Potential effects of nicotine content in cigarettes on use of other substances.

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.

Cumulative vulnerabilities as a potential moderator of response to reduced nicotine content cigarettes.

Risk for smoking increases in a summative manner corresponding to the number of co-occurring vulnerabilities present (cumulative vulnerability). We examined whether cumulative vulnerabilities moderate response to reduced nicotine content cigarettes in a secondary analysis of results from 775 participants in three 12-week randomized clinical trials examining research cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco). Participants were categorized as having 0-1, 2-3, or ≥ 4 cumulative vulnerabilities. Vulnerabilities included: rural residence, current substance use disorder, current affective disorder, low educational attainment, poverty, unemployment, physical disability. The primary outcome was total cigarettes per day (CPD) during Week 12; secondary outcomes included CPD across weeks, toxin exposure, dependence severity, craving/withdrawal (17 dependent measures). Results were analyzed using repeated measures analysis of covariance and growth-curve modeling. Total CPD during Week 12 increased as cumulative-vulnerability increased (P = 0.004), and decreased as nicotine content decreased (P < 0.001), with no significant interaction of cumulative vulnerability and dose (P = 0.67). Effects on other outcomes generally followed that same pattern. The only exception across the other outcomes was on Questionnaire-on-Smoking-Urges Factor-2 ratings for usual-brand cigarettes where cumulative vulnerability, dose, and time interacted (P = 0.007), with craving at the 0.4 and 2.4 mg/g doses decreasing over time, but inconsistently across vulnerability categories. Overall, we saw little evidence that cumulative vulnerabilities moderate response to reduced nicotine content cigarettes suggesting that a policy reducing nicotine content in cigarettes to minimally addictive levels could benefit even highly vulnerable smokers including those residing in rural or other regions with overrepresentation of co-occurring vulnerabilities. Clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

Tobacco and Nicotine Use Among US Adult "Never Smokers" in Wave 4 (2016-2018) of the Population Assessment of Tobacco and Health Study.

INTRODUCTION: A common criterion for being labeled a "never smoker" is having smoked <100 lifetime cigarettes. This category is often used as an unexposed reference group to estimate the relative harm from cigarettes. We examined the amount of current and past cigarette and non-cigarette tobacco/nicotine use among adults who met this "never smoker" criterion. METHODS: We analyzed cross-sectional data from 17 179 adult "never smokers" (ie, reported <100 lifetime cigarettes) in Wave 4 (2016-2018) of the Population Assessment of Tobacco and Health (PATH) Study, a United States nationally representative sample. We used PATH-derived variables to describe "never smokers'" demographics as well as cigarette and non-cigarette tobacco/nicotine use. RESULTS: Approximately half of "never smokers" were young adults (49.3%). Most were white (68.6%) with some college or more (64.4%). Most "never smokers" had tried any cigarette or non-cigarette tobacco/nicotine in their lifetime (66.7%), 8.5% smoked cigarettes in the past 30 days, and 5.3% were current experimental (ie, some days or every day) cigarette smokers. By definition, "never smokers" reported smoking <100 lifetime cigarettes. One fifth (22.8%) had a lifetime history of established regular non-cigarette tobacco/nicotine use and 8.6% were current established regular non-cigarette tobacco/nicotine users. In total, 9.4% of "never smokers" were current experimental or established regular users of combustible tobacco. CONCLUSIONS: The 100-cigarette lifetime threshold includes substantial amounts of current and past tobacco use and thus does not represent lack of exposure to cigarette or non-cigarette tobacco. "Never smoker" reference groups may produce underestimates of the relative harms from cigarettes. IMPLICATIONS: The <100 lifetime cigarettes criterion may not capture what many would consider true "never smokers." Relying on the current definition of "never smokers" as a reference group will include a substantial number of those currently and recently using combustible tobacco and thus produce data that may underestimate the relative harm from cigarettes. Prospective longitudinal research is needed to compare how the 100-cigarette lifetime threshold versus other definitions of regular cigarette smoking differ in predictive validity of clinically meaningful outcomes and health harms to determine the optimal criteria to define established cigarette smoking.

Possible New Symptoms of Tobacco Withdrawal III: Reduced Positive Affect-A Review and Meta-analysis.

