Prospective associations between nicotine type and the continuation of youth e-cigarette use

Abstract

Background

E-cigarettes can contain either “tobacco derived” nicotine, which is comprised of almost entirely S-nicotine isomers, or “synthetic” nicotine, which is comprised of a mixture of R- and S-nicotine isomers (“R/S” nicotine). Emerging studies suggest R/S nicotine may be less pharmacologically potent, which could indicate a lower addictive potential. The purpose of the present study was to examine whether e-cigarette brands containing different nicotine types are associated with the continuation of youth’s e-cigarette use.

Methods

Data came from a prospective cohort study of youth. Analyses were restricted to youth (ages 16–24; N = 216) who, at their baseline assessment in 2021, were using either JUUL (S-nicotine) or Puff Bar (R/S nicotine) e-cigarettes. Multivariable logistic regression tested whether nicotine type at baseline was associated with past-30-day e-cigarette use at the 12-month follow-up.

Results

Compared to participants who used Puff Bar, participants who used JUUL had higher odds of continued use at the 12-month-follow-up (aOR, 1.93, 95% CI, 1.07–3.45, p = 0.029).

Conclusion

Our findings suggest that, when it comes to predicting the continuation of vaping among youth who have already initiated, nicotine type (i.e., the ratio of R- and S-isomers) may play a critical role. It is encouraging that R/S nicotine may have lower addictive potential; however, tobacco control should be vigilant for marketing strategies attempting to establish R/S nicotine e-cigarettes as “starter” products for youth.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12889-025-25481-3.

Background

In the U.S., adolescents and young adults experience the highest prevalence of e-cigarette use. Whereas only 4.5% of U.S. adults currently use e-cigarettes [1], 7.8% of high school students, 10.3% of young adults aged 18–20, and 15.5% of young adults aged 21–24 currently use them [2, 3]. Nationally, 1.63 million U.S. middle and high school students currently use an e-cigarette [2]. Among those youth currently using, more than 1 in 4 (26.3%) used daily [4]. More concerning still, longitudinal data indicate many adolescents and young adults who experiment with e-cigarettes will persist in their use for years [5–8].

The vast majority of e-cigarettes contain nicotine, a highly addictive chemical [9, 10]. Beyond its addictive properties, nicotine has been found to impact adolescent and young adult brain development (which continues until age 25) [11–13]. There is also evidence of nicotine use in adolescence increasing risk of addiction to other drugs later in life [11, 14]. Use of e-cigarettes among youth also puts them at increased risk for adverse respiratory effects, including cough, phlegm, dyspnea, and asthma [14, 15]. Therefore, although e-cigarettes appear to have fewer harmful effects than combustible cigarettes, they are still deemed unsafe for youth [11, 14, 16].

What drives youth to continue their e-cigarette use?

In order to reduce the public health burden of e-cigarettes among youth, it is important to understand the factors that encourage them to keep using. One such factor may be nicotine type: tobacco-derived or synthetic. Tobacco derived nicotine refers to the nicotine that is naturally present in tobacco plants. It contains almost entirely S-nicotine isomers and is the nicotine present in most combustible cigarettes, cigars, and smokeless tobacco [17]. On the other hand, synthetic nicotine (also referred to as “tobacco free” nicotine) is made in a lab; it has a very similar molecular makeup as tobacco derived nicotine, but generally contains a mixture of both R- and S-nicotine isomers [17, 18]. Importantly, although synthetic nicotine is not made from tobacco, it is still a highly addictive substance. Public health research on the addictive effects of e-cigarettes that contain synthetic nicotine (R/S-nicotine) compared to tobacco-derived nicotine (primarily S-nicotine) is lacking [19]. However, animal studies indicate R-nicotine is less pharmacologically potent than S-nicotine [20–22] and is metabolized more quickly [23–26]. In addition, one human participant study found that oral nicotine pouches with primarily S-nicotine delivered more nicotine to the bloodstream than those with a R/S-nicotine mixture [27]. Together, this research suggests that tobacco-derived nicotine has a stronger addictive potential than synthetic nicotine containing an R/S-nicotine mix.

Current study

The purpose of the present study was to examine the prospective association between e-cigarette nicotine type and youth e-cigarette use. Analyses focused on a sample of youth who, at their baseline assessment, were using either a popular e-cigarette brand with tobacco-derived nicotine (JUUL) or another popular e-cigarette brand with synthetic nicotine (Puff Bar). We focused on only these two brands because (1) they were the most prevalent brands for each nicotine type reported by our sample and (2) Puff Bar was one of the few brands whose claims about using synthetic, R/S nicotine had been chemically verified in independent research [28].

