Introduction

Both the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure.

Methods

Herein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions.

Results

To date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth.

Discussion

A coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco.

INTRODUCTION: Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy. METHODS: In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence. RESULTS: At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition. CONCLUSIONS: Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers. IMPLICATIONS: Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.

In the United States, the Food and Drug Administration (FDA) has initiated a public dialogue about reducing the nicotine content of cigarettes. A reduced-nicotine standard could increase withdrawal symptoms among current smokers. We examined the impact of switching smokers to cigarettes that varied in nicotine content on withdrawal symptoms over 6 weeks. A secondary analysis (N = 839) of a 10-site, double-blind clinical trial of nontreatment-seeking smokers was completed. Participants were instructed to smoke study cigarettes, containing 0.4 to 15.8 mg of nicotine/g of tobacco, for 6 weeks and were then abstinent overnight. Using latent growth curves, trajectories of individual withdrawal symptoms were compared between the reduced nicotine content (RNC) conditions and a normal nicotine content (NNC) condition. Path analyses compared symptoms after overnight abstinence. Relative to NNC cigarettes, participants smoking RNC cigarettes had increased anger/irritability/frustration and increased appetite/weight gain during the initial weeks, but the symptoms resolved by Week 6. Individuals who were biochemically verified as adherent with using only the 0.4 mg/g cigarettes had higher sadness levels (Cohen's d = .40) at Week 6 compared with the NNC condition, although symptoms were mild. After a post-Week 6 overnight abstinence challenge, some RNC conditions relative to NNC condition exhibited reduced withdrawal. Individuals who were biochemically confirmed as adherent to the lowest nicotine condition experienced only mild and transient symptom elevations. Thus, a reduced-nicotine standard for cigarettes produced a relatively mild and temporary increase in withdrawal among nontreatment-seeking smokers (ClinicalTrials.gov No. NCT01681875). (PsycINFO Database Record

Theoretical models of alcoholism emphasize the acute reinforcing properties of alcohol as chief determinants of drinking, and animal research suggests adolescents are uniquely sensitive to these effects. Human studies of these phenomena, however, are virtually nonexistent. We used ecological momentary assessment methods to capture adolescents' subjective responses to alcohol in real time in their natural environments. Adolescent participants were 22 problem drinkers, ages 15 to 19 years (M = 18.3, SD = 0.09; 55% female; 55% alcohol dependent). Participants consumed alcohol on 38% of days during a 1-week monitoring period, with an average of 5 drinks per occasion. Momentary data revealed that adolescents experience decreased stimulation and increased sedation and "high" across the ascending limb of the blood alcohol curve. Notably, greater craving predicted higher volumes of subsequent alcohol consumption during the episode, whereas greater "high" attenuated use. To test for developmental differences in these effects, we pooled these data with data from a similarly ascertained sample of 36 adult heavy drinkers, ages 24 to 64 years (M = 38.1, SD = 11.8; 50% female; 61% alcohol dependent). Adolescents were more sensitive to the stimulant effects of alcohol than adults. This study provides novel data on how adolescent problem drinkers experience alcohol in their natural contexts and illustrates how these effects, which appear to differ from adult problem drinkers, confer liability for future drinking.

Combustible cigarettes remain the most harmful and addictive tobacco product, and reducing the prevalence of smoking continues to be a critical public health goal. While nicotine is the constituent primarily responsible for addiction to cigarettes, most of the harm associated with smoking comes from byproducts of tobacco combustion. Recently, two different approaches for reducing the harms of smoking have emerged, both of which focus on breaking the link between the addiction to nicotine and the harms caused by smoking. First, the addictive potential of cigarettes could be minimized by requiring a large reduction in the nicotine content of cigarettes. Evidence for a nicotine reduction policy thus far shows that the use of very low nicotine content cigarettes results in a reduction in the number of cigarettes people smoke per day and a reduction in cigarette dependence. Second, emerging alternative nicotine delivery systems (ANDS) like electronic cigarettes may provide sufficient nicotine to act as substitutes for cigarettes while delivering much lower levels of toxicants. Evidence suggests that the emergence of ANDS has increased the percentage of smokers who are able to quit. The present paper will briefly review the evidence for each of these approaches, and consider what contemporary reinforcement and addiction theories can tell us about their likely success. We argue that the most effective endgame approach is one that pursues both nicotine reduction and alternative nicotine delivery systems as complementary.