INTRODUCTION: Most descriptions of tobacco withdrawal have not changed in >30 years despite new research. This meta-analysis tested whether abstinence leads to decreased positive affect (PA) because abstinence-induced symptom changes are a core feature of the tobacco withdrawal syndrome. In addition, we examined whether reduced PA was due to withdrawal (ie, temporary decrease in a "U-shaped" curve) or offset (ie, return to baseline) effect. METHODS: Our main inclusion criterion was a prospective within-participant test of change in PA during abstinence conditions among people who smoke cigarettes daily who were not using a cessation medication. Our search of PubMed, PsycINFO, and personal libraries yielded a total of 32 tests with 2054 participants. RESULTS: There was a medium effect size indicating an overall decrease in PA following abstinence from cigarettes (Cohen's d = -0.40, 95% CI = -0.30 to -0.49). There was large heterogeneity (I2 = 70.7%). Most (79%) of the 24 trials that conducted significance tests reported that reduction in PA was significant. Seven tests were adequately designed to detect a withdrawal versus offset effect. Over half (57%) displayed a U-shaped curve for abstinence-induced change in PA indicative of a withdrawal symptom rather than offset effect. CONCLUSIONS: Abstinence from cigarettes is associated with a decrease in PA. Whether low PA should be added to withdrawal measures and diagnostic criteria requires replication of the time-course of change in PA and tests of whether abstinence-induced changes in PA and negative affect occur independently. IMPLICATIONS: Though there was substantial heterogeneity among trials, our findings suggest that (1) abstinence from cigarettes decreases positive affect and (2) this decrease may represent a withdrawal effect (vs. an offset effect). However, it is unclear whether abstinence-induced losses in positive affect are independent from increased negative affect.

Abuse liability of cigarettes with very low nicotine content in pregnant cigarette smokers.

The U.S. Food and Drug Administration has proposed reducing the nicotine content of cigarettes to a minimally-addictive level. To our knowledge, this study is the first to examine how pregnant smokers respond to very low nicotine content (VLNC) cigarettes. In Phase 1, participants blindly sampled two VLNC cigarettes (0.4 and 2.4 mg/g of tobacco) and their usual brand (UB) cigarette in separate sessions, then completed a behavioral economic simulation task and measures of subjective effects, craving/withdrawal, and smoking topography. Phase 2 directly compared the relative reinforcing effects of the cigarettes using concurrent choice testing. All possible dose-pair combinations were tested in separate sessions where puffs were earned ad libitum by clicking the code associated with their preferred cigarette 10 times. Phase 3 tested the 0.4 mg/g-UB dose-pair where UB puffs could be earned with a progressively incremented number of clicks (maximum 8400). Ten pregnant smokers in Burlington, VT and Baltimore, MD participated in 2017-2018. Regarding abuse liability, participants chose the 0.4-mg/g dose less than UB (22% vs. 78%) during concurrent choice testing and the 0.4-mg/g dose sustained less demand than the 2.4-mg/g and UB doses on the simulation task. Positive subjective effects were also lower for both VLNC cigarettes vs. UB. Each cigarette reduced nicotine craving/withdrawal and no significant changes indicative of compensatory smoking were noted. Reducing the nicotine content of cigarettes may decrease their abuse liability in pregnant smokers without causing untoward craving/withdrawal or compensatory smoking. Studies of extended exposure to VLNCs in pregnant women are warranted.

Relating individual differences in nicotine dependence severity to underpinning motivational and pharmacological processes among smokers from vulnerable populations.

We examined whether elucidating underpinning smoking motivation and related pharmacological processes enhances understanding of nicotine dependence among smokers from vulnerable populations. Data were obtained between Oct, 2016 and Sept, 2019 from 745 adult smokers with co-morbid psychiatric conditions or socioeconomic disadvantage at University of Vermont, Brown University, Johns Hopkins University. Smoking motivation was assessed using the Cigarette Purchase Task (CPT), a behavioral-economic task that models the relative reinforcing value of smoking under varying monetary constraint. Dependence severity was measured using the Heaviness of Smoking Index (HSI), Fagerström Test for Nicotine Dependence total scores (FTND), and FTND total scores minus items 1 and 4 (FTND2,3,5,6). We also assessed associations between dependence severity and smoking motivation with nicotine levels and metabolism rate. Principal Component Analysis was used to examine the latent structure of the conventional five CPT indices; bivariate and multivariable modeling was used to test associations. Factor analysis resulted in a two-factor solution, Amplitude (demand unconstrained by price) and Persistence (price sensitivity). CPT latent factors were associated with each dependence-severity measure (ps ≤ 0.0001), with associations stronger for Amplitude than Persistence across each, especially HSI which was exclusively associated with Amplitude. Amplitude and each dependence measure were associated with nicotine intake (ps ≤ 0.0002); Persistence was not (p = .19). Demand Amplitude more than Persistence appears key to understanding individual differences in dependence severity. Regarding potential application, the results suggest a need for interventions that more effectively target demand Amplitude to make greater headway in reducing smoking in vulnerable populations. Trial Registration:clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

An Update on Hardening: A Qualitative Review.