We hypothesized that, among youth who used e-cigarettes at baseline, those who used tobacco-derived nicotine would be more likely to still be using e-cigarettes at the 12-month follow-up.

Methods

Participants and recruitment

Data were obtained from the Emerging Adulthood Health Project (EAHP), a longitudinal cohort study in Ohio that examined e-cigarette and other tobacco use among 1,068 adolescents and young adults. Participants were recruited between January and September 2021, via flyers, listervs, and social media advertisements. Inclusion criteria for the EAHP (between ages 15–24 and living in Ohio) were determined by a brief online survey. Quota sampling [29] was utilized to ensure good representation across sociodemographic characteristics (gender, race, and ethnicity). In addition, quota sampling was used to ensure the EAHP sample was approximately half individuals who had never tried any tobacco product and half individuals who had reported nicotine-based e-cigarette use within the past 3 months. Online consent forms were provided to participants over the age of 18; for those under 18 years, assent and permission were obtained from parents over the phone. Follow-up surveys were sent online at 4, 8, and 12 months after the initial baseline survey. Participants were compensated with an online gift card after each survey completion. All study procedures were approved by our University IRB as protocol 2020C0200.

Measures

In the baseline survey, participants were asked if they had ever used an e-cigarette and, if so, when they last used an e-cigarette (response options ranged from “today” to “more than a year ago”). Those who reported use within the last 3 months were asked to report the number of days they had used in the last 30 days. Each follow-up survey (4-months, 8-months, and 12-months) assessed ever use of an e-cigarette, recency of use, and past-30-day use.

Brand was assessed with the question “Which brand of e-cigarette have you used most often? Select all that apply.” There were 35 possible response options, including Blu, Cloud 9, Hyde, JUUL, Puff Bar, and Vuse; participants were also offered the choice of “other,” where they were provided a fill-in response, as well as “don’t know.” For the purpose of the present analyses, we focused on two brands commonly used by young people and that contained either tobacco-derived or synthetic nicotine: JUUL and Puff Bar, respectively.

Flavor preference was assessed by an open-ended question stating, “What is your favorite flavor and what brand of flavored liquid do you prefer?” Participants’ open-ended responses were then coded into the following categories, based on guidance from the literature: [30] fruit, menthol/mint, “ice” fruit, alcohol/beverage, dessert/candy, or don’t know/no preference.

For demographic characteristics, age was determined based on the participants’ reported month and year of birth. An open-ended question was utilized to assess gender, and responses were coded into male, female, and another gender response (e.g. non-binary) [31]. Two questions, assessing sexual orientation and transgender identity [32, 33], were coded into a variable indicating sexual and gender minority status (yes, no). Socio-economic status (SES) was measured with four items that assessed social class growing up, current social class, and parental education [34]. The items were z-scored and then aggregated with higher scores indicating higher SES. Our measures of race and ethnicity [32] were re-coded to create 5 categories (Asian, Hispanic, non-Hispanic Black, Non-Hispanic white, and more than one race). Participants reported county of residence, which were coded as major metro, minor metro, suburb, and rural [35].

Participants were additionally asked about the first tobacco product they ever tried; those who indicated their first tobacco product was an e-cigarette were asked how old they were when they first tried one. We also assessed past-30-day use of cigarettes, cigars, cigarillos or little cigars, smokeless tobacco, hookah, and pipe tobacco; responses to each of these items were aggregated to create a single variable for past-30-day use of another tobacco product.

Analysis

As indicated in our “participants and recruitment” section above, the EAHP was a sample of 1,068 youth, where approximately half of the youth had a history of e-cigarette use (defined as using an e-cigarette within the past 3 months; n = 551). Of these 551 who use e-cigarettes at baseline, participants who did not complete their 12-month follow-up were excluded from the present analyses (n = 202; 63.3% retention). We also excluded 133 participants because they did not use a brand of interest, JUUL or Puff Bar, or reported using both brands often. This left us with a final analytical sample of 216 participants.

Means, standard deviations, and prevalence outcomes were first reported for the analytical sample. We also examined whether participants lost to follow-up differed from those retained on our baseline variables. Next, to identify potential confounding variables, we ran a series of univariate logistic regressions testing the association between factors at baseline and participants past 30-day e-cigarette use at a 12-month follow-up. Finally, a multivariable logistic regression was conducted to test the association between preferred brand at baseline and past 30-day e-cigarette use at the 12-month follow-up, controlling for other factors that were significant in the univariate analyses. This approach, referred to as purposeful selection [36], was chosen because it is useful in risk factor modeling, as it helps retain not just covariates but confounding variables. Finally, due to the rapidly evolving regulatory landscape, which may have impacted the availability of products, we also conducted a sensitivity analysis to determine if our multivariable outcomes occurred in a tighter timeframe, using data from our 4-month follow-up. Listwise deletion was used throughout our analyses (there was no imputation method for missing data).

