Search

Introduction A mandated reduction in the nicotine content of cigarettes may decrease smoking, but also increase demand for other nicotine products. The present study tested the impact of smoking cigarettes with very low nicotine content and concurrent use of a transdermal nicotine patch. Study design A balanced 2 × 2 factorial randomized clinical trial investigating the impact of cigarette nicotine content (double-blind, very low nicotine content versus normal nicotine content) and use of a transdermal nicotine patch (open label, patch versus no patch). Setting/participants Adult daily smokers (n=240) in the Pittsburgh, PA area. Intervention Participants were provided with research cigarettes and transdermal nicotine patches (if assigned to patch condition) for 7 weeks. Cigarettes were Spectrum brand (National Institute on Drug Abuse) and either 15.8 mg nicotine/g tobacco (normal nicotine content) or 0.4 mg nicotine/g tobacco (very low nicotine content). In the 7th week, participants were monetarily incentivized to abstain from smoking. Main outcome measures Participants reported daily cigarette use throughout the trial and the primary outcome was average number of cigarettes smoked per day (study + nonstudy) during Week 6. Participants were recruited from 2015 to 2017 and data were analyzed between 2017 and 2018. Results Assignment to very low nicotine content cigarettes and assignment to wear a nicotine patch both reduced the number of cigarettes smoked per day during Week 6 (p=0.001 and 0.04, respectively). However, assignment to the patch along with very low nicotine content cigarettes did not significantly reduce cigarette smoking compared with assignment to very low nicotine content cigarettes alone. Conclusions A mandated reduction in the nicotine content of cigarettes is likely to reduce the number of cigarettes smoked per day, but the added benefit of concurrent transdermal nicotine is unclear. Future studies should investigate whether alternative sources of noncombusted tobacco, such as e-cigarettes, enhance the effects of very low nicotine content cigarettes on smoking. Trial registration This study is registered at www.clinicaltrials.gov NCT02301325.

Background: The FDA is considering a mandated reduction in the nicotine content of cigarettes. Clinical trials have been limited by non-study cigarette use (noncompliance), which could mask compensation. The goal of this study was to assess whether compensation occurs when smokers provided with very low nicotine cigarettes cannot access normal nicotine cigarettes. Methods: In a within-subjects, crossover design, current smokers (n = 16) were confined to a hotel for two 4-night hotel stays during which they were only able to access the research cigarettes provided. The hotel stays offered normal nicotine cigarettes or very low nicotine content (VLNC) cigarettes, in an unblinded design, available for “purchase” via a study bank. Results: In the context of complete compliance with the study cigarettes (n = 16), there was not a significant increase during the VLNC condition for cigarettes smoked per day, expired carbon monoxide, or N-acetyl-S-(cyanoethyl)-l-cysteine (cyanoethyl-MA, metabolite of acrylonitrile). There was a significant nicotine × time interaction on urine N-acetyl-S-(3-hydroxypropyl)-l-cysteine (hydroxypropyl-MA, metabolite of acrolein), driven by an increase in the VLNC condition during the first 24 hours. By the end of the VLNC condition, there was no evidence of compensation across any measure of smoking or smoke exposure. Conclusions: Among current smokers who exclusively used VLNC cigarettes for 4 days, there was no significant compensatory smoking behavior. Impact: These data, combined with the larger body of work, suggest that a mandated reduction in nicotine content is unlikely to result in an increase in smoking behavior to obtain more nicotine.

Background: A mandated reduction in the nicotine content of cigarettes could reduce smoking rate and prevalence. However, one concern is that smokers may compensate by increasing the intensity with which they smoke each cigarette to obtain more nicotine. This study assessed whether smokers engage in compensatory smoking by estimating the mouth-level nicotine intake of low nicotine cigarettes smoked during a clinical trial. Methods: Smokers were randomly assigned to receive cigarettes with one of five nicotine contents for 6 weeks. An additional group received a cigarette with the lowest nicotine content, but an increased tar yield. The obtained mouth-level nicotine intake from discarded cigarette butts for a subset of participants (51–70/group) was estimated using solanesol as described previously. A compensation index was calculated for each group to estimate the proportion of nicotine per cigarette recovered through changes in smoking intensity. Results: There was no significant increase in smoking intensity for any of the reduced nicotine cigarettes as measured by the compensation index (an estimated 0.4% of the nicotine lost was recovered in the lowest nicotine group; 95% confidence interval, −0.1 to 1.2). There was a significant decrease in smoking intensity for very low nicotine content cigarettes with increased tar yield. Conclusions: Reductions in nicotine content did not result in compensatory changes in how intensively participants smoked research cigarettes. Impact: Combined with data from clinical trials showing a reduction in cigarettes smoked per day, these data suggest that a reduction in nicotine content is unlikely to result in increased smoke exposure.

OBJECTIVES: We compared biomarkers of exposure and potential harm in smokers of American Spirit (AS) to smokers of Marlboro, Newport, Camel, and Pall Mall. METHODS: We conducted secondary analysis on: (1) data from a randomized clinical trial (RCT); and (2) the Population Assessment of Tobacco Use and Health (PATH) Study. Biomarkers analyzed included: total nicotine equivalents (TNE); 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL); N'-nitrosonornicotine and its N-glucuronide (total NNN);3-hydroxypropylmercapturic acid(3-HPMA); 2-hydroxypropylmercapturic acid (2-HPMA), 3-hydroxy-1 methylpropylmercapturic acid (HMPMA); S-phenylmercapturic acid(SPMA); 2-cyanoethylmercapturic acid (CEMA); phenanthrene tetraol(PheT);1-hydroxypyrene (1-HOP);8-iso-PGF(2α); white blood count(WBC); prostaglandin E metabolite(PGEM); and high sensitivity C-reactive protein(hsCRP). RESULTS: AS smokers did not differ in TNE but had higher TNE per cigarette compared to other brands. Total NNAL, total NNN, CEMA, and 3-HPMA were lower in AS smokers. All other biomarkers were no different in AS smokers compared to all or the majority of the other brands. CONCLUSIONS: Levels of total NNAL, total NNN, acrylonitrile, and acrolein were reduced in AS smokers; however, it is not known whether reductions in exposure to these toxicants contribute to reduced harm. Higher TNE per cigarette smoked in AS smokers suggests a greater addictive potential compared to other brands. Regulatory action to ensure that consumers are not misled about the risks of the AS brand are recommended.

The US Food and Drug Administration is considering mandating a substantial reduction in the nicotine level of cigarettes and possibly other combusted tobacco products to render them minimially addictive. This would likely result in several public health benefits, including increased cessation, decreased progression to dependence, and reduced consumption of combusted tobacco products. However, findings from clinical trials of reduced-nicotine cigarettes suggest that many smokers consuming low nicotine–content cigarettes sought out regular nicotine–content cigarettes, even when they were asked to only smoke free low-nicotine cigarettes. If this policy were implemented without ensuring that cessation treatments and appealing alternative products (e.g., e-cigarettes) were readily available, some consumers would be likely to seek banned regular nicotine–content combusted tobacco products from illicit sources: retail, online, and individuals. Left unchecked, this illicit market could undermine the public health benefits of the policy. We describe supply and demand factors in an illicit market. Informed by the literature on controlling Internet tobacco sales and reducing illicit trade in low-cost cigarettes when there are price differentials, we recommend tracking and tracing products and greater surveillance and enforcement efforts to minimize illicit trade in normal nicotine products under a low-nicotine tobacco product standard.

