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The topic of e-cigarettes is controversial. Opponents focus on e-cigarettes’ risks for young people, while supporters emphasize the potential for e-cigarettes to assist smokers in quitting smoking. Most US health organizations, media coverage, and policymakers have focused primarily on risks to youths. Because of their messaging, much of the public—including most smokers—now consider e-cigarette use as dangerous as or more dangerous than smoking. By contrast, the National Academies of Science, Engineering, and Medicine concluded that e-cigarette use is likely far less hazardous than smoking. Policies intended to reduce adolescent vaping may also reduce adult smokers’ use of e-cigarettes in quit attempts. Because evidence indicates that e-cigarette use can increase the odds of quitting smoking, many scientists, including this essay’s authors, encourage the health community, media, and policymakers to more carefully weigh vaping’s potential to reduce adult smoking-attributable mortality. We review the health risks of e-cigarette use, the likelihood that vaping increases smoking cessation, concerns about youth vaping, and the need to balance valid concerns about risks to youths with the potential benefits of increasing adult smoking cessation.

The aim of this study is to advance our understanding of how nicotine dependence level, defined by the Fagerström Test of Nicotine Dependence (FTND), relates to nicotine withdrawal features. We classified nicotine dependence in two categories, 1) low dependence (LD; FTND

Background Initial trials of web-based smoking-cessation programs have generally been promising. The active components of these programs, however, are not well understood. This study aimed to (1) identify active psychosocial and communication components of a web-based smoking-cessation intervention and (2) examine the impact of increasing the tailoring depth on smoking cessation. Design Randomized fractional factorial design. Setting Two HMOs: Group Health in Washington State and Henry Ford Health System in Michigan. Participants 1866 smokers. Intervention A web-based smoking-cessation program plus nicotine patch. Five components of the intervention were randomized using a fractional factorial design: high- versus low-depth tailored success story, outcome expectation, and efficacy expectation messages; high- versus low-personalized source; and multiple versus single exposure to the intervention components. Measurements Primary outcome was 7 day point-prevalence abstinence at the 6-month follow-up. Findings Abstinence was most influenced by high-depth tailored success stories and a high-personalized message source. The cumulative assignment of the three tailoring depth factors also resulted in increasing the rates of 6-month cessation, demonstrating an effect of tailoring depth. Conclusions The study identified relevant components of smoking-cessation interventions that should be generalizable to other cessation interventions. The study also demonstrated the importance of higher-depth tailoring in smoking-cessation programs. Finally, the use of a novel fractional factorial design allowed efficient examination of the study aims. The rapidly changing interfaces, software, and capabilities of eHealth are likely to require such dynamic experimental approaches to intervention discovery.

A conference on the conduct of genomic research on complex behaviors was convened at the University of Michigan to demystify genetic research by describing the tools and methodologies for identifying genes and to assess the feasibility of conducting genomic research on smoking, a complex behavior with major public health import. These proceedings are excerpts based on the presentations at the conference.

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Test strips impregnated with phenylthiocarbamide (PTC) have been used to identify genetic differences based on whether a bitter taste is perceived. To determine whether smokers who perceive PTC as bitter tasting ("tasters") would differ from those who describe it as tasteless ("non-tasters") on smoking-related variables, we studied 464 current smokers (70% female, 79% White; mean age 30.5+/-9 years) recruited to participate in laboratory experiments and clinical trials. Of these, 217 (47%) reported the PTC strips as tasteless and 154 (33%) as tasting bitter. The remaining 93 (20%) described the taste as salty, sweet, or other and were excluded from further analyses. Comparing tasters with non-tasters, we found significant differences in mean (S.D.) total years smoked (14.5 [9.2] for non-tasters, vs. 12.6 [8.4] for tasters, p.05), Fagerstrom Tolerance Questionnaire scores (6.4 [2.1] vs. 5.8 [2.1], p.01), and scores on the Positive Reinforcement scale of the Michigan-Nicotine Reinforcement Questionnaire (8.1 [2.9] vs. 6.8 [3.1], p.05). Results suggest that among smokers, ability to taste PTC may confer some protection from development of nicotine dependence and positive reinforcement from smoking.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

To investigate the accuracy of offspring assessments of parental smoking status, we studied 116 parents and 151 adult children (276 parent-child dyads) who provided data on both their own and their parents' smoking status. All currently smoking and all ex-smoking parents were correctly classified as ever-smokers by their offspring (n = 79 and 100, respectively). Of the 97 offspring who reported on never-smoking parents, 88 correctly classified their parents as never-smokers. Thus, sensitivity for detecting ever-smoking in parents was 100%, and specificity, 91%. Because all incorrect classifications involved never-smoking parents, further analyses focused on this group. Too few parents were misclassified to permit testing of parental characteristics. Offspring who misclassified their parents were significantly older than those who did not; neither sex nor smoking status of the offspring was associated with the increased likelihood of misclassification. No significant differences were discovered for dyadic factors (concordance/discordance for sex; parent-offspring age difference). Overall, these results support the utility of proxy reports of parental smoking phenotype by adult informants when self-report is unavailable.

