SR-0813

Effectiveness of Non-Nicotinic E-Cigarettes to Reduce Cueand Abstinence-Induced Cigarette Craving in Non-Treatment Seeking Daily Dependent Smokers

Ginnie Ng1,2 & Sophia Attwells2 & Peter Selby2,3,4,5 & Laurie Zawertailo1,2

Abstract

Rationale Electronic cigarettes (e-cigarettes) are potential tools for smoking cessation because they deliver nicotine and simulate smoking behaviors. The contribution of sensorimotor versus pharmacological substitution is unknown.
Objectives To evaluate whether non-nicotinic e-cigarettes, used alone or with nicotine lozenges, can attenuate cigarette craving following visual cue presentation or acute (3 h post ad-lib use) abstinence in dependent daily smokers.
Methods Following overnight (12 hours) abstinence, 41 daily smokers were exposed to 4 experimental conditions on separate days: (i) tobacco cigarettes (CIG); (ii) non-nicotinic e-cigarettes with placebo lozenges (EPL); (iii) non-nicotinic e-cigarettes with 4 mg nicotine lozenge (ENL); and (iv) 4 mg nicotine lozenge (NL). Cigarette craving was assessed following presentation of neutral and smoking cues at various time points using the Brief Questionnaire of Smoking Urges (QSU-B) and visual analog scales (VAS).
Results All experimental conditions significantly reduced participants’ baseline overnight abstinence cigarette craving. ENLs and NLs attenuated smoking-cue-induced cravings to a greater extent than CIGs, where cravings were significantly higher with CIGs compared to ENLs [mean difference (MD) ± standard error (SE) in QSU-B = 3.2 ± 0.84, P = 0.002; VAS = 12.7 ± 2.7, P < 0.0005] and NLs [MD ± SE in QSU-B = 2.7 ± 0.92, P = 0.031; VAS = 8.1 ± 2.3, P = 0.005]. Craving responses to cues after 3 h were higher after smoking CIGs compared to ENLs [MD ± SE in QSU-B = 3.9 ± 1.4, P = 0.047; VAS = 14.1 ± 3.6, P = 0.002] and NLs [MD ± SE in QSU-B = 3.2 ± 1.1, P = 0.046; VAS = 9.7 ± 3.1, P = 0.017]. Conclusions Behavioral simulation of smoking with or without nicotine reduces nicotine craving. Compared to cigarettes, ENL with NL or NL alone attenuates cigarette craving over time. Future clinical trials should evaluate the combination of ENL and NL as a method for smoking reduction or cessation. Trial registration NCT02108626 Keywords Electroniccigarettes . Electronicnicotinedeliverysystems . Nicotine craving . Nicotineabstinence . Smokingcues Introduction Tobacco cigarette smoking continues to be a leading cause of preventable death, disability, and impoverishment worldwide (WHO 2019). Nicotine, the primary psychoactive substance found in tobacco cigarettes, underlies many behavioral and addictive properties of smoking (Benowitz 2010). However, compared to combusted tobacco smoke, nicotine itself has minimal effects in increasing the risks of developing smoking-related diseases (Benowitz and Burbank 2016). Thus, many smoking reduction and cessation treatments address nicotine’s pharmacological effects by delivering it through non-combustion pathways or by modulating its binding. Nicotine replacement therapy (NRT) products, such as nicotine lozenges, and varenicline demonstrate good efficacy in helping individuals quit smoking and significantly decrease the risk of developing tobacco-related diseases (Chang et al. 2015; Jordan and Xi 2018; Stead et al. 2012). However, rates of successful smoking cessation remain low, with 15 to 30% of individuals remaining abstinent 6 months following NRT or varenicline treatments (Jackson et al. 2019). Sensorimotor effects of cigarettes, such as cigarette smoke, hand-to-mouth action, and shape and feel of cigarette, may be essential elements of cue conditioning and the experience of craving symptoms (Addicott et al. 2014). These factors may contribute to smoking relapse and addressing them may improve the efficacy of smoking cessation treatments. Electronic cigarettes (e-cigarettes), also known as electronic nicotine delivery systems, present a promising smoking reduction and cessation tool as they uniquely deliver nicotine while also simulating smoking behaviors such as the hand-to-mouth motion and the exhalation of vapor (Polosa et al. 2011). Craving is a prominent symptom of tobacco dependence and predictor of smoking relapse (Germovsek et al. 2020; Shadel et al. 2011). Regular smokers often report high levels of cigarette craving following abstinence (Ussher et al. 2013), and the presentation of visual smoking cues can intensify craving (Conklin et al. 2015; Shiffman et al. 2013). Several randomized clinical trials (RCTs) and reviews have examined the efficacy of e-cigarettes as smoking reduction and cessation aids, and findings suggest nicotinic e-cigarettes may improve abstinence rates (Eisenberg et al. 2020; Hajek et al. 2019; Hartmann-Boyce et al. 2020), but the ability of e-cigarettes to reduce cigarette cravings has been equivocal. Specifically, a systematic review of nineteen studies that investigated the effectiveness of e-cigarettes to reduce cravings or urges to smoke found that e-cigarettes may reduce cravings, but the quality of the overall evidence was poor due to bias (Malas et al. 2016). Contrastingly, NRT products have moderate effects on cigarette craving (Selby et al. 2013). Nicotine lozenges are a form of NRT that are safe and effective for smoking reduction and cessation and are optimal for combination therapy (Lindsonet al. 2019). As such, the combination of e-cigarettes with NRT may be an alternative approach in utilizing these new devices for smoking reduction and cessation, where the combination of nicotine lozenges and ecigarettes may satisfy both the pharmacological effects of nicotine and behavioral components of tobacco dependence. A better understanding of the relationship between e-cigarettes, cigarette craving, and cue reactivity will inform how to best utilize e-cigarettes for smoking reduction and cessation. The primary objectives of the present study were to (1) disentangle the pharmacological and behavioral components of tobacco use and dependence by separating out the delivery of nicotine from the act of using an e-cigarette and (2) investigate the ability of non-nicotinic e-cigarettes with and without the combination of nicotine lozenges to alleviate tobacco cigarette craving. In the present study, non-treatment-seeking daily tobacco cigarette smokers completed four experimental conditions (described in “Methods”) following overnight abstinence. To assess abstinence- and cue-induced craving, participants were presented with series of visual and tactile cues, with craving measured at various time points using validated questionnaires. We hypothesized that smoking cigarettes will produce the largest immediate reduction in craving due to its rapid nicotine delivery. Second, since using non-nicotinic ecigarettes with nicotine lozenges involves nicotine delivery and simulates cigarette smoking behavioral cues, we expected to see a greater reduction in craving from this condition compared to using nicotine lozenges alone. Third, consistent with findings that behavioral cues may affect drug craving, we hypothesized using non-nicotinic e-cigarettes with placebo lozenges will reduce cigarette craving. Methods Participants Forty-three participants who were non-treatment-seeking daily smokers were recruited from the Greater Toronto Area (Fig. 1). All participants were aged 19 to 62 years and in good physical health. Inclusion criteria were age 18 to 65; Fagerström Test for Nicotine Dependence (FTND) score ≥ 3 (Fagerstrom and Schneider1989); smoking ≥ 10 cigarettes per day; and no intention to quit smoking within the next 3 months. Exclusion criteria were prior use of e-cigarettes; having a medical or psychiatric illness requiring treatment; and being pregnant or currently breastfeeding. Medical and psychiatric illnesses and pregnancy were confirmed by selfreport. This study was approved by the Research Ethics Board of the Centre for Addiction and Mental Health (CAMH) and was performed inaccordancewith the ethical standards established in the 1964 Declaration of Helsinki. All participants gave their informed consent prior to undergoing any study-related activities. All details that might disclose the identity of the participants have been omitted. The study was registered on www. clinicaltrials.gov (Identifier: NCT02108626). Nicotine Lozenges and E-Cigarettes Nicotine polacrilex (Nicorette® and Life Brand) 4-mg lozenges were purchased from a local pharmacy. Due to stock shortages, the first 39 participants received Nicorette® Mini Nicotine Lozenges (McNeil Consumer Healthcare, division of Johnson & Johnson, PA, USA) while the remaining four participants received Life Brand Mini Nicotine Lozenges (Perrigo Company plc, Ireland). Both brands of 4-mg lozenges were identical in appearance and similar in flavor to participants through the study. All individuals who declined screening, were ineligible, or declined to participate were referred to the Nicotine Dependence Clinic at the Centre for Addiction and Mental Health (CAMH) the 0-mg placebo lozenges. Participants were instructed to place the lozenge in the oral vestibule (the area between cheek and gum) and allow it to dissolve. Smoke NV Canadian Premium disposable e-cigarettes were used and purchased directly from the Smoke NV website. These disposable e-cigarettes are first-generation devices that visually resembled tobacco cigarettes. The E-liquid contained in the product was nicotine-free and contained food-grade vegetable glycerin and artificial tobacco flavoring. The E-liquid used in the current study did not contain nicotine due to Health Canada regulations at the time the study was conducted. Nicotinic e-cigarettes were legalized for sale in Canada in May 2018. Study Visit Procedures The study was a within-subject, single-blind, and partial Latin square randomized design. Participants attended four visits at the Nicotine Dependence Clinic at CAMH over a period of 4 weeks and were exposed to a different experimental condition each week. To control for order effects, participants were randomly assigned to one of four possible condition sequences (denoted as groups A, B, C, or D in Table 1). The four experimental conditions were: (1) smoke their own tobacco cigarette (CIG); (2) use the study non-nicotinic e-cigarette plus a placebo lozenge (EPL); (3) use the study non-nicotinic e-cigarette