Nicotinic Receptor Alpha-5 Subunit Gene Polymorphism is Associated with Heavy Smoking Under a Range of Nicotine Dosing Conditions.

INTRODUCTION: This study aimed to assess the role of the rs16969968 variant of nicotinic receptor alpha-5 subunit in regulating smoking behavior and nicotine intake in response to nicotine manipulations among dependent smokers in a naturalistic environment. METHODS: Sixty-nine adults (19 females) smoking 10 or more cigarettes per day were asked to complete four 2-week study phases during which they smoked exclusively one of two types of Spectrum nicotine research cigarettes (FTC nicotine yield 0.8 and 1.6 mg, respectively), their usual brand of cigarettes, or their usual brand of cigarettes while wearing a 21-mg nicotine patch. Measurements included rs16969968 genotype, number of cigarettes per day, smoking topography, and plasma cotinine. RESULTS: Compared to controls (G/G carriers), A allele carriers reported smoking 4 to 5 more cigarettes per day across all conditions (all ps < .05). Mean total smoke volume per day and cotinine were greater in A allele carriers than in controls (ps = 0.05, 0.046, respectively). No significant genotype differences were found in smoking compensation indices for the switch from Medium to High nicotine yield cigarettes. Nicotine patch-induced reductions in cigarettes smoked per day and total smoke volume per day showed significant interactions between genotype and pre-patch levels, heavier smokers showing greater effects of genotype (p = .052 and p =.006, respectively). CONCLUSIONS: Results suggest that the rs16969968 variants regulate heaviness of smoking primarily by their impact on daily numbers of cigarettes smoked, but no genotype differences were found in smoking compensation after switching from Medium to High nicotine cigarettes. IMPLICATIONS: The differences in daily cigarette consumption between rs16969968 risk-allele carriers and controls are shown to be consistent regardless of manipulations of cigarette nicotine content and transdermal nicotine supplementation and markedly greater among dependent smokers than those observed in the general smoker populations. G/G allele carriers, relative to A allele carriers, appeared to be more sensitive to the nicotine patch manipulation, reducing their smoking to a greater extent. These findings support continued efforts in the development of personalized intervention strategies to reduce the rs16969968-conveyed genetic propensity for heavy smoking.

Effect of Electronic Cigarette Liquid pH on Retention of 11C-Nicotine in a Respiratory Tract Model.

INTRODUCTION: Based on our preliminary 11C-nicotine positron emission tomography (PET) imaging studies in humans, we speculated that greater deposition of nicotine in the respiratory tract from electronic cigarettes compared to combustible cigarettes could result from the alkaline pH of typical aerosol-producing electronic cigarette liquids (e-liquids). To address this hypothesis, we assessed the effect of e-liquid pH on the retention of nicotine in vitro using 11C-nicotine, PET, and a human respiratory tract model of nicotine deposition. AIMS AND METHODS: A single 2-second 35-mL puff was delivered to a human respiratory tract cast from a 2.8-Ohm cartomizer at 4.1 volts. Immediately after the puff, a 2-second 700-mL air wash-in volume was administered. E-liquids (glycerol and propylene glycol 50/50 vol/vol) containing 24 mg/mL nicotine were mixed with 11C-nicotine. Deposition (retention) of nicotine was assessed using a GE Discovery MI DR PET/CT scanner. Eight e-liquids with different pH values (range 5.3-9.6) were investigated. All experiments were performed at room temperature and at a relative humidity of 70%-80%. RESULTS: Retention of nicotine in the respiratory tract cast was pH dependent and the pH-sensitive component of the retention was well described by a sigmoid curve. In total, 50% of the maximal pH-dependent effect was observed at pH 8.0, which is close to the pKa2 of nicotine. CONCLUSIONS: The retention of nicotine in the respiratory tract conducting airways is dependent on the e-liquid pH. Lowering the e-liquid pH reduces retention of nicotine. Nonetheless, reduction of the pH below 7 has little effect, consistent with the pKa2 of protonated nicotine. IMPLICATIONS: Similar to combustible cigarettes, the retention of nicotine in the human respiratory tract from consumption of electronic cigarettes may have some health consequences and affect nicotine dependence. Here we demonstrated that the retention of nicotine in the respiratory tract is dependent on the e-liquid pH, and lowering pH reduces retention of nicotine in conducting airways of the respiratory tract. Therefore, e-cigarettes with low pH values would result in reduced respiratory tract nicotine exposure and faster delivery of nicotine to the central nervous system (CNS). The latter can be associated with e-cigarette abuse liability and the effectiveness of e-cigarettes as substitutes for combustible cigarettes.