Results

In our analytical sample of 216 youth using JUUL or Puff Bar, the average age was 20.4 (SD = 1.75), with the mean age of first-time e-cigarette use at 16.9 (SD = 1.67). Most of the participants were non-Hispanic white (82.9%) and not a sexual or gender minority (77.3%); with around half (53.5%) identifying as female (Table 1). The majority (81.0%) reported at baseline that they had used an e-cigarette in the past 30 days. The most preferred e-cigarette brand was JUUL (60.2%) and the most commonly preferred flavor was mint/menthol (41.7%). Among the youth enrolled for their e-cigarette use at baseline, those who did not complete the 12-month follow-up had lower SES and a lower prevalence of being an SGM individual, compared to those who were retained. There was no difference in attrition across e-cigarette use history, race and ethnicity, flavor preference, or brand (JUUL vs. Puff Bar).

Table 1.

Baseline characteristics of the analytical sample at baseline (N = 216). Values reflect mean (M) and standard deviation (SD) or prevalence (%) of the factor

Sample Characteristics	M (SD) or %
Age (M)	20.4 (1.75)
Age First Used E-cigarette(M)	16.9 (1.67)
Socioeconomic Status(M)	0.01 (0.69)
Race/Ethnicity (%)
Asian	5.6%
Hispanic	4.2%
Non-Hispanic Black	1.9%
Non-Hispanic white	82.9%
More than one race	5.6%
Gender (%)
Female	53.5%
Male	45.1%
Another gender response	1.4%
Sexual or Gender Minority (%)
Yes	22.7%
No	77.3%
Area (%)
Major Metro	83.9%
Minor Metro	8.1%
Suburb	4.3%
Rural	3.8%
Past 30-day-use of Other Tobacco Productsa
Yes	81.0%
No	19.0%
Preferred E-Cigarette Flavorb
Fruit	34.4%
Mint/Menthol	41.7%
Ice + Fruit	8.3%
Alcohol/Beverage	4.7%
Dessert/Candy	2.1%
No Preference	8.9%
Past 30-day E-cig Use
Yes	81.0%
No	19.0%
Preferred Brand
JUUL	60.2%
Puff Bar	39.8%

^aIncludes any past-30-day use of cigarettes, cigars, cigarillos, smokeless tobacco, hookah, or pipe

^bOnly 4 responses did not fit into these five flavor categories (e.g., tobacco, cucumber) and were excluded from flavor analyses due to low cell size

At the 12-month follow-up, 63% of participants reported past-30-day e-cigarette use. Chi-square analyses indicated that past-30-day use at the 12-month follow-up was more prevalent among those who used JUUL at baseline (68.5%) compared to those who used Puff Bar at baseline (54.7%), X²(1, 216) = 4.23, p < 0.001. Of the participants who used JUUL at baseline, 28.5% were still using JUUL at follow-up, 2.3% had switched to Puff Bar, 10.8% were using both JUUL and Puff Bar, 26.9% were using another e-cigarette brand, and 31.5% had not used an e-cigarette in the last 30 days. Of the participants who used Puff Bar at baseline, 15.1% were still using Puff Bar at follow-up, 7.0% had switched to JUUL, 10.5% were using both JUUL and Puff Bar, 22.1% were using another e-cigarette brand, and 45.3% had not used an e-cigarette in the last 30 days. No one in either group (JUUL or Puff Bar) initiated cigarette smoking between baseline and the 12-month follow-up and, among those who reported no past-30-day e-cigarette use at follow-up, very few were using cigarettes (3 people who had been using JUUL at baseline, 0 people who had been using Puff Bar at baseline).

Across the series of adjusted univariate associations, the only factors associated with past-30-day use of e-cigarettes at the 12-month follow-up were brand, baseline past-30-day e-cigarette use, and baseline past-30-day use of another tobacco product (Table 2). Specifically, those who used JUUL (vs. Puff Bar) at baseline were more likely to report past-30-day e-cigarette use at follow-up (OR, 1.80, 95% CI, 1.03–3.16, p = 0.041). Engaging in past-30-day use of e-cigarettes (OR, 3.00, 95% CI, 1.49–6.03, p = 0.002) and engaging in past-30-day use of another tobacco product (OR, 2.43, 95% CI, 1.09–5.40, p = 0.030) were also associated with a higher odds of subsequent e-cigarette use.