Initial sensitivity to the pharmacological effects of a drug may affect patterns of future use and dependence for a wide variety of drugs. Retrospective reports of sensations experienced upon early experimentation, however, may be limited by recall bias based on time elapsed and subsequent experiences. To validate reports of early experiences with nicotine, we studied 34 smokers who had contributed retrospective data on early experiences with smoking. Half had reported experiencing a buzz from smoking their first cigarette (the "yes" group), the other half had not (the "no" group). To simulate initial sensitivity to nicotine, we asked participants to remain abstinent from smoking for 5 days to allow for the dissipation of tolerance. They then participated in a laboratory session in which they were reexposed to nicotine in an unfamiliar form (nicotine nasal spray) and asked to indicate pleasurable responses by depressing a foot pedal if and when they experienced a "pleasurable buzz." Smokers in the "yes" group were marginally more likely to be male. The two groups did not differ significantly on age or race. The "yes" group smoked significantly more cigarettes/day than the "no" group. When the two groups were compared for response to nasal spray following 5 days' abstinence, smokers in the "yes" group were marginally more likely to have signaled experiencing at least one pleasurable buzz and rated "pleasurable sensation from spray" on a 100-mm visual analogue scale administered 10 min after nicotine dosing significantly higher than were those in the "no" group. To the extent that several days' abstinence can serve as a model for initial sensitivity to nicotine, our findings validate retrospective reports of pleasurable sensations upon early smoking experimentation.

The U.S. Centers for Disease Control defines a never-smoker as someone who has smoked < 100 cigarettes per lifetime. In an attempt to explore differences among nonsmokers and to validate this cutpoint, we surveyed 69 nonsmokers who had smoked between 1 and 200 cigarettes in their lifetime on their experiences during the time they smoked. Of the 7 who classified themselves as ex-smokers, 2 met DSM-IV criteria for nicotine dependence, compared with none who classified themselves as never-smokers. No respondents provided data permitting the computation of a Fagerstrom Test for Nicotine Dependence (FTND) score. Withdrawal effects were minimal, but craving, tolerance, and subjective effects showed a pattern of significant differences that were most prominent between those who smoked only 1 cigarette and those who smoked at least a pack. Our data indicate a graded effect but also suggest that 19 cigarettes per lifetime is a more conservative cutpoint than 99 for defining the never-smoker phenotype. Further investigation of the smoking trajectory and characteristics associated with development of signs of dependence in never- vs. ever-smokers may help refine this cutpoint and shed light on what protects some people who experiment with smoking from becoming chronic users.

This article is a brief history of the Society for Research on Nicotine and Tobacco, now in its 10th year. During its first decade, the Society grew from around 100 to over 900 members, sponsored well-attended annual meetings and highly influential satellite conferences to promote research, provided timely electronic and print services to increase the flow of information, and founded a new journal to facilitate communication of scientific advances. These accomplishments highlight the progress that has been made in meeting the objective of the Society to stimulate new knowledge about nicotine in all its manifestations.

The rate of nicotine metabolism is hypothesized to be a determinant of how much a person smokes. That is, rapid metabolizers would be expected to need more nicotine and, therefore, smoke more than slow metabolizers. Nicotine is metabolized extensively by the liver enzyme CYP2A6, primarily to cotinine. Cotinine is itself metabolized by CYP2A6 to 3'-hydroxycotinine (3-HC). The ratio of metabolite to parent (i.e., 3-HC:cotinine) would be expected to reflect CYP2A6 activity. We measured the ratio of 3-HC:cotinine in the urine of 72 smokers. This ratio was significantly correlated with the number of cigarettes smoked per day (r=.33, p=.005), though not with the Fagerström Test for Nicotine Dependence. This finding supports the hypothesis that the rate of nicotine metabolism is a determinant of the level of cigarette consumption and supports the use of the 3-HC:cotinine ratio as a noninvasive marker of nicotine metabolism.

Positive- and negative-reinforcement consequences of smoking were assessed using a self-report inventory. Data from 429 current smokers (348 women, 81 men) were subjected to an exploratory factor analysis, with concurrent validation of resulting scales in 288 current smokers (235 women, 53 men), controlling for sex and age. The solution with three factors--positive reinforcement, negative reinforcement, and smoking patterns--provided the clearest and most interpretable factor solution. The Michigan Nicotine Reinforcement Questionnaire (M-NRQ), which yields positive- and negative-reinforcement scales, was developed based on these results. Positive-reinforcement smoking was associated with higher scores on novelty seeking, reward dependence, alcohol dependence, and pleasurable sensations upon early smoking experimentation, and with lower scores on displeasurable sensations and nausea upon early smoking experimentation. Negative-reinforcement smoking was associated with higher scores for nicotine dependence, depression, anxiety, and harm avoidance. The M-NRQ has potential as a diagnostic tool for individualizing behavioral intervention and pharmacotherapy and also may be useful in identifying new phenotypes for genetic research on smoking.

Cigarette smokers are known to be overrepresented among adults with Attention Deficit Hyperactivity Disorder (ADHD). To date, however, no attempt has been made to determine the extent to which a lifetime diagnosis of ADHD may be associated with smoking even in the absence of current symptomatology. We hypothesized that nicotine dependence and abstinence effects-especially effects relevant to ADHD symptomatology-would be more pronounced in adult ADHD smokers in comparison with those who reported childhood ADHD symptoms only. Results indicated that, in contrast to controls without ADHD symptomatology, both adult and childhood ADHD groups were significantly more likely to experience a number of nicotine withdrawal symptoms, including irritability and difficulty concentrating; in no instance did the ADHD groups differ from one another in this regard. Thus, studying people with childhood symptoms of ADHD, even in the absence of an adult diagnosis, may shed light on the known association between smoking and ADHD.