plus a nicotine lozenge (ENL); or (4) use a nicotine lozenge alone (NL). Participants were informed that both the lozenges and e-cigarettes assigned to them throughout the study may or may not contain nicotine. Participants refrained from smoking and drinking alcohol for 12 hours prior to each study visit (see Supplemental Methods for details). Participants completed the FTND, World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) (Üstün et al. 2010), Questionnaire of Smoking Urges (QSU-B) (Cox et al. 2001), and five craving-related questions using visual analog scale (VAS) (see Supplemental Methods for details) to assess baseline levels of cigarette craving [time 1: 0 hours (henceforth denoted as T1)]. Participants were then exposed to the assigned experimental condition ad libitum for 5 min (Table 1). To assess cue-induced craving, two series of visual and tactile cues were presented to participants 1 h following exposure to the experimental condition (see Supplemental Methods for rationale). The first series included a 5-min slide show of 30 neutral photographic cues while participants held a pen [time 2: 1 h later, neutral cue (T2N)]. After experiencing the first series of cues, participants completed the QSU-B and VAS. Participants were then presented with the second series of cues which consisted of a 5-min slideshow of 30 smoking-related photographs while holding an unlit cigarette [time 2: 1 h later, cigarette cue (T2C)] (see Supplemental Methods for examples). Following the cue presentation, participants again completed the QSU-B and VAS. Each photograph in both cue series was presented for a total of 10 s. To assess abstinence-induced craving, two series of visual and tactile cues were similarly presented to the participants 3 h following the experimental condition. The first series included viewing 30 neutral photographs while holding a pen [time 3: 3 h later, neutral cue (T3N)], and the second series included viewing 30 smoking-related photographs while holding an unlit cigarette [time 3: 3 h later, cigarette cue (T3C)]. Each photograph was presented for 10 s on a 5-min slideshow. Both series were followed by completion of the QSU-B and VAS (see Supplemental Figure 1 for a schematic of study visit procedures). At the end of each study visit, participants reviewed and completed a 49-item list of potential adverse effects. Data analysis To assess potential experimental order effects, repeatedmeasures univariate analyses of variance (ANOVAs) were conducted. In this analysis, within-subject factors included experimental conditions (CIG, ENL, EPL, and NL) and time (QSU-B and VAS scores at T1, T2N, T2C, T3N, and T3C), while the order group (groups A, B, C, and D) was the between-subject factor (Supplemental Table 1). All findings were considered significant at P ≤ 0.050. Repeated-measures ANOVAs with Bonferroni-adjusted post hoc comparisons were conducted to assess whether there were differences in: 1. Absolute cigarette craving at baseline (QSU-B and VAS scores at T1) and 1 h after the 5-min ad libitum use period (QSU-B and VAS scores at T2N) between experimental conditions 2. Absolute cigarette craving between baseline (QSU-B and VAS scores at T1) and 1 h after the 5-min ad libitum use period (QSU-B and VAS scores at T2N) within each condition, where lower craving scores at T2N indicate greater reductions in craving 3. Acute craving reductions from baseline (QSU-B and VAS scores at T2N normalized to scores at T1) between the four experimental conditions 4. Smoking-cue-induced cravings (QSU-B and VAS scores at T2C normalized to scores at T2N) between conditions 5. Abstinence-induced cravings in the absence of recent smoking-related cues (QSU-B and VAS scores at T3N normalized to scores at T2N) between conditions 6. Combination of both smoking-cue- and abstinenceinduced cravings (QSU-B and VAS scores at T3C normalized to scores at T2N) between conditions 7. Smoking-cue-induced cravings at the end of study visits (QSU-B and VAS scores at T3C normalized to scores at T3N) between conditions Shapiro-Wilk’s test found that the data was not normally distributed (P < 0.05). However, analyses proceeded as repeated-measures ANOVAs are robust to deviations from normality. The assumption of sphericity was violated in the analysis of craving between T1 and T2N scores (“Data analysis,” point 2) and some comparisons of VAS scores between conditions (“Data analysis,” points 4 and 7), as assessed by Mauchly’s test of sphericity (P < 0.05). Greenhouse-Geisser corrections were applied to address these violations. In all other cases, the assumption of sphericity was not violated (P > 0.05). All statistical analyses were performed using SPSS version 25 (IBM Corporation, NY, USA).
To investigate whether the proportions of participants reporting adverse effects were different between experimental conditions, Cochran’s Q tests were conducted.
A priori sample size calculation was conducted with data from (Dawkins et al. 2012). A sample size of 40, with 10 participants in each randomization group, was found to be sufficient to achieve 80% power, detecting significant differences with an alpha value of 0.05.

