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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: J Addict Med. 2020 Sep-Oct;14(5):409–414. doi: 10.1097/ADM.0000000000000610

TIME TO FIRST CIGARETTE: A POTENTIAL CLINICAL SCREENING TOOL FOR NICOTINE DEPENDENCE

Steven A Branstetter 1, Joshua E Muscat 2, Melissa Mercincavage 3
PMCID: PMC7358112  NIHMSID: NIHMS1549017  PMID: 31972768

Abstract

Objectives

The time to first cigarette (TTFC) of the day has been identified as the best single-item indicator of nicotine dependence. However, TTFC has not been extensively used in clinical settings and is not a criteria for tobacco use disorder,, perhaps due to a lack of information about TTFC’s predictive value. This review provides a synthesis of the accumulating literature on TTFC’s relationships with nicotine dependence, identify gaps, and inform future clinical and epidemiologic research of potential uses of TTFC.

Methods

A systematic review of the literature was conducted using PubMed, Google Scholar, and Web of Science ISI databases. We identified sixteen articles examining the relation between TTFC and negative outcomes associated with high levels of nicotine addiction and Tobacco Use Disorders (e.g., high levels of nicotine and toxicant exposure, progressive use over time, failed cessation, head-and-neck cancers).

Results

Earlier TTFC was consistently associated with greater likelihood of cessation failure and relapse, and higher levels of biomarkers of tobacco exposure. Several of these associations were found among both adult and adolescent smokers, and remained even after accounting for smoking behaviors (e.g., cigarettes/day).

Conclusions

Earlier TTFC is a key indicator of greater nicotine dependence. Knowledge of a smoker’s TTFC may allow clinicians to accurately inform smokers of health risks and assign greater resources during cessation attempts. Smokers may be able to use TTFC to self-select cessation aids and accurately assess their unique smoking-related health risks. TTFC may be a better item than cigarettes/day for accurately quantifying dependence and risk in epidemiologic studies.

Keywords: Nicotine dependence, Tobacco use disorder, Time to first cigarette, Cigarette smoking, Nicotine screening tool

Introduction

Although rates of cigarette smoking in the US have declined considerably over the past 50 years, (Centers for Disease Control and Prevention, 2011a) smoking remains the leading cause of preventable death (Centers for Disease Control and Prevention, 2011b) and a significant public health concern. Physiological dependence on nicotine – the primary addictive ingredient in cigarettes (US Department of Health and Human Services, 1988) – is responsible for sustained cigarette use despite negative health consequences. Accordingly, identification of factors indicative of nicotine dependence and Tobacco Use Disorder may provide opportunities for intervention efforts seeking to further reduce smoking rates.

For several decades, the time to the first cigarette (TTFC) of the day has been a component of behavioral measures of nicotine dependence (Fagerström, 2003; Kozlowski, Director, & Harford, 1981). The single TTFC item, “How soon after you wake up do you smoke your first cigarette?” has been included in many similar nicotine dependence questionnaires (e.g., the modified adolescent Fagerström Tolerance Questionnaire [FTQ] (Prokhorov et al., 2000), Fagerström Test for Nicotine Dependence [FTND] (Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991), Heaviness of Smoking Index [HSI] (Heatherton, Kozlowski, Frecker, Rickert, & Robinson, 1989)). Depending on the questionnaire, participants’ responses to TTFC are categorized dichotomously (e.g., FTQ defines TTFC as within vs. after the first 30 minutes of waking) or categorically (e.g., FTND and HSI define TTFC as within 5, 6–30, 31–60, or >60 minutes of waking). In rarer instances, participants may provide open-ended responses in minutes which may be collapsed into the categories used by other scales.

The TTFC question was originally designed as a single-item measure of physical dependence on nicotine. Due to nicotine’s relatively short half-life (i.e., ~2 hours), the majority of the nicotine accumulated in the bloodstream from daily smoking is eliminated overnight during sleep. Consequently, most smokers awaken in a nicotine-deprived state (Kozlowski et al., 1981). Thus, theoretically the smokers most physiologically dependent on nicotine (i.e., those who experience nicotine withdrawal symptoms earliest after waking) should smoke their first cigarette of the day as soon as possible after waking (Heatherton et al., 1991). Indeed, early studies validating TTFC as a measure of nicotine dependence found that earlier TTFC was related to greater levels of biomarkers of cigarette exposure (Heatherton et al., 1991, 1989) as well as lower quit rates following participation in a cessation program (Kozlowski et al., 1981).

