Nicotine Content Cigarettes Research Articles

Whether to push or pull? Nicotine reduction and non-combusted alternatives - Two strategies for reducing smoking and improving public health

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.

Sex differences in tobacco withdrawal and responses to smoking reduced-nicotine cigarettes in young smokers.

Policies that establish a standard for reduced nicotine content in cigarettes can decrease the prevalence of smoking in the USA. Cigarettes with nicotine yields as low as 0.05mg produce substantial occupancy of nicotinic acetylcholine receptors (26%), but women and men respond differently to these cigarettes. This study aimed to measure responses to smoking cigarettes that varied widely in nicotine yields, investigating whether sex differences in the effects on craving, withdrawal, and affect would be observed at even lower nicotine yields than previously studied, and in young smokers. Overnight abstinent young smokers (23 men, 23 women, mean age 22.18) provided self-reports of craving, withdrawal, and affect before and after smoking cigarettes with yields of 0.027, 0.110, 0.231, or 0.763mg nicotine, and evaluated characteristics of each cigarette. Compared to abstinent young men, abstinent young women reported greater negative affect, psychological withdrawal, and sedation, all of which were relieved equally by all cigarettes. Men but not women reported greater craving reduction, perceived nicotine content, and cigarette liking with increasing nicotine dose. Men may experience less smoking-related relief of craving, and enjoy cigarettes less, if nicotine yields are reduced to very low levels. Conversely, women respond equally well to cigarettes with nicotine yields as low as 0.027mg as to cigarettes with nicotine yields 28-fold higher (0.763mg). These differences are relevant for policy regarding reduced nicotine in cigarettes and may influence the efficacy and acceptability of reduced-nicotine cigarettes as smoking cessation aids.

Addiction Potential of Cigarettes With Reduced Nicotine Content in Populations With Psychiatric Disorders and Other Vulnerabilities to Tobacco Addiction

A national policy is under consideration to reduce the nicotine content of cigarettes to lower nicotine addiction potential in the United States. To examine how smokers with psychiatric disorders and other vulnerabilities to tobacco addiction respond to cigarettes with reduced nicotine content. A multisite, double-blind, within-participant assessment of acute response to research cigarettes with nicotine content ranging from levels below a hypothesized addiction threshold to those representative of commercial cigarettes (0.4, 2.3, 5.2, and 15.8 mg/g of tobacco) at 3 academic sites included 169 daily smokers from the following 3 vulnerable populations: individuals with affective disorders (n = 56) or opioid dependence (n = 60) and socioeconomically disadvantaged women (n = 53). Data were collected from March 23, 2015, through April 25, 2016. After a brief smoking abstinence, participants were exposed to the cigarettes with varying nicotine doses across fourteen 2- to 4-hour outpatient sessions. Addiction potential of the cigarettes was assessed using concurrent choice testing, the Cigarette Purchase Task (CPT), and validated measures of subjective effects, such as the Minnesota Nicotine Withdrawal Scale. Among the 169 daily smokers included in the analysis (120 women [71.0%] and 49 men [29.0%]; mean [SD] age, 35.6 [11.4] years), reducing the nicotine content of cigarettes decreased the relative reinforcing effects of smoking in all 3 populations. Across populations, the 0.4-mg/g dose was chosen significantly less than the 15.8-mg/g dose in concurrent choice testing (mean [SEM] 30% [0.04%] vs 70% [0.04%]; Cohen d = 0.40; P < .001) and generated lower demand in the CPT (α = .027 [95% CI, 0.023-0.031] vs α = .019 [95% CI, 0.016-0.022]; Cohen d = 1.17; P < .001). Preference for higher over lower nicotine content cigarettes could be reversed by increasing the response cost necessary to obtain the higher dose (mean [SEM], 61% [0.02%] vs 39% [0.02%]; Cohen d = 0.40; P < .001). All doses reduced Minnesota Nicotine Withdrawal Scale total scores (range of mean decreases, 0.10-0.50; Cohen d range, 0.21-1.05; P < .001 for all), although duration of withdrawal symptoms was greater at higher doses (η2 = 0.008; dose-by-time interaction, P = .002). Reducing the nicotine content of cigarettes may decrease their addiction potential in populations that are highly vulnerable to tobacco addiction. Smokers with psychiatric conditions and socioeconomic disadvantage are more addicted and less likely to quit and experience greater adverse health impacts. Policies to reduce these disparities are needed; reducing the nicotine content in cigarettes should be a policy focus.

