A multitude of factors influence the likelihood to initiate electronic cigarette use (18). Not surprisingly, both adolescent and adult electronic cigarette users are more likely to start smoking tobacco cigarettes within 2 years, as compared to non-users (19, 20). Because of this, it is especially important to understand factors that may predict the onset of electronic cigarette use in never-smokers. For instance, electronic cigarette perception was shown to be a predictor of smoking initiation amongst adolescents and adults (21, 22). Therefore, by deepening our understanding of how different sociodemographic factors and perception interrelate, vulnerable populations can be identified to prevent future initiation of drug use.

The relationship between sociodemographic factors and electronic cigarette use in adolescents is well established. In a recent survey, adolescents between 13 and 18 years of age were found to vary in their perceived harm of electronic cigarettes based on socioeconomic status, ethnic background, and parental educational attainment (23). Specifically, a lower perceived risk of electronic cigarettes was associated with a lower-income family, non-Hispanic Black ethnic background, or both parents having had no college degree (23). Furthermore, adolescents and young adult never users who were non-Hispanic Black reported a greater susceptibility to initiate disposable or reusable electronic cigarette use (24). As adolescents age, perceptions toward electronic cigarettes may persist and thus influence their likelihood of nicotine use. Not surprisingly, the internet and social media have become a powerful source of influence for both adolescents and young adults. Indeed, the advertisement of electronic cigarettes has been mainly found in online sources (25). For instance, a large number of electronic cigarette vaping-related videos are available on TikTok, a short form social media platform popular among adolescents and young adults (26). These vaping-related TikTok videos were largely found to positively depict electronic cigarette use (26). This is alarming given that advertising via social media significantly influences the perception of electronic cigarette harm in adolescents, even when controlling for exposure to warning labels and anti-tobacco advertising (27). Conversely, this highlights the potential by which social media can be used to communicate the harms of electronic cigarette use to these same adolescent and young adult populations.

Interestingly, a study in young adults found that advertising alone did not influence electronic cigarette use, but when individuals who had a low harm perception of electronic cigarettes viewed this advertising, they were then more likely to initiate electronic cigarette use (25). These findings are consistent with another study in adults, in which harm perception of electronic cigarettes in non-users could predict their status a year later (28). Specifically, increased harm perception of electronic cigarettes was significantly correlated with a lower incidence of future electronic cigarette use, whereas decreased harm perception was associated with increased likelihood of drug use (28). Given the recent regulations in over 30 states targeting electronic cigarette advertising, sales, and use (29), it will be interesting to see how electronic cigarette perceptions in adolescents and adults evolve to influence future use patterns.

Over 20 million adults in the United States suffer from depression (30), and multiple studies have demonstrated comorbidity between depression and electronic cigarette use (16, 31–39). This association is also dose-dependent, where greater amounts of nicotine consumed were associated with greater self-reported depressive symptoms (40). Adolescents and adults who suffer from mental illness are more likely to be both electronic and tobacco cigarette users (14, 41–44), so these populations are disproportionately burdened with health consequences associated with both types of cigarettes. Interestingly, electronic cigarette use was associated with subsequent tobacco cigarette initiation, which then correlated with depression symptoms (39), illustrating that the initial use of electronic cigarettes in never-smokers can lead to adverse health consequences. Additionally, self-report studies reveal that never smokers and smokers who have quit report overall higher levels of positive affect and lower levels of negative affect compared to current tobacco smokers (45, 46). Although prior studies provide some insight for the intersection of nicotine use and depression, it had remained unclear as to whether symptoms related to depression led to the initiation of drug use, or if the effects of drug use (e.g., alterations in brain circuitry and/or induction of withdrawal symptoms during periods of abstinence) triggered the onset of depressive symptomology. Two longitudinal studies have investigated this question regarding electronic cigarette use, yielding somewhat conflicting results (18, 47). In the first study (47), college students were surveyed at two time points within 1 year, assessing for changes in electronic cigarette use and self-reported depressive symptoms. In this sample, reported symptoms of depression predicted electronic cigarette use at both 6 month and 1 year follow-ups, whereas electronic cigarette use did not predict depressive symptoms at either time point (47). These data suggest an unidirectional relationship, in which greater depressive symptomology increases the likelihood of electronic cigarette use (47). These data also support the “self-medication” hypothesis, in which people experiencing depression may seek out substances to ameliorate their symptoms. Given that nicotine in electronic cigarettes has been shown to induce transient effects of mild euphoria, increased energy, heightened arousal and relaxation, these effects can theoretically counteract an individual’s perceived depression-associated symptoms (48). Of note, this phenomenon has also been observed in tobacco cigarette users (49, 50). Contrary to these unidirectional effects (47), an interesting longitudinal study by Leventhal and colleagues provides evidence of a bidirectional relationship between nicotine use and depression (18). This study surveyed high school students for 1 year who reported never having used any nicotine products and assessed their self-reported depression symptoms and electronic cigarette use (18). Participants with a self-reported elevation of depression-associated symptoms at baseline were more likely to use both electronic cigarettes and tobacco cigarettes (18), consistent with the former study (47). However, the authors also found that sustained electronic cigarette use predicted an increase in self-reported depression symptoms at 12 months, thereby revealing a bidirectional relationship between depressive symptoms and electronic cigarettes (18). As these two studies suggest differences in directionality between depression and electronic cigarette use, it is important to consider factors mitigating these conclusions. For instance, differences in age, education, and geographic location have all been shown to affect nicotine use (4), and thus, the reported findings may be interdependent on other sociodemographic or developmental factors. In addition, the dose of nicotine contained in the electronic cigarettes or amount consumed by the participants was not recorded or standardized, which may have confounded the correlation with depressive symptoms. Finally, self-reported symptoms are subjective and may not meet the criteria for major depressive disorder (51).

