑ toxic carbonyl compounds	In vivo	[66]
E-liquid and e-liquid aerosol	↑ flavor perception in cartridge aerosol	In vivo	[67]
E-liquid and e-liquid aerosol	↑ heavy metal precipitation, ↑ metallic parts corrosion, ↑ cytotoxic effect ↓ cells viability, neotame suggested as a safer alternative to sucralose	In vitro	[68]
E-liquid and e-liquid aerosol	↑ toxic chloroorganic degradation products, ↑ toxic carbonyl compounds, ↓ cells’ metabolic activity, sucralose ban in e-liquids suggested	In vitro	[69]
E-liquid and e-liquid aerosol	↑ ROS by different manner, depending on nicotine formulation	In vivo	[70]
E-liquid aerosol	↑ enamel contact, ↑ cariogenesis, ↓tooth hardness	In vivo	[71]
E-liquid	↑ enamel contact, ↑ cariogenesis, ↓tooth hardness	In vivo	[72]
E-liquid and e-liquid aerosol	↑ HAP	In vivo	[73]
E-liquid	↑ sucralose degradation rate, ↑ solvents oxidation and dehydratation rate, ↑ toxic chloroorganic degradation products, ↑ toxic carbonyl compounds	In vitro	[74]

.

Therefore, despite the frequent use, sucralose in e-liquids and their aerosols manifest an ample repertoire of negative biological activity, including the degradation to toxic compounds, oxidative and metabolic stress, cariogenesis, and even an impact to human behavior, especially in devices in which the temperature is maintained higher than 119°.

For this reason, its use in e-liquids has to be limited or even banned [48,49,68,69], as the NOAEL and LOAEL of the degradation products are much lower than those of sucralose. Moreover, the exposure time factor, which was less important in the case of common cigarettes, also plays its role in the case of e-cigarettes.

The impact of the presence of other sweeteners on sucralose biological activity in e/liquids is still poorly understood. Nevertheless, there is evidence of the synergism of the toxical action of sucralose and other substances (sweeteners or not) [20,64].

Other synthetic sweeteners, despite being somehow safer, apparently have other types of peril, shown in the next subsection.

3.2.2. Other Sweeteners in E-Cigarettes

Contrarily to sucralose, other artificial sweeteners are less used in e-cigarettes, either due to their thermal instability or due to their bitter aftertaste [75,76,77,78,79,80,81,82,83,84], which becomes enhanced in the presence of nicotine products. Nevertheless, aspartame, neotame, saccharin, and acesulfame K are still used in e-liquids, and their use may even seem safer than that of sucralose [68], but their use implies certain objections.

The work [75], dated 2025, such as the works [76,77,78], mention the use of acesulfame K, aspartame, and saccharin, alongside sucralose, in e-cigarettes and smokeless tobacco products. The use of these three sweeteners in vaping products is rare (and the use of saccharin is nearly unique [77]) due to the possibility of methanol formation during the thermal and metabolic degradation of the mentioned substances. Moreover, there are some doubts concerning the safety of acesulfame K, aspartame, and saccharin to the genome and their possibility to cause intensive oxidative stress. Aspartame was also linked to certain cardiovascular events. The sweeteners most frequently used in e-cigarettes may be consulted in Appendix B.

Neotame [52,79] has been shown to be a hypothetically safe alternative to sucralose, aspartame, acesulfame K, and saccharin for use in e-cigarettes. Nevertheless, there are some objections about the influence of neotame to gut microbiota [80]. Moreover, such as in the case of aspartame, neotame is metabolized primarily by esterases, which yield methanol as a subproduct. Despite the small concentration of methanol produced during the metabolic process, the presence of other toxic components of the vape may generate a cumulative and synergetic effect. Another factor to be considered is the time-dependent realization of oxidative stress caused by these sweeteners, which becomes more intense in the presence of tobacco alkaloids [82,83,84]. For this reason, the FDA has only approved neotame in food, not for inhalation.

4. Discussion

The use of both natural and synthetic sweeteners in electronic cigarettes, despite the clear intention to alleviate or hide the N. tabacum or N. rustica alkaloids taste and smell for the addicted user, bears certain problems not only for the proper smokers but also for the environment. The genomic safety also becomes posed in peril.

For example, the use of sucralose in electronic cigarettes is still the most frequent, despite the ample variety of dangerous biological activity (up to the enhancement of the psychological addiction) it may pose. It is explained by purely perceptive and organoleptic properties. Nevertheless, the oxidative stress, genomic and environmental impact, and enhancement of cytotoxicity of this substance are really important. Moreover, sucralose is not thermally stable at vaping conditions, which may reach 150 and even more degrees centigrade, being decomposed into products that are even more poisonous. For this reason, the use of sucralose in e-cigarettes and vapes should be limited if not banned [68,69].

Aspartame, neotame, saccharin, cyclamate, and acesulfame K could serve as possible synthetic alternatives to sucralose. Nevertheless, their metabolism in the presence of nicotine alkaloids and when inhaled is still poorly investigated. The aspartic acid derivatives neotame and aspartame metabolize yielding methanol, which, even in small concentrations, may enhance the toxic action of other vape components. Moreover, some of them may be associated with carcinogenesis and cardiovascular diseases. For this reason, the use of these sweeteners must be considered with caution.

