Society for Research on Nicotine and Tobacco as an Outgrowth of the 1988 Surgeon General's Report on Nicotine Addiction: Reflections of the Early Presidents.

INTRODUCTION: The Society for Research on Nicotine and Tobacco began in the United States as a scientific organization "to stimulate the generation and dissemination of new knowledge concerning nicotine and tobacco in all its manifestations." Now in its 30th year, the Society is taking on new challenges in tobacco control, nicotine vaping, product regulation, and public policy. AIMS AND METHODS: This Review describes the formative years of the Society from the perspective of researchers who were in leadership positions during that time, documenting how biobehavioral and clinical research in the first 10 years was a continuation of the scientific mission of the 1988 United States Surgeon General's Report on Nicotine Addiction and summarizing organizational innovations during each president's term of office. CONCLUSIONS: The Society's promotion of scientific research served as a catalyst for funding, policy, and regulation, setting the stage for its influence and credibility. IMPLICATIONS: This Commentary provides context and an overview of the scientific research and the organizational innovations that occurred during the early years of the Society for Research on Nicotine and Tobacco using publications and available documentation. The Society was able to thrive because biobehavioral research on nicotine addiction provided the scientific underpinnings for the tobacco control enterprise as a whole. The objective of this Commentary is to describe formative events in the Society's history based on the accomplishments of its early leaders.

Balancing Consideration of the Risks and Benefits of E-Cigarettes.

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.

Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations.

The direct physiological effects that promote nicotine dependence (ND) are mediated by nicotinic acetylcholine receptors (nAChRs). In line with the genetic and pharmacological basis of addiction, many previous studies have revealed significant associations between variants in the nAChR subunit genes and various measures of ND in different ethnic samples. In this study, we first examined the association of variants in nAChR subunits α2 (CHRNA2) and α6 (CHRNA6) genes on chromosome 8 with ND using a family sample consisting of 1,730 European Americans (EAs) from 495 families and 1,892 African Americans (AAs) from 424 families (defined as the discovery family sample). ND was assessed by two standard quantitative measures: smoking quantity (SQ) and the Fagerström Test for ND (FTND). We found nominal associations for all seven tested SNPs of the genes with at least one ND measure in the EA sample and for two SNPs in CHRNA2 in the AA sample. Of these, associations of SNPs rs3735757 with FTND (P = 0.0068) and rs2472553 with both ND measures (with a P value of 0.0043 and 0.00086 for SQ and FTND, respectively) continued to be significant in the EA sample even after correction for multiple tests. Further, we found several haplotypes that were significantly associated with ND in the EA sample in CHRNA6 and in the both EA and AA samples in CHRNA2. To confirm the associations of the two genes with ND, we conducted a replication study with an independent case-control sample from the SAGE study, which showed a significant association of the two genes with ND, although the significantly associated SNPs were not always the same in the two samples. Together, these findings indicate that both CHRNA2 and CHRNA6 play a significant role in the etiology of ND in AA and EA smokers. Further replication in additional independent samples is warranted.

Substance use, trait measures, and subjective response to nicotine in never-smokers stratified on parental smoking history and sex.

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.

Using MIMIC models to examine the relationship between current smoking and early smoking experiences.

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.

Race differences in factors relating to smoking initiation.

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<.01), had higher BMI (28.9+/-1.06 vs. 26.7+/-0.52; p<.05), and smoked significantly fewer cigarettes/day (14.1+/-1.00 vs. 18.4+/-0.74; p<.01). Ninety percent of African-American smokers consumed menthol cigarettes, as opposed to 25% of Caucasian smokers. African-American smokers were significantly older than Caucasian smokers upon initial smoking experimentation (17.4+/-1.1 vs. 14.7+/-0.3; p<.05) and onset of regular smoking (19.7+/-0.9 vs. 17.4+/-0.4; p<.05). African-American smokers were significantly more likely than Caucasian smokers to endorse global pleasurable sensations (48% vs. 30%; p<.05), "pleasurable rush or buzz" (62% vs. 43%; p<.05), and "relaxing" (45% vs. 27%; p<.05) as early experiences with smoking, whereas Caucasian smokers were marginally more likely to report dizziness and difficulty inhaling (61% vs. 45%; p<.10 and 48% vs. 31%; p<.10, respectively). Caucasian smokers were significantly more likely to endorse friends (6.9+/-0.2 vs. 4.8+/-0.4; p<.0001) and "perk me up" (4.2+/-0.3 vs. 3.1+/-0.4; p<.05) and marginally more likely to endorse buzz (4.2+/-0.2 vs. 3.4+/-0.5; p<.10) as reasons for starting to smoke. Further research is needed to determine the relative contributions of genetic, developmental, and socio-cultural factors to these findings.

Never-smokers with a positive family smoking history are more likely to be overweight or obese than never-smokers with a negative family smoking history.

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 > or = 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.

Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with 'pleasurable buzz' during early experimentation with smoking.

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 > or = five cigarettes/day for > or = 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.

Association of withdrawal features with nicotine dependence as measured by the Fagerström Test for Nicotine Dependence (FTND).

The aim of this study was 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<4) and 2) high dependence (HD; FTND> or =4). A sample of 241 smokers was recruited via newspaper ads and public notices. Using a multivariate response model with adjustments for age, sex, age at first cigarette, race, and current or lifetime depression, we observed a small to modest statistically robust association between nicotine dependence level and withdrawal features such as, irritation/anger (adjusted relative risk, aRR=1.2; 95% CI 1.0, 1.3); nervousness (aRR=1.3; 95% CI 1.1, 1.6); restlessness (aRR=1.2; 95% CI 1.1, 1.4); difficulty concentrating (aRR=1.3; 95% CI 1.1, 1.7); and trouble sleeping (aRR=1.8; 95% CI 1.2, 2.6). Our findings are consistent with the inference that the FTND measures "physiological dependence" and that multidimensional approaches are needed to capture the full range of smoking phenotypology.

Web-based smoking-cessation programs: results of a randomized trial.

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.

Genome-wide linkage analysis for smoking-related regions, with replication in two ethnically diverse populations.

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.

Genetic research on complex behaviors: an examination of attempts to identify genes for smoking.

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.

Novel genes identified in a high-density genome wide association study for nicotine dependence.

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.

Differences in smoking-related variables based on phenylthiocarbamide "taster" status.

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.

Unaided smoking cessation among smokers in treatment for alcohol dependence.

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.

Nicotine dependence, depression, and gender: characterizing phenotypes based on withdrawal discomfort, response to smoking, and ability to abstain.

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).

Differences in accuracy of offspring assessment based on parental smoking status.

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.