A Randomized Trial Comparing the Effect of Nicotine Versus Placebo Electronic Cigarettes on Smoking Reduction Among Young Adult Smokers

Abstract

Introduction:

Electronic cigarette (EC) use is growing dramatically with use highest among young adults and current smokers. One of the most common reasons for using ECs is interest in quitting or reducing cigarettes per day (CPD); however there are few randomized controlled trials (RCT) on the effect of ECs on smoking abstinence and reduction.

Methods:

We conducted a two-arm; double-blind RCT. Subjects were randomized to receive 3-weeks of either disposable 4.5% nicotine EC (intervention) or placebo EC. The primary outcome was self-reported reduction of at least 50% in the number of CPDs smoked at week 3 (end of treatment) compared to baseline. Study subjects (n = 99) were young adult (21–35), current smokers (smoked ≥ 10 CPDs) living in NYC.

Results:

Compared with baseline, a significant reduction in CPDs was observed at both study time periods (1 and 3 weeks) for intervention (P < .001) and placebo (P < .001) groups. Between-group analyses showed significantly fewer CPDs in the intervention group compared to the placebo group at week 3 (P = .03), but not at any other follow-up periods. The logistic regression analysis showed that using a greater number of ECs, treatment condition and higher baseline readiness to quit were significantly associated with achieving at least 50% reduction in CPDs at the end of treatment.

Conclusion:

A diverse young adult sample of current everyday smokers, who were not ready to quit, was able to reduce smoking with the help of ECs. Further study is needed to establish the role of both placebo and nicotine containing ECs in increasing both reduction and subsequent cessation.

Implications:

Despite the critical need for well-designed clinical trials on the effect of ECs on cessation and cigarette reduction, the majority of studies have been observational or noncomparative intervention designs. Only three RCTs studying ECs as a cessation or reduction intervention have been published, and none were conducted in the United States. The current study adds knowledge to current literature on the feasibility of using ECs to aid smoking reduction among young smokers in US urban populations.

Introduction

Electronic cigarettes (ECs) are battery-powered devices that deliver vaporized nicotine to the user. Introduced in the United States in 2007, EC use among adults over age 18 has grown dramatically. An analysis of mixed-mode cross sectional surveys in each of 4 years from 2010 to 2013 found significant increases in current use from 0.3% in 2010 to 6.8% in 2013.¹ In 2013 ever and current use was highest among young adults 18–24 (current use 14.2%) and current smokers (current use 30.3% among daily smokers and 34.1% among nondaily smokers). The most common reasons for using ECs include interest in quitting or reducing smoking, seeking a less harmful alternative to combustible cigarettes, and dealing with withdrawal symptoms.^2,3

Although meta-analyses have documented that FDA-approved cessation medications such as nicotine replacement therapy (NRT) can significantly increase quit rates, fewer than 20% of smokers use these products during a quit attempt.⁴ ECs’ growing popularity among smokers, likely attributable to their sensorimotor mimic of cigarette smoking, may suggest a more acceptable and satisfying nicotine delivery system with potential to increase uptake of NRT if cessation rates are found to be comparable to current FDA approved cessation medication options.

Several studies have shown that ECs can reduce nicotine craving and withdrawal symptoms and may be useful as an aid for smoking reduction or cessation.^3–10 In a recent Cochrane report, combined data from two randomized controlled trials found that use of nicotine-containing ECs was associated with higher smoking abstinence rates than placebo EC use (RR 2.29, 95% confidence interval [CI] 1.05 to 4.96).¹⁰ One of the studies included a comparison between nicotine containing EC and nicotine patch and found no difference in 6-month carbon monoxide (CO)-validated smoking abstinence rates.¹¹

These two studies in the Cochrane report also examined the effect of ECs on smoking reduction.^11,12 Both nicotine and placebo ECs were associated with smoking reduction, but nicotine-containing ECs were significantly more effective than placebo, and in combined analysis, were significantly more effective than nicotine patches in helping people achieve 50% or greater reduction in smoking. These findings suggest a potential role for ECs as a strategy for pre-cessation smoking reduction for smokers who are not yet ready to quit. Pre-cessation NRT had been shown to increase the odds of reducing CPD by 50% or more compared to placebo.¹³

Despite the critical need for well-designed clinical trials on the effect of ECs on cessation and cigarette reduction, the majority of studies have been observational or noncomparative intervention designs.^10,14 Only three randomized controlled trials studying ECs as a cessation or reduction intervention have been published, and none were conducted in the United States.^11,12,15 In response to this research priority, we conducted a two-arm double blind randomized controlled trial to compare the effect of nicotine-containing EC versus placebo EC on smokers’ ability to achieve a 50% or greater reduction in baseline cigarette consumption. Given the disproportionally high rates of EC use by young adults we focused our recruitment on this population of smokers.^16,17 Our hypothesis was that subjects in the nicotine EC arm would be more likely to reduce cigarettes smoked per day by 50% or more compared with placebo EC.

