Reduced Nicotine Content Research Articles

Stability of the Nicotine Metabolite Ratio in Smokers of Progressively Reduced Nicotine Content Cigarettes

The nicotine metabolite ratio (NMR), the ratio of trans-3'-hydroxycotinine (3-HC) to cotinine, has been used as a biomarker of the rate of CYP2A6-mediated nicotine metabolism. While stable in smokers who maintain constant smoking consumption, since smoking has been shown to inhibit nicotine metabolism and this inhibition could be mediated by the nicotine in the smoke, NMR could change during nicotine reduction. The objective of this study was to determine the reproducibility (or stability) of plasma NMR in smokers of progressively reduced nicotine content (RNC) cigarettes. We analyzed data from subjects in a clinical trial of smoking progressively RNC cigarettes. Plasma NMR in 30 smokers whose plasma cotinine levels had decreased by at least 50% from the use of the first test cigarette (12mg nicotine content) to the final test cigarette (1mg nicotine content) was measured on 4 occasions over a period of 24 weeks. Plasma cotinine and 3-HC decreased by an average of 85% and 84%, respectively, following the use of the first type of RNC cigarette to the last type. Plasma NMR had an average absolute change of 28.5% over the same period. Using repeated measures analysis, changes in plasma NMR over time were not significant with or without controlling for the effects of age, body mass index, gender, and race (p = .24 and p = .23, respectively). The reliability coefficient for repeated measurements of plasma NMR was .72. The average within-subject coefficient of variation for plasma NMR was 21.6% (SD = 12.0%). The plasma NMR is relatively stable over time as nicotine levels decline in smokers of progressively RNC cigarettes.

A Novel Method to Reducing Nicotine Content in Tobacco with Chinese ‘Kucai’

A Novel Method to Reducing Nicotine Content in Tobacco with Chinese ‘Kucai’

Nicotine reduction: strategic research plan.

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. 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. 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.

Smoking Behavior and Exposure to Tobacco Toxicants during 6 Months of Smoking Progressively Reduced Nicotine Content Cigarettes

Recent federal legislation gives the U.S. Food and Drug Administration authority to regulate the nicotine content of cigarettes. A nationwide strategy for progressive reduction of the nicotine content of cigarettes is a potential way to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted, and to facilitate quitting in established smokers. We conducted a trial of progressive nicotine content tapering over 6 months to determine the effects on smoking behaviors and biomarkers of tobacco smoke exposure and cardiovascular effects. One hundred and thirty-five healthy smokers were randomly assigned 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 smoked for one month. A control group smoked their own brand of cigarettes for the same period of time. Nicotine intake, as indicated by plasma cotinine concentration, declined progressively as the nicotine content of cigarettes was reduced. Cigarette consumption and markers of exposure to carbon monoxide and polycyclic aromatic hydrocarbons, as well as cardiovascular biomarkers remained stable, whereas urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) excretion decreased. No significant changes in biomarkers of exposure or cardiovascular effects were observed in controls. Our data support the proposition that the intake of nicotine from cigarettes of smokers can be substantially lowered without increasing exposure to other tobacco smoke toxins. These findings support the feasibility and safety of gradual reduction of the nicotine content in cigarettes.

Transient compensatory smoking in response to placebo cigarettes

To address the public health problems caused by smoking, researchers have suggested a gradual reduction in the nicotine content of cigarettes. There remain concerns, however, about the potential for smokers to compensate for reductions in nicotine content by altering their smoking behavior. Such compensatory behaviors may negate any potential cessation and/or harm reduction benefits. The purpose of this study was to quantify smoking behavior (e.g., puff number, volume, duration, interpuff interval, and peak flow) in response to cigarettes, varying only in nicotine content, administered repeatedly. Sixty-seven dependent smokers participated in this two-session, within-subject study. Moderate nicotine content and placebo cigarettes (Quest© brand) were administered in a double-blind and counterbalanced manner. Each session required 12 h of tobacco abstinence and included four ad lib smoking bouts of the condition-assigned cigarette with 40 minutes separating each bout. Placebo cigarettes produced increases in total puff volume and duration and decreases in total interpuff interval relative to cigarettes with moderate nicotine content. Differences in total puff volume and duration generally dissipated across smoking bouts, with differences in total puff volume nonexistent by the third and fourth bouts. Placebo cigarettes produce compensatory smoking during initial exposures; however, these effects appear to be short lived. These findings are consistent with the previous work where smoking compensation has been observed in response to a single cigarette, but not over several days of smoking.