To investigate attitudes about weight as they interact with smoking in African American women, we analyzed data from two independent samples of white and African American women smokers--one assembled via a national random-digit-dialing survey, the other consisting of candidates for enrollment in local studies. Findings for the two samples were remarkably consistent. African American women were significantly heavier and significantly more likely to have a self-reported BMI > or = 27. Although the preferred weight for African American women was significantly higher than for white women, the percentage by which they exceeded their preferred body weight did not differ significantly between groups, and the difference between actual and preferred weights was actually greater for African American women. African American women were more likely to be satisfied with their body shape and were significantly less likely to exercise to control weight. They did not differ significantly on binge-eating or dieting. African American women were more likely than white women to be unwilling to gain any weight upon quitting smoking but did not differ significantly on any other smoking-related weight concerns. Our results suggest that weight concerns, though differently conceptualized, may motivate African American women as powerfully as white women. They strongly suggest that race differences need to be considered in designing optimal smoking cessation interventions for weight-concerned women smokers. To accomplish this goal, efforts to identify a vocabulary for the expression of weight concerns in African American women will be needed, as will attention to ways to avoid exacerbating obesity and to encourage exercise.

The present study used logistic regression techniques to examine the extent to which depression, anxiety, disordered eating, and nicotine dependence increased risk of experiencing craving and the eight DSM-IV withdrawal symptoms (depressed mood, insomnia, irritability, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite) during smoking abstinence, assessed retrospectively. Data were provided by a racially diverse sample of 365 male and female smokers recruited to participate in laboratory studies. Results indicate that variables known to be associated with smoking are risk factors for distinct and only somewhat overlapping patterns of symptomatology. Smokers scoring high on measures of anxiety, depression, or disordered eating were at increased risk primarily of experiencing withdrawal symptomatology pathognomonic to their particular disorder, whereas smokers scoring high on nicotine dependence appeared to be at increased risk of experiencing a syndromal pattern of withdrawal, encompassing craving and insomnia as well as cognitive/affective symptoms. Our results support the possibility that some individuals use smoking as a form of self-medication and suggest that elucidation of patterns of withdrawal symptomatology may contribute to improved specification of smoking phenotypes as well as facilitate treatment-matching.

Although considerable progress has been made towards understanding the role of menstrual cycle phase in smoking, little is known about the possible effects of menstrual phase upon nicotine intake, withdrawal symptomatology, and craving in women with psychiatric cofactors. Fourteen women with and without a history of Major Depressive Disorder (MDD) were studied during five biologically-confirmed phases over the course of one menstrual cycle: smoking logs, salivary cotinine, and ratings of craving and withdrawal were collected daily. During a second cycle, subjects remained abstinent for 3 consecutive days during the postmenses and premenstrual phases. Although a significant omnibus F-test emerged for cigarettes per day across phases during ad libitum smoking, only trends were observed post hoc and supported midcycle rather than premenstrual elevations. There were no significant phase differences for cotinine. Withdrawal symptomatology was markedly elevated during smoking abstinence and in women with a history of depression. but showed no evidence of phase effects. Thus, the hypothesis that depressed individuals would be differentially affected by phase and abstinence was not strongly supported by our results, though overall elevations emphasize the need for special attention to withdrawal severity in this population. Craving was significantly elevated during smoking abstinence and was significantly higher during postmenses, consistent with the midcycle elevation in smoking rate, but showed no group differences. Our findings overall lend little support for the need to control for menstrual phase under conditions of ad libitum smoking. The strong association of self-reported menstrually related dysphoria during abstinence with both craving and withdrawal symptoms, however, is consistent with an exacerbation of smoking abstinence effects in women with severe menstrual symptomatology.

Although most studies of weight gain following smoking cessation assess long-term change, weight gain during the critical period immediately following cessation may be more salient to the smoker for whom fear of weight gain constitutes a serious barrier to cessation. The current study examined weight change in 20 highly dependent women smokers provided with monetary incentives to abstain for 1 week, along with concomitant changes in cotinine. Abstaining smokers (n = 7) gained 3.1 pounds, compared with 0.3 pounds in women who continued to smoke (n = 13). Across all subjects, change was significantly negatively correlated with final plasma cotinine concentration and marginally negatively correlated with percent cotinine reduction. Weight gain in women abstainers in the luteal phase of the menstrual cycle exceeded that in women abstainers in the follicular phase; a significant interaction such that continuing smokers showed no phase-related differences in weight suggests that the effect was not an artifact of perimenstrual increases in eating or fluid retention. Although long-term weight gain has been shown to be positively associated with success in quitting, little is known about the effects of short-term weight gain. Since many weight-concerned individuals either do not attempt to quit or terminate their quit attempts very early, it may be that if weight gain can be postponed beyond the first few fragile days of cessation, women with strong weight concerns may actually be good candidates for success.