Combination Lorcaserin and Nicotine Patch for Smoking Cessation Without Weight Gain.

INTRODUCTION: This study explored the efficacy of combination lorcaserin and nicotine patch for smoking cessation treatment and prevention of postsmoking cessation weight gain. METHODS: We conducted a trial in which 61 adult daily smokers were asked to quit smoking using a combination of lorcaserin and nicotine patch. During the first 2 weeks of treatment prior to the quit day, participants were randomized to receive either lorcaserin (10 mg twice daily) plus nicotine patch (21 mg) or placebo plus nicotine patch (21 mg). Following this 2-week period, participants received both medications for 12 weeks. Outcomes included 4-week continuous smoking abstinence at the end of treatment (weeks 7-10 postquit attempt), weight change, ad libitum smoking, withdrawal symptoms, and ratings of cigarette reward. RESULTS: Biochemically confirmed continuous smoking abstinence from 7 to 10 weeks postquit attempt was 31.1% (90% confidence interval, 21.4%-40.8%). Participants who quit smoking showed no weight gain; in fact, mean weight change was minus 0.16 kg (SD = 3.27) over the study period. There was an unexpected but strong association (p = .006) between a decrease in sensory enjoyment of smoking and successful quit outcome on this regimen. During the prequit randomization period, lorcaserin versus placebo reduced the impact of smoking to relieve craving for cigarettes as well as the sensory enjoyment of smoking (p = .005). Adherence and tolerability to lorcaserin and nicotine patch was good. CONCLUSIONS: The combination of lorcaserin and nicotine patch was well tolerated, associated with a relatively high smoking abstinence rate, and effectively prevented weight gain associated with quitting smoking. IMPLICATIONS: This report provides an important contribution to the literature because it details evidence of a medication combination-lorcaserin and nicotine-that is effective for smoking cessation and for ameliorating weight gain associated with smoking cessation. For many smokers, postcessation weight gain is a major obstacle to quitting, and this medication combination provides a suitable treatment option for these smokers. CLINICAL TRIAL REGISTRATION: NCT02906644.

Prolonging the Reduction of Nicotine Self-Administration in Rats by Coadministering Chronic Nicotine With Amitifadine, a Triple Monoamine Reuptake Inhibitor With CYP2B6 Inhibitory Actions.

INTRODUCTION: Existing treatments can aid tobacco smoking cessation, but they have low efficacy. Because there is a network of neural systems involved in tobacco addiction, combination treatments may provide greater efficacy. Chronic nicotine and amitifadine have each been shown to significantly reduce nicotine self-administration in rats. This study was conducted to determine if the combination of chronic nicotine with amitifadine, a triple monoamine reuptake inhibitor with CYP2B inhibitory effects, would reduce nicotine self-administration to a greater extent than either alone or placebo. METHODS: This study tested the combination of nicotine plus amitifadine in young adult female Sprague-Dawley rats self-administering nicotine (0.03 mg/kg/infusion). This combination was compared with each treatment alone and the vehicle during continuing nicotine self-administration as well as during resumption of self-administration after a week of enforced abstinence, modeling a quit attempt. Finally, we studied the residual effects of these therapies after discontinuation of treatment. RESULTS: Treatment with either chronic nicotine or amitifadine alone significantly reduced nicotine self-administration relative to controls. The combination of the treatments significantly enhanced this effect. After treatment withdrawal, all of the groups showed increases in nicotine self-administration, but only the combined treatment group remained significantly below control rates of nicotine self-administration. CONCLUSIONS: This study showed the promise of amitifadine as a possible new treatment for smoking cessation and suggested that amitifadine is more effective when given with chronic nicotine. The improved efficacy of the amitifadine and nicotine combination may be potentiated by amitifadine's inhibitory effects on CYP2B, which slows nicotine metabolism. IMPLICATIONS: This study replicated the effects that chronic nicotine or chronic amitifadine, a triple reuptake inhibitor, significantly reduces nicotine self-administration in rats. It extends those findings by showing that the combination of chronic nicotine plus amitifadine causes significantly greater reduction in nicotine self-administration than either drug treatment alone. The combination of chronic amitifadine and chronic nicotine also causes a persistent significant reduction in nicotine self-administration after the end of treatment. The amitifadine and nicotine treatment should be assessed in humans to determine whether this combination provides greater efficacy in smoking cessation than transdermal nicotine treatment alone.

Combination Varenicline/Bupropion Treatment Benefits Highly Dependent Smokers in an Adaptive Smoking Cessation Paradigm.