Results

Participants

Forty-one of 43 eligible participants completed all study procedures (Fig. 1). Average age of participants was 35.2 years. The mean and standard deviation (SD) of the FTND score was 6.4 ± 2.0 and number of cigarettes smoked per day was 19.7 ± 8.2 (Table 2). Participants’ gender distribution was 22 females and 19 males.

Effect of Condition on Acute Craving Reductions from Baseline

Following 12-h overnight smoking abstinence, participants reported high levels of cigarette craving at baseline (T1) for all visits [mean QSU-B scores (standard error (SE)): 55.9 (1.8) to 57.9 (1.4)] [mean VAS scores (SE), 82.5 (3.2) to 86.1 (2.3)] (Supplemental Table 2). The maximum scores of the QSU-B and VAS are 70 points and 100 points, respectively. No significant differences were found in cigarette craving between experimental conditions (“Data analysis,” point 1) at baseline (ANOVA: QSU-B T1 scores, F3,120 = 1.42, P = 0.241, partial η2 = 0.03; VAS T1 scores, F3,120 = 0.87, P = 0.458, partial η2 = 0.02) and 1 h after the 5-min ad libitum use period (ANOVA: QSU-B T2N scores F3,120 = 1.52, P = 0.212, partial η2 = 0.04). Analysis of T2N VAS scores found that craving after using EPLs were significantly higher than those after smoking CIGs (ANOVA: F3,120 = 5.5, P = 0.001, partial η2 = 0.12) [post hoc: mean difference (SE): CIG–EPL, -17.1 (4.3), P = 0.002]. No differences were found between T2N VAS scores after using CIGs, ENLs, and NLs.
Craving scores changed significantly within all visits (ANOVA: CIG visit: F3,114 = 43.0, P < 0.0005, partial η2 = 0.52; EPL: F2,94 = 19.8, P < 0.0005, partial η2 = 0.33; ENL: F2,81 = 19.2, P < 0.0005, partial η2 = 0.32; NL: F2,76 = 19.2, P < 0.0005, partial η2 = 0.32) (Supplemental Table 2). Notably, all experimental conditions significantly reduced participants’ baseline craving when assessed 1 h after the 5-min ad libitum use period (QSU-B scores at T2N compared to T1 scores) (“Data analysis,” point 2). Compared to T1, QSU-B scores at T2N decreased following use of CIGs [post hoc: mean difference (SE) T2N–T1 scores: -11.2 (1.3), P < 0.0005], EPLs [-9.0 (1.5), P < 0.0005], ENLs [-9.8 (1.8), P < 0.0005], and NLs [-9.0 (1.7), P < 0.0005]. However, there were no significant differences in these acute craving reductions from baseline between experimental conditions (“Data analysis,” point 3) (ANOVA: F3,120 = 0.63, P = 0.60, partial η2 = 0.016) (Table 3, Supplemental Figure 2). Similarly, VAS craving scores changed within all visits (ANOVA: CIG visit: F2,94 = 39.0, P < 0.0005, partial η2 = 0.49; EPL visit: F2,92 = 10.9, P < 0.0005, partial η2 = 0.22; ENL visit: F2,84 = 12.8, P < 0.0005, partial η2 = 0.24; NL visit: F2,84 = 20.3, P < 0.0005, partial η2 = 0.34). Compared to T1, VAS scores at T2N decreased after using CIGs [post hoc: mean difference (SE) T2N–T1 scores, -31.8 (4.2), P < 0.0005], EPLs [-14.9 (3.2), P < 0.0005], ENLs [-19.7 (4.2), P < 0.0005], and NLs [-19.7 (3.2), P < 0.0005]. Moreover, there was a significant difference in acute craving reductions between CIG and EPL experimental conditions (ANOVA: F3,120 = 5.0, P = 0.003, partial η2 = 0.11) [post hoc: mean difference (SE): CIG–EPL = − 16.9 (4.5), P = 0.003] (Table 4, Supplemental Figure 3). Effect of Condition on Cue-Induced Craving One hour following the 5-min ad libitum use period, significant differences in smoking-cue induced cravings (QSU-B scores at T2C normalized to scores at T2N) were found between conditions (“Data analysis,” point 4) (ANOVA: F3,120 = 6.1, P = 0.001, partial η2 = 0.13). Post hoc analyses revealed that ENLs and NLs attenuated smoking-cue-induced cravings to a greater extent compared to CIGs [post hoc: mean difference (SE): CIG–ENL = 3.2 (0.84), P = 0.002; CIG–NL = 2.7 (0.92), P = 0.031] (Fig. 2, Table 3). Although not statistically significant, a trend was observed where ENLs attenuated smoking-cue-induced cravings to a greater extent compared to EPLs [post hoc: EPL–ENL = 2.1 (0.80), P = 0.077]. Similar post hoc analyses revealed that ENLs, NLs, and EPLs attenuated smoking-cue-induced cravings to a greater extent compared to CIGs when measured with VAS (ANOVA: F3,103 = 9.8, P < 0.0005, partial η2 = 0.20) [post hoc: CIG–EPL: 8.5 (2.5), P = 0.009; CIG–ENL: 12.7 (2.7), P < 0.0005; CIG–NL: CI confidence interval, CIG cigarette, ENL