INTRODUCTION: This review examines the evidence for the hardening hypothesis; that is, the prevalence of (1) becoming a former smoker is decreasing over time due to (2) decreased quit attempts, or (3) decreased success on a given quit attempt. METHODS: PubMed, EMBASE, PsychINFO, trial registries, and other databases were searched for population-based surveys that reported whether one of the aforementioned three outcomes decreased over time. RESULTS: None of the 26 studies found that conversion from current to former smoking, number of quit attempts, or success on a given quit attempt decreased over time and several found these increased over time. These results appeared to be similar across survey dates, duration of time examined, number of data points, data source, outcome definitions, and nationality. CONCLUSIONS: These results convincingly indicate hardening is not occurring in the general population of smokers. On the other hand, the prevalence of smoking is declining less among older and women smokers, and smokers with low education, low income, psychological problems, alcohol or drug abuse, medical problems, and greater nicotine dependence, than among those without these characteristics, presumably due to less quitting. Why this has not lead to decreased success in stopping smoking in the general population is unclear. IMPLICATIONS: Some have argued that a greater emphasis on harm reduction and more intensive or dependence-based treatments are needed because remaining smokers are those who are less likely to stop with current methods. This review finds no or little evidence for this assumption. Psychosocial factors, such as low education and psychiatric problems, predict less ability to quit and appear to becoming more prevalent among smokers. Why this is not leading to decreased quitting in the general population is an anomaly that may be worth trying to understand.

Study Characteristics Influence the Efficacy of Substance Abuse Treatments: A Meta-analysis of Medications for Smoking Cessation.

BACKGROUND: Understanding study characteristics' influence on treatment efficacy could improve interpretation of trials' outcomes. We examined study characteristics as predictors of outcomes in clinical trials of medications for tobacco use. METHODS: We obtained and analyzed data on 44 trials of nicotine gum, 37 trials of nicotine patch, 27 trials of varenicline, and 43 trials of bupropion from Cochrane reviews. We extracted and analyzed data for 15 study characteristics, odds ratios (ORs), and percent abstinent in control and medication conditions. We used general linear models to determine which study characteristics explained the variability among outcomes after controlling for medication characteristics. RESULTS: Study characteristics accounted for 12% of the variance in odds ratios among patch trials, 16% among gum trials, 16% among varenicline trials, and 34% among bupropion trials above and beyond medication characteristics. Patch and gum trials with industry funding had larger odds ratios than those without. Among patch trials, this appeared to be due to less abstinence in industry-funded trials' control conditions. Bupropion trials published earlier had larger odds ratios, which appeared to be due to less abstinence in control conditions. The reason for study characteristics' influence on varenicline trials was unclear. DISCUSSION: Study characteristics influenced the assessment of treatment efficacy above and beyond medication characteristics in smoking cessation trials. Our findings that study characteristics are associated with higher or lower efficacy does not suggest that the effect size under one versus another condition is the more valid outcome. Future studies are needed to determine which study characteristics reliably influence efficacy because this would help investigators and clinicians interpret trials. IMPLICATIONS: Study characteristics influenced the estimates of treatment efficacy but individual characteristics' influence on efficacy appeared to differ among different medications for smoking cessation. We encourage researchers to report study characteristics to improve interpretation of findings and systematic reviews, and to account for nontreatment-related variables to better estimate the efficacy of treatments.

Possible New Symptoms of Tobacco Withdrawal II: Anhedonia-A Systematic Review.

