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Rationale: No previous studies examined the discriminative stimulus effects of intravenous (IV) nicotine in humans. Objectives: To evaluate a pulsed IV nicotine infusion procedure designed to mimic inhaled nicotine delivery and to identify a range of nicotine doses that may capture the threshold doses for the subjective and discriminative stimulus effects of nicotine. By determining these thresholds, we can gain valuable insights into the addictive threshold of nicotine. Methods: Eleven participants had 2 Test Sessions following overnight abstinence from smoking. Test Session 1 examined participants' ability to discriminate 0.1 mg nicotine/pulse nicotine from saline. Test Session 2 examined if participants can discriminate 0.05, 0.025, and 0.0125 mg nicotine/pulse of nicotine from saline. These nicotine doses were delivered as a cluster of 4 pulsed-nicotine infusions of 2-second duration with a 28-second interval between each pulse. Results: The lowest doses of nicotine that produced greater responses than saline for discrimination, subjective effects, and heart rate ranged from 0.05 to 0.1 mg nicotine/pulse. Conclusions: These findings support the validity of our pulsed-infusion procedure as a model for nicotine delivery by smoking and its utility in examining factors that may impact the addictive threshold of nicotine. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration has the authority to reduce the nicotine content in cigarettes to minimal or non-addictive levels and could do so immediately or gradually over time. A large clinical trial compared the two approaches. This secondary analysis assesses abstinence and cessation-related outcomes one month after the trial concluded, when participants no longer had access to very low nicotine content (VLNC) research cigarettes. Smokers not interested in quitting (N = 1250) were recruited for the parent trial from 2014 to 2016 across 10 sites throughout the US and randomized to a 20-week study period during which they immediately switched to VLNC cigarettes, gradually transitioned to VLNC cigarettes with five monthly dose reductions, or smoked normal nicotine research cigarettes (control). At the one-month follow-up, both immediate and gradual reduction resulted in greater mean cigarette-free days (4.7 and 4.6 respectively) than the control group (3.2, both p

Aims: To evaluate statewide policies restricting e‐cigarette nicotine strength. Design: A difference‐in‐difference regression analysis was used to compare e‐cigarette sales in states that restrict nicotine strength with states with no restrictions. Because flavor restrictions might affect sales and nicotine strength, states with flavor restrictions were also assessed. Setting and cases: United States e‐cigarette retail sales data during January 2017 to March 2022 were licensed from Information Resources Incorporated. States with restrictions included Massachusetts (restricted maximum nicotine strength to 3.5% and nontobacco flavored e‐cigarette sales in December 2019); Utah (restricted nicotine strength to 3.6% in September 2021); and Rhode Island, New York and Washington (restricted nontobacco flavor sales in October 2019, May 2020 and October 2019 to January 2020, respectively). These were compared with data from 34 states with no e‐cigarette nicotine strength or flavor restrictions. Measurements Weighted mean nicotine strength and total unit sales. Total unit sales per 1000 state population were summed into 4‐week periods by state. Models controlled for emergency responses, state demographics, tobacco control policies, time and state fixed effects. Findings Restricting both nicotine strength and flavors in Massachusetts was associated with a 2.04 percentage point (pp) reduction in mean nicotine strength and 86.76‐unit reduction in monthly unit sales per 1000 persons compared with states with no restrictions (all P < 0.01). Restricting nicotine strength only in Utah was associated with a 1.77 pp (P < 0.01) reduction in mean nicotine strength; however, there was no impact on unit sales. Restricting nontobacco flavor sales only in Rhode Island, New York and Washington slightly reduced mean nicotine strength (0.21, 0.62 and 0.19 pp, respectively) and sales (36.66, 34.51 and 16.37 units, respectively) (all P < 0.01). Conclusions: United States statewide policies restricting e‐cigarette nicotine strength appear to be associated with reductions in average nicotine strength in sales within that state; however, there appears to be no impact on unit sales. When these policies are implemented along with flavor restrictions; reductions in average nicotine strength occur in addition to reduced unit sales. [ABSTRACT FROM AUTHOR]