Study protocol for a randomised trial of nicotine-free cigarettes as an adjunct to usual NRT-based cessation practice, in people who wish to stop smoking

BackgroundCurrent smoking cessation treatments focus on addressing the pharmacological dependence of smokers on nicotine. However, new strategies are needed that address both nicotine dependence and the psychological dependence on cigarettes as the source of nicotine. Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates. This paper describes the protocol for a large randomised-controlled trial to test the effect of using nicotine-free cigarettes together with NRT on long-term quit rates.Methods/designThis single-blind, randomised trial aims to recruit 1,410 participants through the national telephone-based Quitline service in New Zealand. Participants in the treatment arm will be asked to stop smoking nicotine-containing cigarettes on their chosen Quit day and smoke ad libitum nicotine-free (Quest 3) cigarettes for six weeks. At the same time people in this group will be asked to start using NRT patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Participants in the control arm will be asked to stop smoking completely on their chosen Quit day and start using NRT patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Data collection will occur at baseline, three and six weeks, and three and six months after Quit day. The primary outcome is the proportion of participants who self-report seven-day point prevalence abstinence at six months since Quit date.DiscussionSmoking prevalence in New Zealand has changed little in recent years (particularly in Māori, the indigenous people of New Zealand) and additional options for smokers who want to quit are needed. Although a variety of methods are available to help, many are expensive, have side effects, and despite their use most quit attempts still fail. This trial will test the balance of benefits and risks of a new strategy for people to overcome nicotine dependence. Since smoking is the leading cause of lost healthy life years in New Zealand, if proven effective this strategy is likely to have substantial public health benefits.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000410358

Nicotine reduction revisited: science and future directions

Regulation of nicotine levels in cigarettes and other tobacco products is now possible with the passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009, giving the US Food and Drug Administration (FDA) authority to regulate tobacco products, and with Articles 9-11 of the WHO Framework Convention on Tobacco Control. Both regulatory approaches allow establishing product standards for tobacco constituents, including nicotine. The FSPTCA does not allow nicotine levels to be decreased to zero, although the FDA has the authority to reduce nicotine yields to very low, presumably non-addicting levels. The proposal to reduce levels of nicotine to a level that is non-addicting was originally suggested in 1994. Reduction of nicotine in tobacco products could potentially have a profound impact on reducing tobacco-related morbidity and mortality. To examine this issue, two meetings were convened in the US with non-tobacco-industry scientists of varied disciplines, tobacco control policymakers and representatives of government agencies. This article provides an overview of the current science in the area of reduced nicotine content cigarettes and key conclusions and recommendations for research and policy that emerged from the deliberations of the meeting members.

Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation

To examine the effects of reduced nicotine cigarettes on smoking behavior, toxicant exposure, dependence and abstinence. Randomized, parallel arm, semi-blinded study. Setting University of Minnesota Tobacco Use Research Center. Six weeks of: (i) 0.05 mg nicotine yield cigarettes; (ii) 0.3 mg nicotine yield cigarettes; or (iii) 4 mg nicotine lozenge; 6 weeks of follow-up. Measurements Compensatory smoking behavior, biomarkers of exposure, tobacco dependence, tobacco withdrawal and abstinence rate. Unlike the 0.3 mg cigarettes, 0.05 mg cigarettes were not associated with compensatory smoking behaviors. Furthermore, the 0.05 mg cigarettes and nicotine lozenge were associated with reduced carcinogen exposure, nicotine dependence and product withdrawal scores. The 0.05 mg cigarette was associated with greater relief of withdrawal from usual brand cigarettes than the nicotine lozenge. The 0.05 mg cigarette led to a significantly higher rate of cessation than the 0.3 mg cigarette and a similar rate as nicotine lozenge. The 0.05 mg nicotine yield cigarettes may be a tobacco product that can facilitate cessation; however, future research is clearly needed to support these preliminary findings.