The purpose of the present study was to investigate smoking abstinence effects and the dissipation of tolerance (reactivity to nicotine) under controlled laboratory conditions. Seventeen male and female regular smokers were tested first in a session following ad libitum smoking and then in an additional five sessions over the course of 11 days during which they abstained from smoking. A metered dose of nicotine was administered via intranasal spray to ensure standard exposure, and pre- and post-dosing measures of heart rate, blood pressure, cortisol, galvanic skin response (GSR), craving, and several DSM-IV withdrawal symptoms (anxiety, irritability, restlessness, difficulty concentrating, and appetite) were collected. Prior to the nicotine test dose during deprivation sessions, heart rate and systolic blood pressure evinced elements of both an 'offset abstinence pattern' (deflection in a direction opposite to that produced by smoking) and a 'transient abstinence pattern' (deflection followed by a subsequent return); for cortisol, an offset pattern was observed, whereas for GSR and craving, a transient pattern was found. With respect to loss of tolerance, heart rate reactivity was found to increase significantly after 2 days' abstinence from nicotine, and the increase was sustained in subsequent sessions. Cortisol reactivity revealed more gradual dissipation, with significant differences evident only after 9 days of abstinence. These findings extend research on nicotine abstinence effects and on the dissipation of tolerance to nicotine deprivation intervals of nearly 2 weeks and confirm prior observations of variability across different response systems.

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.

The possible impact of menstrual phase upon reactivity to nicotine was investigated in 12 healthy women smokers. Controlled doses of nicotine were administered via an intranasal aerosol delivery device to overnight-deprived women smokers in four hormonally verified menstrual phases. Physiological, biochemical, and subjective measures were collected. Cycle-related symptomatology differed significantly across phase, with lowest values during the mid-follicular phase. No significant differences were found for baseline variables, including withdrawal measures. Nicotine increment was stable across phase, confirming reliability of the dosing method. No significant menstrual phase differences were found for physiological, subjective, or biochemical responses to nicotine. Pending investigations conducted over longer intervals, in a wider variety of subjects, findings suggest that for this type of study, complex strategies to control for menstrual-cycle phase effects may be unnecessary.

In their Viewpoint “Genomic priorities and public health” (Special Section on Genomic Medicine, 24 Oct., p. [599][1]), K. R. Merikangas and N. Risch propose that diseases appearing to be “highly amenable to environmental modification” should take low priority in genomic research. Their

Cortisol can be used to indicate stress level as well as to monitor certain disease states. Although cortisol can be sampled from blood and urine, saliva sampling has decided advantages. Unfortunately, whole saliva contains a number of substances that can metabolize or bind with cortisol, potentially confounding analysis and quantitation. We introduce a semipermeable pouch that accumulates a contaminant-free salivary ultrafiltrate, thereby overcoming a number of the problems encountered with whole saliva. In three studies, we demonstrate accuracy and utility of the device for cortisol determination: (1) in an artificial medium, 60%–77% of the cortisol was recovered in the ultrafiltrate; (2) in vivo, ultrafiltrate cortisol correlated highly with whole-saliva cortisol collected under ideal conditions; and (3) ultrafiltrate cortisol evinced positive relationships with depression and cigarette use, consistent with studies in the literature. We conclude that this device and saliva-filtering technologies in general are useful in applications requiring quantitation of cortisol.

Recent evidence suggests that cigarette smoking has a heritability index around 53%. While related research on underlying mechanisms also supports the idea that genetic factors contribute to nicotine dependence--as well as to cofactors such as substance use and mood disorders--the nature of the behavioral traits and biological capacity for reinforcement that constitutes vulnerability to nicotine dependence is not well understood. The present review explores the problem of why some people become highly nicotine dependent, others develop a pattern of occasional use, and still others avoid the drug entirely despite extensive exposure and widespread experimentation with tobacco in the population. Recent research--both infrahuman and human--suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of tolerance is more rapid and self-administration more extensive in such individuals. Relevant findings from neuroscience and biobehavioral research are reviewed in order to identify variables and methodologies that might improve the reliability and validity of behavioral and molecular genetic studies on cigarette smoking. The integration of research in these areas may lead to new insights in the understanding of nicotine dependence as well as to improved techniques for prevention and treatment.

Hypothesizing the existence of a subgroup of female smokers for whom nicotine masks, and abstinence unmasks, a tendency toward hyperphagia and perhaps even subthreshold disordered eating, we compared female “weight-control smokers” (WC; n = 46) and “non-weight-control smokers” (NWC; n = 52) on smoking- and eating-related variables. We also examined the relationship between weight-control smoking and withdrawal symptomatology during 48hours of nicotine abstinence (n = 23). Although WC were not more depressed, anxious, or nicotine-dependent than NWC, they were significantly more likely to report weight gain and increased hunger during abstinence; they also scored higher on Cognitive Restraint and Disinhibition (Three-Factor Eating Questionnaire). The expected correlation of cotinine with weight emerged for NWC but not for WC. Weight-control smoking correlated with increased eating during abstinence. Our findings suggest that WC use dietary restraint as well as smoking to manage weight, and that abstinence may precipitate episodes of disinhibited or binge eating. If WC overinclude women vulnerable to excess or unpredictable eating and consequently to substantial weight gain that can be managed by nicotine, highly focused’treatment strategies may be helpful. The peculiar and fascinating combination of pharmacological and sociocultural factors involved in weight-control smoking has generated considerable research over the past few years. Despite these efforts, however, attempts to determine the net impact of weight-control smoking on treatment efficacy, both in terms of attracting such smokers to treatment and achieving sustained abstinence, have produced a somewhat confusing picture. In the current climate of interest in treatment matching, a question no less appropriate than that of whether weightcontrol smoking is likely to deter cessation efforts or promote relapse is that of whether treatment success rates for people motivated to smoke by nicotine’s anorectic properties can be improved upon; an answer to that question will