Background: We examined the nicotine metabolite ratio's (NMR) relationship with smoking intensity, nicotine dependence, and a broad array of biomarkers of exposure and biological effect in commercial cigarette smokers. Methods: Secondary analysis was conducted on two cross-sectional samples of adult, daily smokers from Wave 1 (2013–2014) of the Population Assessment of Tobacco Use and Health (PATH) Study and baseline data from a 2014–2017 randomized clinical trial. Data were restricted to participants of non-Hispanic, white race. The lowest quartile of NMR ( Results: Compared with slow metabolizers, normal/fast metabolizers had greater cigarettes per day and higher levels of total nicotine equivalents, tobacco-specific nitrosamines, volatile organic componds, and polycyclic aromatic hydrocarbons. A novel finding was higher levels of inflammatory biomarkers among normal/fast metabolizers versus slow metabolizers. With NMR modeled as a continuous measure, the associations between NMR and biomarkers of inflammation were not significant. Conclusions: The results are suggestive that normal/fast nicotine metabolizers may be at increased risk for tobacco-related disease due to being heavier smokers, having higher exposure to numerous toxicants and carcinogens, and having higher levels of inflammation when compared with slow metabolizers. Impact: This is the first documentation that NMR is not only associated with smoking exposure but also biomarkers of biological effects that are integral in the development of tobacco-related disease. Results provide support for NMR as a biomarker for understanding a smoker's exposure and potential risk for tobacco-related disease.

The available research on switching from normal nicotine to very low nicotine content cigarettes shows minimal evidence of compensatory smoking. Mathematical estimations suggest that substantial compensation after switching to very low nicotine cigarettes would be impossible. It is likely that smokers who are unable to tolerate the extent of proposed nicotine reduction would switch to other sources of nicotine, rather than try to compensate by smoking more very low nicotine content cigarettes more intensely.

The urinary metabolites cyanoethyl mercapturic acid (CEMA) and 3-hydroxypropyl mercapturic acid (3-HPMA) have been widely used as biomarkers of exposure to acrylonitrile and acrolein, respectively, but there are no published data on their consistency over time in the urine of cigarette smokers. We provided, free of charge over a 20 week period, Spectrum NRC600/601 research cigarettes to cigarette smokers in the control arm of a randomized clinical trial of the reduced nicotine cigarette. Urine samples were collected at weeks 4, 8, 12, 16, and 20 and analyzed for CEMA and 3-HPMA, and total nicotine equivalents (TNE) using validated methods. Creatinine-corrected intra-class correlation coefficients for CEMA, 3-HPMA, and TNE were 0.67, 0.46, and 0.68, respectively, indicating good longitudinal consistency for CEMA, while that of 3-HPMA was fair. A strong correlation between CEMA and TNE values was observed. These data support the use of CEMA as a reliable biomarker of tobacco smoke exposure. This is the first report of the longitudinal stability of the biomarkers of acrylonitrile and acrolein exposure in smokers. The data indicate that CEMA, the biomarker of acrylonitrile exposure, is consistent over time in cigarette smokers, supporting its use. While 3-HPMA levels were less stable over time, this biomarker is nevertheless a useful monitor of human acrolein exposure because of its specificity to this toxicant.

Background: As the U.S. Food and Drug Administration considers a low nicotine product standard for cigarettes, it is important to examine how people who smoke, especially individuals from priority populations disproportionately affected by smoking, perceive low nicotine content (LNC) cigarettes and their relative risk perceptions of alternative nicotine delivery system (ANDS) products, including e-cigarettes and snus, and medicinal nicotine. Methods: Data are from Wave 4 (2016–2017) of the adult Population Assessment of Tobacco Use and Health (PATH) Study. We examined respondents’ absolute risk perceptions about nicotine, LNC cigarettes, ANDS products and medicinal nicotine, their relative risk perceptions of LNC cigarettes and ANDS products compared to conventional cigarettes, and their relative risk perceptions of medicinal nicotine compared to ANDS products. Results: The majority of respondents across priority smoking populations indicated snus, e-cigarettes, and LNC cigarettes were ‘about the same’ level of harmfulness or addictiveness as conventional cigarettes. The majority of respondents indicated e-cigarettes to be ‘about the same’ harmfulness as medicinal nicotine. Conclusions: Our study indicates that adults who smoke cigarettes generally have misperceptions about the harms of nicotine and the relative risks of ANDS products and such misperceptions exist regardless of their racial/ethnic identity, sexual orientation, and gender identity.

Introduction The Food and Drug Administration is considering a policy to drastically reduce the allowable nicotine content of cigarettes. The current study examined whether the policy implementation approach, i.e., either immediately reducing nicotine content to very low levels or gradually reducing nicotine content over an extended period, influences policy support among people who smoke cigarettes. Methods Adults who smoked daily were randomly assigned (double-blind) to an immediate nicotine reduction condition (0.4 mg/g nicotine cigarettes), a gradual nicotine reduction condition (15.5 to 0.4 mg/g), or a control condition (15.5 mg/g) for 20 weeks. Participants were asked if they would “support or oppose a law that reduced the amount of nicotine in cigarettes, to make cigarettes less addictive.” Logistic regression analyses assessed if policy support was affected by treatment condition, demographic covariates, interest in quitting, and subjective cigarette effects. Results At Week 20 (N = 957 completers), 60.4% of participants supported the policy, 17.4% opposed, and 22.2% responded “Don’t know.” Policy support did not differ by treatment condition. Support was greater among those interested in quitting (OR = 3.37, 95% CI = 2.49, 4.55). Support was lower among males (OR = 0.49, 95% CI = 0.37, 0.67), those with greater dependence scores (OR = 0.92, 95% CI = 0.86, 0.99) and participants aged 18–24 (OR = 0.53, 95% CI = 0.28, 0.99). No other covariates were associated with policy support. Conclusions The majority of participants supported a nicotine reduction policy. The implementation approach, immediate or gradual reduction, did not affect policy support. Participants interested in quitting smoking were more likely to support a nicotine reduction policy.

Aims 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. Design Double-blind study with participants assigned randomly to receive cigarettes for 6 weeks that were either usual brand or an investigational cigarette with one of five nicotine contents. Setting Ten sites across the United States. Participants A total of 839 eligible adult smokers randomized from 2013 to 2014. Intervention and comparator 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. Measurements The Cigarette Purchase Task was completed at baseline and at the week 6 post-randomization visit. Findings Compared with normal nicotine content controls, the lowest nicotine content (0.4 mg/g) reduced the number of study cigarettes participants estimated they would smoke at a range of prices [mean reduction relative to 15.8 mg/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 15.8 mg/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 15.8 mg/g: $4.39 per day, 95% CI = 1.88,6.90). Conclusions 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.

