Andrew A. Strasser

Varenicline Improves Mood and Cognition during Smoking Abstinence

BACKGROUND Neuronal nicotinic acetylcholine receptors (nAChRs) are a key target in medication development for various neuropsychiatric disorders, including nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, is a new, efficacious medication for nicotine dependence. Its effects on the affective and cognitive dimensions of nicotine withdrawal have yet to be well characterized. METHODS Sixty-seven treatment-seeking smokers were administered varenicline (x 21 days) and placebo (x 21 days) in a double-blind within-subject crossover design. Following medication run-up (Days 1-10), there was a 3-day mandatory smoking abstinence phase (Days 11-13) during which subjective symptoms and cognitive performance were assessed. Participants were reexposed to a scheduled smoking lapse (Day 14) and followed for days to lapse (Days 15-21) in each medication period. RESULTS In the varenicline period, compared with placebo, withdrawal symptoms (p = .04), smoking urges (p < .001), and negative affect (p = .01) during manditory abstinence were significantly lower, and levels of positive affect (p = .046), sustained attention (p = .018), and working memory (p = .001) were significantly greater. Varenicline also significantly reduced subjective rewarding effects of the scheduled smoking lapse (e.g., satisfaction, relief, liking; p = .003). Medication effects on days to lapse following the scheduled smoking lapse were dependent on treatment order (p = .001); among participants who received placebo in the first period, varenicline increased days of abstinence in the follow-up period. CONCLUSIONS These data identify novel affective and cognitive effects of varenicline and may have implications for medication development for other neuropsychiatric conditions.

Working memory deficits predict short-term smoking resumption following brief abstinence.

As many as one-half of smokers relapse in the first week following a quit attempt, and subjective reports of cognitive deficits in early abstinence are associated with increased relapse risk. This study examined whether objective cognitive performance after 3 days of abstinence predicts smoking resumption in a 7-day simulated quit attempt. Sixty-seven treatment-seeking smokers received either varenicline or placebo (randomized double-blind) for 21 days. Following medication run-up (days 1-10), there was a 3-day mandatory (biochemically confirmed) abstinence period (days 11-13) during which working memory (Letter-N-Back Task) and sustained attention (Continuous Performance Task) were assessed (day 13). Participants were then exposed to a scheduled smoking lapse and instructed to try to remain abstinent for the next 7 days (days 15-21). Poorer cognitive performance (slower correct reaction time on Letter-N-Back task) during abstinence predicted more rapid smoking resumption among those receiving placebo (p=0.038) but not among those receiving varenicline. These data lend further support for the growing recognition that cognitive deficits involving working memory are a core symptom of nicotine withdrawal and a potential target for the development of pharmacological and behavioral treatments.

Applying the risk/use equilibrium: use medicinal nicotine now for harm reduction

Both the recent Institute of Medicine (IOM) report1 and the article by Henningfield and Fagerstrom2 in this issue of Tobacco Control consider the value of adding harm reduction products to the main public health strategies for dealing with tobacco use—prevention, cessation, and protection of non-smokers from tobacco smoke pollution.3 4 Harm reducing products are those that lower total tobacco caused morbidity and mortality, even though these products might involve continued exposure to one or more tobacco related toxicants. The IOM committee developed a testing strategy to assess which products (tobacco or pharmaceutical) are truly harm reducing, along with surveillance and regulatory principles for the protection of public health. Henningfield and Fagerstrom2 discussed the possible benefits from an uncontrolled harm reduction “intervention” in Sweden involving Snus (Swedish moist snuff) and to some extent nicotine replacement pharmaceuticals or medicinal nicotine (MN). It will take years, if ever, before any battery of IOM-type tests will be in place. Given the probability of legal and political battles, the final form of testing and regulation may be far from adequate, leading to further decades of the promotion of ostensibly reduced risk products falsely reassuring tobacco users. Cigarette smoking remains the single leading preventable cause of death in most developed countries5 and a major cause of current and future deaths in developing countries.6 For health, non-smokers should never start smoking, and current smokers should become former smokers as soon as possible. Harm reduction, if done well, offers additional promise. Once it was hoped that lower tar cigarettes would have harm reducing properties and be good for the publics health,7but, on current evidence, they have been a public health disaster.8-11 One harm reduction strategy is to alter cigarettes to try to reduce or eliminate toxic ingredients. Such altered …

Randomized Trial of Reduced-Nicotine Standards for Cigarettes

BACKGROUND The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).