Background: Regulations limiting nicotine in electronic cigarettes (e-cigarettes) have been proposed or implemented. Little is known about e-cigarette users' reactions to reducing e-cigarette liquid nicotine concentration. Methods: We used concept mapping to describe e-cigarette users' reactions to a 50% reduction in the nicotine concentration of their e-cigarette liquids. In 2019, current e-cigarette users who used e-cigarette liquid with greater than 0 mg/ml nicotine concentration completed an online study. Participants (n = 71, mean age = 34.9 (SD = 11.0), 50.7% women), brainstormed statements completing a prompt: "If the e-liquid that I use now in my e-cigarette/vaping device was only available in half the nicotine concentration or amount that I use now, a specific action I would take or a specific reaction I would have is...", Participants then sorted a final list of 67 statements into piles of similar content and rated statements on how true the statements would be for them. Multidimensional scaling and hierarchical cluster analyses identified thematic clusters. Results: Eight clusters were identified: (1) Replacement Product Seeking, (2) Mental Preparations and Expectations, (3) Use the New Liquid, (4) Information Seeking, (5) Compensation Behaviors, (6) Opportunity for E-Cigarette Reduction, (7) Physical and Psychological Effects, and (8) Replacement with non-E-Cigarette Products and Behaviors. Cluster ratings suggested many participants would search for other e-cigarette products/liquids to replace their current liquids, but using other tobacco products (e.g., cigarettes) may be less likely. Conclusions: If nicotine concentrations were decreased in e-cigarette liquids, e-cigarette users may attempt to purchase different e-cigarette products or modify their products to achieve desired effects. [ABSTRACT FROM AUTHOR]

Nicotine addiction is the proximate cause of disease and death from cigarette smoking. In 1994, we proposed reducing the nicotine content of cigarettes to non-addicting levels to reduce the risk of youth becoming addicted smokers and promoting quitting in established smokers. In 2009, the Family Smoking Prevention and Tobacco Control Act provided the authority to FDA to reduce nicotine levels as appropriate to benefit public health. Over the past 15 years, considerable research has determined that nicotine reduction is feasible and safe, resulting in reduced nicotine dependence with little evidence of compensatory over-smoking. The availability of acceptable non-combusted form of nicotine would provide support and enhance acceptability of nicotine reduction in tobacco. Most recently, the FDA promulgated a nicotine-based regulatory framework, which includes nicotine reduction combined with ready availability of noncombustible nicotine products. Nicotine reduction could contribute to a virtual end to the use of cigarette smoking, with enormous benefits to public health.

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

Introduction: A joint meeting was held by the World Health Organization (WHO) and the Convention Secretariat of the WHO Framework Convention on Tobacco Control to examine the potential effects of a regulatory policy to reduce nicotine in cigarettes to minimally addictive levels. This paper reviews the feasibility of and approaches to implementing a nicotine product standard.Methods: Prior WHO reports on this topic were consulted and a systematic review of the scientific literature was conducted. The paper was reviewed by the participants at the aforementioned meeting and their feedback was incorporated.Results: The nicotine dose most likely to consistently reduce smoking behavior and dependence is ≤0.4 mg nicotine/g tobacco. An immediate rather than a gradual nicotine reduction approach appears to be more beneficial. Smokers are likely to seek nicotine from alternate sources (e.g., nicotine replacement therapies, e-cigarettes) or potentially, the illegal market. As such, the availability of alternative products, as well as strong policies against illegal markets, can potentially mitigate unintended consequences. An effectively reduced nicotine regulation must be imbedded in a comprehensive and strong tobacco control program that includes public education and surveillance. Barriers and challenges to implementing a nicotine product standard exist, particularly in low-capacity countries.Conclusions: Not all countries will have the capacity to implement a regulation to reduce nicotine in cigarettes (and preferably other combusted tobacco products) to minimally addictive levels. However, for the countries that choose to implement it, such a policy could potentially dramatically reduce the burden of tobacco use.Implications For Tobacco Regulatory Science: Article 9 of the Framework Convention on Tobacco Control provides signatory governments the authority to implement a product standard for reducing nicotine in tobacco products to minimally addictive levels. This product standard has the potential to result in a dramatic reduction in cigarette and other combusted tobacco use and therefore, smoking-caused mortality and morbidity. This article describes the growing scientific evidence to support nicotine regulation in cigarettes, potential regulatory approaches and describes the infrastructure and tobacco control policies needed to implement a reduced nicotine product standard. [ABSTRACT FROM AUTHOR]