INTRODUCTION: This study replicated and extended results of a previous trial, which found that combination varenicline/bupropion treatment increased smoking abstinence in smokers who were male, highly dependent, and who did not respond to prequit nicotine patch treatment with a >50% reduction in expired-air carbon monoxide in the first week. METHODS: One hundred and twenty-two male nicotine patch nonresponders and 52 responders were identified. Smokers in each group were randomized to receive 12 weeks of varenicline plus bupropion treatment versus varenicline plus placebo. The primary outcome was continuous smoking abstinence at weeks 8-11 after the target quit date. RESULTS: For smokers with a high level of dependence, judged by having a baseline Fagerstrom Test for Nicotine Dependence (FTND) score ≥ 6 and cigarette consumption ≥ 20/d, combination varenicline/bupropion treatment increased the abstinence rate relative to varenicline alone: 71.0% versus 43.8% (odds ratio = 3.14; 95% confidence interval = 1.11-8.92, p [one tailed] = .016). In contrast, less dependent smokers did not show a benefit of combination treatment relative to varenicline (abstinence rates of 32.1% vs. 45.6%, respectively); there was a significant interaction of treatment and dependence level. Patch nonresponders tended to benefit the most from combination treatment, which was well tolerated overall. CONCLUSIONS: Combination varenicline/bupropion treatment proved significantly more efficacious than varenicline alone among highly dependent male smokers. These results, together with prior studies, support an adaptive treatment paradigm that assigns smoking cessation treatment according to baseline smoker characteristics and initial response to nicotine patch treatment. IMPLICATIONS: This study replicated, in a prospective manner, an important and surprising retrospective finding from a previous clinical trial, which showed that a specific subpopulation of smokers benefited substantially from receiving a combination treatment of varenicline plus bupropion, relative to varenicline plus placebo. Specifically, male smokers having high baseline nicotine dependence (FTND score ≥ 6 and cigarette consumption ≥ 20/d), showed a marked increase in smoking abstinence rate on combination pharmacotherapy. The present study likewise found an enhancement in end-of-treatment abstinence rate in this subgroup, from 43.8% to 71.0%. The adaptive treatment paradigm, which classifies smokers based on initial dependence level and response to prequit nicotine patch treatment, may be used to identify target populations of smokers whose success can be enhanced by intervening with combination pharmacotherapy before the quit-smoking date. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01806779.

Lorcaserin for Smoking Cessation and Associated Weight Gain: A Randomized 12-Week Clinical Trial.

INTRODUCTION: Lorcaserin is a selective serotonin 2C receptor agonist approved by the Food and Drug Administration for chronic weight management. Preclinical data suggest that it may also be effective in smoking cessation through modulation of the dopaminergic reward system. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled trial conducted in 30 centers in the United States. Six hundred three adult smokers with a Body Mass Index of 18.5-35 kg/m2, averaging at least 10 cigarettes/day with no period of abstinence >3 months for the past year were randomized to lorcaserin 10 mg once daily (QD), 10 mg twice daily (BID) or placebo; all received standardized smoking cessation counseling weekly. The target quit date was day 15. The primary endpoint was the exhaled carbon monoxide confirmed Continuous Abstinence Rate for weeks 9-12 (month 3). RESULTS: Continuous Abstinence Rates for month 3 were 5.6%, 8.7%, and 15.3% for the placebo, QD and BID groups, respectively (BID vs. placebo odds ratio 3.02, 95% confidence interval 1.47, 6.22, p = .0027. Change in weight at week 12 (randomized population) was -0.01, -0.35 and -0.98 kg, respectively (p = .0004, BID vs. placebo), and +0.73, +0.76, and -0.41 kg in participants achieving month 3 continuous abstinence. The most frequent adverse events were headache, nausea, constipation, and fatigue. CONCLUSIONS: Lorcaserin with counseling was associated with dose-related increases in smoking cessation and prevention of associated weight gain over a 3-month period. Further investigation of lorcaserin in smoking cessation is warranted. Trial Registration: ClinicalTrials.gov. Identifier: NCT02044874. IMPLICATIONS: This randomized, controlled trial demonstrated that lorcaserin used in conjunction with standard cessation counseling was associated with dose-related increases in smoking cessation and prevention of associated weight gain. To our knowledge, this is the first demonstration in humans of a potential role of 5-HT2C agonism in the modulation of central neurological circuits involved with reward.

The effects of nicotine and non-nicotine smoking factors on working memory and associated brain function.