Reduced–nicotine content cigarettes: Is there potential to aid smoking cessation?

Current smoking cessation treatments largely address pharmacological dependence on nicotine. New approaches are needed that address both nicotine dependence and psychological dependence on cigarettes as the source of nicotine. One such approach is the use of cigarettes with reduced nicotine content. We reviewed the available literature on the use of reduced-nicotine content cigarettes as a cessation aid. One case series study and trial data indicate that reduction in the level of nicotine in cigarette tobacco can reduce the level of nicotine dependence in smokers and do so without adverse effects on cardiovascular biomarkers or significant compensatory smoking. We identified three clinical trials (total n = 489) that suggest that smokers can dissociate nicotine delivery from the act of smoking if they use reduced-nicotine content cigarettes in combination with nicotine replacement therapy. The identified studies point to a benefit but involved only a small number of participants and provide only limited data on long-term abstinence. More definitive evidence from larger trials with longer follow-up is needed to clarify the role of reduced nicotine cigarettes as an aid to smoking cessation.

Clinical Pharmacology of Nicotine: Implications for Understanding, Preventing, and Treating Tobacco Addiction

Understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment of tobacco addiction. Nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other neurotransmitters that sustain addiction. Neuroadaptation and tolerance involve changes in both nicotinic receptors and neural plasticity. Nicotine addiction can occur in the context of physical dependence characterized by self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional smokers, primarily for positive reinforcement in specific situations. Nicotine is metabolized primarily by CYP2A6. Its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex) factors. Genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. Nicotine dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some neurotransmitter genes, and genes involved in neural connectivity. Novel pharmacotherapies for nicotine dependence include partial agonists for nicotinic receptors and nicotine vaccines. Pharmacogenetic studies suggest various candidate genes and a nicotine metabolism phenotype that influence outcome. Human pharmacology studies of nicotine and smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.

Nicotine and Carcinogen Exposure with Smoking of Progressively Reduced Nicotine Content Cigarette

Reducing the nicotine content of cigarettes to make them non-addictive has been widely discussed as a potential strategy for tobacco regulation. A major concern with nicotine reduction is that smokers will compensate for reduced nicotine by smoking more cigarettes and/or smoking more intensively, thereby increasing their exposure to tobacco smoke toxins. This study examined whether gradual reduction in nicotine exposure increases exposure to tobacco smoke toxins. This 10-week longitudinal study of 20 healthy smokers involved smoking their usual brand followed by different types of research cigarettes with progressively lower nicotine content, each smoked for 1 week. Subjects were followed for 4 weeks after returning to smoking their usual brand (or quitting). Smoking behaviors, chemical biomarkers of tobacco smoke exposure, and cardiovascular effect biomarkers were measured. Intake of nicotine declined progressively as the nicotine content of cigarettes was reduced, with little evidence of compensation. Cigarette consumption and markers of exposure to carbon monoxide and polycyclic aromatic hydrocarbons, as well as cardiovascular biomarkers remained stable, whereas urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol excretion decreased. Twenty-five percent of participants had spontaneously quit smoking 4 weeks after completing the research cigarette taper. Our findings with reduced nicotine content cigarettes differ from those of commercial low yields for which compensatory smoking for lower nicotine delivery is substantial. Our data suggest that the degree of nicotine dependence of smokers can be lowered without increasing their exposure to tobacco smoke toxins. Gradual reduction of nicotine content of cigarettes seems to be feasible and should be further evaluated as a national tobacco regulatory strategy.