Nicotine intake, menstrual and smoking withdrawal symptomatology, and baseline cortisol and MHPG were assessed in nine women smokers under conditions of ad lib smoking and overnight abstinence in three menstrual phases (early follicular, mid-to-late follicular, and late luteal). A trend towards higher nicotine intake (p < 0.10) was observed in the mid-to-late follicular phase. Although menstrual symptomatology was not significantly elevated during the smoking abstinence condition overall, abstinence appeared to prevent the normal reduction in symptomatology during the mid-to-late follicular phase that occurred under conditions of ad lib smoking. Menstrual and withdrawal symptoms were highly correlated, and both were most pronounced during the late luteal/abstinence condition. The smoking-specific item "craving" reflected this pattern, though in attenuated form, suggesting that the observed exacerbation of withdrawal symptomatology was not simply due to generalized dysphoria, as queried in both instruments. MHPG was significantly elevated in the late luteal phase, whereas cortisol was significantly higher during ad lib smoking than during abstinence and tended to be highest in the mid-to-late follicular phase. Further investigation will be needed to determine the functional significance of these findings for understanding and treating smoking in women.

Two studies were conducted to replicate and extend previous demonstrations of smoking-induced, dose-related reports of euphoria, and to confirm this relationship using measures of plasma nicotine. In experiment 1, overnight-deprived subjects, in three different sessions, smoked ultralow-, high-nicotine, and usual-brand cigarettes. In experiment 2, ultralow-, medium-, and high-nicotine cigarettes were used, and plasma nicotine was measured. In both studies, subjects were asked to depress a button during euphoric sensations. Number of sensations for the ultralow-nicotine cigarette was significantly lower than for the high-nicotine cigarette in the first study, and than for both the medium- and high-nicotine conditions in the second; a significant linear trend was observed for number of sensations as a function of plasma nicotine level in the second study. For the high-nicotine cigarette, 19 of 22 subjects experienced at least one sensation (mean around three), starting around 2.5 min after lighting up. Together, these studies support the existence of a dose-response relationship for nicotine-induced euphoric sensations; suggest that they are more pronounced following overnight abstinence than following minimal deprivation, and in more dependent smokers; and characterize in detail the temporal features of these sensations.

The effects of nicotine, like those of other drugs with potential for abuse and dependence, are centrally mediated. The impact of nicotine on the central nervous system is neuroregulatory in nature, affecting biochemical and physiological functions in a manner that reinforces drug-taking behavior. Dose-dependent neurotransmitter and neuroendocrine effects occur as plasma nicotine levels rise when a cigarette is smoked. Circulating levels of norepinephrine and epinephrine increase, and the bioavailability of dopamine is altered as well. Among the neuroendocrine effects are release of arginine vasopressin, beta-endorphin, adrenocorticotropic hormone, and cortisol. Notably, several of these neurochemicals are psychoactive and/or known to modulate behavior. Thus, affective states or cognitive demands may be favorably modified (at least temporarily) by nicotine intake. When nicotine is inhaled, the neuroregulatory effects just described are immediately available and the reinforcing effects of the drug are maximized. On the other hand, nicotine gum and most other nicotine replacement vehicles in current use have a slower onset of action, resulting in less reinforcement value. Recent data suggest that smoking cessation rates may be optimized by tailoring the dose of nicotine replacement (for example, 2 or 5 mg of nicotine gum) to the individual degree of nicotine dependence. In view of the dynamic interactions between the neuroregulatory effects of nicotine and a host of environmental conditions, nicotine replacement therapy is best carried out in combination with behavior modification techniques.

The Tridimensional Personality Questionnaire (TPQ) was developed by Cloninger (1986) to measure heritable variation in three patterns of response to environmental stimuli: novelty seeking, harm avoidance, and reward dependence. Cloninger (1987) used the TPQ to identify two types of alcoholism: Type 1 (low novelty seeking, high harm avoidance and reward dependence; both male and female) and Type 2 (high novelty seeking, low harm avoidance and reward dependence; predominantly male). To determine whether characteristic patterns exist in smokers, we administered the TPQ to 119 female and 121 male smokers, along with the Fagerstrom Tolerance Questionnaire (FTQ, a measure of nicotine dependence), the Russell Motives for Smoking Questionnaire (RMSQ), and the Spielberger State-Trait Anxiety Inventory (STAI/trait). Compared with a normative sample, our sample exhibited elevated scores on the Novelty-Seeking scale; female smokers were somewhat overrepresented in the highest quartile of the Harm-Avoidance scale; both genders tended to be clustered in the lower quartiles of the Sentimentality-Attachment-Dependence subscale of the Reward-Dependence scale and in the highest quartile of the Persistence subscale. Female smokers showed a significant positive association between Harm Avoidance and FTQ scores, and Harm Avoidance was positively correlated with several RMSQ factors (including Additive smoking) in both genders. These findings suggest that the likelihood of becoming a smoker may be a function of novelty seeking and reward dependence, whereas degree of dependence or addiction once the habit is entrained may be linked to harm avoidance. Our observations establish the potential utility of the TPQ as a tool for examining environmental and heritable variation in smoking behavior and may contribute to improved strategies for prevention and treatment of smoking.

Careful, comprehensive, and empirical observations provide the building blocks of the sciences, whereas theory and mechanisms provide the "cement" to hold the blocks together and serve as blueprints to direct future building. This article resulted from several days of discussion regarding theories that may underlie the relation between cigarette smoking and body weight and the relation between smoking cessation and body weight. The working group composed of social and biological scientists who addressed this assignment considered what is already known within the smoking and body weight literature and also considered relevant findings from studies of smoking or body weight regulation that have not directly addressed the interaction of these variables. As expected, we were successful at listing some of what is not known and what is worth knowing. We also tried to identify fruitful possibilities for research activity that might clarify mechanisms of action and eventually lead to theoretical development. Because we do not believe that the present state of our deliberations merits the label of theories, we decided, instead, to report the summary of these deliberations as potential mechanisms relevant to the relation between smoking and body weight.