INTRODUCTION: When animals undergo nicotine deprivation, rewards become less rewarding (ie, anhedonia occurs). We searched for tests of whether anhedonia occurs in abstinent smokers. METHODS: The major inclusion criterion was a within-participants comparison of behavioral measures of reward sensitivity or self-reported anhedonia during smoking versus during abstinence among daily smokers. A computerized search of PubMed, PsychInfo, and Cochrane databases and other methods located 13 studies. All but one were laboratory studies. RESULTS: The number of studies and participants were small and the results mixed. In terms of anticipatory anhedonia (ie, wanting a reward), abstinence appeared to decrease willingness to work for immediately available rewards, but did not appear to influence how much adding rewards to a task increased responding. Abstinence also appeared to produce small increases in self-reported anticipatory anhedonia. In terms of consummatory anhedonia (ie, liking a reward), self-report measures found anhedonia decreased pleasure from rewards in some but not all tests. In terms of learning (ie, learning to choose a more frequent reward), abstinence did not reliably decrease allocating responding to high versus low frequency reward options. CONCLUSIONS: Although results were mixed, abstinence appears to increase anticipatory anhedonia. It is unclear if abstinence increases consummatory or reward learning-based anhedonia. Further studies of anhedonia in clinical settings are needed (1) to estimate the reliability and clinical significance of anhedonia as a symptom of tobacco withdrawal, (2) to assess if effects represent withdrawal versus offset processes, and (3) to assess if anhedonia interferes with the ability to stop smoking. IMPLICATIONS: Anticipatory anhedonia appears to be a symptom of tobacco withdrawal and should be added to tobacco withdrawal checklists and diagnostic criteria. Further study of consummatory and learning-based anhedonia is warranted.

Withdrawal Symptoms From E-Cigarette Abstinence Among Adult Never-Smokers: A Pilot Experimental Study.

INTRODUCTION: Use of e-cigarettes among never-smokers has substantially increased; yet there are few descriptions of the consequences of such use. We assessed whether adult never-smokers can have withdrawal from cessation of e-cigarettes. METHODS: In an un-blinded pre-post clinical trial, 30 never-smoker daily e-cigarette users used their own nicotine-containing e-cigarette for 7 days followed by 6 days of biologically confirmed abstinence. Participants monitored symptoms of nicotine withdrawal nightly via an Interactive Voice Response system. They attended three lab visits/week to provide expired carbon monoxide and urine samples to determine compliance. FINDINGS: Abstinence increased all the DSM5 symptoms of tobacco withdrawal and this occurred in the majority of participants. The increase in severity of withdrawal was small and rarely impaired functioning. CONCLUSIONS: Our finding suggests that withdrawal symptoms can occur in never-smokers who stop e-cigarettes abruptly. However, the severity of withdrawal appears to be small and may not be of clinical or regulatory significance. Although our sample size was small and thus replication tests of our results are indicated, it may be prudent to warn never-smokers that withdrawal symptoms may occur. IMPLICATIONS: This study indicates that withdrawal symptoms can occur in never-smokers who are daily e-cigarette users. However, the severity of withdrawal from e-cigarette abstinence in never-smokers appears to be small and may not be of clinical or regulatory significance. Given our small sample size, replication of our results is warranted. Nevertheless, it might be prudent to warn never-smokers of addiction to e-cigarettes.Clinical Trial Registration = NCT02825459.

Withdrawal Symptoms From E-Cigarette Abstinence Among Former Smokers: A Pre-Post Clinical Trial.

INTRODUCTION: The major aim of this study was to test whether abstinence from e-cigarettes causes withdrawal symptoms in former smokers. METHODS: We conducted an unblinded, within-participants, pre-post clinical trial in which 109 former smokers who were current daily electronic cigarette (e-cigarette) users used their own e-cigarette for 7 days followed by 6 days of biologically confirmed abstinence engendered via an escalating contingency payment system. Participants monitored symptoms of nicotine withdrawal daily via an Interactive Voice Response system. They also attended three laboratory visits per week for carbon monoxide and cotinine testing to verify abstinence. RESULTS: Half of participants completely abstained for a week. All the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) tobacco withdrawal symptoms, craving for e-cigarettes, craving for tobacco cigarettes, and the four possible new withdrawal symptoms (anhedonia, impulsivity, mood swings, and positive affect) increased during abstinence. Weight increased and heart rate decreased with abstinence. Symptoms showed the prototypical inverted U time pattern of a withdrawal state. The magnitude of withdrawal appeared to be somewhat less than that in a prior study of abstinent daily tobacco cigarette smokers. More severe withdrawal on the first 2 days of abstinence did not predict abstinence on the last day of the study. CONCLUSIONS: Former smokers who are daily e-cigarette users transfer physical dependence on tobacco cigarettes to dependence on e-cigarettes. The severity of withdrawal from e-cigarettes appears to be only somewhat less than that from daily tobacco cigarette use. Replication tests that include placebo controls, testing for pharmacological specificity, and including never-smokers, non-daily e-cigarette users and dual users are indicated. IMPLICATIONS: Our results indicate e-cigarettes can maintain physical dependence. This adverse effect should be included in any risk vs. benefit calculation. Also, potential and current e-cigarette users should be informed that abrupt cessation of e-cigarettes can cause withdrawal symptoms. TRIAL REGISTRATION: NCT02825459.