Methods

Study Design

We conducted a two-arm; double blind randomized controlled pilot study. Subjects were randomized to receive 3 weeks of disposable 4.5% nicotine EC (intervention) or non-nicotine EC (placebo). The nicotine ECs used were NJOY, King Bold (NJOY, Inc, Scottsdale, AZ) which resemble the look of conventional cigarettes.¹⁴ NJOY also manufactured the placebo EC. Both nicotine and placebo ECs were tobacco flavored. The products were purchased by the investigators and provided to the subjects free of charge. The randomization scheme was computer generated by using randomly permuted blocks of sizes 2, 4, and 6, and was concealed from research assistants. Blinding of the allocation of nicotine or placebo EC was ensured by the identical appearance of the ECs.

Subjects were screened by phone to assess eligibility and then completed an in-person baseline assessment after providing written consent. Prior to receiving the ECs, subjects were required to complete a 20- to 30-minute telephone counseling session with a trained tobacco cessation counselor. The purpose of the telephone counseling was to review current smoking patterns and offer behavioral and environmental change strategies. These included specific smoking reduction options, such as eliminating cigarettes at work and in the home, carrying only those cigarettes needed for that day, dropping cigarettes associated with less intense triggers first, avoiding smoking triggers, and other strategies to manage urges.¹⁸ Subjects were asked to reduce the number of cigarettes smoked daily by at least 50% of the total number of cigarettes smoked per day at baseline. This threshold level was selected a priori as a clinically significant measure of reduction.^10,19 Upon completion of the counseling session, subjects picked up a 1-week supply of disposable NJOY ECs (placebo or intervention EC). To ensure enough ECs were provided to displace half of baseline cigarette use, we calculated number of ECs needed, based on the manufacturer’s estimates, at the rate of one EC to every three conventional cigarettes. To mimic real-life EC use, we provided minimum EC use instruction. Subjects were encouraged to replace cigarettes with as much or as little use of an EC as needed in order to reduce nicotine withdrawal symptoms. At the end of 1-week of EC use, subjects were asked to return for a 2-week supply of ECs and to complete a second in-person assessment. An end-of-intervention assessment was conducted 3 weeks after starting ECs. To achieve targeted retention rates, we attempted to contact subjects up to 10 times to schedule or reschedule study visits and allowed up to four no shows for each data collection time period.

Participants

Subjects were recruited through advertisements placed in Craigslist as well as flyers distributed on the street and placed in New York City venues with details for how to contact study staff. Eligibility criteria included age 21–35 (confirmed with some form of identification document), daily smoker, smoked ≧ 10 cigarettes a day (verified by a CO level of ≥ 8 ppm), interested in reducing cigarette consumption, able to provide consent, had a cell phone and was willing/able to receive text messages and counseling on their cell phone, and willing to use an EC for 3 weeks. Individuals were excluded if they were pregnant and/or breastfeeding, had a history of asthma, other airways diseases, or heart disease, were currently using smoking cessation medications (including other forms of NRT, bupropion, or varenicline), or enrolled in a smoking cessation program or another cessation trial. Other exclusion criteria included having used an EC in the past 14 days or any other tobacco products (pipe, cigar, cigarillos, snuff, chewing tobacco, rolling tobacco, or hookah/shisha) in the past 30 days, having a moderate to severe drug use disorder defined as a score of at least 5 on the Drug Abuse Screening Test-10 and/or a hazardous or active alcohol use disorder defined as at least 7 for men and at least 5 for women on the Alcohol Use Disorders Identification.^20,21

Measures

Outcome Measures

The primary outcome was self-reported reduction of at least 50% in the number of cigarettes/day smoked at 3-week follow-up compared to baseline. We also examined the percent reduction in number of cigarettes per day (CPD) from baseline. At the 1- and 3-week follow-up assessments, subjects were asked to bring back all used and unused ECs in an effort to verify self-reported EC use. Use of ECs was calculated as the number of completed ECs divided by number of days since last visit. At each follow-up visit, we also measured 7-day point prevalence abstinence validated by alveolar CO levels, satisfaction with ECs (single question on a 5-point likert scale from strongly disagree to strongly agree: overall, I like using e-cigarettes), adverse events and symptoms related to EC use.

