3.1. What We Learned
The observational case for e-cigs as smoking cessation aids is as strong as ever. There is clearly a large group of smokers for whom e-cigs are superior to conventional aids. Nevertheless, there is another large group for whom e-cigs are not interesting or do not work. Current e-cigs will not quickly end smoking, not because they are a gateway to smoking, but because they are not effective enough for every smoker.
Adolescents with smoking risk factors sometimes become e-cig users, but their usual history is that they smoke first. The data are consistent with the hypothesis that adolescents in search of thrills or solace try a variety of risky behaviors, among which e-cigs are one of the least-damaging options. Nevertheless, even this choice could portend a lifelong change in neural function. We need other ways for adolescents to find purpose and contentment.
E-cig and dual users experience about the same declines in some dependence measures that could reflect nicotine clearance. This hints at comparable changes in CYP2A6 activity in e-cig and dual users. Dual users appear to smoke in response to particular cues. If these findings are confirmed, we may need to focus attention on the central nervous system to understand dual use.
At least some vape shops are useful for educating and encouraging new e-cig users. Vape shop personnel can be more knowledgeable than medical staff about both smoking and e-cigs. Online support is also effective.
3.2. What We Want to Learn
There is a lot more to know about e-cig aerosols. We know little about particle evolution in vivo, including dynamic partitioning of semi-volatile compounds between particles and gas phase, which will affect deposition patterns, nicotine delivery, and risk. An efficient process for evaluating and monitoring the myriad flavors could be useful. Additionally, the impact of relatively new developments on safety, such as the substitution of silica wick with cotton and the availability of temperature control, have not been studied. Bystander exposure and health effects will be small but deserve evaluation.
Comparative nicotine metabolism in e-cig users and smokers deserves study. The behaviors repeatedly documented in this special issue [27
] and previous work [40
] cannot be explained by nicotine absorption alone, no matter how efficiently an e-cig aerosol delivers nicotine. Furthermore, the efficiency of current e-cig designs does not explain how older e-cigs changed conventional nicotine dependence measures. These changes continue to suggest a major alteration of nicotine pharmacokinetics, such as creation of a nicotine reservoir or impaired clearance, for instance by the inhibition of CYP2A enzymes [10
The utility of e-cigs as smoking cessation aides remains uncertain, with observational and anecdotal evidence of value, and weak evidence from randomized trials [43
]. At least moderate-sized randomized controlled trials are needed to compare e-cigs to conventional smoking cessation options. However, e-cig use is a behavioral intervention, and randomized trials so far have failed to take into account issues such as flavors preferences, different nicotine levels according to personal need, and throat hit sensitivity. Thus, randomized trials should be designed in a more “unconventional” way compared to trials for medications and should also consider the rapid evolution and development of better-performing devices [44
]. In addition to tracking smoking status and nicotine use, trial designs ought to collect data on illness; costs to users, employers, and insurers; and quality of life. Trials ideally would plan to determine if cessation aide failures are associated with genetic, clinical, environmental, or intervention variables, or interactions thereof.
At least one efficacy trial is needed in which the e-cig arm offers tank-style e-cigs and realistically managed e-liquids, and includes vetted vape shops and Internet sites for counseling and social support. The conventional arm should deliberately tailor state-of the art NRT and prescription options, marshal friends and families for social support, and offer formal smoking cessation classes and physician visits.
Comparable but distinct effectiveness trials also are needed. At least one of these should employ methods suitable for a busy primary care office, e.g., recommend smokers to e-cigs or a conventional treatment, with passive recommendations for finding advice and support from vetted sources. Such pragmatic trials are expected to provide even more valuable information than randomized controlled trials about the impact of e-cigs on smoking status in daily clinical routine.
There are opportunities to improve observational studies. Most surveys related to nicotine use should include questions that attempt to classify respondents’ nicotinic receptor status and nicotine clearance rates, and attempt to identify and rank the common reasons for using nicotine. The amount of nicotine used is easily calculated from volume and concentration, and should be evaluated as a measure of nicotine use. It will be instructive to know whether or not this correlates with addiction, clearance, and behavior. Additionally, use patterns should definitely consider frequency of use. While “ever use of an e-cig” is of minimal interest per se (it is very unlikely to be associated with any risk and equally unlikely to result in smoking behavior changes), the definition of current use as any past 30-day use has also been shown to include a lot of experimenters [45
]. Some harm from e-cig aerosol inhalation is likely, but usually will be overwhelmed by the benefits of smoking cessation. Large data sets with detailed information on changes in smoking and amounts of e-liquid and nicotine consumed may allow health outcome prediction models to disentangle the benefits of smoking reduction and harms of e-cig aerosol inhalation.