electronic cigarette with nicotine lozenge, EPL electronic cigarette with placebo lozenge, NL nicotine lozenge, QSU-B brief questionnaire of smoking urges, SE standard error, T1 time 1, 0 h, T2C time 2: 1 h later, cigarette cue, T2N time 2: 1 h later, neutral cue, T3C time 3: 3 h later, cigarette cue, T3N time 3: 3 h later, neutral cue, vs. versus. *P < 0.05; **P < 0.01 Effect of Condition on Abstinence-Induced Craving Three hours following the 5-min ad libitum use period, significant differences in acute abstinence-induced cravings (QSU-B scores at T3N normalized to scores at T2N) were found between conditions (“Data analysis,” point 5) (ANOVA: F3,120 = 3.5, P = 0.018, partial η2 = 0.080). Post hoc analyses found that ENLs and NLs alone attenuated acute abstinence-induced cravings to a greater extent compared to CIGs [post hoc: mean difference (SE): CIG–ENL = 3.9 (1.4), P = 0.047; CIG–NL = 3.2 (1.1), P = 0.046]. There were no significant differences between the ENL, EPL, and NL conditions (Fig. 2, Table 3). Similar post hoc analyses revealed that ENLs, NLs, and EPLs attenuated acute abstinence-induced cravings to a greater extent compared to CIGs when measured with + Five craving VAS questions were used. Total VAS scores were averaged. Each VAS question was a 100-point scale. CI confidence interval, CIG cigarette, ENL electronic cigarette with nicotine lozenge, EPL electronic cigarette with placebo lozenge, NL nicotine lozenge, SE standard error, T2C time 2: 1 h later, cigarette cue, T2N time 2: 1 h later, neutral cue, T3C time 3: 3 h later, cigarette cue, T3N time 3: 3 h later, neutral cue, VAS visual analog scale, vs. versus. *P < 0.05; **P < 0.01; ***P < 0.001 Effect of Condition on Combined Cue- and Abstinence-Induced Craving Three hours following the 5-min ad libitum use period, there werenosignificantdifferencesbetweenconditionsinattenuating acute smoking-cue- and abstinence-induced cravings (QSU-B scores at T3C normalized to scores at T2N) (“Data analysis,” point 6) (ANOVA: F3,120 = 2.6, P = 0.057, partial η2 = 0.061) (Fig. 2, Table 3). Conversely, ENLs, NLs, and EPLs attenuated acute smoking-cue- and abstinence-induced cravings to a greater extent compared to CIGs when measured with VAS (ANOVA T3C–T2N: F3,120 = 10.9, P < 0.0005, partial η2 = 0.21) [post hoc: CIG–EPL: 17.7 (3.6), P < 0.0005; CIG–ENL: 16.1 (3.7), P = 0.001; CIG–NL: 11.8 (3.3), P = 0.006]. Effect of Condition on Cue-Induced Craving at the End of Study Visits Three hours following the use period, no differences in smoking-cue-induced cravings (craving scores at T3C normalized to scores at T3N) were seen between conditions when measured by the QSU-B (“Data analysis,” point 7) (ANOVA: F3,120 = 0.14, P = 0.93, partial η2 = 0.004) and the VAS (ANOVA: F3,104 = 1.4, P = 0.25, partial η2 = 0.034) (Fig. 3, Table 4). Adverse Effects of Conditions There were no statistically significant differences in the percentage of participants reporting various adverse effects between experimental conditions (P > 0.05) (Supplemental Table 3).

Discussion

The primary objective of this study was to evaluate the effectiveness of non-nicotinic e-cigarettes with and without concurrent nicotine lozenge administration in alleviating subjective cue- and acute 3-hour abstinence-induced tobacco cigarette craving. Non-nicotinic e-cigarettes were used in combination with placebo and nicotine lozenges to disentangle the behavioral and pharmacological effects of nicotine dependence and to assess whether combination therapy involving non-nicotinic e-cigarettes may be effective in attenuating short-term cigarette cravings. One hour following the 5-min ad libitum use period, significant reductions in baseline craving produced by overnight abstinence were observed in all experimental conditions. Additionally, compared to tobacco cigarettes, using non-nicotinic e-cigarettes with nicotine lozenges and nicotine lozenges alone attenuated cue- and abstinence-induced cravings to a greater extent over time (i.e., up to 4 h post ad-lib use) (significant when assessed by both VAS and QSU-B scores). These findings suggest that the combination of non-nicotinic e-cigarettes with a form of NRT, specifically nicotine lozenges, may be an effective strategy for attenuating short-term cigarette craving and in turn promote smoking cessation.