Comprehensive Nicotine Regulation to End the Combustible Tobacco Epidemic.

In late July 2017, the U.S. Food and Drug Administration announced a new plan for tobacco regulation that focuses on regulating nicotine itself to reduce the nicotine content of cigarettes to nonad...

Abstract 2289: B-carotene supplementation and lung cancer risk in the ATBC Study: the role of tar and nicotine

Abstract Background: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Early observational studies reported a protective association between intake of β-carotene rich vegetables and lung cancer risk, which led to interest in β-carotene supplementation as a potential chemopreventive strategy, particularly in high-risk populations such as cigarette smokers. A large randomized controlled trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, demonstrated that β-carotene supplementation increased lung cancer incidence by 18% in smokers, and led to an 8% excess in overall mortality. It is also well-documented that cigarettes with higher (versus lower) tar and nicotine content are associated with a higher risk of lung cancer. To our knowledge, however, no studies have examined whether the increased risk associated with β-carotene supplementation in smokers varies by cigarette tar or nicotine content. Methods: The ATBC Study was a randomized, double-blind vitamin supplementation trial conducted among 29,133 male smokers in southwest Finland. Participants were randomly assigned to one of four groups in a 2x2 factorial design (α-tocopherol alone, β-carotene alone, both supplements, or placebo). A detailed smoking history was collected at baseline, including brands of cigarettes smoked (for which machine measured tar and nicotine content was available). Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of lung cancer risk by trial B-carotene assignment stratified by a priori categories of cigarette tar (ultra-light ≤7 mg, light 8-14 mg, medium/regular 15-20 mg, high/non-filtered/self-made &amp;gt;20 mg) and nicotine content (ventilated filtered ≤0.8 µg, unventilated filtered 0.8-1.3 µg, non-filtered &amp;gt;1.3 µg). Statistical interaction was estimated using the likelihood ratio test. Results: The β-carotene supplemented arm had a statistically significantly higher risk of developing lung cancer in all categories of tar content [yes vs. no β-carotene supplementation - ultra-light: HR=1.31 95% CI=0.91-1.89; non-filtered: HR=1.22 95% CI=0.91-1.64; p-interaction=0.91]. Similarly, there was no apparent interaction with cigarette nicotine content [yes vs. no β-carotene supplementation - ventilated cigarettes: HR=1.23, 95% CI=0.98-1.54; non-filtered cigarettes: HR=1.22, 95% CI=0.91-1.64; p-interaction=0.83]. Conclusion: These findings indicate that supplementation with β-carotene increases lung cancer incidence in smokers regardless of the tar or nicotine content of cigarettes smoked. Our data suggest that all smokers, regardless of the type of cigarette smoked, should continue to avoid β-carotene supplementation. Citation Format: Pooja Middha, Stephanie J. Weinstein, Satu Männistö, Demetrius Albanes, Alison M. Mondul. B-carotene supplementation and lung cancer risk in the ATBC Study: the role of tar and nicotine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2289. doi:10.1158/1538-7445.AM2017-2289

Abstract SY01-03: Reducing harm by targeting the addictiveness of combusted tobacco products through regulated reductions in nicotine content

Abstract Nicotine is the primary addictive constituent in cigarettes, driving chronic dependent use in millions of Americans. Approximately half of those individuals will die as a result of smoking unless they quit. One strategy for greatly reducing the harm caused by smoking is to limit the nicotine content of cigarettes and other combusted tobacco products to levels that are less addictive. This approach differs from so-called “light” and “ultralight” cigarettes, which have nicotine content similar to full-flavored cigarettes; light cigarettes reduce machine-measured nicotine yield as a consequence of ventilation, a design feature that smokers can easily overcome (e.g., by inhaling larger volumes) to maintain high levels of nicotine exposure. True regulated reductions in nicotine content became possible in 2009 when the Family Smoking Prevention and Tobacco Control Act gave the U.S. Food and Drug Administration (FDA) the authority to reduce (but not eliminate) the nicotine in tobacco products. Consequently, the FDA and NIH are supporting a large portfolio of research aimed at evaluating the potential public health impact of product standards that would reduce the nicotine content of cigarettes. This presentation focuses primarily on recent randomized clinical trials in which participants are provided investigational cigarettes with varying levels of nicotine and followed over weeks to months to assess the potential benefits and risks of regulated reductions in nicotine. These studies indicate that reducing the nicotine content of cigarettes by approximately 85% or more leads to fewer cigarettes smoked per day, reduced nicotine exposure, and/or reduced nicotine dependence with little evidence of compensatory smoking or other unintended consequences. In addition, preclinical data from rat models of nicotine self-administration indicate that nicotine reduction would likely also decrease the initiation of use among nicotine-naïve adolescent users. These data, if supported by other ongoing trials, raise critically important questions about whether and how a product standard that limits the nicotine content of all combusted tobacco products might be promulgated to reduce the harms associated with smoking. Further discussion of this approach and how it might interact with the rapidly changing landscape of tobacco products (e.g., e-cigarettes) should be a high priority for all those interested in the prevention of tobacco-related disease. Funding: Research reported in this presentation was supported by the National Institute on Drug Abuse and FDA Center for Tobacco Products (CTP) (U54 DA031659). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. Citation Format: Eric Donny. Reducing harm by targeting the addictiveness of combusted tobacco products through regulated reductions in nicotine content [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY01-03. doi:10.1158/1538-7445.AM2017-SY01-03