Background and aimsClinical trials on the impact and safety of reduced nicotine content cigarettes (RNCs) are ongoing, and an important methodological concern is participant compliance with smoking only RNCs. Our aims were to measure non-compliance biochemically with urine cotinine (COT) and total nicotine equivalents (TNEs), compare with self-reported non-compliance and identify associated covariates.DesignSecondary analysis of a double-blind, parallel, randomized clinical trial.SettingResearch centers from the United States, enrolling participants from June 2013 to July 2014.ParticipantsVolunteer sample of 242 participants (55% Caucasian), average age of 41.2 years, smoking at least five cigarettes per day (CPD).InterventionSmoking very low nicotine cigarettes (VLNCs; 0.4 mg nicotine/g tobacco) for 6 weeks.MeasurementsThe primary outcome was biochemically verified non-compliance, measured as thresholds of COT/CPD and TNE/CPD ratios, considering changes in nicotine content from conventional levels to VLNCs, and as an absolute threshold of week 6 TNEs. Self-reported non-compliance was measured via daily phone calls. Key predictors included age, sex, race, menthol preference, nicotine metabolite ratio, time to first cigarette, dependence, CPD, TNEs, tar level and cigarette evaluation.FindingsEstimates of non-compliance with smoking the VLNCs exclusively include: the biochemical ratios (both 78%), the week 6 TNE threshold (76%) and self-report (39%). Of the key covariates, age, dependence and cigarette evaluations of satisfaction were significant; for age, younger participants more likely to be non-compliant [P = 0.01; odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96-0.99]. Dependence was associated significantly with self-reported non-compliance (P = 0.01; OR = 1.28, 95% CI = 1.06-1.55). Cigarette evaluations of satisfaction were associated significantly with non-compliance (P = 0.001; OR = 0.71, 95% CI = 0.61-0.82).ConclusionsAmong smokers volunteering to smoke only very low nicotine cigarettes for 6 weeks, non-compliance was common and biochemical assessments detected more cases of non-compliance than self-report. Despite high levels of non-compliance, smokers reduced their intake of nicotine by an average of 60%.

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.

Introduction: A national nicotine reduction policy could reduce the public health toll of smoking. However, reducing nicotine in cigarettes may lead to changes in the use of other tobacco products such as nicotine vaping devices, particularly among young people. Product use outcomes may depend on characteristics of available nicotine vaping devices. We aimed to determine the impact of cigarette nicotine content, vaping device nicotine concentration, and vaping device flavors on choices to smoke, vape, or abstain., Methods: Early young adults (ages 18-20 inclusive, N=80) who reported smoking daily and vaping nicotine at least twice in their lifetime participated in a laboratory study. Participants received either Very Low Nicotine Content (VLNC; 0.4 mg nicotine/g of tobacco) or Normal Nicotine Content (NNC; 15.8 mg/g) cigarettes. First, participants chose between their assigned cigarette or abstaining. Subsequently, participants chose between 2 cigarette puffs, 2 vape puffs, or abstaining. Vaping device nicotine concentration (3mg vs. 18mg/ml) and flavor (tobacco vs. non-tobacco) were manipulated within-subjects., Results: When only cigarettes were available, there were no differences between the VLNC and NNC groups on cigarette choices. When the nicotine vaping device was concurrently available, the VLNC group made fewer choices to smoke than the NNC group. Non-tobacco flavors and lower vaping device nicotine concentration were associated with fewer choices to smoke., Conclusions: Nicotine vaping device availability reduced choices to smoke VLNC cigarettes, and vaping devices with lower nicotine and non-tobacco flavors led to the fewest choices to smoke. Regulators should consider that the availability and characteristics of alternative tobacco products can moderate the product standard's impact., Implications: The U.S. Food and Drug Administration may enact a reduced nicotine product standard that would affect all commercially-available cigarettes. One important population affected by this policy would be early young adults who smoke. We aimed to determine the impact of cigarette nicotine content, vaping device nicotine concentration, and vaping device flavors on choices to smoke, vape, or abstain. Lower nicotine in cigarettes, along with non-tobacco flavors and lower nicotine concentration in the vaping device, were associated with the fewest choices to smoke. Regulators should consider that the availability and characteristics of alternative tobacco products can moderate the product standard's impact., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rationale: Reducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies. Objectives: The current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure. Methods: Young adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo. Results: Mixed effect models revealed a significant effect of nicotine dose for positive (i.e., "stimulatory" and "pleasurable"; p <.0001) effects, but not "aversive" effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p =.03–.05). Conclusions: Using our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target. [ABSTRACT FROM AUTHOR]

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.

