Responses to Gradual and Immediate Reduction of Nicotine in Cigarettes in Young Versus Older Adult Smokers.

INTRODUCTION: As the FDA works to determine whether a nicotine reduction policy would benefit public health, one key question is whether to mandate an immediate or gradual reduction in nicotine levels in cigarettes. The aim of this study was to determine whether the effects of gradual versus immediate nicotine reduction on cigarettes per day (CPD), total nicotine equivalents, and subjective responses differed in younger adults versus older adults. METHODS: Using data from a recent randomized trial conducted in the United States (N = 1250) that switched smokers over a 20-week period to very low nicotine content (VLNC) cigarettes either immediately, gradually (via monthly reductions in nicotine content), or not at all (control condition, normal nicotine content research cigarette), we analyzed the moderating effect of age (age 18-24 or 25+). RESULTS: For both age groups, CPD in the immediate condition was significantly lower relative to gradual condition (estimated mean difference of 6.3 CPD in young adults, 5.2 CPD in older adults; p's < .05). Younger and older adults in the immediate and gradual reduction conditions had lower total nicotine equivalents at Week 20 (all p's < .05) than those in the control condition; age group did not moderate this effect. Positive subjective responses to cigarettes were lower among young adults relative to older adults in the immediate condition. CONCLUSIONS: These results indicate that an immediate reduction in nicotine would result in beneficial effects in both young and older adults. Young adults show less positive subjective effects of smoking following switching to VLNC cigarettes relative to older adults. IMPLICATIONS: As researchers work to understand how a potential reduced-nicotine product standard for cigarettes may affect public health, one question is whether nicotine should be reduced immediately or gradually. This study demonstrates that both young and older adults who were switched immediately to the lowest content of nicotine smoked fewer CPD and had lower nicotine intake than those in the gradual condition. Furthermore, young adults appear to show lower positive subjective effects following switching to VLNC cigarettes relative to older adults. This is consistent with previous work demonstrating that young people appear to show lower abuse liability for VLNC cigarettes.

Relationships between the Nicotine Metabolite Ratio and a Panel of Exposure and Effect Biomarkers: Findings from Two Studies of U.S. Commercial Cigarette Smokers.

BACKGROUND: We examined the nicotine metabolite ratio's (NMR) relationship with smoking intensity, nicotine dependence, and a broad array of biomarkers of exposure and biological effect in commercial cigarette smokers. METHODS: Secondary analysis was conducted on two cross-sectional samples of adult, daily smokers from Wave 1 (2013-2014) of the Population Assessment of Tobacco Use and Health (PATH) Study and baseline data from a 2014-2017 randomized clinical trial. Data were restricted to participants of non-Hispanic, white race. The lowest quartile of NMR (<0.26) in the nationally representative PATH Study was used to distinguish slow from normal/fast nicotine metabolizers. NMR was modeled continuously in secondary analysis. RESULTS: Compared with slow metabolizers, normal/fast metabolizers had greater cigarettes per day and higher levels of total nicotine equivalents, tobacco-specific nitrosamines, volatile organic componds, and polycyclic aromatic hydrocarbons. A novel finding was higher levels of inflammatory biomarkers among normal/fast metabolizers versus slow metabolizers. With NMR modeled as a continuous measure, the associations between NMR and biomarkers of inflammation were not significant. CONCLUSIONS: The results are suggestive that normal/fast nicotine metabolizers may be at increased risk for tobacco-related disease due to being heavier smokers, having higher exposure to numerous toxicants and carcinogens, and having higher levels of inflammation when compared with slow metabolizers. IMPACT: This is the first documentation that NMR is not only associated with smoking exposure but also biomarkers of biological effects that are integral in the development of tobacco-related disease. Results provide support for NMR as a biomarker for understanding a smoker's exposure and potential risk for tobacco-related disease.

Pilot Randomized Controlled Trial of a Novel Smoking Cessation App Designed for Individuals With Co-Occurring Tobacco Use Disorder and Serious Mental Illness.