An Association of CYP2A6 Genotype and Smoking Topography

Nicotine is metabolized into biologically inactive cotinine primarily by the cytochrome P450 enzyme CYP2A6. CYP2A6 genetic variations have been phenotypically grouped as slow, intermediate, and normal metabolizers. Slow metabolizers smoke fewer cigarettes daily and weekly, and have lower carbon monoxide (CO) and plasma nicotine levels, suggesting a reduced smoking rate compared with normal metabolizers. CYP2A6 also is involved in the metabolic activation of tobacco-specific procarcinogenic nitrosamines, such as 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). NNK is one of the most abundant and potent procarcinogens in cigarette smoke. The present study investigated the association of CYP2A6 genotype with smoking topography, a quantifiable measure of smoking behavior, in a sample of treatment-seeking smokers prior to treatment. Smoking topography measures indicative of quantity of smoke exposure--number of puffs, mean puff volume, and total puff volume--were the outcome variables. Covariates associated with smoking topography were included in the analyses. Results indicated that CYP2A6 genotype group had a significant effect on mean puff volume and total puff volume, but not number of puffs, such that slow metabolizers exhibited reduced puffing compared with others. Smokers having CYP2A6 variants resulting in low activity metabolize nicotine more slowly, and convert procarcinogen nitrosamines to carcinogens more slowly, than do normal metabolizers. The results from this study also suggest a behavioral mechanism that may account for reduced cancer risk in slow metabolizers.

Nicotine Metabolite Ratio Predicts Smoking Topography and Carcinogen Biomarker Level

Background: Variability in smoking behavior is partly attributable to heritable individual differences in nicotine clearance rates. This can be assessed as the ratio of the metabolites cotinine and 3′-hydroxycotinine (referred to as the nicotine metabolism ratio; NMR). We hypothesized that faster NMR would be associated with greater cigarette puff volume and higher levels of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a carcinogen biomarker. Methods: Current smokers (n = 109) smoked one of their preferred brand cigarettes through a smoking topography device and provided specimens for NMR and total NNAL assays. Results: Faster nicotine metabolizers (third and fourth quartiles versus first quartile) based on the NMR exhibited significantly greater total puff volume and total NNAL; the total puff volume by daily cigarette consumption interaction was a significant predictor of total NNAL level. Conclusion: A heritable biomarker of nicotine clearance predicts total cigarette puff volume and total NNAL. Impact: If validated, the NMR could contribute to smoking risk assessment in epidemiologic studies and potentially in clinical practice. Cancer Epidemiol Biomarkers Prev; 20(2); 234–8. 2011 AACR.

Dopamine receptor genes (DRD2, DRD3 and DRD4) and gene-gene interactions associated with smoking-related behaviors.

Cigarette smoking, like many addictive behaviors, has a genetic component, and the dopamine D2‐like receptor genes (DRD2, DRD3 and DRD4) are candidates for contributing to these behaviors. Phenotypic information concerning smoking‐related behaviors from a nationally representative sample of research volunteers was analyzed for association with polymorphisms in these genes. Genotype status at the DRD2 intron 2 simple tandem repeat was related to cigarettes per day (P = 0.035) and heaviness of smoking index (P = 0.049). The presence of the glycine allele at the S9G polymorphism of the DRD3 gene was associated with frequency/quantity measures of smoking [log‐transformed time to first cigarette (P = 0.031) and heaviness of smoking index (P = 0.035)]. There was a trend for DRD4 long alleles of the variable number of tandem repeats polymorphism to be associated with reduced severity of three withdrawal symptoms [desire/craving (P = 0.054); anger/irritability (P = 0.10); and trouble sleeping (P = 0.068)]. Interactions between genotypes at all three genes were associated with nervousness (P = 0.020) and trouble sleeping (P = 0.015). An interaction between DRD2 and DRD3 was found for trouble concentrating (P = 0.020). These relationships present possible dopamine‐related responses to nicotine that warrant further study.