Background The 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 may have unintended consequences related to weight gain. Methods Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored. Findings There were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups. Conclusions The effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine. Trial registration number NCT01681875, Post-results.

Steven R. Goldberg was a pioneering behavioral pharmacologist whose intravenous drug self-administration studies advanced the understanding of conditioned stimuli and schedules of reinforcement as determinants of pattern and persistence of drug-seeking behavior, and in particular, the importance of nicotine in tobacco use. His passing in 2014 led to invitations to contribute articles to psychopharmacology dedicated to his work. The objectives of this review are to summarize and put into historical perspective Goldberg’s contributions to elucidate the reinforcing effects of nicotine and to summarize the implications of his research for medication development, tobacco regulation, and potential tobacco control policy options. This includes a review of intravenous nicotine self-administration research from the 1960s to 2016. Goldberg’s application of behavioral pharmacology methods to investigate nicotine reinforcement and the influence of schedule of reinforcement and conditioned stimuli on nicotine administration contributed to the conclusions of the US National Institute on Drug Abuse, and the Surgeon General, that nicotine met the criteria as a dependence-producing drug and cigarette smoking as a prototypic drug dependency or “addiction.” Equally important, this work has been systematically extended to other species and applied to address a range of factors relevant to tobacco use, medication development, regulation, and public health policy. Steven R. Goldberg was a pioneering scientist whose systematic application of the science of behavioral pharmacology advanced the understanding of tobacco and nicotine use and contributed to the scientific foundation for tobacco product regulation and potential public health tobacco control policy development.

Large reductions in nicotine content could dramatically reduce reinforcement from and dependence on cigarettes. In this article, we summarise the potential benefits of reducing nicotine in combusted tobacco and address some of the common concerns. We focus specifically on New Zealand because it may be ideally situated to implement such a policy. The available data suggest that, in current smokers, very low nicotine content (VLNC) cigarettes decrease nicotine exposure, decrease cigarette dependence, reduce the number of cigarettes smoked per day and increase the likelihood of contemplating, making and succeeding at a quit attempt. New smokers would almost certainly be exposed to far less nicotine as a result of smoking VLNC cigarettes and, consequently, would probably be less likely to become chronic, dependent, smokers. Many of the concerns about reducing nicotine including compensatory smoking, an exacerbation of psychiatric symptoms, the perception that VLNC cigarettes are less harmful, and the potential for a black market are either not supported by the available data, likely mitigated by other factors including the availability of nicotine-containing e-cigarettes, or unlikely to offset the potential benefit to public health. Although not all concerns have been addressed or can be a priori, the magnitude of the potential benefits and the growing evidence of relatively few potential harms should make nicotine reduction one of the centrepieces for discussion of how to rapidly advance tobacco control. Policies that aim to render the most toxic tobacco products less addictive could help New Zealand attain their goal of becoming smokefree by 2025.

Author(s): Tidey, Jennifer W; Pacek, Lauren R; Koopmeiners, Joseph S; Vandrey, Ryan; Nardone, Natalie; Drobes, David J; Benowitz, Neal L; Dermody, Sarah S; Lemieux, Andrine; Denlinger, Rachel L; Cassidy, Rachel; al'Absi, Mustafa; Hatsukami, Dorothy K; Donny, Eric C | Abstract: BackgroundThe 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.MethodsIn 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.ResultsOf 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 l .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 l 16 and no change in CES-D score for those with baseline CES-D scores ≥ 16.ConclusionsThese findings provide initial evidence that a reduced-nicotine standard for cigarettes may reduce smoking, without worsening depressive symptoms, among smokers with elevated depressive symptoms.ImplicationsThis 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 Numerous studies have shown that nicotine (NIC) can enhance the reinforcing effects of non-NIC stimuli through a nonassociative mechanism. To date, it is unclear whether NIC reinforcement enhancement serves to increase behaviors motivated by rewarding stimuli only, or whether NIC potentiates behavior motivated by all stimuli, regardless of valence. Methods The current study used a place conditioning procedure to examine whether acute NIC injection modulates avoidance of an environment previously associated with an aversive stimulus. Separate groups of rats underwent place conditioning using either lithium chloride (125mg/kg/ml, i.p.) or footshock (0.75 mA) as the aversive stimulus. Other rats served as nonconditioned controls. The magnitude of place avoidance was assessed after acute NIC (0.1 or 0.4mg/kg/ml, s.c.) or saline. Results Rats avoided chambers previously paired with either lithium chloride or footshock, and conditioned place avoidance was significantly enhanced by NIC pre-treatment. Conclusions These results demonstrate that the ability of NIC to enhance motivated behavior extends to behaviors elicited by aversive stimuli, evidence that NIC affects behavior motivated by a broader range of stimuli than previously appreciated. Implications The current study examined whether the reinforcement enhancement properties of NIC apply to aversive stimuli by testing NIC enhancement of conditioned place avoidance in rats. The results demonstrate that NIC enhances the motivational impact of these distinct aversive stimuli, providing novel evidence that NIC affects behavior motivated by a broader range of stimuli than has previously been demonstrated.

INTRODUCTION Nicotine's interoceptive stimulus effects likely help explain smoking's reinforcing efficacy, but human studies have been limited by difficulties controlling dosing via tobacco inhalation. Our objective was to describe a procedure to study nicotine discrimination via smoking. METHODS Dependent smokers abstinent overnight (>12 hours) were first "trained" to discriminate between two cigarettes differing in nicotine content, based on four puffs of exposure, and then tested on whether they successfully acquired that discrimination. After piloting with Quest brand commercial cigarettes, 29 subjects engaged in the main study with cigarettes available through NIDA (Spectrum; 16mg vs. 0.4mg nicotine content). Discrimination training first involved two trials, one with each cigarette, prior to six testing trials. Due to results with the first 20 subjects, the remaining nine received two training trials with each cigarette (four total). Subjective perceptions were also assessed during each testing trial, and puff choice between the two cigarettes available concurrently was assessed after testing, on the last two trials. RESULTS All five pilot subjects successfully discriminated Quest 1 versus Quest 3 (defined by at least five out of six trials correct, ie, >80%). Yet, only 10 of 20 subjects (50%) were able to discriminate the two Spectrum cigarettes based on two training trials. After changing to four training trials, eight of nine subjects were able to discriminate (89%). Subjective perceptions and puff choice differed between cigarettes more in those able versus unable to discriminate them. CONCLUSIONS With sufficient training exposures, smokers can discriminate nicotine between cigarettes differing in nicotine contents. IMPLICATIONS The interoceptive stimulus effects of nicotine are critical to understanding reinforcement from cigarette smoking behavior. Because of the very recent availability of Spectrum research cigarettes from NIDA, with specific known amounts of nicotine content, the study of nicotine discrimination in humans via cigarette smoking may now be feasible. Our results demonstrate that, with sufficient training, smokers can behaviorally discriminate nicotine from four puffs' exposure between cigarettes differing in nicotine contents. Future research should evaluate human discrimination of nicotine from greater amounts of cigarette smoke exposure, as well as in response to other procedural variations.