It is plausible that the attenuation of cue- and abstinenceinduced cravings over time was purely pharmacological, specifically produced by slower plasma uptake of nicotine from lozenges. However, nicotine plasma concentrations at 1 h and 3 h following single administration of nicotine lozenge or tobacco cigarette are comparable (Rasmussen et al. 2018; Benowitz et al. 2009; Marchand et al. 2017). Interestingly, our findings also demonstrate that compared to smoking tobacco cigarettes, using non-nicotinic e-cigarettes combined with placebo lozenges and using non-nicotinic e-cigarettes with nicotine lozenges were as effective or more effective in attenuating craving over several hours (significant when assessed by craving VAS scores, but not QSU-B scores). These findings suggest that the behavioral simulation of smoking, with and without concurrent nicotine administration, could potentially reduce short-term craving for tobacco cigarettes. These results are consistent with previous investigations and reviews that assessed the effects of sensorimotor cues on craving reduction in cigarette smokers (Dawkins et al. 2016; Przulj et al. 2012; Rose et al. 2003; Stein et al. 2018). For example, several studies found the fulfillment of sensorimotor cues in the absence of nicotine may effectively reduce short-term cigarette craving (Rose et al. 2003); conducting the hand-to-mouth habitual motion significantly reduces cigarette craving regardless of the presence or absence of nicotine (Stein et al. 2018); and visual similarities in vaping and smoking play an important role in subjective effects (Dawkins et al. 2016).
Furthermore, in the present study, the differences in cueinduced craving and abstinence-induced craving were greatest between smoking tobacco cigarettes and using non-nicotinic e-cigarettes with nicotine lozenges. More specifically, craving increases were significantly smaller after using non-nicotinic e-cigarettes with nicotine lozenges compared to smoking tobacco cigarettes. This suggests the effects of combining nicotine administration and sensorimotor cues on acute cigarette craving may be additive, and the combination of NRT and non-nicotinic e-cigarettes may attenuate craving over time. More notably, since craving is a contributor to continued drug use and relapse (Drummond 2001; Germovsek et al. 2020; Shadel et al. 2011), the addition of non-nicotinic e-cigarettes may potentially enhance current NRT-only smoking cessation treatments long-term.
A major limitation of NRT is its long-term effectiveness, where 1-year abstinence rates drop to less than 15% (Jackson et al. 2019). A recent large RCT of smokers seeking smoking cessation treatment highlights the potential for e-cigarettes to sustain long-term smoking abstinence (Hajek et al. 2019). Although the primary outcome measure was 1-year abstinence rate, both NRT and nicotinic e-cigarettes were perceived as less satisfying than cigarettes, but nicotinic ecigarettes provided greater satisfaction compared to NRT (Hajek et al. 2019). In addition, a recent Cochrane review on the efficacy of e-cigarettes in smoking cessation found quit rates to be higher in participants who used nicotinic ecigarettes compared to NRT and non-nicotinic e-cigarettes alone (Hartmann-Boyce et al. 2020). It is plausible that the long-term abstinence rates from these studies represent smokers displacing their nicotine addiction from conventional tobacco cigarettes to nicotinic e-cigarettes. Given the ongoing safety concerns as to whether nicotinic e-cigarettes may produce lung-related illnesses following long-term use, investigations utilizing the combination of e-cigarettes and nicotinetapering strategies such as NRT are of utmost importance. A recent RCT investigating smoking abstinence rates in smokers found that non-nicotinic e-cigarettes plus counselling had the highest smoking abstinence rate at 24-week follow-up compared to nicotinic e-cigarettes plus counselling and counselling alone (Eisenberg, 2020). This study highlights the potential for non-nicotinic e-cigarettes combined with counselling and potentially NRT to satisfy the behavioral component of tobacco dependence and promote long-term smoking abstinence.
One limitation of the present study is that only e-cigarettenaïve participants were included. As a result, findings cannot be generalized to experienced e-cigarette users. In addition, at the time the study was conducted, the sale of nicotinic eliquids was prohibited in Canada. Since the study used nonnicotinic e-cigarettes with and without a nicotine lozenge, the findings from the present study do not reflect the effectiveness of nicotinic e-cigarettes to reduce cigarette cravings and withdrawal symptoms. However, this methodological design is also a strength, as it allowed for the independent study of how nicotine administration and sensorimotor cues may influence cigarette craving. Our methodology highlights the potential benefits and use of non-nicotinic e-cigarettes as tools for combination therapy with NRT since they address the behavioral component of tobacco dependence. Furthermore, current RCTs evaluating the efficacy of e-cigarettes on smoking cessation solely focus on abstinence rates and generally do not directly investigate the behavioral component of tobacco dependence, highlighting the relevance of the present study. Another limitation of the present study is the lack of a zero nicotineand no-cuecontrol condition toverifythat the craving reductions were not influenced by the passage of time and/or habituation to the environment. To control for these issues, we utilized a randomized cross-over Latin square design. Furthermore, another limitation of the present study includes the lack of assessment of “real-world” factors that may influence long-term abstinence rates. As previously discussed, long-term abstinence rates following NRT are low, but ecigarettes may improve these rates. Factors that may influence long-term cessation outcomes include feelings of satisfaction, preferences, environment, and adverse effects. While our study found no differences in adverse effects between conditions, these other factors were not assessed. A recent RCT attempted to simulate a “real-world” environment, by allowing participants to choose their form of NRT and eliquid nicotine dose, and found nicotinic e-cigarettes to improve long-term (1-year) abstinence rates more effectively than NRT (Hajek et al. 2019). Future studies should similarly evaluate the effectiveness of nicotinic e-cigarettes and nonnicotinic e-cigarettes with NRT in attenuating cigarette cravings in both short-term and long-term real-world settings.