Experimental evaluation of antitobacco PSAs: Effects of message content and format on physiological and behavioral outcomes

INTRODUCTION Antitobacco media campaigns using public service announcements (PSAs) have shown promise in reducing smoking initiation and increasing intentions to quit. Research on what makes an effective PSA has had mixed outcomes. The present study tested the effects of specific message features in antitobacco PSAs, using theory-based physiological and self-report outcomes. METHODS PSAs were categorized as high or low in message sensation value (MSV) and strength of argument and presented to 200 current smokers in a 2 x 2 factorial design. Physiological responses-specifically, heart rate, skin conductance, zygomaticus major, and corrugator supercilii-were assessed while participants viewed the PSAs. Beliefs, attitudes, efficacy, norms, and intentions to quit were assessed immediately following viewing. RESULTS Corrugator activity was significantly greater in the high MSV condition. Among those low in sensation seeking, low MSV PSAs elicited higher self-efficacy, whereas the reverse was true for high sensation seekers. High MSV PSAs elicited higher negative beliefs in low sensation seekers. Adding physiological measures to a model predicting intention to quit did not improve the explained variance. DISCUSSION The present study represents the first comprehensive theory-based experimental investigation of the effects of different features of antitobacco PSAs and provides a framework for future research in identifying effective features of such PSAs. Results illustrate the importance of considering individual differences, characterizing both PSA content and format, and outcome and response measures when evaluating antitobacco PSAs.

Graphic Warning Labels Elicit Affective and Thoughtful Responses from Smokers: Results of a Randomized Clinical Trial.

Objective Observational research suggests that placing graphic images on cigarette warning labels can reduce smoking rates, but field studies lack experimental control. Our primary objective was to determine the psychological processes set in motion by naturalistic exposure to graphic vs. text-only warnings in a randomized clinical trial involving exposure to modified cigarette packs over a 4-week period. Theories of graphic-warning impact were tested by examining affect toward smoking, credibility of warning information, risk perceptions, quit intentions, warning label memory, and smoking risk knowledge. Methods Adults who smoked between 5 and 40 cigarettes daily (N = 293; mean age = 33.7), did not have a contra-indicated medical condition, and did not intend to quit were recruited from Philadelphia, PA and Columbus, OH. Smokers were randomly assigned to receive their own brand of cigarettes for four weeks in one of three warning conditions: text only, graphic images plus text, or graphic images with elaborated text. Results Data from 244 participants who completed the trial were analyzed in structural-equation models. The presence of graphic images (compared to text-only) caused more negative affect toward smoking, a process that indirectly influenced risk perceptions and quit intentions (e.g., image->negative affect->risk perception->quit intention). Negative affect from graphic images also enhanced warning credibility including through increased scrutiny of the warnings, a process that also indirectly affected risk perceptions and quit intentions (e.g., image->negative affect->risk scrutiny->warning credibility->risk perception->quit intention). Unexpectedly, elaborated text reduced warning credibility. Finally, graphic warnings increased warning-information recall and indirectly increased smoking-risk knowledge at the end of the trial and one month later. Conclusions In the first naturalistic clinical trial conducted, graphic warning labels are more effective than text-only warnings in encouraging smokers to consider quitting and in educating them about smoking’s risks. Negative affective reactions to smoking, thinking about risks, and perceptions of credibility are mediators of their impact. Trial Registration Clinicaltrials.gov NCT01782053

The effect of smoking cues in antismoking advertisements on smoking urge and psychophysiological reactions.

INTRODUCTION Studies have found that smoking-related cues elicit smoking urges in addicted smokers. This work presents the first cue-reactivity study in the context of antismoking advertisements. METHODS Using a two (no cue vs. smoking cue) by two (high vs. low argument strength) mixed design, we tested the hypothesis that smoking cues presented in antismoking advertisements elicit smoking urges. The study tested 96 adult smokers using both self-reported and psychophysiological measures of smoking urge. It also explored gender differences during the urge elicitation. RESULTS Smoking cues in antismoking advertisements elicited smoking urges in the weak argument condition. DISCUSSION Antismoking advertisements with smoking cues and weak antismoking arguments could produce boomerang effects on smokers through urge elicitation.