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.

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

Smokers with serious mental illness (SMI) are less responsive to cessation treatments than those without SMI. In this study, we compared smokers with and without SMI on validated measures of biological and psychosocial factors associated with tobacco use. Smokers with (n = 58) and without SMI (n = 83) who were enrolled in parallel clinical trials were compared on measures of carbon monoxide (CO) exposure, nicotine exposure, tobacco-specific nitrosamine exposure, craving, smoking motives, affect, perceived stress, environmental exposure to smoke/smokers, respiratory symptoms, tobacco-related health risk perceptions, and whether they had received recent advice to quit smoking from a health care provider. Data were collected between 2013 and 2017 in Providence, Rhode Island, USA. Samples were compared using independent-sample t-tests and chi-squared tests. Smokers with SMI had higher CO, nicotine, and tobacco-specific nitrosamine exposure levels, greater cigarette dependence, higher craving, and higher scores on eight out of eleven smoking motives (p's 0.05). Smokers with SMI reported more severe respiratory symptoms but lower perceived health risks of tobacco (p's 0.05). These smokers were more likely to report having received advice to quit from a medical provider in the past 6 weeks (p 0.05). Affect, stress, and exposure to smoke/smokers did not differ across samples. Our findings advance the understanding of the elevated smoking rates of people with SMI by comparing smokers with and without SMI on validated biopsychosocial measures. There is a need for interventions that reduce craving, reduce smoking motives, and increase risk awareness among smokers with SMI.

Introduction Patients with schizophrenia (SCZ) smoke at a rate of 4–5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited. Methods The present experiments examined self-administration of NIC, alone or in combination with other reinforcers, across a range of doses in the methylazoxymethanol acetate (MAM) rodent model of SCZ. Results MAM and control animals did not differ in NIC self-administration across a range of doses and schedules of reinforcement, in both standard 1-hour self-administration sessions and 23-hour extended access sessions. However, MAM animals responded less for sucrose or reinforcing visual stimuli alone or when paired with NIC. Conclusions To the extent that MAM-treated rats are a valid model of SCZ, these results suggest that increased NIC reinforcement does not account for increased smoking in SCZ patients. Implications This study is the first to utilize nicotine self-administration, the gold standard for studying nicotine reinforcement, in the methylazoxymethanol acetate model of schizophrenia, which is arguably the most comprehensive animal model of the disease currently available. Our assessment found no evidence of increased nicotine reinforcement in methylazoxymethanol acetate animals, suggesting that increased reinforcement may not perpetuate increased smoking in schizophrenia patients.

RATIONALE: The ability of nicotine to suppress body weight is cited as a factor impacting smoking initiation and the failure to quit. Self-administered nicotine in male rats suppresses weight independent of food intake, suggesting that nicotine increases energy expenditure. OBJECTIVE: The current experiment evaluated the impact of self-administered nicotine on metabolism in rats using indirect calorimetry and body composition analysis. METHODS: Adult male rats with ad libitum access to powdered standard rodent chow self-administered intravenous infusions of nicotine (60 μg/kg/infusion or saline control) in daily 1-h sessions in the last hour of the light cycle. Indirect calorimetry measured respiratory exchange ratio (RER), energy expenditure, motor activity, and food and water consumption for 22.5 h between select self-administration sessions. RESULTS: Self-administered nicotine suppressed weight gain and reduced the percent of body fat without altering the percent of lean mass, as measured by Echo MRI. Nicotine reduced RER, indicating increased fat utilization; this effect was observed prior to weight suppression. Moreover, nicotine intake did not affect motor activity or energy expenditure. Daily food intake was not altered by nicotine self-administration; however, a trend in suppression of meal size, a transient suppression of water intake, and an increase in meal frequency was observed. CONCLUSION: These data provide evidence that self-administered nicotine suppresses body weight via increased fat metabolism, independent of significant changes in feeding, activity, or energy expenditure.

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 The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P

Although nicotine is the primary reinforcing constituent in cigarettes, there is evidence that other constituents in cigarette smoke may interact with nicotine to reinforce smoking behavior.The present experiments investigated whether a novel combination of these cigarette smoke constituents would increase nicotine self-administration in adult male rats. The constituents included five minor alkaloids (anabasine, nornicotine, cotinine, myosmine, and anatabine), two β-carbolines (harman and norharman), and acetaldehyde. All doses were indexed to be proportional to concentrations in cigarette smoke given a standard dose of nicotine used in rodent self-administration, or ten times higher than this standard. To model MAO inhibition seen in chronic smokers, some groups received separate injections of tranylcypromine prior to each self-administration session.Tranylcypromine increased low-dose nicotine self-administration independent of other smoke constituents, which had no effect on self-administration behavior. The effect of tranylcypromine was confirmed across a large range of reinforcement schedules. The effect of tranylcypromine on low-dose nicotine self-administration was observed regardless of whether the injection was delivered 1-h or 23-h prior to the self-administration session, consistent with the interpretation that MAO inhibition was responsible for the increase in self-administration, instead of acute off-target effects.These data suggest that this cocktail of constituents does not significantly alter the primary reinforcing effects of nicotine, but constituents that inhibit MAO may increase the primary reinforcing effects of nicotine, especially at low doses.

Noncompliance or non-adherence to randomized treatment is a common challenge when interpreting data from randomized clinical trials. The effect of an intervention if all participants were forced to comply with the assigned treatment (i.e., the causal effect) is often of primary scientific interest. For example, in trials of very low nicotine content (VLNC) cigarettes, policymakers are interested in their effect on smoking behavior if their use were to be compelled by regulation. A variety of statistical methods to estimate the causal effect of an intervention have been proposed, but these methods, including inverse probability of compliance weighted (IPCW) estimators, assume that participants' compliance statuses are reported without error. This is an untenable assumption when compliance is based on self-report. Biomarkers (e.g., nicotine levels in the urine) may provide more reliable indicators of compliance but cannot perfectly discriminate between compliers and non-compliers. However, by modeling the distribution of the biomarker as a mixture distribution and writing the probability of compliance as a function of the mixture components, we show how the probability of compliance can be directly estimated from the data even when compliance status is unknown. To estimate the causal effect, we develop a new approach which re-weights participants by the product of their probability of compliance given the observed data and the inverse probability of compliance given confounders. We show that our proposed estimator is consistent and asymptotically normal and show that in some situations the proposed approach is more efficient than standard IPCW estimators. We demonstrate via simulation that the proposed estimator achieves smaller bias and greater efficiency than ad hoc approaches to estimating the causal effect when compliance is measured with error. We apply our method to data from a recently completed randomized trial of VLNC cigarettes.