Objective: In this paper, we evaluate the effectiveness of agricultural approaches and manufacturing techniques that can be applied to reduce nicotine content of tobacco to minimally addictive levels (< 0.4 mg/g). Methods: Using a semi-structured approach, we searched scientific and grey literature including patents and internal industry documents, using keywords like tobacco, nicotine, alkaloids, denic(otinized) tobacco, reduced nicotine content, very low nicotine tobacco. Results: Nicotine can be reduced via genetic modification or traditional breeding techniques. Contents and emissions are similar to regular cigarettes, but consumers rated them as less satisfactory. Extraction techniques yield less palatable tobacco too, due to co-extraction of flavor components in tobacco. Microbial and enzymatic degradation lead to other, mostly undesirable, changes to tobacco. Supercritical extraction resulted in a taste most similar to regular cigarettes, but still failed in the marketplace. Conclusions: Most of the available techniques are successful in reducing nicotine levels, sometimes to levels lower than 0.4 mg/g. However, in almost all cases, the resulting tobacco leads to a less satisfactory smoking experience. Although reduction of nicotine to a non-addictive level is feasible from a technical perspective, it is not clear whether such measures could be successfully implemented. [ABSTRACT FROM AUTHOR]

Rationale: The smallest difference in nicotine that can change a smoker's cigarette preference is not clearly known. Objective: A procedure to efficiently identify the difference in nicotine needed to change cigarette preference could help inform research to gauge effects of a nicotine reduction policy. Methods: Using a within-subject design, we assessed preference for research cigarettes varying in nicotine contents (NIC; 18.7, 10.8, 5.3, 2.3, and 1.3 mg/g of tobacco), relative to a very low nicotine cigarette (VLNC; 0.4 mg/g), in 17 adult-dependent non-menthol smokers abstinent overnight. Only one NIC was compared vs. the VLNC per session, with order of the five NIC contents randomized across sessions on five separate days. Preference for each NIC vs. VLNC was determined by validated forced choice procedure, with those NIC chosen more than VLNC indicating greater reinforcement due to greater nicotine per se. Secondarily, less preference for lower NIC (vs. VLNC), relative to choice for the highest NIC, 18.7 mg/g (vs. VLNC), indexed reduced reinforcement. Results: Overall, NIC choices increased as their nicotine increased, as anticipated. Relative to the 0.4 mg/g VLNC, choice was greater for NIC ≥ 5.3 mg/g but not ≤ 2.3 mg/g. Correspondingly, relative to choice for 18.7 mg/g, choice was less for NIC ≤ 2.3 mg/g but not ≥ 5.3 mg/g. Conclusions: Although replication with larger samples and longer access is needed, results indicate that nicotine reduction to ≤ 2.3 mg/g in cigarettes would attenuate reinforcement. This choice procedure may efficiently inform future clinical trials to assess relative reinforcing effects of smoking reduced nicotine cigarettes. [ABSTRACT FROM AUTHOR]

Objectives: In 2017, the US Food and Drug Administration (FDA) announced a potential new product standard lowering nicotine in cigarettes to minimally or non-addictive levels. Understanding why the public supports or opposes this standard could inform messaging efforts. Methods: We collected online survey data in 2017 from 2508 respondents. We coded and analyzed the open-ended text responses describing reasons for support or opposition among those who strongly agreed (39.9% of sample) and strongly disagreed (11.4%) with the proposed nicotine standard. Results: The most common reasons for opposition were viewing the new standard as a threat to personal freedom and believing that it would lead themselves or others to smoke more. The most common reasons for support were believing the standard would help themselves or others quit smoking and recognizing the harms of smoking and nicotine. Some responses reflected inaccurate understanding of nicotine's effects, and some themes (eg, believing the standard could prevent addiction) were more common among smokers than nonsmokers. Conclusions: Findings could inform public health campaign messages from the FDA and other agencies by building on existing reasons for support (eg, would help with cessation) and counteracting inaccurate beliefs (eg, would make people smoke more). [ABSTRACT FROM AUTHOR]

Current FDA plans include proposed nicotine reduction mandates by the end of 2023. Most research on reduced nicotine cigarettes has been dose-blinded, while a mandate would be known to the public. Few laboratory studies have examined specifically how low nicotine content labeling impacts behavioral response. The purpose of this within-subject, balanced-placebo, human laboratory study was to evaluate the main and interactive effects of nicotine dose expectancy and dose reduction on cigarette reinforcement, withdrawal alleviation, and puff topography. Participants who smoke daily (N =21; 9 female) completed one practice and four experimental sessions in which expectancy (labeled "average" versus "very low" nicotine) and nicotine dose (0.80 mg versus 0.03 mg yield) were manipulated. Participants in acute withdrawal sampled experimental cigarettes followed by withdrawal alleviation and puff topography measures. Cigarette demand was measured using an incentivized purchase task. Analyses evaluated main and interactive effects of expectancy and nicotine dose. Nicotine dose manipulation produced expected physiological effects (e.g., heart rate increases) and both reduced nicotine dose and expectation manipulations reduced perceived nicotine content. Expectation of reduced nicotine alone or in combination with reduced nicotine dose did not alter demand, withdrawal alleviation, or topography. Effective withdrawal alleviation was observed in all conditions. These data inform nicotine regulation policy by suggesting limited compensatory harms caused by reduced nicotine expectations. The minimal acute effects of reduced nicotine expectancy or exposure on demand suggests that reduced nicotine standards are likely to generate their greatest public health benefit through the slowing of newly initiating cigarette smoking. • Reduced nicotine mandates have been proposed by the FDA. • We evaluated effects of nicotine expectancy and reduction on behavioral response. • Effective manipulations of expectancy and dose were achieved. • Limited effects of expectation on use motivation, withdrawal alleviation, or topography. • The data suggest limited compensatory harms caused by reduced nicotine expectations.. [ABSTRACT FROM AUTHOR]