In conclusion, the present study is one of few to dissociate the effects of nicotine delivery and behavioral cues on subjective cigarette craving. Study results suggest that while nicotine administration contributes to craving and withdrawal symptom reduction, other factors such as behavioral and sensory cues may have influence. Using non-nicotinic e-cigarettes in combination with and without nicotine lozenges attenuated cue- and acute 3-h abstinence-induced cravings over time. These findings highlight the ability of e-cigarettes to reduce cigarette craving regardless of concurrent nicotine delivery and suggest that non-nicotinic e-cigarettes used in combination with nicotine lozenges may be an effective method of smoking reduction and cessation. Future studies investigating 3-, 6-, and 12-month abstinent rates following combination treatment using e-cigarettes and nicotine lozenges or other forms of NRT for smoking reduction and cessation should be evaluated.

References

Addicott, M. A., Froeliger, B., Kozink, R. V., Van Wert, D. M., Westman, E. C., Rose, J. E., & McClernon, F. J. (2014). Nicotine and non-nicotine smoking factors differentially modulate craving, withdrawal and cerebral blood flow as measured with arterial spin labeling. Neuropsychopharmacology, 39(12), 2750-2759. doi: https://doi.org/10.1038/npp.2014.108
Benowitz NL (2010) Nicotine addiction. N Engl J Med 362(24):2295– 2303. https://doi.org/10.1056/NEJMra0809890
Benowitz NL, Burbank AD (2016) Cardiovascular toxicity of nicotine: implications for electronic cigarette use. Trends Cardiovasc Med 26(6):515–523. https://doi.org/10.1016/j.tcm.2016.03.001
Benowitz NL, Hukkanen J, Jacob P 3rd (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol 192:29– 60. https://doi.org/10.1007/978-3-540-69248-5_2
Chang PH, Chiang CH, Ho WC, Wu PZ, Tsai JS, Guo FR (2015) Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and metaanalysis of randomized controlled trials. BMC Public Health 15: 689. https://doi.org/10.1186/s12889-015-2055-0
Conklin CA, Vella EJ, Joyce CJ, Salkeld RP, Perkins KA, Parzynski CS (2015) Examiningthe relationship between cue-induced cravingand actual smoking. Exp Clin Psychopharmacol 23(2):90–96. https://doi.org/10.1037/a0038826
Cox LS, Tiffany ST, Christen AG (2001) Evaluation of the brief questionnaire of smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res 3(1):7–16. https://doi.org/10.1080/ 14622200020032051
Dawkins L, Turner J, Hasna S, Soar K (2012) The electronic-cigarette: effects on desire to smoke, withdrawal symptoms and cognition. Addict Behav 37(8):970–973. https://doi.org/10.1016/j.addbeh. 2012.03.004
Dawkins L, Munafò M, Christoforou G, Olumegbon N, Soar K (2016) The effects of e-cigarette visual appearance on craving and withdrawal symptoms in abstinent smokers. Psychol Addict Behav 30(1):101–105. https://doi.org/10.1037/adb0000112
Drummond DC (2001) Theories of drug craving, ancient and modern. Addiction 96(1):33–46. https://doi.org/10.1080/ 09652140020016941
Eisenberg M, Hébert-Losier A, Windle SB, Greenspoon T, Brandys T, Fulop T, Nguyen T, Elkouri S, Montigny M, Wilderman I, Bertrand OF, Bostwick JA, Abrahamson J, Lacasse Y, Pakhale S, Cabaussel J, Filion KB (2020) JAMA 324(18):1844–1854. https://doi.org/10. 1001/jama.2020.18889
Fagerstrom KO, Schneider NG (1989) Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J Behav Med 12(2):159–182. https://doi.org/10.1007/bf00846549
Germovsek E, Hansson A, Karlsson MO, Westin A, Soons PA, Vermeulen A, Kjellsson MC (2020) A time-to-event model relating integrated craving to risk of smoking relapse across different nicotine replacement therapy formulations. Clin Pharmacol Ther. https:// doi.org/10.1002/cpt.2000
Hajek P, Phillips-Waller A, Przulj D, Pesola F, Myers Smith K, Bisal N, Li J, Parrott S, Sasieni P, Dawkins L, Ross L, Goniewicz M, Wu Q, McRobbie HJ (2019) A Randomized trial of E-cigarettes versus Nicotine-replacement therapy. N Engl J Med 380(7):629–637. https://doi.org/10.1056/NEJMoa1808779