Predictors of Smoking Cessation Attempts and Success Following Motivation-Phase Interventions Among People Initially Unwilling to Quit Smoking.

INTRODUCTION: Most people who smoke cigarettes are not willing (ie, not ready) to make a quit attempt (QA) at any given time. Unfortunately, interventions intended to increase QAs and the success of QAs are only modestly effective. Identifying processes leading to QAs and quitting success could guide intervention development. AIMS AND METHODS: This is a secondary analysis of a randomized factorial trial of 6 weeks of motivation-phase interventions among primary care patients (N = 517) who were initially unwilling to quit but were willing to reduce their smoking. Using logistic regression, we controlled for treatment condition and tested whether baseline or change in smoking-related constructs after 6 weeks of treatment predicted (1) making an at least 24 h QA between weeks 6 and 26 and (2) quitting success at week 26 (7-day point-prevalence abstinence among those who made a QA). Predictors included cigarettes/day, time to first cigarette, motivation to quit, quitting self-efficacy, anticipated urges to smoke if quit, positive affect, negative affect, and time spent around others who smoke. RESULTS: In multivariable models that included all smoking-related constructs, changes in the following variables predicted initiating a QA above and beyond other variables: greater baseline time to first cigarette (odds ratio [OR] = 1.60), increases in time to first cigarette (OR = 1.27), and increases in quitting self-efficacy (OR = 1.14). Increased motivation to quit predicted conversion of a QA into quitting success at 26 weeks (OR = 1.36). CONCLUSION: Predictors of making a QA differed from predictors of quitting success. Predictors of QAs and success could each serve as important treatment targets of motivation-phase interventions. IMPLICATIONS: Motivation-phase interventions for people initially unwilling to quit smoking cigarettes may be improved by striving to increase their (1) time to first cigarette and quitting self-efficacy to promote QAs and (2) motivation to quit to promote quit success. Future experimental tests of such interventions are needed to identify causal determinants of QAs and quitting success.

Potential Moderating Effects of Sex/Gender on the Acute Relative Reinforcing and Subjective Effects of Reduced Nicotine Content Cigarettes in Vulnerable Populations.

INTRODUCTION: Reports in relatively healthy smokers suggest men are more sensitive than women to the subjective effects of reduced nicotine content cigarettes (RNCCs). We know of no reports examining sex differences in the relative reinforcing effects of RNCCs, an important outcome in assessing smoking's addiction potential. The aim of the present study is to address this gap by examining sex/gender differences on reinforcing effects while examining whether sex differences in subjective effects are discernible in vulnerable populations. METHODS: Secondary analysis of a within-subject, double-blinded experiment examining acute effects of cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg/g) among 169 adult smokers with psychiatric conditions or socioeconomic disadvantage. Effects of dose, sex, and their interaction were examined on reinforcing (concurrent-choice and Cigarette Purchase Task [CPT] testing), and subjective effects (Cigarette Evaluation Questionnaire [CEQ] and craving/withdrawal ratings). RESULTS: Reducing nicotine content decreased the relative reinforcing effects of smoking in concurrent-choice and CPT testing (p's < .05) with no significant effects of sex nor dose × sex/gender interactions. Reducing nicotine content decreased CEQ ratings with only a single significant effect of sex (higher Psychological Reward scores among women than men, p = .02) and no significant dose × sex/gender interactions. Results on craving/withdrawal paralleled those on the CEQ. CONCLUSIONS: Reducing nicotine content decreases the addiction potential of smoking independent of sex in populations highly vulnerable to smoking and addiction, with no indication that women are less sensitive to subjective effects of RNCCs or would benefit less from a policy reducing the nicotine content of cigarettes. IMPLICATIONS: A policy reducing the nicotine content of cigarettes has the potential to reduce the addiction potential of smoking across men and women who are especially vulnerable to smoking, addiction, and tobacco-related adverse health impacts.

Initial Information on a Novel Nicotine Product.