More recent studies on TTFC emerging over the past decade have found associations between TTFC and biomarkers of tobacco exposure, smoking tolerance, sleep disturbances, cessation success, relapse, and menthol cigarette use. Many of these associations have been found among both adult and adolescent populations, as well as among daily and non-daily smokers, demonstrating TTFC’s ability to predict nicotine dependence and health risks regardless of differences in smoking frequency. Additionally, several of these associations have remained even after controlling for number of cigarettes smoked per day (CPD), suggesting that the relation of TTFC with these outcomes is independent of smoking frequency.

Despite the accumulating evidence that TTFC is an important indicator of nicotine dependence, these findings have not been extensively applied to diagnosing tobacco addiction and treatment. (e.g. tobacco use disorder). Knowledge of a smokers’ TTFC prior to a cessation attempt may allow researchers and clinicians to identify those most at risk of cessation failure or relapse, and consequently assign treatment dose or additional aides for these smokers to promote cessation success (Shiffman et al., 2002; Shiffman, Sembower, Rohay, Gitchell, & Garvey, 2013). Additionally, TTFC may be utilized by clinicians as a screening tool to identify the degree of nicotine dependence. However, few have adapted these strategies. Similarly, because TTFC is predictive of biomarkers of exposure (e.g., cotinine) independent of the number of cigarettes smoked per day, this measure may serve as a better or additional indicator of use and dependence beyond self-reported than subjective experience with tobacco smoking.

The purpose of this narrative review is to summarize and synthesize the emerging evidence from studies evaluating TTFC as a predictor of nicotine dependence. We further aim to discuss the implications of these findings regarding TTFC’s utility in clinical and epidemiological research and describe directions for future such research.

Methods

A systematic review was conducted using PubMed, Web of Science ISI, and Google Scholar databases to identify relevant articles using the following search terms: “time to first cigarette”, “waking cigarette”, “morning cigarette”, “FTND”, “HSI”, “FTQ”, “Fagerstrom”, “first cigarette of the day,” “TTFC.” Although these search terms discovered well over 600 articles which examined relations of FTND or FTQ with outcomes of interest, these articles were not included in this review unless they explicitly addressed TTFC’s independent relation with these outcomes. Additional articles were found through using a ‘snowball’ approach of examining the references within included articles, as well as articles cited in those references. Using these methods, we identified sixteen articles which [directly] examined the relation between TTFC and outcomes associated with high levels of nicotine dependence and Tobacco Use Disorders, including higher levels of nicotine and toxicant exposure, progressive tobacco/nicotine use over time, failed smoking cessation, and smoking-related illness). All authors independently reviewed the articles identified through the search and agreed with their inclusion.

Results

Evidence for TTFC as an indicator of nicotine dependence

Relationship with cessation outcomes

Quit status

Kozlowski and colleagues (Kozlowski et al., 1981) conducted the first study examining the relation of TTFC with quit status among 56 adult smokers participating in a four-week cessation program. Participants’ self-reported smoking status was assessed at program end (i.e., two-weeks following the target quit date), and again at three- and six-month follow-ups. Participants who remained abstinent by the six-month follow-up (n = 12) had a later TTFC compared to those who had not quit or relapsed. Further, a stepwise discriminant function analysis demonstrated that TTFC was the best predictor of abstinence, even over CPD, presence of another smoker in participant’s household, and spouse’s reaction to participant’s smoking.

Kabat and Wynder (Kabat & Wynder, 1987) conducted a large case-control study exploring factors predictive of quit rates among 5,201 adult ex- and current smokers matched by hospitalization for tobacco-related and non-tobacco-related conditions. Researchers found that among both male and female ever-smokers, lifetime quit rates increased with self-reported later TTFC. Smokers reporting a TTFC within the first 15 minutes of waking reported the lowest quit rates while those reporting a TTFC after the first hour of waking reported the highest quit rates.

