Higher nicotine content and flavors increase e-cig abuse liability

As debates over nicotine and flavors in e-cigarettes continues to heat up, Mari Gades, Aleksandra Alcheva, Amy Riegelman, and Dorothy Hatsukami just published “The role of nicotine and flavor in the abuse potential and appeal of electronic cigarettes for adult current and former cigarette and electronic cigarette users: A systematic review” in Nicotine and Tobacco Research. This comprehensive review summarizes and synthesizes results from 104 epidemiological studies ranging from human epidemiology to animal studies. The picture that emerges is very clear: “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.”

In particular:

  • Increased nicotine concentrations in e-liquid were associated with higher abuse potential and appeal in animals and for adult cigarette, e-cigarette, and dual users.
  • Flavors, especially non-tobacco flavors, were related to increased abuse potential, especially through increasing the appeal of e-cigarettes.
  • While nicotine and flavor have their own rewarding effects, their interaction may further increase the abuse potential and appeal of an e-cigarette through decreasing negative sensory experiences and increasing positive ones.

The major substance of the scientific review is thorough and represents an important contribution to our understanding of how nicotine levels and flavors impact abuse liability of e-cigarettes.

The paper, unfortunately, is shallow when assessing the health and policy implications of these findings.

In particular, the authors see higher abuse potential and product appeal as a good thing because is “may help facilitate complete switching from cigarettes to e-cigarettes.”  (The FDA made the same assumption when authorizing the sale of Vuse Solo e-cigarettes.) 

The authors take it as given that e-cigarettes are an effective smoking cessation tool (for “switching completely”), positing that, “Despite the controversy, there is ―moderate-certainty evidence that [e-cigarettes] with nicotine increase quit rates compared to [nicotine replacement therapies].” This statement is based on a citation to a single Cochrane review of randomized controlled trials and uncontrolled intervention studies. These studies are relevant to use of e-cigarettes as supervised medical interventions.

In contrast, the authors ignore the much larger body of strong and consistent evidence that, when used as consumer products, e-cigarettes don’t help smokers quit. Indeed, two recent large-scale national longitudinal population studies of smokers interested in quitting show that e-cigarettes (as consumer products) make it harder not easier to quit smoking.

In light of this fact and because they only consider the Cochrane review of e-cigarettes as medicines, Gades and colleagues’ conclusion that “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” is only relevant to FDA and other regulatory body decisions about whether, and under what circumstances to authorize use of e-cigarettes as medicines.

Given the high abuse potential, the implications of their results are, however, just the opposite of what they say when considering e-cigarettes as consumer products, particularly because the authors did not consider the youth literature.  In fact, the high abuse liability that they so carefully document is yet a powerful reason to ban flavors and limit nicotine levels in the consumer market, which is also widely accessible to kids.

Rather than engaging the true implications of the fact that flavors increase abuse liability, the authors simply state, “Other regulatory strategies such as restrictions on marketing, access and sales of e-cigarette to youth might be considered over flavor bans and caps on nicotine concentrations in e-liquids to attenuate adolescent uptake while allowing adults to use this nicotine product as a harm reduction tool for cigarette smokers.”  The FDA (and others) have been trying to restrict youth access to e-cigarettes since they came on the market 15 years ago.  While this is an important thing to do, it has not prevented the epidemic of youth e-cigarette use.  While restrictions on advertising is also a good idea, the FDA has been reluctant to exercise its authority in this area, probably because of concern that the Supreme Court would simply strike down such rules as a violation of the First Amendment.

The appropriate conclusion to draw from the compelling data that Gades an colleagues summarize on the high abuse potential of flavored e-cigarettes would be to make them available a prescription cessation medicines, assuming that the risk/benefit ratio was favorable. 

Limiting e-cigarettes to prescription use would accomplish two good things: (1) It would ensure that they are available to interested adults and administered used under medical supervision are similar to the clinical trials that Cochrane reviewed; and (2) It would make it much more difficult for kids to get them.

Another benefit of limiting e-cigarettes to supervised use as medicines would be to cut down on unsupervised use and reduce the chances that e-cigarettes actually make it harder for adults to stop smoking cigarettes.  This is key since the only studies showing positive effects of e-cigarettes on helping adults quit cigarettes are those involving supervised care.

One could argue that this is being overly restrictive because NRT is available over the counter and e-cigarettes should not be restricted more than NRT.  There are two problems with this argument.  First, NRT was approved as a medicine – not a consumer product – by the FDA Center for Drug Evaluation and Research.  More important, NRT, used over the counter does not help smokers quit and may actually lower quitting.  To be effective, it needs to be used as part of a smoking cessation intervention, combined with counseling.

The tobacco companies have known this since the 1900s, which is why they don’t oppose NRT.  Indeed, some tobacco companies have started marketing nicotine products under the guise of being OTC NRT.

Thus, the scientific results in this paper combined with the full range of evidence on the effects of e-cigarettes on smoking cessation actually represent a strong contribution to the case for banning flavors in e-cigarettes sold as consumer products.

Here is the abstract:

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.

The full citation is: Gades MS, Alcheva A, Riegelman AL, Hatsukami DK. The role of nicotine and flavor in the abuse potential and appeal of electronic cigarettes for adult current and former cigarette and electronic cigarette users: A systematic review. Nicotine Tob Res. 2022 Mar 19:ntac073. doi: 10.1093/ntr/ntac073. Epub ahead of print. PMID: 35305014. It is available here.

Nicotine and Tobacco Research published a letter from me making similar points on April 2, 2022.

Published by Stanton Glantz

Stanton Glantz is a retired Professor of Medicine who served on the University of California San Francisco faculty for 45 years. He conducts research on tobacco and cannabis control and cardiovascular disease/

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