Often closely associated with depression, electronic cigarette use is also positively correlated with both self-reported anxiety symptoms and generalized anxiety disorder (GAD) in humans (17, 52–56). While the directionality of this association is unclear, like depression, the relationship between anxiety and electronic cigarette use may also be bidirectional. Evidence demonstrates that people with a greater score as assessed with the GAD survey are more likely to initiate future electronic cigarette use (17). Further, adolescent populations self-report vaping for relaxation and stress and anxiety coping (54). Conversely, electronic cigarette use may increase the risk of anxiety disorders, including phobias, obsessive–compulsive disorder, or a panic disorder (57). Among adolescents and young adults, electronic cigarette use increased the likelihood of anxiety-related disorders by 37% (57). In addition to electronic cigarette initiation and continued use, increased anxiety is also evidenced during nicotine withdrawal (58). Interestingly, individuals that self-report greater anxiety sensitivity experience greater barriers for cessation (56) and individuals with depression diagnoses are more likely to experience more severe withdrawal symptoms (59). All in all, these findings suggest an intertwined relationship between electronic cigarette use, anxiety, and depression, which put those already experiencing these disorders at greater risk for electronic cigarette use, difficulties in cessation, and increased withdrawal symptomology.

Nicotine is the main psychoactive constituent present in both tobacco cigarettes and electronic cigarette liquid. Nicotine acts on ionotropic nicotinic acetylcholine receptors (nAChRs), where ligand binding results in channel pore opening and cation influx across the membrane (89). nAChRs are pentameric, assembling with various combinations of α and β nAChR subunits for a wide variety of nAChR subtypes with distinct pharmacokinetics, expression patterns, and actions on the cholinergic system (90, 91). Acting on nAChRs, nicotine exerts its reinforcing properties through the mesolimbic dopaminergic pathway (92). Systemic nicotine administration results in dopamine release in the nucleus accumbens (93), an effect shown to be mediated by β2* nAChRs in the ventral tegmental area (92, 94). Subsequent studies have demonstrated that the α4α6β2* nAChRs are necessary for nicotine self-administration in rodents (94). Moreover, nicotine also exerts aversive properties, particularly though the medial habenula to interpeduncular nucleus pathway (95). The medial habenula is enriched in α5*, α3*, β4* nAChRs, which have been shown to mediate nicotine aversion, drug-taking behavior, and/or withdrawal (96–101).

Propylene glycol and vegetable glycerin are additives commonly used as humectants (e.g., to control moisture levels in food and beauty products) and are the main liquids used to dissolve nicotine into solution to generate electronic cigarette aerosol for inhalation. Electronic cigarette solutions are marked commercially as “nicotine juice,” “e-juice,” “nicotine liquid,” or “nicotine solution.” Although the Food and Drug Administration recognizes propylene glycol and vegetable glycerin as “generally safe” for oral consumption, they have not yet been approved for inhalation (102). With electronic cigarette development and use significantly increasing within the last decade (4), the potential long-term effects of inhaled propylene glycol, vegetable glycerin, or both together on the brain and body have yet to be fully elucidated. Although propylene glycol and vegetable glycerin are both used in the electronic cigarette solutions, studies have focused on propylene glycol or the combined effects of vegetable glycerin and propylene glycol, rather than investigating vegetable glycerin alone.