Introduction 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. Methods 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. Results 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. Conclusions 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. Implications 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.

Background Theories of addiction suggest that chronic smoking may be associated with both hypersensitivity to smoking and related cues and hyposensitivity to alternative reinforcers. However, neural responses to smoking and nonsmoking rewards are rarely evaluated within the same paradigm, leaving the extent to which both processes operate simultaneously uncertain. Behavioral evidence and theoretical models suggest that dysregulated reward processing may be more pronounced during deprivation from nicotine, but neuroimaging evidence on the effects of deprivation on reward processing is limited. The current study examined the impact of deprivation from smoking on neural processing of both smoking and monetary rewards. Methods Two separate functional magnetic resonance imaging scans were performed in 38 daily smokers, one after smoking without restriction and one following 24 hours of abstinence. A rewarded guessing task was conducted during each scan to evaluate striatal blood oxygen level–dependent response during anticipation of both smoking and monetary rewards. Results A significant reward type by abstinence interaction was observed in the bilateral caudate and medial prefrontal cortex during reward anticipation. The blood oxygen level–dependent response to anticipation of smoking reward was significantly higher and anticipation of monetary rewards was significantly lower during abstinence compared with nonabstinence. Attenuation of monetary reward–related activation during abstinence was significantly correlated with abstinence-induced increases in craving and withdrawal. Conclusions These results provide the first direct evidence of dissociated effects of smoking versus monetary rewards as a function of abstinence. The findings suggest an important neural pathway that may underlie the choice to smoke in lieu of alternative reinforcement during a quit attempt.

© 2014 Elsevier Inc. 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.

Objective Reducing the nicotine content of cigarettes is a potential regulatory strategy that may enable cessation. The present study investigated the effect of nicotine exposure while smoking very low nicotine content (VLNC) cigarettes on cessation outcomes. The roles of possible sources of nicotine were also explored, including the VLNC cigarette and co-use of cigarettes with normal nicotine content. Methods A secondary data analysis of two analogous randomised trials of treatment seeking, adult daily smokers (n=112) who were instructed to smoke VLNC cigarettes for 6 weeks and then make a quit attempt. Controlling for baseline demographic and smoking features, the association between reductions in nicotine exposure during the 6-week trial, assessed by urinary total cotinine and biomarker-confirmed smoking abstinence 1 month later, was tested. Subsequent analyses controlled for the effects of the frequency of VLNC and normal nicotine content cigarette use and the nicotine yield of the VLNC cigarette (0.05 vs 0.09 mg). Results Greater reductions in nicotine exposure while smoking VLNC cigarettes predicted abstinence independent of individual differences in baseline smoking, cotinine, dependence, gender and study. Nicotine reduction was largest among individuals who were assigned to smoke a VLNC cigarette with lower nicotine yield and who smoked fewer normal nicotine content and VLNC cigarettes. Conclusions In the context of nicotine regulations and corresponding research, factors that undermine nicotine reduction must be addressed, including the availability and use of cigarettes with normal nicotine content and not sufficiently reducing the nicotine yield of cigarettes. Maximising nicotine reduction may facilitate smoking cessation. Trial registration numbers NCT 101050569 and NCT 00777569.

Nicotine has been shown to enhance the motivational properties of non-nicotine stimuli. This reinforcement-enhancing property of nicotine has the potential to promote the use of other illicit substances as well as maladaptive patterns of food intake. Therefore, the current study aimed to examine whether nicotine enhances preference for contexts paired with cocaine or sucrose utilizing a place conditioning procedure. Separate groups of adult male rats were administered sucrose or cocaine in one of two compartments of a standard CPP chamber on four consecutive days. Preference was then assessed following no injection, a single subcutaneous (s.c.) injection of nicotine, and a s.c. saline injection. The animals preferred the chamber paired with either sucrose or cocaine, as evident from an increased time spent in the paired chamber compared to baseline. Nicotine further increased the time spent in the sucrose- or cocaine-paired chamber, consistent with a reinforcement-enhancement effect. Previous results demonstrate an interaction between nicotine and intake of other drugs or food. The present findings provide an additional mechanism that may underlie these effects and which may have implications for drug dependence and obesity.

Tobacco control policies should aim to decrease the number of people who become smokers and better enable current smokers to quit smoking. Smoking initiation rates are still high, with one in four U.S. high school seniors smoking daily (US Department of Health and Human Services, 2012). Additionally, two thirds of current smokers express that they would like to quit smoking, but only 6.2% of smokers actually quit each year (CDC, 2011). In 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act which permits the regulation of tobacco products and their constituents, including the reduction, but not elimination, of the nicotine content in cigarettes (US Congress, 2009). A policy that reduces the nicotine content of a cigarette below a threshold for addiction could substantially decrease initiation and increase smoking cessation (Benowitz and Henningfield, 1994), but such a policy requires an understanding of the dose range that supports initiation as well as maintenance of smoking behavior. Importantly, a history of smoking may shift the dose-response curve for the primary reinforcing effects of nicotine to the left (sensitization) or to the right (tolerance). In this case, a nicotine reduction policy may impact individuals who start smoking reduced nicotine content cigarettes (i.e., new smokers) differently from those who were smoking prior to policy implementation (i.e., current smokers). If a history of smoking normal nicotine content cigarettes increases sensitivity to low doses of nicotine, ongoing research on reduced nicotine cigarettes that uses current smokers as participants might underestimate the public health impact of regulation on individuals who try smoking for the first time after regulation. Understanding the impact of prior nicotine and tobacco use is critical in determining the likely effects of a reduction in nicotine content on smoking behavior. Non-human research is valuable for studying how a nicotine reduction policy would differentially affect new and experienced cigarette smokers because ethical issues make experimentally manipulating the initiation of smoking impossible. Nicotine self-administration research, in which animals respond for intravenous (i.v.) infusions of nicotine, is likely to be particularly informative. Two dose-response curves, each plotting the rate of self-administration across low nicotine doses, can be compared: one for acquisition in which rats are first given the opportunity to respond for low doses of nicotine (analog for “new smokers”), and one following reduction after rats have a history of responding for a higher dose of nicotine (analog for “current smokers”). While the exact doses used are unlikely to translate to humans, the relation between the two dose-response curves may provide important information about the functional effects of a history of self-administering a higher dose of nicotine. To date, the relationship between acquisition and reduction dose-response curves is unknown. While there are studies investigating self-administration across doses of acquisition (Chen, Matta, & Sharp, 2007; Cox, Goldstein, & Nelson, 1984; Donny et al., 1998; Sorge & Clarke, 2009) and reduction (Grebenstein, Burroughs, Zhang, & LeSage, 2013; Smith, Levin, Schassburger, Buffalari, Sved, & Donny, 2013), it is difficult to compare the results of these studies to previous studies investigating the acquisition dose-response curve because of methodological differences including strain of rat, nicotine-paired environmental stimuli, schedule of reinforcement, and daily duration of access (Donny et al., 2012). Research has shown that exposure to nicotine alters subsequent self-administration (Adriani et al., 2003; Shoaib, Schindler, & Goldberg, 1997), and in one small study, Cox et al. (1984), demonstrated a nicotine-dose reduction to 3 μg/kg/infusion produced an increase in behavior compared to the pre-reduction baseline of 30 μg/kg/infusion, even though 3 μg/kg/infusion failed to produce acquisition in a separate group of rats. If replicated, these data indicate that individuals with a history of smoking cigarettes with higher nicotine contents may smoke low-nicotine cigarettes at a higher rate than individuals who initiate smoking with low-nicotine cigarettes. The present experiment directly compared the dose-response curve for acquisition to the one for reduction, using both a between-subjects and a within-subjects approach. For the between-subjects comparison, a large group of rats acquired nicotine self-administration at a high nicotine dose (60 μg/kg/infusion) before experiencing a reduction to one of three low doses of nicotine (3.75, 7.5, or 15 μg/kg/infusion) or vehicle alone. The self-administration behavior of these rats at the low doses of nicotine may be thought of as an analog for current smokers who experience a large reduction in the nicotine content of their cigarettes. Their self-administration behavior at the low doses was compared to a group of rats who were given the opportunity to acquire nicotine self-administration for the first time at one of the same low doses or vehicle alone. The self-administration behavior of these rats may be thought of as an analog for new smokers who begin smoking after the nicotine content in cigarettes has been reduced. Second, we examined the effects of a history of high nicotine dose self-administration using a within-subjects comparison of self-administration behavior before and after experience self-administering a high dose of nicotine. Techniques were employed to more appropriately model a policy scenario in which the nicotine content of cigarettes is greatly reduced. A light stimulus was paired with nicotine infusions to model the experience of smoker who experiences environmental cues paired with their smoking. Additionally, a cocktail of non-nicotine cigarette smoke constituents was included along with nicotine infusions to better model the experience of a smoker. Some of these constituents have been shown to have behavioral effects on their own or in combination with nicotine (Bardo, Green, Crooks, & Dwoskin, 1999; Belluzzi, Wang, & Leslie, 2005; Clemens, Caille, Stinus, & Cador, 2009; Guillem et al., 2005; Hoffman & Evans, 2013; Villegier, Lotfipour, McQuown, Belluzzi, & Leslie, 2007). Although these manipulations make it difficult to isolate the mechanism(s) responsible for a shift in self-administration, they have the advantage of being more directly relevant to the critical regulatory questions faced by the FDA that cannot be easily addressed in clinical samples (Donny et al., 2012).

Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown. In the current experiment, body weight gain of adult male rats maintained on a high energy diet (31.8% kcal from fat) distributed into obesity-prone (OP), obesity-resistant (OR) and an intermediate group, which was placed on standard rodent chow (Chow). These rats were surgically implanted with intravenous catheters and allowed to self-administer nicotine (0 or 60 μg/kg/infusion, a standard self-administration dose) in 1-h sessions for 20 consecutive days. Self-administered nicotine significantly suppressed body weight gain but not food intake in OP and Chow rats. Self-administered nicotine had no effect on body weight gain in OR rats. These data suggest that: 1) OR rats are also resistant to nicotine-induced suppression of body weight gain; and 2) nicotine may reduce levels of obesity in a subset of smokers prone to obesity.

Introduction The Family Smoking Prevention and Tobacco Control Act authorized the FDA to reduce the nicotine content in cigarettes. Research is needed to guide proposed regulations, including evaluation of consequences to public health. This study evaluated how a reduced nicotine product standard might be moderated by and impact cannabis use. Methods Secondary analysis of a controlled clinical trial examining the effects of nicotine content in cigarettes in adult daily smokers. Linear regression assessed whether baseline cannabis use moderated behavioral, subjective, or physiological effects of smoking very low nicotine content (VLNC) versus normal nicotine content (NNC) cigarettes. Repeated measures analysis of associations between nicotine condition and prevalence and frequency of cannabis use was completed using generalized estimating equations (GEE). Results Cannabis use did not moderate most of the following effects of VLNC cigarettes: Among cannabis users and non-users, smokers randomized to VLNC cigarettes reported lower nicotine dependence, cigarettes per day, biomarkers of nicotine exposure, and craving compared to smokers randomized to NNC cigarettes. Non-cannabis using smokers randomized to VLNC cigarettes also reported lower smoking dependence motives and had lower tobacco-specific nitrosamine exposure and total puff volume versus smokers randomized to NNC cigarettes. For cannabis users, smokers randomized to VLNC cigarettes reported decreased positive affect. VLNC cigarette use did not impact the prevalence or frequency of cannabis use. Discussion Findings provide evidence that nicotine reduction in cigarettes could have beneficial effects on cigarette smoking regardless of cannabis use. Results suggest that transitioning to VLNC cigarettes is unlikely to alter current rates of cannabis use.

A mandated reduction in the nicotine content of cigarettes may improve public health by reducing the prevalence of smoking. Animal self-administration research is an important complement to clinical research on nicotine reduction. It can fill research gaps that may be difficult to address with clinical research, guide clinical researchers about variables that are likely to be important in their own research, and provide policy makers with converging evidence between clinical and preclinical studies about the potential impact of a nicotine reduction policy. Convergence between clinical and preclinical research is important, given the ease with which clinical trial participants can access nonstudy tobacco products in the current marketplace. Herein, we review contributions of preclinical animal research, with a focus on rodent self-administration, to the science of nicotine reduction. Throughout this review, we highlight areas where clinical and preclinical research converge and areas where the two differ. Preclinical research has provided data on many important topics such as the threshold for nicotine reinforcement, the likelihood of compensation, moderators of the impact of nicotine reduction, the impact of environmental stimuli on nicotine reduction, the impact of nonnicotine cigarette smoke constituents on nicotine reduction, and the impact of nicotine reduction on vulnerable populations. Special attention is paid to current research gaps including the dramatic rise in alternative tobacco products, including electronic nicotine delivery systems (ie, e-cigarettes). The evidence reviewed here will be critical for policy makers as well as clinical researchers interested in nicotine reduction. Implications 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.