Even natural sweeteners, including carbohydrates, phenolic compounds, and amino acid derivatives, may be dangerous in the e-cigarette condition due to their thermal instability. The special cases among them are perillartine (an unsaturated aldoxime, nearly exclusive to Japan) and mogroside V (trisaccharide terpenic derivative), which are thermally more stable than the rest of the sweeteners and more sweet than some of them. For this reason, the use of perillartine and mogroside V, which are of natural origin and most thermally stable in the vaping conditions, as an alternative to other sweeteners in the dangerous vaping conditions, becomes viable.

5. Future Perspectives of the E-Cigarette Sweetening Investigation

The safety aspect of the use of sweeteners in electronic cigarettes is still under a thorough investigation, due to the high uncertainty about the following:

-

The comparison of the biological action of taken and inhaled sweeteners due to the metabolic differences;

-

The metabolic profile of the sweeteners in the presence of each other and their influence on the biological activity of standard cigarette and cigarette smoke components, including N. tabaccum alkaloids, and their decomposition and combustion products, including polycyclic arenes and hetarenes [85,86]. This interaction may be synergetic, summary, or antagonic, and it is certainly concentration dependent.

Therefore, the sweetener determination in electronic cigarette liquids and their aerosol is really up-to-date [87,88,89,90,91,92,93,94]. Spectrophotometric, chromatographic, and, sometimes, electrochemical methods may be applied to it.

As for 2025, the biological action of the sweetener or a couple of them in the presence of standard tobacco smoke toxins is still poorly studied, although some of the studies are still worth mentioning.

Tian et al. [95] exposed Sprague–Dawley rats to a xylitol-based aerosol for 90 days. The xylitol caused temporary hematological and bronchoalveolar alterations, which were reverted after the 28-day recovery period. The NOAEL of inhaled xylitol for rats was calculated as 2,9 mg/L, indicating the relative safety of inhaled xytitol as it is but not in the presence of e-cigarette components, which still needs to be discussed.

Kassem et al. [96] investigated the chemical safety of waterpipe tobacco smoking, which is somehow similar to e-cigarettes, as the WPT is also aromatized and sweetened. Both natural and synthetic sweeteners are found in WPT, being responsible directly or indirectly (as their thermal dehydratation products) on the augmentation of carcinogenesis, DNA alterations, and oxidative stress. For this reason, the presence of the sweeteners in WPT also has to be regulated by state organisms.

Afolabi [97] compared traditional tobacco smoking (TTS} with the use of e-cigarettes. Both of them have their specific toxic effects, and whereas TTS products are well studied, the health effect of e-liquids is still a concern. The flavorants and sweeteners added to e-cigarettes may be responsible for neuroinflammation, oxidative stress, CNS impacts, and reprotoxicity. Therefore, the influence of e-liquids with and without sweeteners has to be thoroughly studied in order to estimate their spermo- and ootoxic effects.

The review article [98] mentions that ethyleneglycol, propyleneglycol, and vegetal glycerol, and also their dehydratation products, do influence negatively the homeostasis of the epithelial cells. Moreover, the sweeteners may dehydratate, yielding the same and similar compounds, which might enhance this influence. For this reason, the sweeteners’ behavior in e-cigarettes during vaping might be extensively studied.

In summary, while sweeteners are generally recognized as safe for oral consumption (with certain limitations), their behavior and biological impact upon inhalation remain far from fully understood. The current body of evidence suggests that thermal decomposition, aerosolization, and interactions with other e-liquid constituents may significantly alter their toxicological profiles. These processes can lead to the formation of reactive or even carcinogenic intermediates, which may potentiate oxidative stress and inflammation in respiratory tissues. Moreover, the potential synergistic effects between sweeteners and nicotine, propylene glycol, glycerol, or flavoring agents necessitate further multidisciplinary research integrating toxicology, analytical chemistry, and molecular biology. Until comprehensive inhalation studies and standardized regulatory assessments are conducted, the use of sweeteners in e-cigarettes should be approached with caution, as their long-term health consequences cannot yet be reliably predicted.

6. Conclusions

From this brief review of the use of natural and artificial sweeteners as correctors of organoleptic and sensorial properties of e-liquids and their aerosols, it is possible to conclude that both natural and synthetic sweeteners (sugars and sugar substitutes) are added to vape liquids for the pure purpose of smell and taste correction, taking in mind neither the biological action of these substances and their metabolites nor their influence on the stability of cellular structure and even vaping equipment.

Sucralose is the most used sweetener in e-cigarettes. Nevertheless, its use in the vaping condition is highly compromised by both thermal instability and its chloroorganic nature. As a result, various negative influences to the genome (micronuclei formation, clastogenesis, DNA glycation, ROS-provoked DNA changes), environment, human metabolism, and even human behavior force the use of sucralose in electronic cigarettes to be restricted.

Synthetic sweeteners (aspartame, saccharin, neotame, acesulfame K, and cyclamate) are more rarely used in e-liquids. Although they may seem less dangerous than sucralose, their metabolism may yield toxic and conditionally toxic compounds and give a negative effect to well-being.

Even natural sweeteners are mostly unstable in the vaping condition, being thermally degraded by dehydratation. This statement includes sugars, polyphenolic compounds, ethers, and esters, which dehydratate yielding toxic carbonyls. For this reason, the most viable sweeteners for e-cigarettes as of 2025 seem to be perillartine and mogroside V, as they are natural and thermally stable. Nevertheless, the lacuna formed by the lack of state regulation on the use of the sweeteners in electronic cigarettes must be fulfilled.