Nicotine—Friend or Foe? The Complex Interplay Between Its Role in Dependence, Harm Reduction, and Risk Communication

Our field has a difficult relationship with nicotine. On the one hand, Michael Russell’s famous observation “People smoke for nicotine, but they die from the tar”¹ paved the road for the development of effective smoking cessation treatments in the 1980s, including nicotine replacement therapy (NRT), which helped drive down smoking rates. Over 20 years later, the proliferation of e-cigarettes, delivering nicotine effectively without combustion, meant that harm reduction became a reality. E-cigarettes help those unable or unwilling to stop smoking with medication to switch to a reduced-risk product without complete cessation of tobacco constituents, namely nicotine, resulting in ever-lower smoking rates.² On the other, we know that nicotine is not an innocuous substance. There are well-documented cardiovascular effects,³ nicotine is dependence-forming and may impact the developing brain.⁴ The increasing youth use of e-cigarettes, first seen in the United States⁵ and now in Europe,⁵ is therefore concerning, particularly if it occurs among never-smoking adolescents. This issue of NTR sheds some light on the multifacted role that nicotine plays in our efforts to curb the tobacco epidemic and the need for nuanced communication regarding its effects.

Huang et al.’s study⁶ underlines nicotine’s utility for testing of potential medications to treat tobacco addiction. In a rodent model, dextromethorphan (a cough suppressant used in over-the-counter medication) was shown to reduce nicotine-induced reward and drug-seeking behavior in nicotine-dependent rats during withdrawal. Of course, such animal models using nicotine rely on this being a useful proxy for studying human addiction. One concern is that these models use noncontingent administration rather than self-administration, as is the case for smokers. Chellian et al.’s review⁷ summarizes that, similar to humans, rodents become gradually dependent on nicotine over time across various self-administration paradigms, highlighting the usefulness of this approach. Complementing growing evidence that e-cigarettes use may result in dependence in humans, nicotine aerosol self-administration also leads to dependence in rodents. However, animal models exclusively use adult rodents and, it is argued, using newer self-administration paradigms, the gradual development of dependence needs to be studied over a longer time, starting in adolescence, to increase ecological validity, and reflect human experience.

The paper by Walters et al.⁸ dives deeper into the drivers of dependence in young adulthood, showcasing the use of ­nicotine craving as a tool for investigating potential behavioral interventions. In this ecological momentary assessment study, 18–25-year-old smokers and vapers were asked to stop product use and, via periodical app prompts, recorded positive and negative affect, emotion differentiation (the ability to distinguish emotional states), and craving over a month. Both positive and negative affect were associated with greater cravings in the moment, but this relationship was attenuated among those with higher negative emotion differentiation. This suggests heightened emotional states may be misinterpreted as nicotine cravings for those with low emotion differentiation. As a modifiable treatment target, training in emotion differentiation may therefore support young adults particularly vulnerable to intense affect to stop product use. At the population level, Teh et al.’s age-period-cohort model⁹ assesses changes in smoking intensity across cross-sectional representative surveys in Malaysia, covering a 20-year period. Although smoking intensity, operationalized as cigarette consumption, is an imperfect measure of addiction,¹⁰ there are two key findings here relevant to the discussion of nicotine dependence and harm reduction. First, more recent cohorts displayed higher smoking intensity, consistent with the much debated “hardening hypothesis”¹¹—the idea that those persisting with smoking over time will be more resistant, hard-core smokers. Notwithstanding the fact that this recency effect may reflect other sociocultural differences, it also underscores the need for harm reduction to help those increasingly more addicted smokers to switch away from combustible cigarettes. Second, smoking intensity increased up to the age of 60, again supporting the “hardening hypothesis,” but the authors also link it to early smoking initiation, more common in older smokers. As also discussed in Chellian et al., this highlights the developmental stage-dependent effects of nicotine, with earlier exposure related to later, more powerful cigarette addiction and thus nicotine dependence.

This leaves us with a conundrum. Nicotine has been invaluable for the development of effective cessation treatment and harm reduction methods for addicted smokers. However, many in our community are deeply concerned about the increasing availability of nicotine in appealing e-cigarettes, which—even if these may divert youth away from cigarettes,¹² the most harmful of nicotine-delivery products—may lead to a new wave of nicotine-dependent adolescents, with all the unknowable effects this entails. So, how should we ­communicate the risks of nicotine? The quixotic attitude towards nicotine in our field has unintended consequences elsewhere. O’Brien et al.’s study of adolescents in the PATH study¹³ confirms findings in adults, including medical professionals,¹⁴ that nicotine is believed to cause smoking-related harms beyond addiction, such as cancer. Encouragingly, those having higher risk perceptions were less likely to start using nicotine-containing products a year later. Concerningly, even among adolescent smokers nearly half believed that nicotine in NRT was harmful, which may reduce the use of effective medication to help them stop smoking. Similarly, Emery et al.,¹⁵ reporting on the development of a questionnaire on NRT for smoking cessation in pregnancy, acknowledge the need to take misperceptions about nicotine in NRT into account and assess these. This new scale can be used to measure beliefs prior to treatment and, if necessary, address wrong beliefs to increase low adherence rates to NRT in this population. Both studies highlight the very real implications of the, at times, problematic treatment of nicotine in research, driven mainly by concerns about nicotine dependence per se. Clearly, no one wants to see a generation of nicotine-dependent youth, and more effective measures to limit access to nicotine, especially combustible nicotine, are needed. But when it comes to communicating research to the wider public, we must avoid conflating the relatively limited harm of nicotine dependence with its effects on maintaining tobacco addiction, and therefore well-established tobacco-related harm, not least because of the impact this has on risk perceptions of those most in need of nicotine-based treatment: Tobacco users.

Funding

This work was supported by Cancer Research UK grants (C27061/A24788; PPRCTAGPJT\100009 and PRCRPG-Nov21\100002).

Author Contributions

LS conceived of and wrote this editorial and is guarantor for the article.

Declaration of Interest

LS has received a research grant and honoraria for a talk and travel expenses from manufacturers of smoking cessation medications (Pfizer and Johnson & Johnson). The author has never received personal fees or research funding of any kind from electronic cigarette or tobacco companies.