BACKGROUND AND OBJECTIVES: This is the first study to assess the appeal and interest among adults in a new consumer tobacco product, ZYN. We also describe ZYN users, patterns of use, and reasons for use. METHODS: Two data sets, consisting of a ZYN-naive consumer panel (n = 5179) and ZYN users (n = 1266), were provided by Swedish Match North America. Descriptive, cross-sectional analyses and logistic regression assessed the perceptions of and likelihood of buying ZYN in the consumer panel and the characteristics of ZYN users. RESULTS: The majority of current smokeless tobacco (ST) users in the consumer panel found that ZYN was moderately-extremely appealing, while never and former tobacco users indicated much less interest; the former were more likely to buy ZYN than other groups. The highest percentage of ZYN users were former tobacco users (43%); very few were never users (4%). The most popular reason for using ZYN was "Less harmful to my health than other tobacco products," followed by "ease of use." DISCUSSION AND CONCLUSIONS: Nonusers of tobacco had very little interest in ZYN. ST users are not only more interested and likely to buy ZYN than other tobacco users, they were the largest group of regular users. SCIENTIFIC SIGNIFICANCE: The first assessment of a new nicotine product, ZYN, suggests that current and former tobacco users may perceive ZYN as a reduced-risk product. ZYN potentially could be used as a smoking/tobacco-cessation aid based on reasons of current users. (Am J Addict 2020;00:00-00).

Increasing Quit Attempts by Transitioning to Very Low Nicotine Content Cigarettes Versus Reducing Number of Cigarettes Per Day: A Secondary Analysis of an Exploratory Randomized Trial.

INTRODUCTION: The Food and Drug Administration (FDA) has proposed reducing nicotine with very low nicotine content (VLNC) cigarettes. In contrast, reducing nicotine by reducing number of cigarettes per day (CPD) is common. Our prior findings demonstrate that VLNC cigarettes decreased dependence more and were more acceptable than reducing CPD. This secondary analysis explored which reduction strategy increased quit attempts (QA), self-efficacy, or intention to quit more. METHODS: This is a secondary analysis of 68 adult daily smokers not ready to quit randomized to smoke VLNC cigarettes versus reduce CPD over 5 weeks. All participants smoked study cigarettes with nicotine yield similar to most commercial cigarettes ad lib for 1 week (baseline). Participants were then randomized to gradually reduce to 70%, 35%, 15%, and 3% of baseline nicotine over 4 weeks by either (1) transitioning to lower nicotine VLNC cigarettes or (2) reducing the number of full nicotine CPD. All participants received nicotine patches to aid reduction. We assessed (1) QAs using nightly and weekly self-reports, (2) Velicer's Self-Efficacy to Quit measure weekly, and (3) the Intention-to-Quit Ladder nightly. RESULTS: More CPD (41%) than VLNC (17%) participants made any QA (odds ratio = 3.4, 95% confidence interval = 1.1, 10.5). There was no difference in QAs ≥24 h. Self-efficacy increased for VLNC but not CPD participants (interaction: F = 3.7, p < .01). The condition by time interaction for intention-to-quit was not significant. CONCLUSIONS: Reducing number of CPD increased QAs more than reducing nicotine via switching to VLNC cigarettes. The lack of difference in longer QAs suggests replication tests are needed. IMPLICATIONS: Reducing the frequency of smoking behavior (ie, CPD) could be a more effective strategy to increase QAs than reducing the magnitude of nicotine in each cigarette (ie, VLNC) per se.

Reduction in Cigarettes per Day Prospectively Predicts Making a Quit Attempt: A Fine-Grained Secondary Analysis of a Natural History Study.

INTRODUCTION: Reducing cigarettes per day (CPD) aided by medication increases quit attempts (QA) among smokers not trying to quit. If this is due to reducing CPD per se, then a greater reduction should predict making a QA. AIMS AND METHODS: In this secondary analysis, 132 smokers completed nightly calls to report CPD, intention to quit tomorrow, and QAs over 12 weeks. We provided no treatment. We identified episodes of reduction and tested whether (1) percent reduction in CPD, (2) absolute reduction in CPD, (3) duration of reduction, or (4) CPD on the final day predicted a QA immediately after a reduction episode. We tested this separately among reduction episodes that began with and without an intention to quit. RESULTS: Among the 1179 episodes that began without intention to quit, all four measures of reduction predicted making a QA. Greater percent reduction, longer duration, and fewer CPD on the final day were retained in a multivariate model (all p < .05). Among the 85 episodes that began with intention to quit, greater percent reduction and greater absolute reduction predicted making a QA. Only mean percent reduction was retained in a multivariate model (p < .001). CONCLUSIONS: Our results replicate and extend earlier studies by using fine-grained analyses and examining immediately proximal QAs in a sample of self-quitters. Findings suggest that reducing CPD per se increases the probability of a QA among smokers without intention to quit in a dose-related manner. Whether this is the case among smokers who intend to quit remains unclear. IMPLICATIONS: Reducing CPD appears to be an effective strategy to increase the probability of making a QA for the majority of smokers who do not intend to quit in the near future. However, our findings are mixed regarding the effectiveness of reducing among smokers who intend to quit. Clinical interventions and policies that promote reducing CPD are likely to be an effective way to increase QAs. Reduction may be especially helpful for smokers who have not responded to traditional advice to stop abruptly.