Smoking abstinence impairs executive function, which may promote continued smoking behavior and relapse. The differential influence of nicotine and non-nicotine (i.e. sensory, motor) smoking factors and related neural substrates is not known. In a fully factorial, within-subjects design, 33 smokers underwent fMRI scanning following 24 hours of wearing a nicotine or placebo patch while smoking very low nicotine content cigarettes or remaining abstinent from smoking. During scanning, blood oxygenation level-dependent (BOLD) signal was acquired while participants performed a verbal N-back task. Following 24-hour placebo (versus nicotine) administration, accuracy on the N-back task was significantly worse and task-related BOLD signal lower in dorsomedial frontal cortex. These effects were observed irrespective of smoking. Our data provide novel evidence that abstinence-induced deficits in working memory and changes in underlying brain function are due in large part to abstinence from nicotine compared with non-nicotine factors. This work has implications both for designing interventions that target abstinence-induced cognitive deficits and for nicotine-reduction policy.

Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system.

Direct actions of nicotine in the CNS appear to be essential for its reinforcing properties. However, activation of nicotinic acetylcholine receptors (nAChRs) on afferent sensory nerve fibers is an important component of addiction to, and withdrawal from, cigarette smoking. The aim of the present study was to identify the neuroanatomical substrates activated by the peripheral actions of nicotine and to determine whether these sites overlap brain structures stimulated by direct actions of nicotine. Mouse brains were examined by immunohistochemistry for c-Fos protein after intraperitoneal injection of either nicotine hydrogen tartrate salt (NIC; 30 and 40 µg/kg) or nicotine pyrrolidine methiodide (NIC-PM; 20 and 30 µg/kg). NIC-PM induced c-Fos immunoreactivity (IR) at multiple brain sites. In the brainstem, c-Fos IR was detected in the locus coeruleus, laterodorsal tegmental nucleus, and pedunculotegmental nucleus. In the midbrain, c-Fos IR was observed in areas overlapping the ventral tegmental area (VTA), which includes the paranigral nucleus, parainterfascicular nucleus, parabrachial pigmental area, and rostral VTA. Other structures of the nicotine brain-reward circuitry activated by NIC-PM included the hypothalamus, paraventricular thalamic nucleus, lateral habenular nucleus, hippocampus, amygdala, accumbens nucleus, piriform cortex, angular insular cortex, anterior olfactory nucleus, lateral septal nucleus, bed nucleus of stria terminalis, cingulate and medial prefrontal cortex, olfactory tubercle, and medial and lateral orbital cortex. NIC, acting through central and peripheral nAChRs, produced c-Fos IR in areas that overlapped NIC-PM-induced c-Fos-expressing sites. These neuroanatomical data are the first to demonstrate that the CNS structures that are the direct targets of nicotine are also anatomical substrates for the peripheral sensory impact of nicotine.

NIH electronic cigarette workshop: developing a research agenda.

BACKGROUND: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. PURPOSE: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. RESULTS AND CONCLUSIONS: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

Comparison of brain nicotine accumulation from traditional combustible cigarettes and electronic cigarettes with different formulations.

Rapid brain accumulation is critical for the acute reinforcing effects of nicotine. Although nicotine formulation (free-base vs. protonated or salt) in electronic cigarette (E-cig) liquid affects user satisfaction, its impact on brain nicotine accumulation (BNA) from E-cig use has not been evaluated in comparison with traditional combustible cigarettes (C-cigs) using a within-subjects design. BNA was directly assessed with 29 adult dual users (13 females) of E-cigs and C-cigs, using [11C]nicotine and positron emission tomography (PET). Participants underwent two 15-min upper body (from chest to head) scanning sessions during which they inhaled a single puff of [11C]nicotine-labeled vapor from E-cigs with free-base nicotine or C-cig smoke in a randomized order. Seventeen of them also went through another session during which they inhaled from E-cigs with nicotine salt. A full-body scan was also conducted at each session to measure total absorbed dose of [11C]nicotine. Mean maximum nicotine concentration (Cmax) in brain following inhalation of free-base nicotine E-cig vapor was 19% and 15% lower relative to C-cig smoke and nicotine salt E-cig vapor (ps = 0.014 and 0.043, respectively). The Cmax values did not differ significantly between the C-cig and nicotine salt E-cig. Mean values of time to the maximum concentration (Tmax) were not significantly different between the two types of E-cig, but they were 64% and 40% longer than that for C-cig smoking (ps = 0.0005 and 0.004, respectively). Mean Cmax with C-cigs and free-base nicotine E-cigs were greater in females relative to males and correlated with T1/2 of lung nicotine clearance and participants' pack-years. These results suggest that while E-cigs with free-base nicotine formulation can deliver nicotine rapidly to the brain, those with nicotine salt formulation are capable of even more efficient brain nicotine delivery closely resembling combustible cigarettes. Therefore, nicotine formulation or pH in E-liquid should be considered in evaluation of E-cigs in terms of abuse liability and potential in substituting for combustible cigarettes.