Table 2.

Odds ratios and 95% confidence intervals (CIs) for a series of univariate logistic regressions testing the associations between a single factor at baseline and past-30-day e-cigarette use at the 12-month follow-up

Variable	Odds ratio	95% CI	p-value
Age	1.05	0.89–1.24	0.541
Age First Used an E-Cigarette	0.87	0.71–1.06	0.158
SES	1.19	0.80–1.78	0.397
Race/Ethnicity (ref: non-Hispanic white)
Asian	1.67	0.17–16.38	0.660
Hispanic	0.45	0.12–1.72	0.240
Non-Hispanic Black	0.40	0.12–1.30	0.128
More than one race	1.67	0.44–6.34	0.454
Gender (ref: Male)a
Female	1.30	0.74–2.23	0.370
SGM (ref: Not SGM status)	0.53	0.28–1.00	0.051
Area (ref: Major Metro)
Minor Metro	0.50	0.19–1.40	0.179
Suburb	0.71	0.18–2.73	0.616
Rural	1.70	0.33–8.67	0.524
Past 30-day-use of Another Tobacco Product (ref: No)
Yes	2.43	1.09–5.40	0.030*
Preferred E-Cigarette Flavor (ref: No Preference)
Fruit	1.28	0.44–3.75	0.647
Mint/Menthol	2.67	0.91–7.84	0.075
Ice + Fruit	1.48	0.37–5.95	0.579
Alcohol/Beverage	3.11	0.50–19.54	0.226
Dessert/Candy	0.89	0.10–7.86	0.916
Past 30-day E-cig Use (ref: No)
Yes	3.00	1.49–6.03	0.002*
Brand (ref: Puff Bar)
JUUL	1.80	1.03–3.16	0.041*

^aDue to low cell size, the other gender response category was excluded from analysis

^bIncludes any past-30-day use of cigarettes, cigars, cigarillos, smokeless tobacco, hookah, or pipe

^cOnly 4 responses did not fit into these five flavor categories (e.g., tobacco, cucumber) and were excluded from flavor analyses due to low cell size

^*Indicates a statistically significant effect

In the multivariable logistic regression, which adjusted for the two baseline covariates, past-30-day e-cigarette use at baseline (aOR, 3.17, 95% CI, 1.55–6.52, p = 0.002) and past-30-day use of another tobacco product at baseline (aOR, 2.29, 95% CI, 1.01–5.22, p = 0.048), the effect of e-cigarette brand was again significant (aOR, 1.93, 95% CI, 1.07–3.45, p = 0.029; Table 3). Thus, compared to individuals using Puff Bar at baseline, individuals who used JUUL at baseline had nearly twice the odds of engaging in current e-cigarette use by the 12-month follow-up. Sensitivity analyses showed the use of JUUL was also significant in a model predicting use by the 4-month follow-up (aOR, 2.60, 95% CI, 1.40–4.84, p = 0.003; analyses adjusted for baseline past-30-day e-cigarette use and past-30-day other tobacco use).

Table 3.

Odds ratios and 95% confidence intervals (CIs) for the single multivariable logistic regression on e-cigarette use at the 12-month follow-up (N = 216)

Variable	Odds ratio	95% CI	p-value
Past 30-day-use of Another Tobacco Product (ref: No)
Yes	2.29	1.01–5.22	0.048*
T1 Past 30-Day E-cigarette Use (ref: No)
Yes	3.17	1.55–6.52	0.002*
Brand (ref: Puff Bar)
JUUL	1.93	1.07–3.45	0.029*

^*Indicates a statistically significant effect

Discussion

The present study found preliminary support to suggest that the type of nicotine in an e-cigarette has an impact on youths’ continued use. Specifically, when comparing e-cigarette brands JUUL (which contains almost entirely S-nicotine isomers) and Puff Bar (which contains a mixture of S- and R-nicotine isomers), youth using JUUL had nearly 2 times the odds of continued use at the 12-month follow-up.

Our main finding—that those using JUUL at baseline were more likely than those using Puff Bar at baseline to report past-30-day use 12 months later—is also consistent with the emerging literature on nicotine type. Specifically, it appears that nicotine comprised of both R/S nicotine (like Puff Bar) may deliver less nicotine to the bloodstream [27]. E-cigarettes containing primarily S-nicotine (like JUUL), which are more efficient in their nicotine delivery, likely carry greater addictive potential; this would explain their association with participants’ continued use.