Baseline Measures

Nicotine dependence was evaluated using the Heaviness of Smoking Index, which uses a four-category scoring scheme for “time to the first cigarette of the day” and “average daily consumption of cigarettes.”²² Behavioral dependence was measured by the 11-item Smoking Behavioral Dependence Scale, which uses a 5-point likert scale.²³ Smoking cessation self-efficacy was assessed by a single question: “How confident are you that you could quit smoking completely and stay quit” on a scale of 0–10 (0 = not confident at all, 10 = extremely confident), and readiness to quit was assessed using the Readiness to Quit Ladder.²⁴

Data Analysis

We conducted both intent-to-treat and per-protocol analyses (completers). Using the intent-to-treat approach, all 99 eligible subjects who completed baseline assessment were included, and those with missing data were treated as having experienced no reduction in cigarettes smoked per day. In per-protocol analyses, only subjects who completed follow-up assessments were included. Baseline characteristics were described and compared between two treatment groups using t tests and chi-square analyses (Table 1). We used repeated measures analysis of variance to examine both within-subject changes in CPD and between-group differences in CPD at each time period for both groups (Figure 1). Variables demonstrating significant or marginally significant (P < .10) bivariate associations (Table 2) with 50% smoking reduction were included in a multiple logistic regression analysis to examine the contribution of the predictors to the smoking reduction outcome (Table 3).

Table 1.

Baseline Characteristics

Baseline variable	Mean ± SD, n (%)a
	Total (N = 99)	Nicotine EC (N = 50)	Placebo EC (N = 49)	P b
Demographics
Age in years	28.43±4.07	27.90±4.01	28.98±4.11	.789
Gender
Female	32 (32.3%)	16 (32.0%)	16 (32.7%)	.945
Male	67 (67.7%)	34 (68.0%)	33 (67.3%)
Education
HS degree or less	25 (25.3%)	9 (18.0%)	16 (32.7%)	.235
Some college	39 (39.4%)	21 (42.0%)	18 (36.7%)
College or post-graduate degree	35 (35.4%)	20 (40.0%)	15 (30.6%)
Race/ethnicity
Non-Hispanic African American/black	30 (30.9%)	16 (32.7%)	14 (29.2%)	.514
Non-Hispanic white	29 (29.9%)	17 (34.7%)	12 (25.0%)
Other non-Hispanic	14 (14.4%)	5 (10.2%)	9 (18.8%)
Hispanic of any race	24 (24.7%)	11 (22.4%)	13 (27.1%)
Tobacco use
Number of cigarettes per day	14.33±4.93	13.86±4.30	14.81±5.51	.343
Time to first cigarette
5 minutes or less after waking	22 (23.4%)	10 (21.3%)	12 (25.5%)	.923
6–30 minutes after waking	39 (41.5%)	19 (40.4%)	20 (42.6%)
31–60 minutes after waking	22 (23.4%)	12 (25.5%)	10 (21.3%)
>60 minutes after waking	11 (11.7%)	6 (12.8%)	5 (10.6%)
Made serious quit attempts (≥1 day) in last year	46 (46.5%)	25 (50%)	21 (42.9%)	.476
How confident are you that you could quit smoking  completely and stay quit (0–10 scale)	6.35±2.53	6.41±2.38	6.29±2.71	.809
Readiness to quit (1–10 scale, 1–8 apply to current smokers)	5.57±1.49	5.63±1.59	5.51±1.39	.685
Smoking behavioral dependence scale (11 items)
Mild	17 (17.2%)	9 (18.0%)	8 (16.3%)	.951
Moderate	51 (51.5%)	26 (52.0%)	25 (51.0%)
Strong to very strong	31 (31.3%)	15 (30.0%)	16 (32.7%)

EC = electronic cigarette; HS = high school.

^aValues are means with standard deviations or n with percentages in the column.

^b t tests were used for continuous variables and chi-square analyses were used for categorical variables.

Figure 1.