Development and initial validation of a new self-report measure to assess perceived dependence on tobacco and nicotine products.

How nicotine is administered has evolved from cigarettes to various delivery systems. Assessing perceived dependence on nicotine-containing products now requires accounting for product specificity while allowing comparisons across products and users. This study aims to develop a new self-report measure to assess perceived dependence on tobacco and nicotine products (TNPs) among exclusive and poly-TNP users. A draft version of the new measure, the ABOUT-Dependence, was constructed based on literature review, qualitative research, and expert opinion. Data for scale formation and psychometric assessment was obtained through a US-based web survey (n = 2334) that included additional dependence measures for convergent validity assessment. Qualitative research confirmed a preliminary conceptual framework with seven sub-concepts. Following a cognitive debriefing, 19 items were considered to best represent the different sub-concepts. Psychometric findings supported a three-domain structure [i.e., behavioral impact (five items), signs and symptoms (five items), and extent/timing of use (two items)] and an overall total composite score. The data confirmed convergent and known-group validity, as well as test-retest reliability. The ABOUT-Dependence is a 12-item, psychometrically sound, self-report measure that may be used as a tool for research and further understanding of perceived dependence across the spectrum of TNP and TNP users.

Effect of Flavored on! Nicotine Pouch Products on Smoking Behaviors: Protocol for a Sequential, Multiple Assignment, Randomized Controlled Trial.

BACKGROUND: Cigarette smoking is a leading cause of morbidity and mortality. For adults who smoke cigarettes and cannot or will not quit smoking, smoke-free products, such as nicotine pouches, have been recognized as a potential alternative to smoking combusted cigarettes to reduce harm due to cigarette smoking. The role of flavors in these smoke-free products in tobacco harm reduction has not been fully understood. OBJECTIVE: This study evaluates the effect of flavors in on! nicotine pouch products (research products) in the reduction of cigarette smoking among adults who smoke cigarettes in their natural environment. METHODS: This study uses a sequential, multiple assignment, randomized trial design. Approximately 400 eligible adults who smoke cigarettes will be enrolled and randomized to have access to either the Original (unflavored) on! nicotine pouch product only or a complete flavor profile (ie, Berry, Cinnamon, Citrus, Coffee, Mint, Original, and Wintergreen) of on! nicotine pouch products. After 3 weeks, participants in the Original-only arm will be randomized again, with half remaining in the Original-only arm and half having access to the complete flavor profile for another 3 weeks. Primary outcomes are expired-air carbon monoxide (CO) levels. Secondary outcomes are self-reported cigarette consumption and CO-verified cigarette abstinence. RESULTS: Recruitment and data collection started in September 2023 and is projected to last until March 2025. We anticipate completing the data analysis in 2025. As of May 2024, we have enrolled 314 participants. CONCLUSIONS: This study will provide empirical evidence about the effect that flavor availability in smoke-free products may have in reducing cigarette smoking. TRIAL REGISTRATION: ClinicalTrials.gov NCT06072547; https://clinicaltrials.gov/study/NCT06072547. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56565.

Nicotine flux and pharmacokinetics-based considerations for early assessment of nicotine delivery systems.

In the past few years, technological advancements enabled the development of novel electronic nicotine delivery systems (ENDS). Several empirical measures such as "nicotine flux" are being proposed to evaluate the abuse liability potential of these products. We explored the applicability of nicotine flux for clinical nicotine pharmacokinetics (PK) and 52-week quit success from cigarettes for a wide range of existing nicotine delivery systems. We found that the differences in nicotine flux for various nicotine delivery systems are not related to changes in PK, as nicotine flux does not capture key physiological properties such as nicotine absorption rate. Further, the 52-week quit success and abuse liability potential of nicotine nasal sprays (high nicotine flux product), and nicotine inhalers (nicotine flux similar to ENDS) are low, suggesting that nicotine flux is a poor metric for the assessment of nicotine delivery systems. PK indices are more dependable for characterizing nicotine delivery systems, and a nicotine plasma C max T max > 1 could improve 52-week quit success from cigarettes. However, a single metric may be inadequate to fully assess the abuse liability potential of nicotine delivery systems and needs to be further studied. A combination of in vitro and in silico approaches could potentially address the factors influencing the inhaled aerosol dosimetry and resulting PK of nicotine to provide early insights for ENDS assessments. Further research is required to understand nicotine dosimetry and PK for ad libitum product use, and abuse liability indicators of nicotine delivery systems. This commentary is intended to (1) highlight the need to think beyond a single empirical metric such as nicotine flux, (2) suggest potential PK-based metrics, (3) suggest the use of in vitro and in silico tools to obtain early insights into inhaled aerosol dosimetry for ENDS, and (4) emphasize the importance of considering comprehensive clinical pharmacology outcomes to evaluate nicotine delivery systems.

Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine.

Tobacco smoking is a chronic, relapsing disorder that constitutes one of the primary preventable causes of death in developed countries. Two of the popular hypotheses to explain the development and maintenance of strong nicotine dependence in cigarette smokers posit (i) a rapid brain nicotine accumulation during cigarette smoking and/or (ii) puff-associated spikes in brain nicotine concentration. To address these hypotheses, we investigated the dynamics of nicotine accumulation in the smoker's brain during actual cigarette smoking using PET with 3-s temporal resolution and (11)C-nicotine loaded into cigarettes. The results of the study, performed in 13 dependent smokers (DS) and 10 nondependent smokers (NDS), suggest that puff-associated spikes in the brain nicotine concentration do not occur during habitual cigarette smoking. Despite the presence of a puff-associated oscillation in the rate of nicotine accumulation, brain nicotine concentration gradually increases during cigarette smoking. The results further suggest that DS have a slower process of brain nicotine accumulation than NDS because they have slower nicotine washout from the lungs and that DS have a tendency to compensate for their slower rate of brain nicotine accumulation compared with NDS by inhaling a larger volume of smoke. For these reasons, smokers' dependence on cigarette smoking, or the resistance of NDS to becoming dependent, cannot be explained solely by a faster brain nicotine accumulation.

Adaptive Smoking Cessation Using Precessation Varenicline or Nicotine Patch: A Randomized Clinical Trial.

Importance: Adaptive pharmacotherapy, ie, starting a medication regimen and then modifying that regimen based on patient response, is common in many medical domains but is not common in smoking cessation. Recently, studies have found that adaptive treatment using precessation nicotine patches is efficacious for smoking cessation; however, adaptive treatment using precessation varenicline and adaptive treatment in clinical practice settings have not been fully assessed. Objective: To determine whether adaptive pharmacotherapy leads to higher smoking abstinence rates than standard pharmacotherapy in a clinical practice setting. Design, Setting, and Participants: This double-blinded stratified placebo-controlled randomized clinical trial compared adaptive treatment with standard treatment for smoking cessation. The study was conducted at a university health system in Durham, North Carolina, from February 2018 to May 2020 and was stopped early due to COVID-19. Data were analyzed as intent-to-treat from May 24, 2021, to February 27, 2022. Interventions: Participants were allowed to choose varenicline or nicotine patches and were then randomized to adaptive or nonadaptive (standard) treatment. Participants started on their chosen medication (adaptive) or placebo (standard) 4 weeks before their target quit day. Two weeks later, participants were assessed for treatment response. Adaptive participants who did not decrease daily cigarettes smoked by at least 50% (nonresponders) received bupropion in addition to their chosen medication. Participants in the adaptative treatment group who did decrease daily cigarettes smoked by at least 50% (responders) and participants in the standard treatment group received additional placebo bupropion. Participants in the standard treatment group received varenicline starting 1 week before the target quit date or nicotine patches starting on the target quit day. All participants received brief behavioral support. Main Outcome and Measures: The main outcome was biochemically verified 30-day continuous smoking abstinence 12 weeks after their target quit smoking day. Other measures included demographic characteristics, smoking history, and repeated smoking assessments. Results: Of the planned 300 participants, a total of 188 participants (mean [SD] age, 49.1 [12.5] years; 102 [54%] female) were enrolled before the trial was stopped because of the COVID-19 pandemic. A total of 127 participants chose to use varenicline, including 64 randomized to adaptive treatment and 63 randomized to standard treatment, and 61 participants chose to use nicotine patches, including 31 randomized to adaptive treatment and 30 randomized to standard treatment. At baseline, participants smoked a mean (SD) of 15.4 (7.3) cigarettes per day. At 12 weeks after the target quit day, biochemically verified 30-day continuous smoking abstinence was observed in 23 of 95 participants (24%) in the adaptive treatment group and 8 of 93 participants (9%) in the standard treatment (odds ratio [OR], 3.38; 95% CI, 1.43-7.99; P = .004); among participants who used varenicline, 30-day continuous abstinence was 18 participants (28%) in the adaptive treatment group, and 5 participants (8%) in the standard treatment group (OR, 4.54; 95% CI, 1.57-13.15); among participants who used nicotine patches, 30-day continuous abstinence was 5 participants (16%) in the adaptive treatment group and 3 participants (10%) in the standard treatment group (OR, 1.73; 95% CI, 0.38-7.99). Sleep problems were more common for participants in the varenicline adaptive treatment group than in the varenicline standard treatment group (rate ratio, 1.74; 95% CI, 1.18-2.58; P = .03). Conclusions and Relevance: This randomized clinical trial found that adaptive pharmacotherapy was efficacious for smoking cessation treatment in a practice setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02501265.