Animal Research on Nicotine Reduction: Current Evidence and Research Gaps.

This review will provide policy makers and clinical researchers interested in nicotine reduction with an overview of the preclinical animal research conducted on nicotine reduction and the regulatory implications of that research. The review also highlights the utility of preclinical research for research questions related to nicotine reduction.

Cigarette Nicotine Content as a Moderator of the Relationship Between Negative Affect and Smoking.

Research suggests a strong association between negative affect (NA) and smoking. However, little is known about the association between NA and smoking among individuals who switch to reduced-nicotine cigarettes. The goal of this study was to examine the extent to which cigarette nicotine content moderates the relationship between NA and smoking over time. Seven hundred and seventeen participants, 237 in the normal nicotine content (NNC; 15.8 mg/g and usual brand) cigarette group and 480 in the very low nicotine content (VLNC; 2.4 mg/g nicotine or less) cigarette group, participated in a randomized trial that examined the effects of cigarette nicotine content on smoking behavior over 6 weeks. We used parallel process latent growth curve modeling to estimate the relationship between changes in NA and changes in the numbers of cigarettes smoked per day (CPD), from baseline to 6 weeks, as a function of cigarette nicotine content. The relationship between NA and investigational CPD reduced over time for those in the VLNC group, but not for those in the NNC group. There was no significant relationship between change in PA and CPD over time for either cigarette group. Smoking VLNC cigarettes disrupts the relationship between smoking and negative affect, which may help reduce nicotine dependence. This study suggests that the association between NA and smoking behavior is reduced over time among those that smoked reduced-nicotine content cigarettes. This provides additional evidence that smoking reduced-nicotine content cigarettes may help reduce nicotine dependence.

Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects.

The use of cigarettes delivering different nicotine doses allows evaluation of the contribution of nicotine to the smoking experience. We compared responses of 46 young adult smokers to research cigarettes, delivering 0.027, 0.110, 0.231, or 0.763 mg nicotine, and conventional cigarettes. On five separate days, craving, withdrawal, affect, and sustained attention were measured after overnight abstinence and again after smoking. Participants also rated each cigarette, and the nicotine metabolite ratio (NMR) was used to identify participants as normal or slow metabolizers. All cigarettes equally alleviated craving, withdrawal, and negative affect in the whole sample, but normal metabolizers reported greater reductions of craving and withdrawal than slow metabolizers, with dose-dependent effects. Only conventional cigarettes and, to a lesser degree, 0.763-mg nicotine research cigarettes increased sustained attention. Finally, there were no differences between ratings of lower-dose cigarettes, but the 0.763-mg cigarettes and (even more so) conventional cigarettes were rated more favorably than lower-dose cigarettes. The findings indicate that smoking-induced relief of craving and withdrawal reflects primarily non-nicotine effects in slow metabolizers, but depends on nicotine dose in normal metabolizers. By contrast, relief of withdrawal-related attentional deficits and cigarette ratings depend on nicotine dose regardless of metabolizer status. These findings have bearing on the use of reduced-nicotine cigarettes to facilitate smoking cessation and on policy regarding regulation of nicotine content in cigarettes. They suggest that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to <0.763 mg/cigarette may contribute to temporary attentional deficits.

A two-site, two-arm, 34-week, double-blind, parallel-group, randomized controlled trial of reduced nicotine cigarettes in smokers with mood and/or anxiety disorders: trial design and protocol

BackgroundThe U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks.MethodsAdult smokers (N = 200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms).DiscussionResults from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes.Trial registrationTRN: NCT01928758, registered August 21, 2013.