INTRODUCTION Male and female never-smokers stratified on parental history of smoking were tested for possible differences in susceptibility to the hedonic effects of nicotine. METHODS We recruited nicotine-exposed never-smokers with two never-smoking biological parents (PH-) or two ever-smoking biological parents (PH+). After completing a baseline assessment battery focusing on conditions or behaviors associated with smoking, participants were tested for subjective and hedonic effects in response to administration of three different nicotine doses (0.0, 0.5, and 1.0 mg) via nasal spray. Physiological and biochemical reactivity also was monitored. RESULTS PH+ were significantly more likely to report having experienced a "buzz" upon early smoking experimentation and to have histories of alcohol abuse and alcoholism; they also scored higher on disordered eating. In response to nicotine dosing, PH+ reported an increase in depressed mood, compared with a minimal response in PH-, in keeping with our expectation that nicotine would have more pronounced effects in PH+. Regardless of parental history, women reported experiencing greater anxiety in response to the highest nicotine dose, compared with men. DISCUSSION Further exploration in larger samples, using more stringent selection criteria, a wider range of measures, and a less aversive dosing method, may provide a full test of the possible utility of the parental history model for illuminating biobehavioral mechanisms underlying response to nicotine. Also important would be broadening the scope of inquiry to include comparisons with ever-smokers to determine what protected PH+ from becoming smokers, despite the presence of factors that might be expected to decrease resilience and increase susceptibility.

INTRODUCTION The present study expands previous research on early experiences with tobacco by using a Multiple Indicator Multiple Causes (MIMIC) model, which permits combining indicators tapping into pleasant experiences into one latent construct and those indicators of unpleasant experiences into another latent construct. METHODS A sample of 458 participants was recruited via newspaper advertisements. Response to early experimentation with cigarettes was assessed using the Early Smoking Experiences questionnaire, in which participants were asked the following question: "The first time you tried cigarettes, did you experience any of the following? (pleasurable and displeasurable sensations [overall], pleasurable rush or buzz, dizziness, relaxation, nausea, cough, difficulty inhaling)." These experiences were rated on a scale ranging from 1 = none to 4 = intense. RESULTS The MIMIC model revealed that current smoking status and age of initial experimentation with cigarettes were significantly associated with both early pleasant and unpleasant experiences (p < .05). African Americans were less likely than Whites to have early unpleasant experiences (p < .05). No association was found between race and early pleasant experiences. DISCUSSION Our findings are consistent with the inferences that pleasant experiences in response to early experimentation with smoking lead to regular smoking and that positive experiences play a stronger role than negative experiences in the transition to regular smoking. Our study also demonstrates that the MIMIC model is pertinent and practicable in nicotine and smoking research. We recommend it as a useful tool for identifying endophenotypes related to nicotine dependence and tobacco use latent constructs.

To investigate race differences in retrospectively-reported early smoking experiences, we studied African-American (n=48) and Caucasian (n=155) current smokers who participated in a study designed to identify phenotypic and genotypic factors associated with smoking. Compared with Caucasian smokers, African-American smokers were less educated (mean+/-s.e.m.: 13.3+/-0.25 vs. 14.3 +/- 0.16; p

Despite evidence that smoking behaviour increases in the context of stress, there has yet to be a clear-cut demonstration that nicotine intake is similarly enhanced. Although nicotine intake has been shown to reduce reported anxiety in the context of stress, the controlling conditions (type of stressor, intensity, temporal relationships, etc.) need further exploration. Recent findings involving nicotine's effects on the hypophyseal-adrenal axis provide a new perspective on these issues, in that increased nicotine intake during exposure to a stressor may represent, at least in part, behavioral compensation for diminished sensitivity to nicotine brought about by nicotine-stimulated corticosteroid release. Corticosteroids may decrease central nervous system excitability in a way that could account for anxiety reduction; on the other hand, anxiety reduction may be an epiphenomenon with respect to the reinforcement of smoking behaviour. The integration of behavioural, physiological, and biochemical research exemplified by the above approach should lead to a better understanding of stress and smoking.