Hartmann-Boyce J, McRobbie H, Lindson N, Bullen C, Begh R, Theodoulou A, Notley C, Rigotti NA, Turner T, Butler AR, Hajek P (2020) Electronic cigarettes for smoking cessation. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD010216. pub4
Jackson SE, McGowan JA, Ubhi HK, Proudfoot H, Shahab L, Brown J, West R (2019) Modelling continuous abstinence rates over time from clinical trials of pharmacological interventions for smoking cessation. Addiction 114(5):787–797. https://doi.org/10.1111/add. 14549
Jordan CJ, Xi ZX (2018) Discovery and development of varenicline for smoking cessation. Expert Opin Drug Discovery 13(7):671–683. https://doi.org/10.1080/17460441.2018.1458090
Lindson N, Chepkin SC, Ye W, Fanshawe TR, Bullen C, HartmannBoyce J (2019) Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 4:CD013308. https://doi.org/10.1002/ 14651858.CD013308
Malas, M., van der Tempel, J., Schwartz, R., Minichiello, A., Lightfoot, C., Noormohamed, A., Andrews, J., Zawertailo, L., Ferrence, R. (2016). Electronic cigarettes for smoking cessation: a systematic review. Nicotine Tob Res, 18(10), 1926-1936. doi:https://doi.org/ 10.1093/ntr/ntw119
Marchand M, Brossard P, Merdjan H, Lama N, Weitkunat R, Ludicke F (2017) Nicotine SR-0813 Population pharmacokinetics in healthy adult smokers: a retrospective analysis. Eur J Drug Metab Pharmacokinet 42(6):943–954. https://doi.org/10.1007/s13318017-0405-2.
Polosa R, Caponnetto P, Morjaria JB, Papale G, Campagna D, Russo C (2011) Effect of an electronic nicotine delivery device (e-Cigarette) on smoking reduction and cessation: a prospective 6-month pilot study. BMC Public Health 11:786. https://doi.org/10.1186/14712458-11-786
Przulj D, McRobbie H, Hajek P (2012) The effect of sensorimotor replacement on smoking cessation and craving. Open Addict J 5:41– 50. https://doi.org/10.2174/1874941001205010041
Rasmussen SC, Becker WD, Shanga GM (2018) Sing-dose bioequivalence of two mini nicotine lozenge formulations. Clin Pharmacol Drug Dev 7(5):498–505. https://doi.org/10.1002/cpdd.415Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003)
Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76(2):243–250. https:// doi.org/10.1016/j.pbb.2003.07.002
Selby P, Andriash K, Zawertailo L, Persad D, Zack M, Busto UE (2013) Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving. J Clin Psychopharmacol 33(5): 667–674. https://doi.org/10.1097/JCP.0b013e31829a829d
Shadel WG, Martino SC, Setodji C, Cervone D, Witkiewitz K, Beckjord EB, Scharf D, Shih R (2011) Lapse-induced surges in craving influence relapse in adult smokers: an experimental investigation. Health Psychol 30(5):588–596. https://doi.org/10.1037/a0023445
Shiffman S, Dunbar M, Kirchner T, Li X, Tindle H, Anderson S, Scholl S (2013) Smoker reactivity to cues: effects on craving and on smoking behavior. J Abnorm Psychol 122(1):264–280. https://doi.org/10. 1037/a0028339
Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T (2012) Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 11:CD000146. https://doi.org/ 10.1002/14651858.CD000146.pub4
Stein JS, Koffarnus MN, Stepanov I, Hatsukami DK, Bickel WK (2018) Cigarette and e-liquid demand and substitution in e-cigarette-naïve smokers. Exp Clin Psychopharmacol 26(3):233–243. https://doi. org/10.1037/pha0000192
Ussher M, Beard E, Abikoye G, Hajek P, West R (2013) Urge to smoke over 52 weeks of abstinence. Psychopharmacology 226(1):83–89. https://doi.org/10.1007/s00213-012-2886-7
Üstün T, Kostanjsek N, Chatterji S, Rehm J (2010) Measuring health and disability: manual for WHO disability assessment schedule WHODAS 2.0. World Health Organization
WHO. (2019). World Health Organization Report on the global tobacco epidemic. Retrieved from Geneva, Switzerland: https://www.who. int/tobacco/global_report/en//