Distal Measurements Can Produce False Negative Results: A Prospective Secondary Analysis of a Natural History Study.

INTRODUCTION: Most prospective studies of quit attempts (QAs) or abstinence measure the ability of variables to predict quitting many weeks or months later. This design ignores more proximal fluctuations in the predictor that may be more relevant. The present secondary analysis compares 6-week (distal) and daily (proximal) changes in cigarettes per day (CPD) as predictors of making a QA. METHODS: Daily smokers reported CPD and QAs nightly throughout a 12-week natural history study. We provided no treatment. In the distal analysis, we tested whether reduction in CPD between baseline and 6 weeks predicted making a QA during the following 6 weeks. In the proximal analysis, we identified episodes of one or more days of ≥10% reduction in CPD and tested whether reduction predicted making a QA on the day immediately after the reduction episode. We tested the following predictors: (1) reduction in CPD of ≥10% (yes/no), (2) percent reduction, (3) absolute magnitude of reduction, and (4) CPD at the end of reduction. RESULTS: In the distal analysis, reduction did not predict making a QA. In the proximal analysis, any reduction (OR = 3.0), greater percent reduction (OR = 1.6), greater absolute reduction (OR = 1.3), and fewer CPD on the final day of an episode (OR = 11.8) predicted making a QA the next day (all p < .001). DISCUSSION: Relying on distal measurements to identify causes of a behavior may produce false-negative results. Increased use of technological advances will make assessments of the more valid proximal measurements more feasible. IMPLICATIONS: This secondary analysis tested distal and proximal predictors of making a quit attempt among the same participants and found that distal tests did not, but proximal tests did predict quit attempts. Relying on distal measurements may result in false negatives.

Potential Moderating Effects of Psychiatric Diagnosis and Symptom Severity on Subjective and Behavioral Responses to Reduced Nicotine Content Cigarettes.

INTRODUCTION: Given FDA's authority to implement a cigarette nicotine reduction policy, possible outcomes of this regulation must be examined, especially among those who may be most affected, such as those with comorbid psychiatric disorders. METHODS: In this secondary analysis of a multisite, randomized, clinical laboratory study, we used analyses of variance to examine the effects of nicotine dose (0.4, 2.4, 5.2, and 15.8 mg/g of tobacco), depressive and anxiety diagnoses (depression only, anxiety only, both, or neither), and depressive and anxiety symptom severity on cigarette choice, smoke exposure, craving, and withdrawal across three vulnerable populations: socioeconomically disadvantaged women of reproductive age, opioid-dependent individuals, and those with affective disorders (n = 169). RESULTS: Diagnosis and symptom severity largely had no effects on smoking choice, total puff volume, or CO boost. Significant main effects on craving and withdrawal were observed, with higher scores in those with both anxiety and depression diagnoses compared with depression alone or no diagnosis, and in those with more severe depressive symptoms (p's < .001). These factors did not interact with nicotine dose. Cigarettes with <15.8 mg/g nicotine were less reinforcing, decreased total puff volume, and produced significant but lower magnitude and shorter duration reductions in craving and withdrawal than higher doses (p's < .01). CONCLUSIONS: Reducing nicotine dose reduced measures of cigarette addiction potential, with little evidence of moderation by either psychiatric diagnosis or symptom severity, providing evidence that those with comorbid psychiatric disorders would respond to a nicotine reduction policy similarly to other smokers. IMPLICATIONS: Thus far, controlled studies in healthy populations of smokers have demonstrated that use of very low nicotine content cigarettes reduces cigarette use and dependence without resulting in compensatory smoking. These analyses extend those findings to a vulnerable population of interest, those with comorbid psychiatric disorders. Cigarettes with very low nicotine content were less reinforcing, decreased total puff volume, and produced significant but lower magnitude and shorter duration reductions in craving and withdrawal than higher doses. These nicotine dose effects did not interact with psychiatric diagnosis or mood symptom severity suggesting that smokers in this vulnerable population would respond to a nicotine reduction strategy similarly to other smokers.

