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Introduction Many adult cigarette smokers use electronic cigarettes (e-cigarettes) to cut down on or quit smoking cigarettes. E-cigarettes with higher abuse potential and appeal might facilitate complete switching. E-liquid nicotine concentration and flavor are two of the characteristics that may affect the abuse potential and appeal of e-cigarettes. The objective of this systematic review was to compile results from survey, animal, human laboratory, and clinical studies to understand the possible effects of nicotine concentration and flavor on abuse potential and appeal of e-cigarettes in adult current and former cigarette and e-cigarette users. Methods A comprehensive literature search was conducted in Ovid Medline and PsycINFO followed by citation tracking in Web of Science Core Collection. Peer-reviewed studies published in English between 2007 and August 2020 were selected that analyzed differences between e-liquid nicotine concentration and/or flavors, had outcome measures related to abuse potential and/or appeal, and included adult humans (18+) or animals. 1624 studies were identified and screened. A qualitative synthesis of results was performed. Results Results from 104 studies included in this review suggest that higher nicotine concentration and access to a variety of flavors are likely to be associated with higher abuse potential and appeal of e-cigarettes for adult current and former cigarette and e-cigarette users. Conclusions Higher nicotine concentrations and the availability of a variety of flavors in e-cigarettes might facilitate complete substitution for cigarettes. Future e-cigarette regulations should take into account their impact on smokers, for whom e-cigarettes may be a cessation tool or reduced-harm alternative. Implications E-cigarettes may provide a reduced-harm alternative to cigarettes for smokers unwilling/unable to quit or serve as a path for quitting all nicotine products. Higher nicotine concentrations and flavor variety are associated with higher abuse potential and appeal of e-cigarettes. Higher abuse potential and appeal products may help facilitate complete switching from cigarettes to e-cigarettes. Regulation of nicotine concentration and flavors aimed at decreasing naïve uptake may inadvertently decrease uptake and complete switching among smokers, reducing the harm reduction potential of e-cigarettes. Evidence-based effects of regulating nicotine concentration and flavors must be considered for the population as a whole, including smokers.

Conventional tobacco cigarettes appear to have greater abuse liability than non-combusted products such as electronic cigarettes (ECs) and nicotine replacement therapy (NRT). This may be due to the higher levels of behaviorally active non-nicotine constituents [e.g., monoamine oxidase (MAO) inhibitors such as β-carbolines] in cigarette smoke (CS) compared to non-combusted products. To evaluate this hypothesis, the current studies compared the relative abuse liability of CS and EC aerosol extracts containing nicotine and a range of non-nicotine constituents to that of nicotine alone (NRT analog) using intracranial self-stimulation (ICSS) in rats. Effects of formulations on brain MAO activity in vitro and ex vivo were also studied to evaluate the potential role of MAO inhibition in the ICSS study. CS extract contained higher levels of several behaviorally active non-nicotine constituents (e.g., the β-carbolines norharmane and harmane) than EC extract. Nicotine alone reduced ICSS thresholds at a moderate nicotine dose, suggesting a reinforcement-enhancing effect that may promote abuse liability, and elevated ICSS thresholds at a high nicotine dose, suggesting an aversive/anhedonic effect that may limit abuse liability. CS extract elevated ICSS thresholds to a greater degree than nicotine alone at high nicotine doses. Effects of EC extract on ICSS did not differ from those of nicotine alone. Finally, CS extract significantly inhibited MAO-A and MAO-B activity in vitro, whereas EC extract and nicotine alone did not. None of the formulations inhibited MAO measured ex vivo. These findings indicate greater acute aversive/anhedonic effects for CS extract compared to nicotine alone, suggesting lower abuse liability. Although confirmation of our findings using other dosing regimens, preclinical addiction models, and tobacco product extracts is needed, these findings suggest that the centrally-mediated effects of MAO inhibitors and other non-nicotine constituents may not account for the greater abuse liability of cigarettes compared to non-combusted products. Nonetheless, identifying the specific constituent(s) mediating the effects of CS extracts in this study could help clarify mechanisms mediating tobacco addiction and inform FDA product standards.

Exposure to tobacco smoke chemicals and toxicants may cause unique changes to an individual’s oral microbiome, impacting immuno-inflammatory responses, the metabolism of tobacco smoke carcinogens, and overall health status. In our previous study, HPB-releasing DNA adducts (DNA damage derived from tobacco-specific nitrosamines) were higher in oral cells of African American (AA, n=75) when compared to White (WH, n=71) persons who smoke, even after adjusting for key confounders such as smoking dose. In this study, we examined the relationship between the levels of HPB-releasing DNA adducts and microbiome composition in these individuals. 16S rRNA gene sequencing, targeting the V4 hypervariable region, was performed on DNA isolated from mouthwash samples. Sequences were clustered into Amplicon Sequence Variants (ASV) using QIIME, and metagenomic content was inferred using PICRUSt. Our results showed a significant difference in alpha-diversity metrics: observed richness and Shannon indexes (Kruskal-Wallis test, H = 8.42, p <0.01 and H = 6.85, p <0.03, respectively) across levels of DNA damage (low, intermediate, and high). Post hoc tests with pairwise comparisons showed that, for both indexes, individuals with high levels of HPB-releasing DNA adducts had significantly lower alpha diversity than those with intermediate levels (p <0.05). However, there were no differences in beta diversity as measured by Bray-Curtis (R2 = 1.15, p = 0.2) and Jaccard (R2 = 1.1, p = 0.1) indices across individuals with different levels of HPB-releasing DNA adducts. Multivariable association tests revealed that high levels of the DNA adducts were positively associated with Enterobacteriaceae, while intermediate levels were associated with Porphyromonas endodontalis, Prevotella spp, Neisseria spp, Actinomyces spp, and Fusobacterium. In addition, predicted functional profiling showed that intermediate levels of HPB-releasing DNA adducts were positively associated with amino acid, carbohydrate, and hem biosynthesis, along with reductive tricarboxylic acid cycle and formaldehyde degradation pathways. Comparisons between AA and WH persons who smoke showed that AA had significantly higher alpha diversity as assessed by observed bacterial richness and The Shannon index (Wilcoxon rank-sum tests, q-value=0.03 and 0.004, respectively). Differences between AA and WH were also found for beta diversity (Bray-Curtis: R2=2.4, p=0.01, Jaccard: R2=1.9, p=0.01, weighted Unifrac R2=0.02 p=0.007). The abundance of taxa associated with intermediate levels of DNA damage (Prevotella spp, Neisseria spp, Actinomyces spp, Fusobacterium) was also higher in AA persons who smoke. Together, our findings suggest that certain compositional and functional characteristics of the oral microbiome may serve as indicators of macromolecular responses to harmful chemical exposures from tobacco. The potential mechanistic contribution of the oral microbiome to such responses and its potential role in the observed racial/ethnic differences in cancer risk due to smoking should be further investigated. Citation Format: Aleksandra Alcheva. Relationship between the oral microbiome and tobacco-induced DNA damage in African American and White persons who smoke [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C030.