Implications

Findings from the present study are promising, as they suggest that manipulation of nicotine could produce a less addictive product. Encouragingly, Keller-Hamilton and colleagues found that, among adults who already smoked cigarettes, R/S nicotine products did not differ from an S-nicotine product in terms of appeal [27]. Thus, a shift in the tobacco market from S- to R/S-nicotine could potentially promote harm reduction. However, we should also be wary of how the tobacco industry may leverage nicotine type to their pecuniary advantage. For example, a youth’s first exposure to nicotine can result in many physiological reactions (e.g., a “buzz,” dizziness, coughing, nausea), and more pleasant reactions are associated with the development of nicotine dependence [37]. An e-cigarette with R/S nicotine could, therefore, be positioned as a “starter” product. Indeed, the tobacco industry has a long history of pairing strategic marketing with product manipulation to “graduate” users from palatable “starter” products to stronger, more addictive “robust” products [38, 39]. Therefore, it is critical to monitor industry practices to prevent youth-targeted campaigns.

Our findings highlight the importance of further regulation surrounding the nicotine in e-cigarettes. For instance, labelling rules and regulations have been recommended to identify a product’s level of R- and S-nicotine [40]. Especially when it comes to protecting our youth (who often struggle to understand nicotine information [19, 41–44]), regulators should also consider stronger marketing restrictions regarding the promotion of R/S nicotine products, so they are not incorrectly believed to be safer [40]. Lastly, it is recommended that policymakers and regulators use language that is not only inclusive of the full range of nicotine isomers currently available, but that is also inclusive enough to apply to products that may emerge in the future [40].

Study strengths, limitations, & directions for future research

The present study is, to our knowledge, the first to examine the prospective associations between nicotine type and youth e-cigarette use. By using data from a longitudinal cohort study, we were able to clarify temporal associations and examine the role of nicotine type in “real-world” scenarios. There were, however, limitations. As participants were not randomly assigned to an e-cigarette brand at baseline, it is possible there were other, unmeasured differences between groups that could have contributed to our observed effects. It is also possible that there were other differences between brands, beyond nicotine type, that could have confounded our results. Although longitudinal studies can control for some confounding, it is difficult to account for all factors that could influence our study’s variables. It is also worth noting that our flavor analyses compared fruit, mint/menthol, and no preference; other studies have found stronger effects when comparing against a “no-flavor” or “tobacco-flavor” category. Effects may have also been biased by attrition (we had 63% retention at the 12-month follow-up among those using e-cigarettes) and a somewhat small sample size. Our sample was also limited to a single U.S. state, and results may not generalize to locations with different e-cigarette markets or advertising environments. Our study also did not consider intersectional factors that could impact a youth’s e-cigarette use. For example, sexual minority Black girls are more likely to currently use e-cigarettes compared to their heterosexual counterparts [45]. Future studies should consider interactions with other risk factors to best promote health equity. Finally, data were collected throughout a dynamic regulatory period in the U.S. For example, in 2020 (prior to the start of data collection), the U.S. FDA restricted flavors other than menthol or tobacco in mod pod e-cigarettes devices [19]. This led to an increase in sales of disposable e-cigarettes. And in April of 2022 (near the end of data collection for our 12-month follow-up), the FDA gained authority to regulate synthetic nicotine as a tobacco product, which hampered Puff Bar sales [19]. Future studies should examine whether similar outcomes appear under different regulatory landscapes and with different brands.

Conclusions

Overall, our study findings support what researchers have been saying for years about youth and e-cigarettes: “They come for the flavours, but stay for the nicotine.” [46] In other words, it is the nicotine that leads to addiction [9, 10, 13, 47]—and likely perpetuates e-cigarette use. These findings underscore the critical need for further regulation of R/S nicotine devices, including product standards, labeling requirements, and marketing restrictions.

Authors’ contributions

TH and MR conducted the analyses and wrote the first manuscript draft. AF, BL, and DW reviewed the first draft and provided substantiative comments. All authors read and approved the final manuscript.

Funding

This paper was supported by American Heart Association grant 20YVNR35490079 and by grant U54CA287392 from the NCI and FDA Center for Tobacco Products (CTP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the FDA.

Data availability

Per our IRB protocol, data are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved as protocol #2020C0200 by The Ohio State University IRB, which adheres to the ethical standards for the protection of research participants summarized by the Belmont Report and the Declaration of Helsinki. Informed consent and/or assent was obtained for all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.