INTRODUCTION: High rates of tobacco use among people with serious mental illness (SMI), along with their unique needs, suggest the importance of developing tailored smoking cessation interventions for this group. Previous early-phase work empirically validated the design and content of Learn to Quit, a theory-based app designed for this population. METHODS: In a pilot randomized controlled trial, we compared the feasibility, acceptability, and preliminary efficacy of Learn to Quit versus QuitGuide, an app designed for the general population. All participants received nicotine replacement therapy and technical assistance. Daily smokers with SMI (N = 62) participated in the trial with outcomes assessed at weeks 4, 8, 12, and 16. RESULTS: Compared to QuitGuide, Learn to Quit participants had similar number of days of app use (34 vs. 32, p = .754), but larger number of app interactions (335 vs. 205; p = .001), longer durations of app use (4.24 hrs. vs. 2.14 hrs; p = .044), and higher usability scores (85 vs. 79, p = .046). At week 16, Learn to Quit led to greater reductions in cigarettes per day (12.3 vs. 5.9 for QuitGuide; p = 0.10). Thirty-day point prevalence abstinence was verified in 12% of Learn to Quit participants versus 3% of QuitGuide participants (odds ratio = 3.86, confidence interval = 0.41 to 36, p = .239). Changes in psychiatric symptoms and adverse events were not clinically significant between conditions. CONCLUSIONS: This pilot trial provides strong evidence of Learn to Quit's usability, feasibility, and safety. Preliminary evidence suggests the app may be efficacious. A randomized controlled efficacy trial is needed to test the app in a larger sample of smokers with SMI. IMPLICATIONS: This study suggests that the Learn to Quit app is a feasible approach to deliver smoking cessation treatment in patients with co-occurring tobacco use disorder and SMI. This means that, if found efficacious, this technology could be used to deploy smoking cessation treatment to larger segments of this population, hence improving public health. Therefore, a randomized controlled trial should be conducted to examine the efficacy of this digital intervention.

Age Moderates Smokers' Subjective Response to Very-Low Nicotine Content Cigarettes: Evidence from a Randomized Controlled Trial.

INTRODUCTION: Reducing the level of nicotine in cigarettes is a regulatory strategy that has the potential to greatly improve public health. If nicotine levels are reduced in all commercially available cigarettes, current smokers might find it easier to quit and young people might be less likely to become dependent. However, it is not yet known whether age moderates subjective or behavioral responses to low-nicotine cigarettes. METHODS: Recently, a large, multisite randomized clinical trial was conducted to compare the effects of cigarettes differing in nicotine content (either usual-brand or research cigarettes containing 15.8, 5.2, 2.4, 1.3, or 0.4 mg nicotine/g tobacco) across 6 weeks of exposure. In this secondary analysis, we tested whether age moderated smokers' subjective (measures of psychological reward, smoking satisfaction) and behavioral (cigarettes smoked per day, smoking topography, and nicotine exposure) responses to cigarettes varying in nicotine content after 2 and 6 weeks of use, while controlling for baseline dependence and demographic factors. RESULTS: Results indicated that younger adults (age 18-24) who smoked cigarettes with 2.4-0.4 mg/g nicotine reported significantly less smoking satisfaction and psychological reward, and smoked fewer cigarettes per day, than older adults (25+ years) after 2 weeks of use. No differences in topography were observed at either time point. After 6 weeks of use, differences had diminished on all measures. CONCLUSIONS: The reduced positive effects of reduced-nicotine content cigarettes in young adults suggests that this regulatory policy may reduce smoking reinforcement in this vulnerable population. IMPLICATIONS: As the FDA considers reducing the level of nicotine in cigarettes to make them less addictive, understanding the potential impact of this policy on young people is of crucial importance. We found that young adults had significantly lower positive subjective effects to very-low nicotine content (VLNC) cigarettes and smoked fewer VLNC cigarettes than older adults after 2 weeks of use, indicating that this policy may reduce smoking reinforcement more quickly in young adults. These data add to the growing body of evidence on the potential for this policy to positively affect public health.

Formative, multimethod case studies of learn to quit, an acceptance and commitment therapy smoking cessation app designed for people with serious mental illness.