Objectives: Lowering the nicotine content in combustible cigarettes may be a viable strategy for reducing dependence and toxin exposure. Understanding how marketing and education may affect initial uptake is an important avenue of inquiry prior to any policy change. There has yet to be an investigation of how framing reductions in nicotine may affect intentions to purchase and consume these cigarettes using the behavioral economic framework. Methods: Participants from Amazon Mechanical Turk completed several tasks, including the Cigarette Purchase Task and Experimental Tobacco Marketplace, under conditions in which a new, reduced-nicotine cigarette alternative is the only cigarette available. Results: Cigarette purchasing was largely unaffected by stated nicotine concentration, but lower concentrations suggested the potential of small estimated compensatory purchasing. Exposure to a narrative detailing how others have perceived the negative subjective effects of lower nicotine cigarettes (eg, less satisfaction) significantly reduced the perceived value of cigarettes. Conclusions: These results suggest information about nicotine content alone is unlikely to reduce initial uptake without accompanying narratives about the effects of this reduced-nicotine content. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we investigated potential effects of being a menthol smoker on response to reduced nicotine content (RNC) cigarettes in smokers especially vulnerable to smoking. Method: Participants were 169 smokers (61 menthol and 108 non-menthol smokers) with comorbid mental illness, substance use disorder, or socioeconomic disadvantage. Participants completed a double-blind study assessing addiction potential, withdrawal/craving, and compensatory smoking across 4 research cigarettes varying in nicotine content from very low levels to commercial levels (0.4, 2.4, 5.2, 15.8mg/g of tobacco). Repeated measures analysis of variance was used to examine potential moderating effects of menthol status. Results: Statistically significant effects of nicotine dose were noted across measures, with higher doses producing greater economic demand and relief from withdrawal/craving. The relationships between nicotine dose and response to RNC cigarettes do not differ by menthol status. Conclusions: Results of this study suggest menthol does not have a differential impact on response to RNC cigarettes across measures of economic demand, withdrawal/craving, or smoking topography. These results suggest that any potential beneficial effects of RNC cigarettes should extend to menthol smokers including those especially vulnerable to smoking. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to assess young adult dual e-cigarette (EC) and combusted cigarette (CC) users' anticipated responses to a hypothetical very low nicotine content product standard and menthol ban in CC.Methods: Data came from 240 young adult (18-29 years) dual CC and EC users recruited via Amazon Mechanical Turk between June 20-22, 2017. Descriptive statistics were used to report sample characteristics. McNemar's tests were used to assess differences between product categories in terms of anticipated responses to hypothetical regulations.Results: A hypothetical very low nicotine content product standard in CC resulted in reported intentions to quit or reduce CC use and increase use of EC (p's<0.001). Hypothetical restrictions regarding the availability of menthol CC resulted in marginally significant reported intentions to increase EC use (p = 0.080). Anticipated responses to regulation were associated with baseline EC and CC use characteristics.Conclusions: This work provides preliminary evidence of the impact that regulations regarding nicotine content and menthol in CC may have on the use of EC among young adult dual users. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: We estimated whether recent cannabis use moderates response to cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg/g) among smokers with concurrent affective disorders, opioid dependence, or socioeconomic disadvantage. Methods: We conducted a secondary analysis of a multi-site, double-blind, laboratory study examining acute response to reduced nicotine content cigarettes (RNCC) in 169 adult smokers with co-morbid conditions. Participants positive for recent cannabis use or self-reported past 30-day cannabis use at baseline were categorized as current cannabis users (N = 63). Repeated measures analysis of variance tests assessed whether baseline cannabis use moderated cigarette reinforcement, tobacco withdrawal, craving, smoking topography, or carbon monoxide boost. Results: Cannabis users were younger, less educated, and had more depression and anxiety than non-users (p < .05). Cannabis use status did not moderate the effects of nicotine dose on concurrent choice testing, subjective effects of RNCCs, or smoking topography. After adjusting for sociodemographic characteristics, cannabis users had higher ratings on Smoking Satisfaction, Enjoyment of Respiratory Tract Sensations, and Craving Reduction across all nicotine doses. Cannabis users reported longer withdrawal symptom duration and more rapid decline of carbon monoxide boost than non-users. Conclusions: Findings suggest RNCCs decrease the addiction potential of cigarettes in vulnerable populations independent of cannabis use status. [ABSTRACT FROM AUTHOR]