Background Web-based programs for health promotion, disease prevention, and disease management often experience high rates of attrition. There are 3 questions which are particularly relevant to this issue. First, does engagement with program content predict long-term outcomes? Second, which users are most likely to drop out or disengage from the program? Third, do particular intervention strategies enhance engagement? Objective To determine: (1) whether engagement (defined by the number of Web sections opened) in a Web-based smoking cessation intervention predicts 6-month abstinence, (2) whether particular sociodemographic and psychographic groups are more likely to have lower engagement, and (3) whether particular components of a Web-based smoking cessation program influence engagement. Methods A randomized trial of 1866 smokers was used to examine the efficacy of 5 different treatment components of a Web-based smoking cessation intervention. The components were: high- versus low-personalized message source, high- versus low-tailored outcome expectation, efficacy expectation, and success story messages. Moreover, the timing of exposure to these sections was manipulated, with participants randomized to either a single unified Web program with all sections available at once, or sequential exposure to each section over a 5-week period of time. Participants from 2 large health plans enrolled to receive the online behavioral smoking cessation program and a free course of nicotine replacement therapy (patch). The program included: an introduction section, a section focusing on outcome expectations, 2 sections focusing on efficacy expectations, and a section with a narrative success story (5 sections altogether, each with multiple screens). Most of the analyses were conducted with a stratification of the 2 exposure types. Measures included: sociodemographic and psychosocial characteristics, Web sections opened, perceived message relevance, and smoking cessation 6-months following quit date. Results The total number of Web sections opened was related to subsequent smoking cessation. Participants who were younger, were male, or had less formal education were more likely to disengage from the Web-based cessation program, particularly when the program sections were delivered sequentially over time. More personalized source and high-depth tailored self-efficacy components were related to a greater number of Web sections opened. A path analysis model suggested that the impact of high-depth message tailoring on engagement in the sequentially delivered Web program was mediated by perceived message relevance. Conclusions Results of this study suggest that one of the mechanisms underlying the impact of Web-based smoking cessation interventions is engagement with the program. The source of the message, the degree of message tailoring, and the timing of exposure appear to influence Web-based program engagement.

Aims To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. Design, setting, participants Case–control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). Measurements Cases had smoked ≥ five cigarettes/day for ≥ 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. Findings A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). Conclusions We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence.

To shed light on the complex relationship between smoking and body weight, we used never-smokers stratified on family smoking history to model the effects of a diathesis for smoking on body weight without the potential confound of metabolic changes or decreased physical activity caused by chronic tobacco smoke exposure. Participants were 100 family history negative never-smokers (FH−; 2 never-smoking parents) and 71 family history positive never-smokers (FH+; 2 ever-smoking parents). Controlling for significant group differences in race and age, BMI was significantly higher in FH+ (26.7 ± .6) than in FH− (24.5 ± .4; F = 10.351 p < .01). Further analysis using logistic regression showed that FH+ were 2.7 times as likely to be overweight/obese (BMI ≥ 25; 95% C.I. 1.398–5.351; p < .01). FH+ scored significantly higher on the Dieting and Bingeing Severity Scale than FH− and were significantly more likely to score in the severe or at-risk range. FH+ drank significantly more alcohol than FH−; they scored significantly higher on the CAGE and on the Michigan Alcohol Screening Test. Our analyses provide support for the role of inherited and/or environmentally-driven tendencies towards disinhibited eating and/or risky behaviors in general in the observed differences in BMI. No group differences in BMI or likelihood of being overweight/obese emerged based on prenatal exposure to nicotine in FH+ smokers, although our sample was too small to rule out an association. Further research in larger samples, using more complex statistical models, will be needed to disentangle these issues and identify causal pathways.

Both smoking and psychological stress produce marked effects upon cardiovascular function, and several studies have demonstrated that in combination they produce additive or potentiating effects. More recently, it has been reported that individuals strongly reactive to psychological stress are also strongly reactive to nicotine. In an attempt to replicate and extend those findings, we examined reactivity to smoking and competitive mental arithmetic across several physiological and biochemical variables. Despite stable responding across mental arithmetic trials, we were unable to demonstrate significant correlations between reactivity to smoking and to a psychological stressor. We further observed that anxiety level, when low, was a poor predictor of desire to smoke and of withdrawal, whereas higher anxiety levels were more tightly linked to these measures. These findings have implications for the identification of individuals at risk of cardiovascular disease as well as for the design of smoking treatment and relapse prevention programs.

What does research on nicotine and tobacco use have to offer that is relevant and possibly useful to an alcohol researcher? First and foremost, nicotine and tobacco research may provide some helpful insights into addiction processes and substance use treatment in general. Smoking can be seen as a model disorder, not only because of its prevalence and its importance as a public health problem, but because the consistency of smoking behavior and the frequency of dosing (nicotine has a short addictive cycle) allow human experimentation in the laboratory without compromising relevance.' Recent technological developments in the topographical analysis of smoking behavior and in the assay of nicotine in biological substrates have facilitated both laboratory and field research, and comprehensive biobehavioral explanations of smoking/nicotine dependence have been proposed.^ Increasingly sophisticated public health campaigns have produced a dramatic decrease in smoking, with the level of smoking in the United States down from over 60% of the adult population in the early 196O's to fewer than 30% in the late 198O's. Over the same time period, therapeutic innovations have resulted in improved treatment strategies, with sustained abstinence rates of up to 50% reported for pharmacological interventions such as nicotine replacement in combination with behavior-change procedures.' The twentieth

Numerous observers have reported that smokers smoke more under stressful conditions. The most frequent explanation is that nicotine reduces anxiety, an intervening variable identified as a negative reinforcer for smoking behaviour. The conditions under which anxiety reduction occurs in response to smoking, however, have not been well defined, nor are underlying mechanisms well understood. There are several possible explanations, including Schachter's theory based on stress-induced changes in urinary pH and the hypothesis of endogenous opioid involvement. The work of Collins and his associates in animals has shown that genetic variations in corticosteroid responsiveness to nicotine are associated with differences in sensitivity to nicotine. Research in our laboratory has extended to humans Collins' findings that sensitivity to nicotine is inversely related to corticosteroid activity. We also found that the combination of a psychological stressor and smoking produced additive effects on cortisol release in humans. These findings suggest a novel way of explaining the interaction between smoking and stress, in that increased nicotine intake in the context of stress may in part reflect behavioural compensation for diminished sensitivity to nicotine when corticosteroid activity is enhanced by the stressor.