Background and aims

Clinical trials on the impact and safety of reduced nicotine content cigarettes (RNCs) are ongoing, and an important methodological concern is participant compliance with smoking only RNCs. Our aims were to measure non-compliance biochemically with urine cotinine (COT) and total nicotine equivalents (TNEs), compare with self-reported non-compliance and identify associated covariates.

Design

Secondary analysis of a double-blind, parallel, randomized clinical trial.

Setting

Research centers from the United States, enrolling participants from June 2013 to July 2014.

Participants

Volunteer sample of 242 participants (55% Caucasian), average age of 41.2 years, smoking at least five cigarettes per day (CPD).

Intervention

Smoking very low nicotine cigarettes (VLNCs; 0.4 mg nicotine/g tobacco) for 6 weeks.

Measurements

The primary outcome was biochemically verified non-compliance, measured as thresholds of COT/CPD and TNE/CPD ratios, considering changes in nicotine content from conventional levels to VLNCs, and as an absolute threshold of week 6 TNEs. Self-reported non-compliance was measured via daily phone calls. Key predictors included age, sex, race, menthol preference, nicotine metabolite ratio, time to first cigarette, dependence, CPD, TNEs, tar level and cigarette evaluation.

Findings

Estimates of non-compliance with smoking the VLNCs exclusively include: the biochemical ratios (both 78%), the week 6 TNE threshold (76%) and self-report (39%). Of the key covariates, age, dependence and cigarette evaluations of satisfaction were significant; for age, younger participants more likely to be non-compliant [P = 0.01; odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96-0.99]. Dependence was associated significantly with self-reported non-compliance (P = 0.01; OR = 1.28, 95% CI = 1.06-1.55). Cigarette evaluations of satisfaction were associated significantly with non-compliance (P = 0.001; OR = 0.71, 95% CI = 0.61-0.82).

Conclusions

Among smokers volunteering to smoke only very low nicotine cigarettes for 6 weeks, non-compliance was common and biochemical assessments detected more cases of non-compliance than self-report. Despite high levels of non-compliance, smokers reduced their intake of nicotine by an average of 60%.

Introduction

Reports in relatively healthy smokers suggest men are more sensitive than women to the subjective effects of reduced nicotine content cigarettes (RNCCs). We know of no reports examining sex differences in the relative reinforcing effects of RNCCs, an important outcome in assessing smoking's addiction potential. The aim of the present study is to address this gap by examining sex/gender differences on reinforcing effects while examining whether sex differences in subjective effects are discernible in vulnerable populations.

Methods

Secondary analysis of a within-subject, double-blinded experiment examining acute effects of cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg/g) among 169 adult smokers with psychiatric conditions or socioeconomic disadvantage. Effects of dose, sex, and their interaction were examined on reinforcing (concurrent-choice and Cigarette Purchase Task [CPT] testing), and subjective effects (Cigarette Evaluation Questionnaire [CEQ] and craving/withdrawal ratings).

Results

Reducing nicotine content decreased the relative reinforcing effects of smoking in concurrent-choice and CPT testing (p's < .05) with no significant effects of sex nor dose × sex/gender interactions. Reducing nicotine content decreased CEQ ratings with only a single significant effect of sex (higher Psychological Reward scores among women than men, p = .02) and no significant dose × sex/gender interactions. Results on craving/withdrawal paralleled those on the CEQ.

Conclusions

Reducing nicotine content decreases the addiction potential of smoking independent of sex in populations highly vulnerable to smoking and addiction, with no indication that women are less sensitive to subjective effects of RNCCs or would benefit less from a policy reducing the nicotine content of cigarettes.

Implications

A policy reducing the nicotine content of cigarettes has the potential to reduce the addiction potential of smoking across men and women who are especially vulnerable to smoking, addiction, and tobacco-related adverse health impacts.