Time-course of changes in cigarettes consumption from baseline. Note: Error bars represent standard errors to the mean. Per-protocol evaluation of within-subject analyses showed significant reduction from baseline at each study visit for both groups (repeated-measure analysis of variance, P < .001 for Nicotine electronic cigarette [EC] and Placebo EC groups at both visits). When significant, between-group difference was indicated.

Table 2.

Bivariate Analyses on Correlates of 50% Smoking Reduction at Week 3^a

Variableb	OR	P	95% CI	N c
Demographics
Age in years	1.01	.820	0.92, 1.12	99
Gender
Male	ref	—	—	99
Female	0.55	.172	0.23, 1.30
Education
College or post-graduate degree	ref	—	—	99
Some college	1.97	.152	0.78, 5.01
HS degree or less	1.83	.254	0.65, 5.20
Race/ethnicity
Non-Hispanic white	ref	—	—	97
Non-Hispanic African American/black	1.07	.895	0.39, 2.98
Hispanic of any race	1.07	.907	0.36, 3.16
Other non-Hispanic	0.80	.739	0.22, 2.90
Baseline tobacco use
Baseline heaviness of smoking index (scores 0–6)	0.86	.389	0.61, 1.21	94
How confident are you that you could quit smoking  completely and stay quit (0–10 scale)	1.19	.045**	1.00, 1.40	99
Readiness to quit (1–10 scale, 1–8 apply to current smokers)	1.43	.018**	1.06, 1.93	99
Smoking behavioral dependence scale (11 items)
Strong to very strong	ref	—	—	99
Moderate	1.00	.996	0.41, 2.45
Mild	1.74	.367	0.52, 5.74
Treatment condition
Placebo	ref	—	—	99
Nicotine EC	2.01	.088*	0.90, 4.48
EC use
Number of ECs per day at week 1	1.77	.108	0.88, 3.55	80
Number of ECs per day at week 3	2.08	.053*	0.99, 4.35	76

CI = confidence interval; EC = electronic cigarette; HS = high school; OR = odds ratio.

^aMissing data in end-of-treatment cigarette consumption are considered as no reduction (intent-to-treat approach).

^bIn categorical variables, each group is compared with the reference group, which is marked as ref.

^cSubjects with missing data in each predicting variable are excluded from the bivariate analysis.

*P < .1; **P < .05.

Table 3.

Predictors of 50% Smoking Reduction at End-of-Treatment (n = 75)^a

Variable	OR	P	95% CI
Number of ECs per day at week 3	2.59	.033*	1.08, 6.23
Nicotine EC interventionb	3.20	.034*	1.09, 9.37
Baseline readiness to quit (1–10 scale, 1–8 apply to current smokers)	1.54	.026*	1.05, 2.26

CI = confidence interval; EC = electronic cigarette; OR = odds ratio.

^aMultiple logistic regression analysis is conducted using per-protocol approach to evaluate enrolled subjects who did not drop out. Three subjects with missing “number of ECs per day at week 3” and one subject with missing “baseline readiness to quit” are excluded from the analysis.

^bNicotine EC intervention is compared with placebo control.

*P < .05.

Results

A consort diagram is shown in the Supplementary Appendix. From July 1 through October 29, 2014, we screened 443 potential subjects for eligibility. Ninety-nine subjects were randomized and 81 and 79 completed the 1- and 3-week follow-up assessments, respectively. There was no difference in retention rates between the two study groups across study time periods. Table 1 shows that there were no significant baseline differences in demographic characteristics and tobacco use behavior between the two study groups. More than 50% of the sample was either black or Hispanic.

There was no difference in reported side effects between groups (34.1% for intervention and 17.5% for placebo group at week 1, P = .09; 22.5% for intervention and 10.3% for placebo group at week 3, P = .14; chi-square test) or between study time points in each group (P = .39 for intervention and P = .63 for placebo group; McNemar test). Common side effects included mouth or throat irritation, cough, insomnia or difficulty sleeping, abnormal dreams, headache and fatigue. At the 1- and 3-week visits, there were also no differences between the two groups in the number of ECs used per day (average number of EC ± SD at week 1 was 1.02±0.84 for intervention and 1.11±0.63 for placebo, P = .59 and at week 3 was 0.92±0.89 for intervention and 1.06±0.62 for placebo, P = .43; t tests) or satisfaction with ECs (70.7% intervention and 67.5% placebo group subjects strongly agreed or agreed that they liked using ECs at week 1, and 65.0% intervention and 71.8% placebo group subjects strongly agreed or agreed that they liked using ECs at week 3).