Aims To determine (1) if nicotine content affects study attrition – a potential behavioral measure of acceptability – in a trial that required compliance with three levels of reduced nicotine content (RNC) cigarettes, and (2) if attrition is associated with subjective and behavioral responses to RNC cigarettes. Design Secondary analysis of a 35-day, parallel design, open-label, randomized controlled trial. After a 5-day baseline period, participants were randomized to smoke for three, 10-day periods: their preferred brand (control group), or RNC cigarettes with three nicotine levels in a within-subject, stepdown (1 group: high-moderate-low) or non-stepdown (5 groups: high-low-moderate, low-moderate-high, low-high-moderate, moderate-low-high, moderate-high-low) fashion. Setting A single site in Philadelphia, Pennsylvania, USA. Participants 246 non-treatment-seeking daily smokers (M age = 39.52, CPD = 20.95, 68.3% White) were recruited from October 2007 to June 2013. Measurements The primary outcome was attrition. Key predictors were nicotine content transition and study period. Exploratory predictors were taste and strength subjective ratings, total puff volume, and carbon monoxide (CO) boost. Covariates included: age, gender, race, education, and nicotine dependence. Findings Overall attrition was 31.3% (n = 77): 24.1% of the control and 25.0% of the stepdown RNC cigarette groups dropped out vs. 44.6% of non-stepdown groups (p = 0.006). Compared with controls, attrition odds were 4.5 and 4.7 times greater among smokers transitioning from preferred and the highest RNC cigarettes to the lowest RNC cigarettes, respectively (p’s = .001 and .003). Providing more favorable initial taste ratings of study cigarettes decreased attrition odds by 2% (p = .012). Conclusions The majority of participants completed a 35-day trial of varying levels of reduced nicotine content cigarettes. Participant drop-out was greater for cigarettes with lower nicotine content and less in smokers reporting more favorable subjective ratings of the cigarettes.

The reduced nicotine content cigarette and the emergence of non-combusted nicotine products like e-cigarettes should be viewed not as alternatives but as complementary components of regulatory interventions that could virtually end combusted tobacco use.

Cigarettes are the most addictive tobacco product and also the most deadly, causing the highest rates of tobacco-caused mortality and morbidity in most areas of the world.1 ,2 Although current tobacco control efforts have led to significant reductions in smoking prevalence, innovative strategies that can result in a more rapid elimination of cigarette smoking should be a high priority.1 ,3 In the US Surgeon General's report,1 reducing nicotine in cigarettes was considered as one potential strategy. In an article written by Tengs et al ,4 in which the authors modelled the effects of reducing nicotine in cigarettes on public health, taking into account a potential black market, the following statement was made: ‘Policy makers would be hard-pressed to identify another domestic public health intervention, short of historical sanitation efforts, that has offered this magnitude of benefit to the population’. Hence, the main goal of the Advisory Note, Global Nicotine Reduction Strategy, issued by the Study Group on Tobacco Product Regulation (TobReg), was to provide a scientific review and examine the potential feasibility of reduced nicotine content cigarettes as an approach to tobacco control, and to describe the context in which this approach could be considered. This approach is bold, but worth serious consideration. Why? Because the tobacco control community has known for decades that the harms associated with smoking are primarily driven by its addictiveness. If the reinforcing effects of a drug are reduced, then continued use and consequently toxicant exposures will substantially diminish. However, this strategy is not suitable for all countries. As acknowledged in …

The ventral and dorsal striatum are critical substrates of reward processing and motivation and have been repeatedly linked to addictive disorders, including nicotine dependence. However, little is known about how functional connectivity between these and other brain regions is modulated by smoking withdrawal and may contribute to relapse vulnerability. In the present study, 37 smokers completed resting state fMRI scans during both satiated and 24-h abstinent conditions, prior to engaging in a 3-week quit attempt supported by contingency management. We examined the effects of abstinence condition and smoking outcome (lapse vs non-lapse) on whole-brain connectivity with ventral and dorsal striatum seed regions. Results indicated a significant condition by lapse outcome interaction for both right and left ventral striatum seeds. Robust abstinence-induced increases in connectivity with bilateral ventral striatum were observed across a network of regions implicated in addictive disorders, including insula, superior temporal gyrus, and anterior/mid-cingulate cortex among non-lapsers; the opposite pattern was observed for those who later lapsed. For dorsal striatum seeds, 24-h abstinence decreased connectivity across both groups with several regions, including medial prefrontal cortex, posterior cingulate cortex, hippocampus, and supplemental motor area. These findings suggest that modulation of striatal connectivity with the cingulo-insular network during early withdrawal may be associated with smoking cessation outcomes.

Author(s): Denlinger, Rachel L; Smith, Tracy T; Murphy, Sharon E; Koopmeiners, Joseph S; Benowitz, Neal L; Hatsukami, Dorothy K; Pacek, Lauren R; Colino, Cirielle; Cwalina, Samantha N; Donny, Eric C | Abstract: Objectives:Research using very low nicotine content (VLNC) cigarettes has shown that participants underreport use of non-study cigarettes. Biomarkers of nicotine exposure could be used to verify compliance with VLNC cigarettes. This study aimed to characterize biomarkers of exposure when participants exclusively use VLNC cigarettes. Methods:23 participants stayed in a hotel that permitted smoking for 5 days and 4 nights. They were provided 2 packs of VLNC cigarettes each day (0.4 mg of nicotine/g of tobacco; Spectrum cigarettes) and did not have access to other tobacco products. 24-hour urine samples were collected to assess exposure to nicotine and anatabine. Results:After 4 days of exclusive use, the geometric means for urinary total cotinine, total nicotine equivalents (TNE), and anatabine were 1.13 nmol/ml (92% reduction), 3.17 nmol/ml (94% reduction) and 0.0031 nmol/ml (93% reduction). The population estimates of the 95th percentile of cotinine, TNE, and anatabine levels were 2.69, 6.41, and 0.0099 nmol/ml, respectively. Conclusions:Study participants exclusively smoking 0.4 mg/g Spectrum cigarettes are unlikely to have biomarker values above these levels. The data presented here will be valuable to researchers conducting research on use of VLNC cigarettes.

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 6 weeks 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 (0.4 mg/g) reduced the number of study cigarettes participants estimated they would smoke at a range of prices [mean reduction relative to 15.8 mg/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 15.8 mg/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 15.8 mg/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.

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.

Product standards reducing the nicotine content in cigarettes could improve public health by reducing smoking behavior and toxicant exposure. However, relatively little is known about how the regulatory strategy could impact alcohol use. The primary objective of this project was to examine the effect of smoking cigarettes with varying nicotine levels on alcohol outcomes. Furthermore, the processes underlying the effect of smoking very low nicotine content (VLNC) cigarettes on alcohol outcomes were examined, including the role of nicotine exposure per se, as well as the indirect effects of cigarettes and withdrawal. In a double-blind, randomized clinical trial, non-treatment seeking daily smokers (N = 840) were randomly assigned to smoke cigarettes for 6 weeks of varying nicotine content. This investigation focused on current drinkers (n = 476). The nicotine contents examined corresponded with a normal nicotine content (NNC) control condition (15.8 mg/g), a moderate nicotine content condition (5.2 mg/g), and several VLNC cigarette conditions (0.4 mg/g to 2.4 mg/g). Using latent growth curve models, each reduced nicotine content condition was compared to the NNC control condition with respect to the trajectories of average daily alcohol use and occurrence of binge drinking. Several moderating variables of these effects were also explored (i.e., gender, drinking to cope motives, baseline drinking level, history of problem drinking, nicotine dependence level). Furthermore, using mediation analyses, processes that may explain the effect of VLNC cigarettes on alcohol outcomes were investigated, including changes in nicotine exposure, smoking behavior, and withdrawal. Reducing the nicotine content of cigarettes appeared to reduce alcohol use and binge drinking, particularly among less nicotine dependent smokers. The reduction in alcohol use appeared to be driven by a combination of interrelated processes, notably nicotine exposure and smoking rate. An important subgroup, however, that warrants further study is highly nicotine dependent individuals, who tended to increase their drinking in response to nicotine reduction. Regulatory strategies reducing the nicotine content in cigarettes may also impact health behaviors that are closely related to smoking, like alcohol use and binge drinking. It is necessary to broadly define the public health impact to include unintended health consequences on non-smoking behaviors.