Low Nicotine Content Descriptors Reduce Perceived Health Risks and Positive Cigarette Ratings in Participants Using Very Low Nicotine Content Cigarettes.

Understanding how smokers perceive reduced nicotine content cigarettes will be important if the FDA and global regulatory agencies implement reduced nicotine product standards for cigarettes. Prior research has shown that some smokers incorrectly believe "light" cigarettes are less harmful than regular cigarettes. Similar misunderstandings of health risk could also apply to reduced nicotine cigarettes. To date, most studies of reduced nicotine cigarettes have blinded subjects to the nicotine content. Therefore, little is known about how smokers experience reduced nicotine content cigarettes when they are aware of the reduced content, and how use may be impacted. The present study was a within-subjects experiment with 68 adult daily smokers who smoked two identical very low nicotine content Quest 3 (0.05 mg nicotine yield) cigarettes. Subjects were told that one cigarette contained "average" nicotine content, and the other contained "very low" nicotine content. After smoking each cigarette, subjects completed subjective measures about their smoking experience. Subjects rated the "very low" nicotine cigarette as less harmful to their health overall compared to the "average" nicotine cigarette; this effect held true for specific smoking-related diseases. Additionally, they rated the "very low" nicotine cigarette as having less desirable subjective effects than the "average" nicotine cigarette and predicted having greater interest in quitting smoking in the future if only the "very low" nicotine cigarette was available. Explicit knowledge of very low nicotine content changes smokers' perceptions of very low nicotine content cigarettes, resulting in reduced predicted harm, subjective ratings and predicted future use. Before a reduced nicotine product standard for cigarettes can be implemented, it is important to understand how product information impacts how smokers think about and experience very low nicotine content cigarettes. Prior research has shown that smokers incorrectly believed light cigarettes were less harmful products. As such, smokers may also misunderstand the health risks associated with smoking very low nicotine content cigarettes. This study highlights the importance of smokers' perceptions of nicotine content in cigarettes on the perceived health risks and the subjective effects of smoking very low nicotine content cigarettes.

Impact of smoking reduced nicotine content cigarettes on sensitivity to cigarette price: further results from a multi-site clinical trial.

To assess the impact of a reduction in the nicotine content of cigarettes on estimated consumption of reduced nicotine cigarettes and usual brand cigarettes at a variety of hypothetical prices. Double-blind study with participants assigned randomly to receive cigarettes for 6weeks that were either usual brand or an investigational cigarette with one of five nicotine contents. Ten sites across the United States. A total of 839 eligible adult smokers randomized from 2013 to 2014. Participants received their usual brand or an investigational cigarette with one of five nicotine contents: 15.8 (primary control), 5.2, 2.4, 1.3, or 0.4 mg/g. The Cigarette Purchase Task was completed at baseline and at the week 6 post-randomization visit. Compared with normal nicotine content controls, the lowest nicotine content (0.4mg/g) reduced the number of study cigarettes participants estimated they would smoke at a range of prices [mean reduction relative to 15.8mg/g at a price of $4.00/pack: 9.50, 95% confidence interval (CI)=6.81,12.19]. The lowest nicotine content also reduced the maximum amount of money allocated to study cigarettes and the price at which participants reported they would stop buying study cigarettes [median reduction relative to 15.8mg/g, 95% CI=$8.21 (4.27,12.15) per day and $0.44 (0.17,0.71) per cigarette, respectively]. A reduction in nicotine content to the lowest level also reduced the maximum amount of money allocated to usual brand cigarettes (median reduction relative to 15.8mg/g: $4.39 per day, 95% CI=1.88,6.90). In current smokers, a reduction in nicotine content may reduce cigarette consumption, reduce the reinforcement value of cigarettes and increase cessation if reduced nicotine content cigarettes were the only cigarette available for purchase.

Reducing nicotine exposure results in weight gain in smokers randomised to very low nicotine content cigarettes

BackgroundThe Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but...

Response to varying the nicotine content of cigarettes in vulnerable populations: an initial experimental examination of acute effects.