Smoking reduction using electronic nicotine delivery systems in combination with nicotine skin patches.

RATIONALE: Electronic nicotine delivery systems (ENDS) are used by smokers seeking to reduce combustible cigarette (CC) use, but the role of nicotine replacement vs. behavioral and sensory factors is still poorly understood. We hypothesized that providing nicotine from ENDS in addition to nicotine skin patches would promote smoking reduction relative to non-nicotine control ENDS. OBJECTIVES: To assess the effects on smoking behavior of using nicotine vs. placebo ENDS in smokers using nicotine vs. placebo patches. METHODS: Ninety-four daily smokers were enrolled in a study that randomly assigned them to receive ENDS with nicotine vs. without nicotine and skin patches with vs. without nicotine. Smoking reduction and cessation were assessed over an 8-week period by self-report and by expired air carbon monoxide (CO) measurements. The primary outcome was defined as reduction in expired air CO. RESULTS: The use of nicotine in ENDS led to significant reductions in smoking (ENDS nicotine vs. placebo difference in CO change = -9.2 ppm; 90% CI (-1.5 ppm, -16.9 ppm)) and was highly correlated with reductions in self-reported cigarettes per day (r=0.6). The effect of nicotine in nicotine patches was not statistically significant (patch nicotine vs. placebo difference in CO change = -0.1 ppm; 90% CI (-7.8 ppm, 7.6 ppm)). CONCLUSIONS: The presence of nicotine in ENDS was associated with a large reduction in smoking. Additional studies will be needed to determine whether there may be additive effects of nicotine ENDS and nicotine patches on smoking abstinence.

Using varenicline in combination with electronic nicotine delivery systems (ENDS).

BACKGROUND: Varenicline is efficacious for smoking cessation, but a return to smokingusually occurs after treatment ends. Electronic nicotine delivery systems (ENDS) may enhance smoking reduction and cessation by providing a behavioral substitute for smoking and may deter smoking in the long term if an individual's nicotine dependence can be transferred to ENDS. The goal of this study was to evaluate varenicline in conjunction with ENDS to promote switching to ENDS. METHODS: Twenty-five individuals who smoked cigarettes, interested in switching but not seeking cessation treatment, received ENDS for 13 weeks; during weeks 2-13 they received varenicline. Assessments included self-reported cigarette and ENDS use, expired air carbon monoxide (CO), reward ratings, tolerability/side effects, and dependence measures. RESULTS: Cigarette smoking decreased from 15.6 cigarettes/day (SD=5.6) at baseline to 2.8 cigarettes/day (SD=5.1) at week 13 (paired t(22)=10.24, p<0.0001). 28% of participants were confirmed to be abstinent in the last 4 weeks of treatment. ENDS use remained relatively constant, averaging 11.8 occasions per day (SD=10.6). Cigarette dependence (assessed by time to first use of the day) decreased after introduction of ENDS (paired t(23) = -3.27, p=0.003), and again after the first week of full-dose varenicline (paired t(23) = -4.27, p=0.0003). Dependence on ENDS did not change, starting out lower than cigarettes (paired t(21) = 5.52, p<0.0001), but ending higher (paired t(22) = 2.94, p=0.008). Smoking satisfaction declined markedly, while satisfaction for ENDS remained relatively constant. Treatment tolerability and adherence were high. CONCLUSIONS: ENDS in combination with varenicline shows promise as a means to reduce dependence on cigarettes and facilitate switching from cigarettes to ENDS.

Neuroanatomical evidence for a putative autocrine/paracrine signaling system involving nicotinic acetylcholine receptors, purinergic receptors, and nitric oxide synthase in the airways.