Propylene glycol has been shown to interact with other compounds present in electronic cigarettes to induce synergistic effects. For example, HEK-293T cells exposed to both propylene glycol and vanilla electronic cigarette flavorant exhibited increased calcium signaling, which was attributed to activation of the aldehyde-sensitive receptor TRPA1 (103). Specifically, at higher concentrations, vanilla flavorant and propylene glycol together induced more robust calcium influx than either alone (103). TRPA1 receptors are expressed in brain microvasculature and play a functional role to maintain blood–brain-barrier integrity (104). Since acute exposure to non-flavored electronic cigarette aerosol was also shown to activate TRPA1 receptors in endothelial cells, this suggests that combined effects of propylene glycol and vanilla chemical flavorant may potentiate the adverse effect of each other or may exert greater side effects in vivo (105). Moreover, propylene glycol has also been shown to interact with nicotine to affect brain reward thresholds in male rats, as assessed with ICSS (78). While propylene glycol alone did not alter ICSS thresholds, co-administration of propylene glycol and nicotine decreased the aversion-associated increase in ICSS thresholds, which was induced by the high dose of nicotine alone (78). These findings indicate that at doses found in commercial electronic cigarette liquids, propylene glycol mitigates nicotine’s aversive properties and thus may promote higher levels of nicotine consumption (78), thereby increasing the product’s addiction liability. Maternal electronic cigarette exposure has also been shown to affect offspring. Surprisingly, prenatal exposure to vegetable glycerin with propylene glycol vapor was sufficient to induce deficits in long-term novel object memory (106), thus highlighting the importance of understanding the impact of electronic cigarette exposure in utero.

When heated together, propylene glycol and vegetable glycerin decompose to generate carbonyls in the aerosol, which most notably include acrolein, acetaldehyde, and formaldehyde (107–109). Many studies have found detectable levels of carbonyls in electronic cigarette aerosol, but variable levels have been reported across these studies, likely due to differences in the vape solution’s pH, heating temperature, propylene glycol/vegetable glycerin ratios, and individual differences in user vaping behavior (109–112). Importantly, in humans, these carbonyls can be detected in the airway following electronic cigarette use (113), and their respective metabolites can be further detected in the urine (108, 114, 115). While it is important to acknowledge that electronic cigarettes emit significantly fewer carbonyls than tobacco cigarettes (116), limited studies have investigated the level of carbonyl emission from electronic cigarettes, nor have they investigated the implications with long-term exposure.

Both acetaldehyde and acrolein are considered neurotoxins due to their effects on oxidative stress, which has been proposed to underlie neurodegenerative diseases including Alzheimer’s and Parkinson’s (117–119). Acetaldehyde and acrolein have been detected in both nicotine-free and nicotine-containing electronic cigarette aerosol, but interestingly, they are often not detected in the liquids themselves (86, 109, 120). These findings indicate that the process of heating the chemicals in the electronic cigarette liquid causes the formation of the aerosolized carbonyls. Metabolites of acetaldehyde and acrolein can also be detected in the urine following electronic cigarette vapor exposure (108, 115). Interestingly, both acetaldehyde and acrolein similarly impair cellular respiration. Acetaldehyde was shown to alter cellular respiration in cultured microvascular endothelial hBMVEC cells, which mainly comprise the blood–brain-barrier, thereby suggesting negative effects on blood–brain-barrier integrity (121).Further, in cultured primary cortical neurons, acetaldehyde impaired mitochondrial respiration via NOX-mediated activation (122), and in brain mitochondria in vitro, acrolein inhibited mitochondrial respiration via complex I (123). Similar effects have also been observed in vivo, as 3 days of electronic cigarette vapor exposure resulted in NOX2-mediated changes in mitochondrial respiration in the frontal cortex of male mice (124). In this study, acrolein was proposed to induce the NOX2-mediated impairments in cellular respiration (124). Interestingly, a study in humans revealed that current electronic cigarette use, but not past electronic cigarette use, was significantly correlated with mitochondrial DNA damage and dysfunction (82), which supports the translational relevance of these pre-clinical findings. Together, these findings indicate the acute nature of electronic cigarette exposure in mitigating negative outcomes.