The purpose of this study was to begin researching the effects of very low nicotine content cigarettes in smokers especially vulnerable to dependence to assess their potential as a less dependence-producing alternative to current commercial cigarettes. Participants were 26 adult, daily cigarette smokers from one of three populations: economically disadvantaged women of reproductive age (n=9), opioid-dependent individuals (n=11), and individuals with affective disorders (n=6). Participants completed fourteen 2-4-h experimental sessions in a within-subjects research design. Sessions were conducted following brief smoking abstinence. Four research cigarettes varying in nicotine content (0.4, 2.4, 5.2, and 15.8mg/g) were studied under double-blind conditions, assessing smoking topography, subjective effects, and relative reinforcing effects of varying doses in concurrent choice tests. Results were collapsed across vulnerable populations and analyzed using repeated measures ANOVA. No significant differences between doses were discernible in smoking topography. All doses were equi-effective at reducing nicotine withdrawal. Ratings of satisfaction from smoking were lower at the 0.4 compared to 15.8mg/g dose. Participants preferred the 15.8mg/g dose over the 0.4 and 2.4 but not the 5.2mg/g doses in concurrent choice testing; no differences between the two lowest doses were noted. All cigarettes effectively reduced nicotine withdrawal with no differences in smoking topography, suggesting minimal compensatory smoking. Dependence potential was lowest at the 0.4mg/g dose. These initial results are promising regarding the feasibility of lowering nicotine content in cigarettes to very low levels in vulnerable populations without untoward effects.

Characterizing the relationship between increases in the cost of nicotine and decreases in nicotine content in adult male rats: implications for tobacco regulation.

A large reduction in the nicotine content of cigarettes may benefit public health by reducing the rate and the prevalence of smoking. A behavioral economics framework suggests that a decrease in nicotine content may be considered an increase in the unit price of nicotine (unit price=reinforcer cost/reinforcer magnitude). Increasing the price of cigarettes (i.e., increasing reinforcer cost) would be considered an equivalent change in unit price to reducing nicotine content (i.e., reducing reinforcer magnitude). The goal of the present experiments was to characterize the relationship between increases in nicotine cost and decreases in nicotine dose. A rat self-administration model was used to assess this relationship across three experiments, with an emphasis on very low nicotine doses to model a potential nicotine reduction policy. Cost was manipulated via changes in the number of responses required to earn an infusion. Results show that increases in the cost of nicotine and decreases in nicotine content were not equivalent manipulations. Nicotine consumption was more sensitive to nicotine dose than to nicotine cost. Nicotine consumption was also not equivalent across a variety of cost and dose combinations forming a single unit price. Results of the present studies suggest that nicotine reduction is likely to have a large impact on nicotine exposure from cigarettes.

Effects of 6-Week Use of Reduced-Nicotine Content Cigarettes in Smokers With and Without Elevated Depressive Symptoms.

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. 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. 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. 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. 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.

A Randomized Controlled Trial of Progressively Reduced Nicotine Content Cigarettes on Smoking Behaviors, Biomarkers of Exposure, and Subjective Ratings.

The U.S. FDA has the authority to reduce cigarette nicotine content if found to benefit public health. Reduced nicotine content (RNC) cigarette use does not appear to increase harm exposure, but studies have not rigorously assessed smoking behavior or used a comprehensive panel of biomarkers. This study examined the effects of progressively decreasing RNC cigarettes on smoking behaviors, biomarkers of exposure, and subjective ratings. One hundred and fifty-eight daily, non-treatment-seeking smokers participated in a 35-day randomized, unblinded, parallel study. After a 5-day baseline period, participants were randomly assigned to an experimental group (n = 80) that smoked progressively decreasing RNC cigarettes during three 10-day periods, or control group (n = 78) that smoked their own brand throughout the study. Daily cigarette consumption significantly increased for the intermediate RNCs (P's < 0.001) but approached baseline rate for the lowest RNC (P = 0.686); in contrast, puffing behavior significantly decreased at intermediate levels and increased for the lowest RNC (P's < 0.001). Cotinine and NNAL significantly decreased by RNC period (P's ≤ 0.001-0.02), whereas CO boost initially increased (P's = 0.001-0.005). 1-HOP did not change by period (P = 0.109). Smoking behaviors changed by RNC period via CPD and puffing behavior. Biomarkers of exposure generally decreased with nicotine content. Findings suggest that RNC use does not ubiquitously reduce smoking behaviors or biomarkers, yet the lowest RNC level tested may reduce harm exposure. This emphasizes the importance of using multiple behavioral and biologic measures to address the impact of RNC cigarette smoking. Cancer Epidemiol Biomarkers Prev; 25(7); 1125-33. ©2016 AACR.

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine.