Despite public health efforts, individuals with serious mental illness (SMI) still have very high rates of tobacco smoking. Innovative approaches to reach this population are needed. These series of case studies aimed to descriptively evaluate the usability, user experience (UX), and user engagement (UE) of Learn to Quit (LTQ), an acceptance and commitment therapy smoking cessation app designed for people with SMI, and to compare it with an app designed for the general population, NCI (National Cancer Institute) QuitGuide (QG). Both apps were combined with nicotine replacement therapy and technical coaching. Inspired by the ORBIT model, we implemented two case studies with crossover AB interventions, two B-phase training designs, and three bi-phasic AB single-case designs with Start-Point and Order randomization (A = QG, B = LTQ). Study outcomes were measured using the System Usability Scale, UX interviews, and background analytics. LTQ's usability levels were above the standard cutoff and on average higher than QG. UX outcomes suggested the relative benefits of LTQ's visual design, gamification and simple design structure. LTQ's overall UE was high; the app was opened for an average of 14 min per day (vs. QG: 7 min). However, users showed low levels of UE with each of the app's tracking feature. Measures of psychiatric functioning suggested the safety of LTQ in people with SMI. LTQ appears to be a usable and engaging smoking cessation app in people with SMI. An optimized version of LTQ should be tested in a Phase II study.

Childhood ADHD Symptoms and Future Illicit Drug Use: The Role of Adolescent Cigarette Use.

Objectives: The aim of this study is to understand how early cigarette use might predict subsequent illicit drug use, especially among individuals with attention-deficit hyperactivity disorder (ADHD) symptoms during childhood. Methods: Data were drawn from the National Longitudinal Study of Adolescent Health (Waves I-IV). The analysis sample involves participants who had not used illicit drugs at Wave I, with no missing responses for studied predictors (N = 7,332). Results: Smoking status at Wave I (ever regular vs. never regular) and childhood ADHD symptoms predicted subsequent illicit drug use at Waves II to IV. No interaction effect of smoking status at Wave I and childhood ADHD symptoms was found. However, an indirect effect from childhood ADHD symptoms on illicit drug use was identified, through smoking status at Wave I. Similar results were observed for predicting illicit drug dependence. Conclusions: The findings support the notion that smoking status during early adolescence may mediate the association between childhood ADHD symptoms and risk of later adult drug use. Interventions to prevent smoking among adolescents may be particularly effective at decreasing subsequent drug use, especially among children with ADHD symptoms.

Increased Functional Connectivity in an Insula-Based Network is Associated with Improved Smoking Cessation Outcomes.

Little is known regarding the underlying neurobiology of smoking cessation. Neuroimaging studies indicate a role for the insula in connecting the interoceptive awareness of tobacco craving with a larger brain network that motivates smoking. We investigated differences in insula-based functional connectivity between smokers who did not relapse during a quit attempt vs those who relapsed. Smokers (n=85) underwent a resting-state functional connectivity scan and were then randomized into two groups (either smoking usual brand cigarettes or smoking very low nicotine cigarettes plus nicotine replacement therapy) for 30 days before their target quit date. Following the quit date, all participants received nicotine replacement therapy and their smoking behavior was observed for 10 weeks. Participants were subsequently classified as nonrelapsed (n=44) or relapsed (i.e., seven consecutive days of smoking ⩾1 cigarette/day; n=41). The right and left insula, as well as insula subdivisions (posterior, ventroanterior, and dorsoanterior) were used as seed regions of interest in the connectivity analysis. Using the right and left whole-insula seed regions, the nonrelapsed group had greater functional connectivity than the relapsed group with the bilateral pre- and postcentral gyri. This effect was isolated to the right and left posterior insula seed regions. Our results suggest that relapse vulnerability is associated with weaker connectivity between the posterior insula and primary sensorimotor cortices. Perhaps greater connectivity in this network improves the ability to inhibit a motor response to cigarette cravings when those cravings conflict with a goal to remain abstinent. These results are consistent with recent studies demonstrating a positive relationship between insula-related functional connectivity and cessation likelihood among neurologically intact smokers.

Effects of varenicline and cognitive bias modification on neural response to smoking-related cues: study protocol for a randomized controlled study.