IMAGING STUDY: Selectively reduced responses to smoking cues in amygdala following extinction‐based smoking cessation: results of a preliminary functional magnetic resonance imaging study

Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment. The aims of this study was to evaluate the effect of an extinction-based smoking cessation treatment on brain responses to smoking cues using blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Sixteen (n = 16) dependent smokers were scanned using BOLD fMRI at baseline, following 2-4 weeks of smoking RNC cigarettes while wearing a 21-mg nicotine patch, and 2-4 weeks following quitting smoking. During scanning, participants viewed smoking-related pictures (e.g. lit cigarette) and pictures of people engaged in everyday activities (e.g. using a stapler). Event-related BOLD responses to smoking and control cues were analyzed in regions of interest (ROIs) known to subserve reward, attention, motivation and emotion. The extinction-based treatment simultaneously attenuated responses to smoking cues in amygdala while potentiating responses to control cues. Exploratory analysis indicated that this pattern was also observed in the thalamus of future abstinent but not relapsing smokers. The results of this preliminary study suggest that an extinction-based treatment for smoking cessation alters brain responses to smoking and control cues in amygdala--a region previously associated with drug cue reactivity and extinction.

Nicotine intake and dose response when smoking reduced–nicotine content cigarettes

The progressive reduction of the nicotine content of cigarettes has been suggested as a way to wean smokers from nicotine and tobacco. As a first step in evaluating this strategy, we studied smokers smoking cigarettes containing tobacco with differing nicotine content. Twelve healthy smokers participated in a semiblinded, within-subject, crossover study. Subjects were asked to smoke 1 of their usual brand of cigarette and then on 5 subsequent occasions to smoke a research cigarette, each with differing nicotine content. The research cigarettes contained 0.6 to 10.1 mg nicotine per cigarette. Plasma nicotine and blood carboxyhemoglobin levels, as well as subjective and cardiovascular responses, were measured after smoking. Systemic nicotine intake per cigarette was estimated by use of plasma nicotine concentrations over time and clearance data from the general population. Systemic nicotine intake (0.26-1.47 mg per cigarette) varied with nicotine content of the cigarette (r = 0.82, P < .001). Compensation when smoking single low-nicotine content cigarettes ranged from -1% (95% confidence interval, -23% to 21%) to 34% (95% confidence interval, -39% to 107%) for 1-mg to 8-mg research cigarettes. Carbon monoxide intake and estimated tar exposure were similar across cigarettes. Low-nicotine content cigarettes were rated as being of lower quality and less satisfying than the 12-mg research cigarette or the usual brand (P < .05 for both comparisons). Cigarette smoking increased heart rate and decreased skin temperature, but the nicotine dose-response curve flattened at higher doses, with a maximal response being observed in cigarettes at a nicotine content level of about 8 mg. Our study suggests that reduced-nicotine content cigarettes are reasonable candidates for trying to reduce the level of nicotine addiction in smokers. The flat nicotine dose-cardiovascular response curve is consistent with other studies demonstrating tolerance to the cardiovascular effects of nicotine.

Influence of Biopost and Organo upon Flue‐cured Tobacco Grown on Semigley. II. Chemical Composition of Tobacco Leaf and Changes in the Chemical Soil Complex

AbstractThe paper deals with the results achieved in investigating the effects of biopost and organo, in comparison with stable manure and mineral fertilization as well as one with the other, on the chemical composition of flue‐cured tobacco leaf and on the changes in the chemical soil complex. Investigations were carried out on semigley in the central Drava Valley in Northern Croatia. While biopost is an organic fertilizer, organo is defined as an organic‐mineral fertilizer since, in addition to an organic component, it also contains a mineral component. Both fertilizers affected the chemical composition of tobacco leaf, though they were applied in relatively small quantities. This was primarily reflected in a reduction of nicotine content and an increase in the content of reducing sugars in comparison with mineral fertilizing, though not always proportional to the rate applied. Here, biopost showed a certain advantage over organo.The calcium content in tobacco leaf does not indicate any marked influence of the fertilizing treatments tested in the trial. Existence of such a relation seems more likely in the case of magnesium, while in the case of potassium, fertilizing with this bioelement had the crucial role with regard to its content in tobacco leaf.As regards the changes in the chemical soil complex, the effect of the tested fertilizers, depending on the parameters studied, was either non‐existent or very slight.

Augmentation of elastase-induced emphysema by cigarette smoke. Effects of reduced nicotine content.

