In May 2018, the Secretariat for the World Health Organization Framework Convention on Tobacco Control convened a meeting to discuss the potential for reducing the addictiveness of tobacco products. ...A central focus was to review research findings on the behavioral effects of reducing the addictiveness of cigarettes.
This manuscript reports the results of a review of the behavioral science literature, updated through April 2021, with special attention to both the potential benefits and unintended consequences of reducing nicotine in cigarettes.
Available evidence suggests that reducing nicotine content in cigarettes to very low levels could benefit public health in three primary ways, by 1) decreasing uptake of regular smoking, 2) decreasing the amount people smoke, and 3) increasing the likelihood of smoking cessation. Current evidence also suggests that reducing nicotine in cigarettes may produce similar benefits across many important subpopulations of people who smoke, including those with psychiatric comorbidities, those who use other substances, those with low socioeconomic status, young people, people who smoke infrequently and people who prefer menthol cigarettes. Cigarette nicotine reduction could also lead to some undesirable outcomes, such as experiencing withdrawal, product manipulation, an illicit market, and harm misperceptions; strategies that may mitigate each are discussed.
Overall, behavioral research suggests product standards that limit the nicotine content of combusted tobacco products could render cigarettes and similar products less addictive. The availability of legal, non-combusted products that effectively substitute for cigarettes and the dissemination of public health campaigns that clarify misperceptions about the relationship between nicotine, tobacco and disease may facilitate the extent to which a nicotine reduction policy reduces smoking.
Nadia Chaudhri worked with us as a graduate student in the Center for Neuroscience at the University of Pittsburgh from 1999 until she earned her PhD in 2005, a time that coincided with the discovery ...in our lab of the dual reinforcing actions of nicotine, a concept that she played an important role in shaping. The research that was described in her doctoral thesis is among the foundational pillars of the now well-accepted notion that nicotine acts as both a primary reinforcer and an amplifier of other reinforcer stimuli. This reinforcement-enhancing action of nicotine is robust and likely to be a powerful driver of nicotine use. Below, we discuss the evidence that these two actions of nicotine — primary reinforcement and reinforcement enhancement — are distinct and dissociable, a finding that Nadia was closely associated with. We go on to address two other topics that greatly interested Nadia during that time, the generalizability of the reinforcement-enhancing action of nicotine to multiple classes of reinforcing stimuli and potential sex differences in the dual reinforcing actions of nicotine. The research has greatly expanded since Nadia’s involvement, but the core ideas that she helped to develop remain central to the concept of the dual reinforcing actions of nicotine and its importance for understanding the drivers of nicotine use.
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.
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.
The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes.
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.
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<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups.
In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).
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.
The current study pilot tested the effect of a single, brief exposure to nicotine education messages on beliefs about nicotine, nicotine-replacement therapy (NRT), E-cigarettes, and cigarettes with ...reduced nicotine content (RNC).
Five hundred and twenty-one U.S. adults (aged ≥18 years) completed a 15-minute survey on Amazon Mechanical Turk in 2018. After completing items on sociodemographics, literacy, and cancer risk behaviors, participants were randomized in a 2:1:1 ratio to 1 of 3 conditions: nicotine education (n=263), sun safety education (attention control, n=128), or no message control (n=130). All participants completed items regarding nicotine, NRT, E-cigarette, and RNC cigarette beliefs, as well as norms about nicotine use, behavioral control regarding cigarette/tobacco use, and intention to use cigarettes, NRT, E-cigarettes, and RNC cigarettes in the next 12 months. Analyses were conducted in 2019.
Following exposure, nicotine education participants reported fewer false beliefs about nicotine (p<0.001), NRT (p<0.001), E-cigarettes (p<0.05), and RNC cigarettes (p<0.05) compared with the control conditions. Nicotine messaging doubled the probability of a correct response (false, 78.3% vs 36.8%) to nicotine is a cause of cancer and dramatically reduced the probability of responding don't know to this item (5.3% vs 26.0%). There was no impact of the intervention on beliefs about other substances within cigarette, norms, or behavioral intentions.
Findings from the current study support the hypothesis that a brief nicotine messaging intervention—similar to the messages likely to be seen on warning labels or in media campaigns—is likely to correct misperceptions of nicotine, NRT, E-cigarettes, and RNC cigarettes.
Although considerable progress has been made, we do not yet fully understand the behavioral and neurobiological basis of nicotine reinforcement, and without this knowledge, treatment strategies aimed ...at reducing smoking remain deficient.
This review describes an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. We hypothesize that nicotine reinforcement derives from at least two sources: (1) primary reinforcement, an action that requires response-dependent drug administration and is capable of conveying secondary reinforcing effects on associated stimuli, and (2) the reinforcement-enhancing effect of nicotine, which directly enhances behavior maintained by salient nonnicotine stimuli and does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing effects of psychostimulants. Empirical support for this hypothesis, based largely on animal models of reinforcement, will be presented.
Animal models of drug reinforcement have evolved to reflect our growing awareness of the multidimensional nature of drug dependence in humans. Investigating the interaction between nicotine and nonpharmacological stimuli within the context of the drug self-administration paradigm in rats has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in self-administration and in smoking. The hypothesis presented in this paper--that nicotine acts as both a primary reinforcer and an enhancer of other nonnicotine reinforcers--provides important direction for future investigations into the neurobiology of nicotine reinforcement and treatments for smoking cessation.
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.
The optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined.
To determine the effects of immediate vs ...gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure.
A double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017.
(1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes.
Between-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention.
Among 1250 randomized participants (mean age, 45 years; 549 women 44%; 958 77% completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, -4.06 parts per million ppm 95% CI, -4.89 to -3.23; P < .0055), 3-HPMA (ratio of geometric means, 0.83 95% CI, 0.77 to 0.88; P < .0055), and PheT (ratio of geometric means, 0.88 95% CI, 0.83 to 0.93; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, -3.38 95% CI, -4.40 to -2.36; P < .0055), 3-HPMA (ratio of geometric means, 0.81 95% CI, 0.75 to 0.88; P < .0055), and PheT (ratio of geometric means, 0.86 95% CI, 0.81 to 0.92; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 95% CI, -0.31 to 1.67; P = .18), 3-HPMA (ratio of geometric means, 0.98 95% CI, 0.91 to 1.06; P = .64), and PheT (ratio of geometric means, 0.98 95% CI, 0.92 to 1.04; P = .52).
Among smokers, immediate reduction of nicotine in cigarettes led to significantly greater decreases in biomarkers of smoke exposure across time compared with gradual reduction or a control group, with no significant differences between gradual reduction and control.
clinicaltrials.gov Identifier: NCT02139930.
PDF