Figure 1 displays within-group changes and between-group differences in daily cigarette consumption from baseline to week 3. A significant reduction was observed at both follow-up visits (1 and 3 weeks) compared with baseline for intervention (P < .001) and placebo (P < .001) groups (pre-protocol evaluation). Between-group analyses showed significantly fewer CPDs in the intervention group than in the placebo group at week 3 (P = .03) but not at week 1 (P = .07). No between-group difference in exhaled CO was observed at any time point.

Table 2 shows correlates of 50% smoking reduction at week 3 (ie, end of treatment). Using an intent-to-treat approach identified significant and marginally significant associations between 50% smoking reduction at 3-weeks and the following variables: abstinence self-efficacy (odds ratio [OR] = 1.19, 95% CI = 1.00–1.40) and readiness to quit at baseline (OR = 1.43, 95% CI = 1.06–1.93), number of ECs used at week 3 (OR = 2.08, 95% CI = 0.99–4.35), and treatment group (56% of subjects in intervention group and 39% in placebo group achieved a 50% or more reduction in CPDs at 3-weeks, OR = 2.01, 95% CI = 0.90–4.48). Demographic variables, behavioral dependence and baseline heaviness of smoking were not correlated with the smoking reduction outcome.

The regression model is shown in Table 3. When included in a multiple logistic regression analysis using per-protocol approach, baseline abstinence self-efficacy was no longer significant and was therefore removed from the final analysis. The analysis revealed that treatment condition, EC consumption, and baseline readiness to quit smoking were all significant predictors of at least 50% smoking reduction at week 3. Using a greater number of ECs at week 3 was associated with reaching a 50% or greater reduction in smoking, with each additional EC used increasing the odds of a 50% reduction by 2.59 times (95% CI = 1.08–6.23). The odds of achieving at least 50% smoking reduction in users of nicotine ECs (intervention) was 3.20 (95% CI = 1.09–9.37) times the odds of those using placebo ECs.

Although the primary outcome of interest was smoking reduction, we also measured CO-validated smoking abstinence at week 1 and 3 follow-up visits. None of the subjects were abstinent at week 1, and three achieved CO-validated abstinence at week 3 (2 in Intervention and 1 in Placebo).

Discussion

A diverse young adult sample of current everyday smokers, who were not ready to quit, was able to reduce smoking with the help of ECs. Both groups (placebo and intervention [nicotine containing] EC) achieved significant reductions in overall number of cigarettes smoked per day with continued reductions over time. The intervention group was more likely to reduce by 50% or more at end of treatment (3 weeks), only after adjusting for EC consumption and baseline readiness to quit. The association between EC consumption and odds of achieving 50% smoking reduction at week 3 suggests that smokers were using ECs to displace cigarette use. However no early intervention impact on smoking reduction nor association between EC consumption and odds of achieving 50% reduction (data not shown, P = .51) was observed at week 1, suggesting there might be a learning curve for using ECs.

The significant decline in smoking among even the placebo group, and similar levels of satisfaction and number of ECs used per day, support an additional effect of ECs on non-nicotine related factors that sustain cigarette use.^25–27 Previous research has underlined the importance of the non-nicotine aspects of cigarette addiction.^27,28 Smokers enjoy the sensations and behavioral rituals (eg, hand to mouth gestures) related to cigarette smoking. When the sensory components of smoking were removed by local anesthesia of the respiratory airway, smoking satisfaction declines.^25,29 Smokers also exhibit preference to cigarette-like devices over other forms of nicotine administration.²⁷ For example, denicotinized cigarettes were found to substantially alleviate smoking withdrawal symptoms and craving, and were preferred over intravenous nicotine infusions among smokers.^30,31

The finding that use of placebo ECs can lead to levels of reduction that are almost equivalent to nicotine containing ECs is consistent with prior work. Caponnetto et al.’s three arm study comparing two levels of nicotine ECs to a placebo EC found that the observed reduction in CPD appear unrelated to nicotine content at most time points.¹² Similarly, Bullen et al. reported a borderline significant difference in the rate of smokers who reduced by 50% at 6 months between nicotine EC group and placebo EC group (57% vs. 45%, P = .08).¹¹ Placebo ECs also reduced cravings and withdrawal symptoms in the Bullen study.¹¹ Our findings and previous research suggest that ECs address sensorimotor behavioral dependence beyond the pharmacological benefit of nicotine replacement.³² ECs may therefore serve as a source of nicotine replacement for those who find FDA approved NRT unacceptable as well as a potential product to test recent proposals calling for tobacco product standards to reduce nicotine content levels to the point that they pose no threat of addiction.³³ Further studies comparing nicotine and placebo EC that include an assessment of the relative influence of nicotine and behavioral dependence could provide important information that may help differentiate those smokers for whom relief from behavioral cravings can lead to reduction and cessation from those who are unable to quit without nicotine.