Background: Mandating a reduction in the nicotine content of cigarettes to a minimally addictive level could dramatically reduce smoking rates in the US. However, little is known about the effects of reduced nicotine content cigarettes in adolescents.Methods: Following overnight abstinence, adolescent daily smokers (ages 15-19, n = 50) reported on their craving, withdrawal, and positive and negative affect pre- and post- ad lib smoking of one cigarette containing varying nicotine content (15.8, 5.2, 1.3 and 0.4 mg/g of tobacco) in the laboratory and reported their subjective evaluations of each cigarette. Carbon monoxide (CO) boost from pre- to post-cigarette was calculated to determine if lower-nicotine cigarettes led to differential acute changes in toxicant exposure.Results: All four nicotine cigarette types significantly reduced abstinence-induced craving, withdrawal, and negative affect (all p's < .05). Mixed models evaluating the effect of nicotine content, with nicotine dependence level and gender included as covariates, revealed a significant effect of nicotine content on craving and subjective evaluations: higher nicotine content resulted in greater reductions in craving and increases in both positive and negative subjective evaluations. There were no significant effects of nicotine dose on withdrawal symptoms, negative affect, or CO boost.Conclusions: These results suggest that lower nicotine cigarettes might result in reduced abuse liability compared to higher nicotine content cigarettes due to reduced positive subjective effects, while still reducing withdrawal, in adolescents. These results highlight the potential feasibility of this policy approach and support continued research on how a nicotine reduction policy may affect adolescent smoking patterns. [ABSTRACT FROM AUTHOR]

Objectives: We tested the substitutability of nicotine replacement therapy (NRT), electronic cigarettes (ECs), and very low nicotine cigarettes (VLNCs) in the context of an online experimental tobacco marketplace (ETM) that was designed to mimic the choices of smokers under 4 policy scenarios. Methods: Dutch cigarette smokers (N = 840) completed an online survey in July 2015. The ETM was comprised of conventional cigarettes, VLNCs, ECs (disposable/cartridge/tank systems), and NRT (lozenges/patches/tabs). All participants completed a scenario in which conventional cigarettes were banned. To test additional policy scenarios participants were randomized to one of 3 experiments: (1) no VLNCs; (2) all products available; or (3) no ECs. Hypothetical weekly purchases were made when the cost for conventional cigarettes was one-half market price (MP), MP, 2x MP, and 4x MP. We measured substitutability by the change in estimated consumption as cigarette prices increased. Results: Tank and cartridge ECs and VLNCs were stronger cigarette substitutes than disposable ECs and NRT products. Substitution of ECs and NRT for cigarettes was dampened when VLNCs were available. Conclusions: The ETM offers a method to predict how smokers might respond to policies that alter the availability of potentially substitutable products available in the marketplace. [ABSTRACT FROM AUTHOR]

Background: 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). Objectives: The goal of the present experiments was to characterize the relationship between increases in nicotine cost and decreases in nicotine dose. Materials and methods: 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: 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. Conclusions: Results of the present studies suggest that nicotine reduction is likely to have a large impact on nicotine exposure from cigarettes. [ABSTRACT FROM AUTHOR]

Objectives: Reducing the negative health effects caused by tobacco products continues to be a public health priority. The Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food Drug Administration authority to pursue several new strategies, including regulating levels of nicotine and other ingredients in tobacco products. A nicotine reduction strategy proposed by Benowitz and Henningfield may reduce the nicotine content of tobacco products to an amount below a threshold that supports neither the development nor maintenance of addiction. However, many factors must be considered to determine the viability and efficacy of this approach. For example, the policy should be based on precise information on the dosedependent effects of nicotine on reinforcement and factors that contribute to individual differences in these effects. To date there have been few studies on these topics in humans. Methods: We review nicotine pharmacology and reinforcement then present several studies illustrating the application of intravenous (IV) nicotine delivery to study nicotine reinforcement in humans. Results: Nicotine delivery by IV infusion may be uniquely suited for studying nicotine's dose-dependent effects. Conclusion: This procedure can inform tobacco regulatory science to facilitate the development of effective tobacco control policies. [ABSTRACT FROM AUTHOR]