Nicotine in tobacco smoke is thought to stimulate sensory nerve fibers by receptors that are located on airway epithelial cells and on terminal branches of C-fiber afferents, but the exact neurochemical substrate that mediates the sensory effects of nicotine associated with cigarette smoking is not clear. ATP and nitric oxide (NO) have both been implicated in lung responsiveness to airborne chemicals such as nicotine. However, the neuroanatomical and functional relationships between nicotinic acetylcholine receptors (nAChRs), purinergic signaling, and NO are not known, and the main source of NO in the airways is not clear. In the present study, we performed RT-PCR to confirm the presence of mRNA for all three isoforms of nitric oxide synthase (NOS), neuronal (n-NOS), endothelial (e-NOS), and inducible (i-NOS), in the lung. Sequential double labeling was performed to assess the site of expression of the different NOS isoforms with respect to nAChRs and purinergic receptors (P2X3R) of the intrapulmonary airways. RT-PCR confirmed the presence of n-NOS, e-NOS, and i-NOS in the lung, and immunohistochemical studies verified their expression by epithelial cells at all levels of the intrapulmonary airways, including the terminal and respiratory bronchioles. Sequential double labeling demonstrated coexpression of n-NOS and/or i-NOS with nAChR- and P2X3R-expressing cells. These neuroanatomical findings suggest that bronchial epithelial cells may be a primary source of NO in the intrapulmonary airways and that the production and release of NO may be regulated by an autocrine/paracrine signaling system involving nAChRs and P2X3Rs.

Bupropion/zonisamide combination to assist smokers to switch from combustible cigarettes to electronic nicotine delivery systems (ENDS).

INTRODUCTION: Electronic nicotine delivery systems (ENDS) may offer a much less harmful alternative to combustible cigarettes (CC) for adult smokers unwilling or unable to relinquish nicotine. However, dual use of CC and ENDS undermines potential harm reduction, and progress needs to be made to assist smokers to switch to ENDS. This study explored the promise of a novel treatment combination of the smoking cessation medication bupropion and an FDA-approved anti-seizure medication, zonisamide, to facilitate switching from CC to ENDS. Both medications have been found to reduce craving for CC and possibly offset each other's side effects. METHODS: Twenty-four smokers participated in a 13-week treatment during which they were provided with ENDS, bupropion and zonisamide. Assessments included CC and ENDS use, expired air carbon monoxide (CO), smoking withdrawal symptoms, reward ratings and tolerability/side effects. RESULTS: 33% of participants achieved biochemically confirmed, complete CC abstinence by the end of treatment. Those who did not achieve complete abstinence nonetheless showed a 44% reduction in expired air CO. Craving and other withdrawal symptoms were minimal, and CC smoking satisfaction declined markedly, while satisfaction ratings for ENDS increased over time to overtake those of CC. Side effects were generally mild, and adherence to the medication use was excellent. CONCLUSIONS: The use of combination bupropion/zonisamide to facilitate switching from CC to ENDS is a promising approach that merits follow-up randomized controlled trials. Combining short-term medication approaches with long-term nicotine substitution using ENDS may be a promising strategy to help smokers sustain smoking abstinence in the long term.

Novel rapid-acting sublingual nicotine tablet as a cigarette substitution strategy.

RATIONALE: Current nicotine replacement products provide a much slower onset of nicotine delivery than cigarettes, and hence are only marginally effective at supplanting cigarette smoking. Therefore, more effective forms of nicotine replacement are needed. OBJECTIVES: This initial investigation characterized the pharmacokinetic (PK) and subjective effects of a novel sublingual (SL) nicotine tablet designed to deliver nicotine more rapidly to the bloodstream of smokers. METHODS: Study 1 (N = 6) characterized the pharmacokinetics of a 2 mg nicotine SL tablet in comparison to an FDA-approved, marketed 2 mg nicotine lozenge. Study 2 (N = 24) assessed subjective responses of smokers to a single use of a 1 mg and 2 mg SL tablet. RESULTS: Study 1 found that the time to maximum blood nicotine concentrations was significantly shorter for the SL tablet (14 min) than for the lozenge (82 min), and the initial rate of nicotine absorption was higher (0.4 ng/mL*min vs. 0.0 ng/mL*min), supporting the hypothesis that the SL tablet delivered nicotine more rapidly. Study 2 found that participants reported immediate relief of nicotine withdrawal symptoms after tablet administration, and craving reduction after the 2 mg tablet approached the degree reported for their usual brands of cigarettes (4.2 vs. 4.6 on a 7-point scale). Other subjective responses showed the tablet to be an appealing alternative to smoking. CONCLUSIONS: The novel SL tablet studied shows promise as a nicotine substitution strategy for tobacco harm reduction and smoking cessation treatment. Additional studies are warranted to further investigate the potential of this new approach.