Our findings also suggest that ECs may have a role in pre-cessation treatment for quitting smoking. A 2012 Cochrane analysis found that among smokers not ready to quit, reduction aided by NRT increases the probability of later quitting, and among smokers ready to quit, the success of abrupt and gradual cessation is identical. The reviewers concluded, therefore, that smokers could be given the choice to quit in either of these ways.³⁴ Concern that pre-cessation NRT use will result in fewer quit attempts and impede cessation has not been supported by the literature.³⁵ However, long-term studies are needed to examine whether EC-aided smoking reduction could ultimately lead to complete cessation or if instead it leads to persistent dual use, a consequence that could undermine rather than promote abstinence from combustible cigarettes.³⁶

One of the strengths of the study was the recruitment of a predominantly minority sample of young adult smokers demonstrating interest in EC use. Most existing research on use of ECs, including a number of large-scale observational studies, included predominately white smokers and did not report racial and ethnic variations.^2,6,37–39 Given the evidence that non-white racial/ethnic groups are less likely to use cessation aids⁴⁰ it is important to ensure that studies testing ECs as a pre-cessation or cessation strategy include minority populations. With an intensive follow-up protocol, we successfully demonstrated the feasibility of retaining a racially and ethnically diverse sample in the intervention for 3 weeks.

This study has several limitations. First, the sample size and intervention duration were modest. Post hoc power analysis indicates that this pilot study was under-powered to detect the small-moderate effect size observed in smoking reduction at the end-of-intervention. Detection of an effect similar in size to that observed here would have required a sample size of 90 participants in each arm (N = 180) to achieve statistical significance (with a type I error rate of 0.05 and type II error rate of 0.25). Despite being under-powered, the utility of the present findings is supported by the fact that while the main-effect of nicotine assignment did not reach statistical significance, it was in the expected direction, and it reached statistically significance after variance due to EC consumption and baseline readiness to quit was reduced, effectively improving power to detect the main effect. Second, the smoking reduction outcome was based on self-report. Although we also measured exhaled CO, variability in the time lapse from the last cigarette smoked before the measurements might cause an inconsistent association between changes in CO level and in number of CPD, and thus made it difficult to verify self-reported smoking reduction. Finally, the results of the study might only relate to the particular EC brand and flavor (tobacco) tested, while there is wide variation among products available in the market.⁴¹ The nicotine delivery of the product used in this and other first generation studies is fairly low compared with newer generation devices, and this may explain the lack of an overall main effect prior to adjusting for EC consumption and baseline readiness to quit. Newer products may demonstrate more significant effect sizes for nicotine ECs compared to placebos.¹⁴ Replication of this trial with newer generation ECs with purported higher nicotine delivery is needed. Research is also needed to compare nicotine and non-nicotine ECs with FDA approved NRT to explore the role of behavioral replacement by ECs. Future study designs should also consider providing ECs in a way that resembles real-life EC use, for example, take into account individual preferences of flavors and devices, and allow switching between or concurrent use of multiple flavors.^42,43

In conclusion, we found that smokers who were not ready to quit were able to reduce CPD with the help of ECs. Smokers are demonstrating an interest in nicotine delivery that closely mimics the experience of smoking without combustion. Without FDA oversight the safety of these products is unclear, therefore recommendations for cessation pharmacotherapy should still prioritize FDA approved cessation medications.⁴⁴ However, to ignore the overwhelming evidence of smoker preference for these new products would be a missed opportunity for reducing tobacco-related morbidity and mortality. Continued investment in robust a research agenda that addresses questions about the safety of ECs, the long-term impact of placebo ECs, patterns of dual use and whether ECs facilitates or hinders long-term cessation.

Supplementary Material

Supplementary Appendix can be found online at http://www.ntr.oxfordjournals.org

Funding

This work was supported by the National Center for Advancing Translational Sciences at the National Institutes of Health (grant number UL1TR000038).

Declaration of Interests

None declared.