BACKGROUND: Reducing cigarette addictiveness has the potential to avert millions of yearly tobacco-related deaths worldwide. Substantially reducing nicotine in cigarettes decreases cigarette consumption, but no large clinical trial has determined the effects of reduced-nicotine cigarettes when other nicotine-containing products are available. The aim of this study was to examine the effects of reduced-nicotine cigarettes in the context of the availability of alternative nicotine delivery systems. METHODS: In a U.S. six-site, open-label, parallel-arm study, smokers were randomized for twelve weeks to an experimental marketplace containing cigarettes with either 0.4 mg or 15.8 mg nicotine per gram of tobacco; all had access to non-combusted alternative nicotine delivery systems (e.g., e-cigarettes; medicinal nicotine). Group differences in the primary outcomes (cigarettes per day, number of smoke-free days) were examined using linear and negative binomial regression, respectively (Trial Registration: NCT03272685). FINDINGS: Among 438 randomized participants (mean [standard deviation (SD), range] age, 44.5 [11.9, 20-73] years, 225 [51.4%] women, 282 [64.4%] White and 339 [77.4%] trial completers), those in the 0.4 mg vs. 15.8 mg nicotine cigarette condition experienced significantly lower cigarettes per day at the end of intervention (mean [SD], 7.05 [7.88] vs. 12.95 [9.07], adjusted mean difference, -6.21 [95% CI, -7.66 to -4.75], P < 0.0001) and greater smoke-free days during intervention (mean [SD], 18.59 [27.97] vs. 5.06 [13.77], adjusted rate ratio, 4.25 [95% CI, 2.58-6.98], P < 0.0001). INTERPRETATION: A reduced-nicotine cigarette standard in the context of access to other non-combusted nicotine products has the potential to benefit public health. FUNDING: U.S. NIH/FDA U54DA03165.

Background

The FDA recently acquired regulatory authority over tobacco products, leading to renewed interest in whether reducing the nicotine content of cigarettes would reduce tobacco dependence in the United States. Given the association between depressive symptoms and cigarette smoking, it is important to consider whether smokers with elevated depressive symptoms experience unique benefits or negative consequences of nicotine reduction.

Methods

In this secondary analysis of a randomized clinical trial that examined the effects of cigarettes varying in nicotine content over a 6-week period in non-treatment-seeking smokers, we used linear regression to examine whether baseline depressive symptom severity (scores on the Center for Epidemiologic Studies Depression Scale [CES-D]) moderated the effects of reduced-nicotine content (RNC) cigarettes, relative to normal-nicotine content (NNC) cigarettes, on smoking rates, depressive symptom severity, and related subjective and physiological measures.

Results

Of the 717 participants included in this analysis, 109 (15.2%) had CES-D scores ≥ 16, indicative of possible clinical depression. Relative to NNC cigarettes, RNC cigarettes reduced smoking rates, nicotine dependence, and cigarette craving, and these effects were not significantly moderated by baseline CES-D score. A significant interaction between baseline CES-D score and cigarette condition on week 6 CES-D score was observed (p < .05); among those with CES-D scores ≥ 16 at baseline, those assigned to RNC cigarettes had lower week 6 CES-D scores than those assigned to NNC cigarettes. Among those in the lowest nicotine content conditions, biochemically confirmed compliance with the RNC cigarettes was associated with an increase in CES-D score for those with baseline CES-D scores < 16 and no change in CES-D score for those with baseline CES-D scores ≥ 16.

Conclusions

These findings provide initial evidence that a reduced-nicotine standard for cigarettes may reduce smoking, without worsening depressive symptoms, among smokers with elevated depressive symptoms.

Implications

This secondary analysis of a recent clinical trial examined whether depressive symptom severity moderated the effects of reduced-nicotine cigarettes on smoking and depressive symptoms. Results indicate that, regardless of baseline depressive symptoms, participants randomized to reduced-nicotine cigarettes had lower smoking rates, nicotine intake, nicotine dependence, and craving at week 6 post-randomization than those assigned to normal-nicotine cigarettes. In participants with higher baseline depressive symptoms, those assigned to reduced-nicotine cigarettes had lower week 6 depressive symptoms than those assigned to normal-nicotine cigarettes. These results suggest that a nicotine reduction policy could have beneficial effects for smokers, regardless of depressive symptom severity.

Introduction

Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy.

Methods

In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence.

Results

At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition.

Conclusions

Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers.

Implications

Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.