BACKGROUND: Smoking-related cues can trigger drug-seeking behaviors, and computer-based interventions that reduce cognitive biases towards such cues may be efficacious and cost-effective cessation aids. In order to optimize such interventions, there needs to be better understanding of the mechanisms underlying the effects of cognitive bias modification (CBM). Here we present a protocol for an investigation of the neural effects of CBM and varenicline in non-quitting daily smokers. METHODS/DESIGN: We will recruit 72 daily smokers who report smoking at least 10 manufactured cigarettes or 15 roll-ups per day and who smoke within one hour of waking. Participants will attend two sessions approximately one week apart. At the first session participants will be screened for eligibility and randomized to receive either varenicline or a placebo over a seven-day period. On the final drug-taking day (day seven) participants will attend a second session and be further randomized to one of three CBM conditions (training towards smoking cues, training away from smoking cues, or control training). Participants will then undergo a functional magnetic resonance imaging scan during which they will view smoking-related pictorial cues. Primary outcome measures are changes in cognitive bias as measured by the visual dot-probe task, and neural responses to smoking-related cues. Secondary outcome measures will be cognitive bias as measured by a transfer task (modified Stroop test of smoking-related cognitive bias) and subjective mood and cigarette craving. DISCUSSION: This study will add to the relatively small literature examining the effects of CBM in addictions. It will address novel questions regarding the neural effects of CBM. It will also investigate whether varenicline treatment alters neural response to smoking-related cues. These findings will inform future research that can develop behavioral treatments that target relapse prevention. TRIAL REGISTRATION: Registered with Current Controlled Trials: ISRCTN65690030. Registered on 30 January 2014.

Nicotine and non-nicotine smoking factors differentially modulate craving, withdrawal and cerebral blood flow as measured with arterial spin labeling.

Smoking cessation results in withdrawal symptoms such as craving and negative mood that may contribute to lapse and relapse. Little is known regarding whether these symptoms are associated with the nicotine or non-nicotine components of cigarette smoke. Using arterial spin labeling, we measured resting-state cerebral blood flow (CBF) in 29 adult smokers across four conditions: (1) nicotine patch+denicotinized cigarette smoking, (2) nicotine patch+abstinence from smoking, (3) placebo patch+denicotinized cigarette smoking, and (4) placebo patch+abstinence from smoking. We found that changes in self-reported craving positively correlated with changes in CBF from the denicotinized cigarette smoking conditions to the abstinent conditions. These correlations were found in several regions throughout the brain. Self-reported craving also increased from the nicotine to the placebo conditions, but had a minimal relationship with changes in CBF. The results of this study suggest that the non-nicotine components of cigarette smoke significantly impact withdrawal symptoms and associated brain areas, independently of the effects of nicotine. As such, the effects of non-nicotine factors are important to consider in the design and development of smoking cessation interventions and tobacco regulation.

Individual differences in nicotine dependence, withdrawal symptoms, and sex predict transient fMRI-BOLD responses to smoking cues.

Exposure to smoking cues increases craving for cigarettes and can precipitate relapse. Whereas brain imaging studies have identified a distinct network of brain regions subserving the processing of smoking cues, little is known about the influence of individual difference factors and withdrawal symptoms on brain cue reactivity. Multiple regression analysis was used to evaluate relations between individual difference factors and withdrawal symptoms and event-related blood oxygen level-dependent responses to visual smoking cues in a sample of 30 smokers. Predictors were self-report nicotine dependence (Fagerström test of nicotine dependence, FTND), prescan withdrawal symptoms (craving and negative affect), and sex. The unique variance of each predictor was examined after controlling for each of the others. Positive associations were observed between FTND and reactivity to cues in right anterior cingulate and orbitofrontal cortex (OFC) whereas negative associations were observed between prescan craving and reactivity in ventral striatum. Higher negative affect or being male was associated with greater reactivity in left hippocampus and left OFC. Women exhibited greater cue reactivity than men in regions including the cuneus and left superior temporal gyrus. Individual difference factors and withdrawal symptoms were uniquely associated with brain reactivity to smoking cues in regions subserving reward, affect, attention, motivation, and memory. These findings provide further evidence that reactivity to conditioned drug cues is multiply determined and suggest that smoking cessation treatments designed to reduce cue reactivity focus on each of these variables.