Nicotine addiction is the proximate cause of disease and death from cigarette smoking. In 1994, we proposed reducing the nicotine content of cigarettes to non-addicting levels to reduce the risk of youth becoming addicted smokers and promoting quitting in established smokers. In 2009, the Family Smoking Prevention and Tobacco Control Act provided the authority to FDA to reduce nicotine levels as appropriate to benefit public health. Over the past 15 years, considerable research has determined that nicotine reduction is feasible and safe, resulting in reduced nicotine dependence with little evidence of compensatory over-smoking. The availability of acceptable non-combusted form of nicotine would provide support and enhance acceptability of nicotine reduction in tobacco. Most recently, the FDA promulgated a nicotine-based regulatory framework, which includes nicotine reduction combined with ready availability of noncombustible nicotine products. Nicotine reduction could contribute to a virtual end to the use of cigarette smoking, with enormous benefits to public health. [ABSTRACT FROM AUTHOR]

A national nicotine reduction policy has the potential to reduce cigarette smoking and associated adverse health impacts among vulnerable populations. However, possible unanticipated adverse effects of reducing nicotine content in cigarettes, such as increasing the use of alcohol or other abused substances, must be examined. The purpose of this study was to evaluate the effects of exposure to varying doses of nicotine in cigarettes on use of other substances. This was a secondary analysis (n = 753) of three simultaneous, multisite, double-blind, randomized-controlled trials examining 12 weeks of exposure to study cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco) among daily smokers from three vulnerable populations: individuals with affective disorders (n = 251), individuals with opioid use disorder (n = 256), and socioeconomically-disadvantaged women of reproductive age (n = 246). Effect of study cigarette assignment on urine toxicology screens (performed weekly) and responses to drug and alcohol use questionnaires (completed at study weeks 6 and 12) were examined using negative binomial regression, logistic regression, or repeated measures analysis of variance, controlling for sex, age, and menthol status. The most common substances identified using urine toxicology included tetrahydrocannabinol (THC; 44.8%), cocaine (9.2%), benzodiazepine (8.6%), and amphetamines (8.0%), with 57.2% of participants testing positive at least once for substance use (27.3% if excluding THC). No significant main effects of nicotine dose were found on any of the examined outcomes. These results suggest that reducing nicotine content does not systematically increase use of other substances, even among individuals at increased risk of substance use. ClinicalTrials.gov Identifiers: NCT02232737, NCT2250664, NCT2250534. [ABSTRACT FROM AUTHOR]

There has been long-standing interest in a reduced-nicotine product standard for combusted tobacco, which is within the regulatory purview of the Food and Drug Administration (FDA). In weighing whether to establish this standard, it is important to consider potential responses among people who are at elevated risk for tobacco-related health harms. In this narrative review, we summarize studies of very low nicotine content (VLNC) cigarettes conducted between 2010 and 2021 in groups that the FDA has identified as vulnerable populations. Studies conducted to date in adults with mental health conditions, adults with opioid use disorder, socioeconomically-disadvantaged adults, and youth or young adults indicate that immediate switching to VLNC cigarettes decreases smoking, with minimal or no unintended negative consequences. Few studies have investigated the effects of VLNC cigarettes in racial or ethnic minorities, people who smoke menthol cigarettes, and pregnant women, but initial findings suggest that responses of these individuals are similar to responses observed in other vulnerable populations. We are not aware of studies that have investigated VLNC cigarettes in military/veteran populations, sexual or gender minority individuals, or people living in underserved rural environments. Future research directions include understanding how to promote cessation in the context of a reduced-nicotine standard, and how to correct VLNC misperceptions in vulnerable populations. Nevertheless, the evidence to date indicates that a reduced-nicotine standard is likely to have the same beneficial effects on smoking reductions as it does in less vulnerable populations, which should provide some confidence in pursuing this regulatory approach. [ABSTRACT FROM AUTHOR]

The author discusses the need to allow markets to assess the value of optional very-low-nicotine cigarettes prior to deciding on mandatory government-based public health regulations, and it mentions the U.S. Food and Drug Administration's tobacco product regulation strategy and the World Health Organization Framework Convention on Tobacco Control Conference of the Parties in 2016. Nicotine addiction prevention is addressed in relation to legal sales of cigarettes.