As part of the Genetic Epidemiology Network of Arteriopathy, hypertensive sibships were collected and smoking behavior recorded. Using an affected sibpair design and genome-wide microsatellite data markers ( approximately 10 cM coverage), we identified 214 non-Hispanic White sibships (502 sibpairs) from Rochester, Minnesota (M (age) [SD] = 55.68 years [10.56]) and 206 Black sibships (376 sibpairs) from Jackson, Mississippi (M (age) = 57.97 [8.94]), who had smoked for at least 3 years, and performed nonparametric linkage analysis using GENEHUNTER. We found evidence of linkage on chromosome 3 in both Whites (LOD = 1.76@109 cM) and Blacks (LOD = 2.03@122 cM). Each of these peaks had a secondary smaller peak at 140-147 cM that was statistically suggestive only in the Black sample (LOD = 1.4). The peak for the combined samples was suggestive of strong linkage (LOD = 3.24@124 cM). Additional suggestive peaks (LOD>1.3) were found in the White (chromosomes 8 [26 cM] and 19 [36 cM]) and Black sibships (chromosome 10 [153 cM]) but did not overlap with corresponding regions in the other ethnic group. This is the first study to identify a chromosomal region that has replicate evidence of linkage to smoking in two independent samples of similar size differing both geographically and ethnically. The gene for serotonin receptor 1F (HTR1F) is located in the region of the chromosome 3 linkage signal, representing at least one potential candidate gene. Fine mapping may well provide useful new information about genetic factors underlying nicotine dependence.

Smoking is often viewed as a comprehensive phenotype rather than a complex set of traits involving intermediate phenotypes. To explore this issue in a laboratory setting, we tested 69 smokers stratified on depression, nicotine dependence, and gender. On the third day of an initial withdrawal period, we tested for differences among participants in uncued and cued craving and withdrawal; on the fourth day, we exposed them to a controlled dose of smoke and assessed them for physiological and hedonic effects and reduction of craving and withdrawal. Following resumption of smoking for at least a week, we then tested participants on their ability to abstain for an 11-day interval. During the withdrawal test, high-depressed smokers and men exhibited elevated craving and withdrawal scores overall, whereas no differences emerged for dependence. Cue exposure produced significant increases in craving but not withdrawal. During the smoke-exposure test, men were significantly more likely than women, and high-depressed smokers more likely than low-depressed smokers, to show evidence of experiencing pleasurable "buzzes." High-dependent smokers showed significant increases in diastolic blood pressure, possibly suggestive of greater sensitivity to nicotine. During the quit test, high-dependent smokers had more difficulty abstaining than low-dependent smokers, and women more than men; no differences emerged based on depression. Independently of group membership, inability to abstain was predicted by increased anxiety, depression, and difficulty concentrating in response to cue exposure. These findings provide support for the existence of phenotypes that can be distinguished by withdrawal symptomatology (primarily driven by depression) and ability to remain abstinent (primarily driven by dependence).

We investigated whether 52 same-sex sibling pairs discordant for ever-smoking differed on psychiatric cofactors, alcohol and caffeine use, and responses to initial exposure to smoking. Ever-smokers scored significantly higher on measures of novelty seeking, depression, and childhood ADHD, and on alcohol dependence, alcohol intake, and caffeine intake. They reported significantly more pleasurable experiences, dizziness, "buzz," and relaxation upon initial exposure to smoking and significantly fewer displeasurable sensations, nausea, and cough than did nicotine-exposed, never-smoking siblings. Ever-smokers had significantly fewer years of education than their never-smoking siblings, suggesting that the concentration of smokers in lower socioeconomic strata may be partly due to downward mobility among smokers, possibly because of the observed elevation in psychiatric cofactors, which may interfere with academic performance. These findings are consistent with differences previously identified in unrelated ever- and never-smokers. Because same-sex siblings typically share a large set of common environments during childhood, our findings could be due either to genetic differences among siblings and/or (excepting educational level and responses to early exposure) to differences in adult environments.

To investigate the possible impact of treatment of alcohol dependence on smoking, we studied 144 smokers in an alcohol treatment center for whom 6-month data were available. Of those, 18 reported not smoking at 6 months. No significant differences in age, gender, or race were observed between quitters and continuing smokers. Quitters at 6 months were significantly more likely to be low dependent smokers than were continuing smokers and were significantly more likely to report no drinking during the past 28 days at the end of 1 month's treatment (93%) than continuing smokers (62%). These findings suggest that quitting smoking may be associated with low levels of nicotine dependence and favorable alcohol treatment response in alcoholic smokers.

Initial sensitivity to substances may affect patterns of future use and dependence. Because smoking and alcohol use are strongly linked, because animal studies indicate cross-sensitivity, and because genetic determinants of nicotine and alcohol dependence overlap, we studied the relationships between retrospectively reported responses to both substances in current smokers (n = 111) and never-smokers (n = 86). Early smoking experiences were correlated with comparable responses to alcohol in smokers, and to a lesser extent, in never-smokers. Both pleasurable early experiences with nicotine and pleasurable experiences with alcohol predicted current alcohol intake; pleasurable early experiences with alcohol also predicted alcohol dependence. Neither pleasurable nor displeasurable experiences with either substance predicted current amount smoked or degree of nicotine dependence. These preliminary findings may have implications for understanding the mechanisms underlying the smoking-alcohol link.