WITHDRAWN: Reduction versus abrupt cessation in smokers who want to quit.

BACKGROUND: The standard way to stop smoking is to quit abruptly on a designated quit day. A number of smokers have tried unsuccessfully to quit this way. Reducing smoking before quitting could be an alternative approach to cessation. Before this method is adopted it is important to determine whether it is at least as successful as abrupt quitting. OBJECTIVES: 1. To compare the success of reducing smoking to quit and abrupt quitting interventions. 2. To compare adverse events between arms in studies that used pharmacotherapy to aid reduction. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Review Group specialised register using topic specific terms. The register contains reports of trials of tobacco addiction interventions identified from searches of MEDLINE, EMBASE and PsycInfo. We also searched reference lists of relevant papers and contacted authors of ongoing trials. Date of most recent search: July 2012. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that recruited adults who wanted to quit smoking. Studies included at least one condition which instructed participants to reduce their smoking and then quit and one condition which instructed participants to quit abruptly. DATA COLLECTION AND ANALYSIS: The outcome measure was abstinence from smoking after at least six months follow-up. We pooled the included trials using a Mantel-Haenszel fixed-effect model. Trials were split for two sub-group analyses: pharmacotherapy vs no pharmacotherapy, self help therapy vs behavioural support. Adverse events were summarised as a narrative. It was not possible to compare them quantitatively as there was variation in the nature and depth of reporting across studies. MAIN RESULTS: Ten studies were relevant for inclusion, with a total of 3760 participants included in the meta-analysis. Three of these studies used pharmacotherapy as part of the interventions. Five studies included behavioural support in the intervention, four included self-help therapy, and the remaining study had arms which included behavioural support and arms which included self-help therapy. Neither reduction or abrupt quitting had superior abstinence rates when all the studies were combined in the main analysis (RR= 0.94, 95% CI= 0.79 to 1.13), whether pharmacotherapy was used (RR= 0.87, 95% CI= 0.65 to 1.22), or not (RR= 0.97, 95% CI= 0.78 to 1.21), whether studies included behavioural support (RR= 0.87, 95% CI= 0.64 to 1.17) or self-help therapy (RR= 0.98, 95% CI= 0.78 to1.23). We were unable to draw conclusions about the difference in adverse events between interventions, however recent studies suggest that pre-quit NRT does not increase adverse events. AUTHORS' CONCLUSIONS: Reducing cigarettes smoked before quit day and quitting abruptly, with no prior reduction, produced comparable quit rates, therefore patients can be given the choice to quit in either of these ways. Reduction interventions can be carried out using self-help materials or aided by behavioural support, and can be carried out with the aid of pre-quit NRT. Further research needs to investigate which method of reduction before quitting is the most effective, and which categories of smokers benefit the most from each method, to inform future policy and intervention development.

Response to reduced nicotine content cigarettes among smokers differing in tobacco dependence severity.

This study examines whether tobacco dependence severity moderates the acute effects of reducing nicotine content in cigarettes on the addiction potential of smoking, craving/withdrawal, or smoking topography. Participants (N = 169) were daily smokers with mild, moderate, or high tobacco-dependence severity using the Heaviness of Smoking Index. Following brief abstinence, participants smoked research cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg nicotine/g tobacco) in a within-subject design. Results were analyzed using repeated measures analysis of co-variance. No main effects of dependence severity or interactions with nicotine dose were noted in relative reinforcing effects in concurrent choice testing or subjective effects on the modified Cigarette Evaluation Questionnaire. Demand for smoking in the Cigarette Purchase Task was greater among more dependent smokers, but reducing nicotine content decreased demand independent of dependence severity. Dependence severity did not significantly alter response to reduced nicotine content cigarettes on the Minnesota Tobacco Withdrawal Scale nor Questionnaire of Smoking Urges-brief (QSU) Factor-2 scale; dependence severity and dose interacted significantly on the QSU-brief Factor-1 scale, with reductions dependent on dose among highly but not mildly or moderately dependent smokers. Dependence severity and dose interacted significantly on only one of six measures of smoking topography (i.e., maximum flow rate), which increased as dose increased among mildly and moderately but not highly dependent smokers. These results suggest that dependence severity has no moderating influence on the ability of reduced nicotine content cigarettes to lower the addiction potential of smoking, and minimal effects on relief from craving/withdrawal or smoking topography.