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. [ABSTRACT FROM AUTHOR]

Despite notable progress in recent decades, cigarette smoke persists as a leading cause of premature death and preventable disease. To weaken the link between nicotine reinforcement and the toxicity associated with combusted tobacco, the United States Food and Drug Administration is considering a product standard targeting cigarette nicotine content. In this review, we summarize research assessing the potential impacts of reducing nicotine in cigarettes. Evidence to date suggests cigarette smoking, toxicant exposure and dependence would decline following substantial reductions in nicotine content. However, reduced nicotine content may not eliminate smoking entirely. Regulatory efforts that shape the nicotine and tobacco marketplace should consider that non-nicotine reinforcing factors and decision-making biases can contribute to the value of smoking. The impact of reducing nicotine in cigarettes will likely depend on the alternative nicotine products available to current smokers. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'. • Limiting cigarette nicotine content reduces use, toxicant exposure and dependence. • Yet limits do not eliminate smoking, as low nicotine cigarettes remain reinforcing. • Non-nicotine factors and decision-making biases can also affect reinforcing value. • The relative value of alternatives will affect the use of low nicotine cigarettes. [ABSTRACT FROM AUTHOR]

Reduction of nicotine content in tobacco products is a regulatory control strategy intended to decrease smoking dependence, and is hypothesized to produce gradual reductions of nicotine intake. Rats were initially trained to self-administer 0.06 mg/kg/infusion nicotine (Phase 1), which was followed by a threshold procedure to determine nicotine demand via a behavioral economics (BE) paradigm (Phase 2). Rats then either self-administered the training dose (high dose group), or were switched to a low dose of nicotine (0.001 mg/kg/infusion; low dose group) in Phase 3. Both groups then underwent a second threshold procedure and demand curves were re-determined (Phase 4). In Phase 5, responding for nicotine was extinguished over the course of 21 sessions. Cue-induced reinstatement was then evaluated (Phase 6). Rats in the low dose group maintained a steady amount of infusions, and thus, did not compensate for nicotine reduction. Rats in the low dose group also showed similar demand elasticity and nicotine seeking (Phase 6) compared to the high dose group, indicating that nicotine reduction did not decrease nicotine demand or seeking. Further, both groups displayed resistance to extinction, indicating that nicotine reduction did not facilitate extinction learning. These results suggest that although compensation of intake does not occur, decreasing the dose of nicotine does not alter nicotine reinforcement value or relapse vulnerability. Further, these results indicate persistence of nicotine-motivated behavior after self-administration of a low nicotine dose. Translationally, these results suggest that alternative strategies may be needed to achieve positive smoking cessation outcomes. [ABSTRACT FROM AUTHOR]

Cigarette preference increases as a function of greater nicotine content, but manipulating cost can shift preference. The aims of the present study are to model whether (1) the behavioral-economic metric unit price (cost/reinforcer magnitude) accounts for preference shifts and (2) whether preference shifts toward reduced nicotine content are associated with smoking reductions. In a multisite study between 2015 and 2016, 169 daily smokers from vulnerable populations completed two concurrent-choice conditions examining preference for smoking normal (15.8 mg/g) and reduced (0.4 mg/g) nicotine content cigarettes. In Condition 1, both products were available at 10 responses/choice. In Condition 2, availability of the 0.4 mg/g dose remained at 10 responses/choice while the 15.8 mg/g dose was available on a progressive-ratio (PR) schedule wherein response cost increased following each choice. Unit prices were calculated by dividing dose by response requirement. Results were analyzed using ANOVA and binomial tests (p < .05). Participants preferred the 15.8 over 0.4 mg/g dose in Condition 1, but shifted preference to the 0.4 mg/g dose in Condition 2 (p < .001) immediately before the point in the PR progression where unit price for 15.8 dose exceeded unit price for the 0.4 dose (p < .001). This shift was associated with a reduction in smoking (p < .001). The unit price of nicotine appears to underpin cigarette product preference and may provide a metric for predicting preference and potentially impacting it through tobacco regulations. These results also demonstrate that reduced compared to normal nicotine content cigarettes sustain lower smoking rates discernible even under acute laboratory conditions and in vulnerable populations. [ABSTRACT FROM AUTHOR]

In this article the author discusses a study on the science base establishment for tobacco product regulation particularly on nicotine reduction. He sees that the study could help to scientifically inform the proposed policy of reducing the nicotine delivery of cigarettes to reduce tobacco dependence. He thinks that the study is encouraging since it suggests the possibility for the creation of such policy.