To examine the role of nicotine in the augmentation of elastase-induced emphysema by cigarette smoke, animals that had been pretreated with porcine pancreatic elastase (PPE) were exposed to cigarette smokes that had a five-fold difference in their nicotine concentrations. Young adult female Long-Evans rats were divided into seven groups: (1) untreated controls; (2) low nicotine cigarette smoke exposure (Kentucky 2A1 reference cigarettes; 35.0 mg total particulate matter, 0.42 mg nicotine, and 0.38 mg nitrogen oxides per cigarette); (3) high nicotine cigarette smoke exposure (Kentucky 2R1 reference cigarettes; 38.8 mg total particulate matter, 2.2 mg nicotine, and 0.34 mg nitrogen oxides per cigarette; (4) PPE alone; (5) PPE + sham smoke exposure; (6) PPE + 2A1 smoke exposure; and (7) PPE + 2R1 smoke exposure. Three days after intratracheal administration of PPE (400 IU/kg), animals in the smoke-treated groups were exposed to 10 puffs of cigarette smoke daily, 7 days/wk for 14 wk. Sham-treated animals received room air in place of cigarette smoke. After the exposures, pulmonary function tests were performed under general anesthesia. Whole lungs were examined for gross pathologic changes, and samples of lung tissue were harvested for quantitative morphometry. Cigarette smoke exposure alone did not produce significant changes in pulmonary function or structure. On the other hand, treatment with elastase alone produced a constellation of pulmonary functional and structural changes that were pathognomonic of emphysema. Exposure to 2R1 but not 2A1 cigarette smoke significantly augmented the emphysematous changes produced by PPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled smoking, with or without carbon monoxide feedback, as an alternative for chronic smokers

Sixty chronic cigarette smokers were randomly assigned to one of three treatment conditions: controlled smoking, controlled smoking plus weekly carbon monoxide feedback, or delayed treatment control. The controlled smoking treatments lasted 5 weeks and sequentially focused on making 50% reductions in nicotine content of brand smoked, number of cigarettes smoked per day, and percentage of each cigarette smoked. Self-monitoring records indicated that subjects in the two controlled smoking conditions were successful in making reductions in each of the target behaviors and that the timing of these changes immediately followed the initiation of treatment within the multiple baseline across behaviors design. There were few differences between the two treatment conditions, and both treatments produced greater change than the control condition on all targeted behaviors. Carbon monoxide levels were also reduced significantly more in the treatment conditions than in the control condition. The carbon monoxide, as well as smoking behavior, reductions were maintained at 3- and 6-month follow-ups. The results suggest that controlled smoking can be successfully implemented in a group context with long-term, heavy smokers and that carbon monoxide feedback, at least as implemented in the present study, is not essential to treatment success.

Controlled smoking for chronic smokers: An extension and replication

Nine long-term cigarette smokers participated in a seven session controlled smoking program. Employing a multiple baseline across behaviors design, the program focused on making sequential reductions in nicotine content of the cigarette brand smoked, percent of each cigarette smoked and, finally, number of cigarettes smoked per day. Self-monitoring records indicated that subjects were successful in making reductions in each of three target behaviors and that the timing of these changes closely followed the initiation of treatment for each specific behavior. The magnitude of change was greatest for nicotine content (49% reduction) and somewhat less for number of cigarettes (28% reduction) and amount smoked (24% reduction). Carbon monoxide levels were also reduced and these reductions, as well as the smoking behavior changes, were generally maintained at a 6-month follow-up. This study provides a systematic replication of an earlier study and illustrates the usefulness of single subject designs for studying cigarette smoking. It is concluded that controlled smoking can be achieved by chronic smokers without significant relapse or compensation for at least six months following treatment. Limitations of the study and directions for future research are also discussed.

Tobacco of reduced nicotine content : E. M. Bailey ( Conn. Agric. Exp. Sta. Bull., 307, 844–847, 1929)

Tobacco of reduced nicotine content : E. M. Bailey ( Conn. Agric. Exp. Sta. Bull., 307, 844–847, 1929)