Nicotine is the most abundant alkaloid in tobacco accounting for 95% of the alkaloid content. There are also several minor tobacco alkaloids; among these are nornicotine, anatabine, and anabasine. We developed and applied a 96 well plate-based capillary LC-tandem mass spectrometry method for the analysis of nornicotine, anatabine, and anabasine in urine. The method was validated with regard to accuracy and precision. Anabasine was quantifiable to low levels with a limit of quantitation (LOQ) of 0.2 ng/mL even when nicotine, which is isobaric, is present at concentrations2500-fold higher than anabasine. This attribute of the method is important since anatabine and anabasine in urine have been proposed as biomarkers of tobacco use for individuals using nicotine replacement therapies. In the present study, we analyzed the three minor tobacco alkaloids in urine from 827 smokers with a wide range of tobacco exposures. Nornicotine (LOQ 0.6 ng/mL) was detected in all samples, and anatabine (LOQ, 0.15 ng/mL) and anabasine were detected in 97.7% of the samples. The median urinary concentrations of nornicotine, anatabine, and anabasine were 98.9, 4.02, and 5.53 ng/mL. Total nicotine equivalents (TNE) were well correlated with anatabine (r(2) = 0.714) and anabasine (r(2) = 0.760). TNE was most highly correlated with nornicotine, which is also a metabolite of nicotine. Urine samples from a subset of subjects (n = 110) were analyzed for the presence of glucuronide conjugates by quantifying any increase in anatabine and anabasine concentrations after β-glucuronidase treatment. The median ratio of the glucuronidated to free anatabine was 0.74 (range, 0.1 to 10.9), and the median ratio of glucuronidated to free anabasine was 0.3 (range, 0.1 to 2.9). To our knowledge, this is the largest population of smokers for whom the urinary concentrations of these three tobacco alkaloids has been reported.

Introduction Experimental cigarettes are needed to conduct studies examining the effects of varying doses of nicotine content on smoking behavior. The National Institute on Drug Abuse contracted with Research Triangle Institute to make such cigarettes available to researchers. The goal of this study was to determine whether cigarettes that vary in nicotine content produce an expected dose-response effect. Method Two studies were conducted. The first study recruited subjects from 3 sites and consisted of a single, within-subject laboratory session. Subjects first smoked 4 puffs on their usual-brand cigarette and then in double-blind, random-order, smoked 4 puffs on each experimental cigarette that contained either low nicotine (LN, 0.4 mg/g), intermediate nicotine (IN, 5.7-5.8 mg/g), or high nicotine (HN, 11.4-12.8 mg/g). Each puffing bout was separated by a 30-min interval. Subjects completed questionnaires and were assessed for vital signs after each cigarette. The second study involved 1 site and used a between-subject design in which subjects were assigned to 1 of the 3 experimental cigarettes for 1 week. Subjective responses and biomarkers of exposure were assessed. Results In the first study, significant dose-response effects were observed, particularly between the LN and HN cigarettes. The second study showed decreases in cigarette smoking and exposure biomarkers predominantly in the LN group, with no changes in the HN cigarette group. Conclusions These results are similar to those observed in prior literature, confirming that these experimental cigarettes can be used safely and with the expected pharmacological effects.

Background: Reducing nicotine content in cigarettes and other combustible products to levels that are not reinforcing or addictive has the potential to substantially reduce tobacco-related morbidity and mortality. The authority to reduce nicotine levels as a regulatory measure is provided in the U.S. Family Smoking Prevention and Tobacco Control Act and is consistent with the general regulatory powers envisioned under the relevant articles of the World Health Organization's Framework Convention on Tobacco Control. Many experts have considered reducing nicotine in cigarettes to be a feasible national policy approach, but more research is necessary. Purpose: This article describes proceedings from a conference that had the goals of identifying specific research gaps, describing methods and measures to consider for addressing these gaps, and considering ways to foster collaboration. Results and Conclusion: Identified research gaps included determining the dose of nicotine that would be optimal for reducing and extinguishing cigarette use, examining approaches for reducing nicotine levels in the general and special populations of smokers, understanding how constituents other than nicotine may contribute to the reinforcing effects of tobacco, and identifying unintended consequences to determine ways to mitigate them. Methods that can be used ranged from brain imaging to large human clinical trials. The development and availability of valid biomarkers of exposure and effect are important. Infrastructures to facilitate collaboration need to be established. © The Author 2012. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.

Introduction: The Family Smoking Prevention and Tobacco Control Act in the United States and the World Health Organization Framework Convention on Tobacco or Health ratified by over 170 countries render scientific investigations into the abuse liability, harm, and effects of tobacco more critical than ever. A key area to explore relates to the potential regulation of nicotine content in cigarettes. Determining the nicotine content per cigarette below which smokers reliably reduce their consumption of and dependence on cigarettes, an idea proposed almost 20 years ago (Benowitz & Henningfield, 1994), could be a powerful approach to reduce the abuse liability and consequent harm from cigarettes. However, this approach is laden with potentially complex issues. Many of these complications can be studied using animal models, but they require a particular perspective. Methods: Herein, we review several challenges for animal researchers interested in nicotine reduction as examples of how this perspective dictates new approaches to animal research. These include defining the threshold nicotine dose for maintaining self-administration, evaluating the differential impact of various implementation strategies, assessing the factors that could interact with nicotine to alter the reinforcement threshold, describing the role of cues in maintaining low dose nicotine self-administration, and examining individual differences in response to nicotine reduction. Conclusions: Researchers who study tobacco using animal models have the opportunity to play a central role in the regulatory science of tobacco and conduct studies that directly inform policy decisions that could impact the lives of millions.

Cigarette smoking remains highly prevalent in the U.S. and contributes significantly to cardiovascular disease (CVD). Tobacco control policies, including product regulation, can reduce smoking-related harm. One approach being considered in the U.S. is for the FDA to set a low nicotine standard for cigarettes. Such a standard could result in multiple beneficial outcomes including reduced cardiovascular toxicity related to nicotine, reduced smoking intensity in current smokers, increased cessation rates, decreased development of smoking dependence in youth, and decreased passive smoke exposure. Consequently, CVD risk in the U.S. could be dramatically improved by nicotine reduction in cigarettes. Possible pathways linking nicotine reduction in cigarettes to decreased CVD risk are discussed, while potential unintended consequences that could offset expected gains are also presented. Gaps in the literature, including limited data on CVD biomarkers and long-term CVD outcomes following the use of very low nicotine cigarettes, are discussed to highlight areas for new research.