In addition to acetaldehyde and acrolein, formaldehyde is also a product of propylene glycol and vegetable glycerin degradation (107–109). Formaldehyde is a well-documented carcinogen associated with adverse health consequences following acute exposure at higher doses, in addition to chronic lower levels of exposure (125). Formaldehyde levels in electronic cigarette aerosol have been documented to range from 0.07–0.15 parts per million (ppm), which is below the 5 ppm threshold for acute toxicity (126). Nevertheless, evidence demonstrates that chronic exposure to even low levels of formaldehyde can induce significant behavioral and molecular changes. For example, 7 days of gaseous exposure to a low dose of formaldehyde impaired spatial learning in the Morris water maze in male mice (127, 128). Furthermore, a chronically administered low dose of formaldehyde altered monoamine levels, including norepinephrine, epinephrine, dopamine, and serotonin, in the brain of male mice (127). Specifically, following 7 days of formaldehyde exposure at levels much lower than those emitted from electronic cigarettes, 0.0005 ppm formaldehyde exposure decreased norepinephrine and epinephrine levels, whereas 0.003 ppm decreased all of the monoamine levels (127). Moreover, 12 weeks of exposure of a low dose of aerosolized formaldehyde induced an upregulation in the number of corticotropin releasing hormone immunoreactive neurons in the paraventricular nucleus of female mice (129). Interestingly, an increased number of corticotropin releasing hormone neurons in the paraventricular nucleus has been observed in individuals diagnosed with major depressive disorder, as compared to healthy controls (130), suggesting clinical relevance of the findings from mice. Taken together, these studies provide evidence that long-term formaldehyde exposure at levels similar to electronic cigarette emission can lead to significant changes in brain mechanisms underlying cognitive function, potentially including depression.

Electronic cigarettes have been considered ‘safer’ than combustible tobacco cigarettes, such as with lower carbonyl levels. However, a main counterindication of this ‘safe’ assessment is the presence of inhaled metal particulates in electronic cigarette aerosols, which are at levels greater than that found in tobacco cigarette smoke (131, 132). Metals are likely leached into electronic cigarette liquids and vape during aerosol production, when electronic cigarette liquids come into contact with the metal heating coil (133). Like carbonyls, these metals can also be detected in the urine, saliva, exhaled breath, and blood of electronic cigarette users (131, 133). Electronic cigarette-emitted metal particulates have been shown to readily cross the blood–brain-barrier, as evidenced by metal accumulation in the mouse brain (134). Moreover, following electronic cigarette exposure, arsenic, chromium, copper, iron, manganese, nickel, lead, selenium, strontium, and zinc were found to accumulate across different regions of the brain, with the greatest accumulation observed in the anterior frontal cortex and striatum (134). Specifically, in the anterior frontal cortex, copper and strontium were enriched, whereas arsenic, chromium, copper, iron, lead, and selenium were enriched in the striatum (134). Like other types of electronic cigarette emissions, the type and relative proportion of metals that might accumulate in the brain are expected to vary among commercially available brands due to differences in the vape liquid constituents and electronic cigarette device characteristics (135). Of note, metal inhalation has been shown to induce behavioral changes in male rats, including a decrease in locomotor activity following chromium inhalation (136). Both arsenic and lead are well-known neurotoxins, with the greatest negative effects occurring during earlier neurodevelopmental stages. Maternal exposure to either arsenic or lead during gestation or developmental exposure during adolescence has been shown to result in an overall increase in monoamine signaling in the brain, which persisted into adulthood in rats (137). Unexpectedly, co-exposure of both arsenic and lead led to an opposing effect with decreased monoamine signaling (137). These data highlight the potential differential effects of each constituent and unknown effects with multiple metals present in the aerosols. This illustrates the need to expand our understanding of the effects of metals in electronic cigarettes for various stages of neurodevelopment. It is also important to note that metal components are often found in higher concentrations in less expensive products (24, 138–140), which would presumably be purchased at higher levels by those of lower socioeconomic status or adolescent users with limited income. Given this, future research should be directed at investigating whether increased health disparities will become more evident with long-term product use by marginalized communities of lower socioeconomic status.

As the electronic cigarette market constantly evolves, more palatable flavorants consistently emerge to attract a broader audience of consumers. In 2014, a study identified over 7,000 commercially available electronic cigarette flavors (141), which does not take into account the many variations of chemicals used to create a singular flavor (e.g., fruit or candy). Mint and fruit electronic cigarette flavors are preferred by individuals across ages (young adult to adult) and smoking status (never, current, or former electronic cigarette/tobacco cigarette user) (142–144). Thus, an enhanced understanding of how the chemicals used to generate the variety of electronic cigarette flavorants impact the reinforcing properties of nicotine, drug use patterns, and health outcomes will be essential to ascertain. However, this has been difficult for the scientific community given the numerous chemical combinations used to generate the flavors and limited time/resources as commercialized flavors constantly evolve from company to company and across time.