The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats. In a series of experiments, rats responded for intravenous nicotine infusions or a moderately-reinforcing visual stimulus in daily 1-h sessions. Rats received pre-session injections of known MAO inhibitors. The results show that (1) tranylcypromine (TCP), a known MAO inhibitor, increases sensitivity to the primary reinforcing effects of nicotine, shifting the dose-response curve for nicotine to the left, (2) inhibition of MAO-A, but not MAO-B, increases low-dose nicotine self-administration, (3) partial MAO-A inhibition, to the degree observed in chronic cigarette smokers, also increases low-dose nicotine self-administration, and (4) TCP decreases the threshold nicotine dose required for reinforcement enhancement. The results of the present experiments suggest cigarette smoke constituents that inhibit MAO-A, in the range seen in chronic smokers, are likely to increase the primary reinforcing and reinforcement enhancing effects of low doses of nicotine. If the FDA reduces the nicotine content of cigarettes, then variability in constituents that inhibit MAO-A could impact smoking.

The Impact of Smoking Very Low Nicotine Content Cigarettes on Alcohol Use.

Reducing the nicotine content in cigarettes could improve public health by reducing smoking and toxicant exposure, but may also have unintended consequences on alcohol use. The primary objective of this study was to examine the effect of reducing the nicotine content in cigarettes on alcohol outcomes. The secondary aim was to examine whether the effects of these cigarettes on alcohol outcomes were mediated by changes in nicotine exposure, smoking behavior, or withdrawal. Between June 2013 and July 2014, we conducted a 7-arm, double-blind, randomized clinical trial at 10 U.S.-based sites. Daily smokers not currently interested in quitting (n=839) were assigned to equally sized groups to smoke for 6weeks cigarettes containing either normal nicotine content (NNC; 15.8mg/g, 9mg tar), moderate nicotine content (5.2mg/g nicotine, 9mg tar), or very low nicotine content (VLNC; 0.4 to 2.4mg/g, 9 to 13mg tar). This investigation focused on a subsample of current drinkers (n=403). Each reduced nicotine content cigarette condition was compared to the NNC control condition with respect to trajectories over the 6-week period of average daily alcohol use and occurrence of binge drinking. Moderating variables were considered. Mediation analyses tested potential explanatory processes including changes in nicotine exposure, cigarettes per day, and withdrawal. Over time, reduced nicotine exposure and smoking rate mediated effects of VLNC cigarette use on reduced alcohol use. There was no evidence of compensatory drinking in response to nicotine reduction or nicotine withdrawal, even among subgroups expected to be at greater risk (e.g., relatively heavier drinkers, highly nicotine-dependent individuals). The findings suggest that compensatory drinking is unlikely to occur in response to switching to VLNC cigarettes. In contrast, reducing the nicotine content of cigarettes may reduce alcohol use (clinicalTrials.gov number, NCT01681875).

Effect of reducing the nicotine content of cigarettes on cigarette smoking behavior and tobacco smoke toxicant exposure: 2-year follow up.

A broadly mandated reduction of the nicotine content (RNC) of cigarettes has been proposed in the United States to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted and to facilitate quitting in established smokers. The primary aim of this study was to determine whether following 7 months of smoking very low nicotine content cigarettes (VLNC), and then returning to their own cigarettes, smokers would demonstrate persistently reduced nicotine intake compared with baseline or quit smoking. In a community-based clinic 135 smokers not interested in quitting were randomized to one of two groups. A research group smoked their usual brand of cigarettes, followed by five types of research cigarettes with progressively lower nicotine content, each for 1 month, followed by 6 months at the lowest nicotine level (0.5 mg/cigarette) (53 subjects) and then 12 months with no intervention (30 subjects completed). A control group smoked their usual brand for the same period of time (50 subjects at 6 months, 38 completed). Smoking behavior, biomarkers of nicotine intake and smoke toxicant exposure were measured. After 7 months smoking VLNC, nicotine intake remained below baseline (plasma cotinine 149 versus 250 ng/ml, P<0.005) with no significant change in cigarettes per day or expired carbon monoxide (CO). During the 12-month follow-up, cotinine levels in RNC smokers rose to baseline levels and to those of control smokers. Quit rates among RNC smokers were very low [7.5 versus 2% in controls, not significant). In smokers not interested in quitting, reducing the nicotine content in cigarettes over 12 months does not appear to result in extinction of nicotine dependence, assessed by persistently reduced nicotine intake or quitting smoking over the subsequent 12 months.