Few studies further examined the relation between TTFC and quit status until Baker and colleagues (Baker et al., 2007) presented data for four placebo-controlled clinical trials and one epidemiologic study examining TTFC’s ability to predict early (i.e., one week) and late (i.e., 6 or 12-month) cessation outcomes following a quit attempt. Data from three clinical trials conducted at the University of Wisconsin demonstrated that TTFC was the best predictor of 1-week and 6-month abstinence, over and above other factors such as cigarettes per day. Further, results from the two-wave epidemiologic study conducted at Roswell Park Cancer Institute found an inverse relationship between TTFC and quit success among smokers who had attempted to quit between waves 1 and 2: quit rates were lowest among individuals who reported smoking within 5 minutes of waking, while quit rates were highest among individuals reporting a TTFC >60 minutes (Baker et al., 2007).

Borland and colleagues (Borland, Yong, O’Connor, Hyland, & Thompson, 2010) evaluated TTFC as a predictor of quitting behaviors and how scoring of TTFC (i.e., categorical vs. transformed continuous) might affect its relationship with quit outcome. Using four waves of data from the International Tobacco Control (ITC) study, researchers compared associations between TTFC at one wave and self-report of a quit attempt of at least 24 hours by the next wave. Among those who had made an attempt, researchers also examined the association of TTFC with maintaining quit status for one month. Both categorical and continuous scorings of TTFC were independently predictive of making a quit attempt and maintaining quit status, with earlier TTFC related to decreased likelihood of making and sustaining a quit attempt. Researchers concluded that regardless of scoring approach, there was a robust association between TTFC and cessation outcomes.

Similarly, a study by Li and colleagues (Li et al., 2011) used data from two waves of the ITC China study to identify prospective predictors of quitting behaviors among smokers. During the first wave, researchers conducted face-to-face interviews with 4,732 smokers. 81.6% of the 4,732 smokers participating in face-to-face interviews of the first wave completed interviews during the second wave 16 months later. Of these individuals, 25.6% reported making a quit attempt between the two waves. Researchers found that a later TTFC was an independent predictor of making a quit attempt between the first and second waves, but that TTFC was not related to maintaining abstinence.

Only one study to date has examined TTFC’s relationship with cessation outcomes in adolescent smokers. Mercincavage and colleagues (Mercincavage, Branstetter, Muscat, & Horn, 2013) found that among 1,167 adolescents participating in a school-based cessation program, those who reported a TTFC after (vs. within) 30 minutes of waking were twice as likely to report being quit at the end of the program. The relation between adolescent TTFC and quit status remained even after accounting for factors such as number of cigarettes smoked per day at baseline, age, gender, treatment condition, and quitting motivation and confidence.

In summary, all five studies examining the relation of TTFC with cessation outcomes found that earlier TTFC was associated with decreased likelihood of making a quit attempt. Only one study (Li et al., 2011) found no association of TTFC with maintaining quit status after making an initial quit attempt.

Relapse

To date, two studies have examined the relation between TTFC and relapse following a cessation attempt. In the first of these studies, Baker and colleagues (Baker et al., 2007) examined the association of TTFC with relapse following participation in a cessation trial. TTFC was a significant predictor of both lapse latency (i.e., the time between quit day and first cigarette smoked even if this cigarette did not lead to a resumption of smoking) and lapse-relapse latency (i.e., the time between quit day and ultimate relapse). In general, there was a linear relationship between relapse and TTFC categories, such that the earlier relapses were associated with earlier TTFC categories.

A second study by Sweitzer and colleagues (Sweitzer, Denlinger, & Donny, 2012) examined the relation between TTFC and relapse among non-treatment seeking daily smokers participating in a 1-week, novel incentive-based model of relapse. In this study, 56 participants were asked to make a short-term quit attempt and were initially paid a high incentive to encourage abstinence. The incentive amount decreased progressively with each day of sustained abstinence in order to simulate individual differences in relapse following a cessation attempt. TTFC was a significant predictor of time to first lapse, such that a TTFC within 30 minutes of waking was associated with greater likelihood of lapse, even after controlling for number of cigarettes smoked per day and craving during abstinence.

In summary, earlier TTFC was a significant predictor of sooner relapse both following a cessation attempt and in a laboratory-simulated model of relapse.

Relationship with biomarkers of cigarette exposure

Cotinine

A large body of extant literature has documented the relationship of TTFC with cotinine, the primary metabolite of nicotine, as this was originally used as a way of determining TTFC’s validity as a measure of physiological dependence on nicotine. Early studies (Heatherton et al., 1991, 1989) interested in determining the best classification of TTFC responses (e.g., categorical scoring of the FTND and HSI vs. dichotomous scoring of the FTQ) found that regardless of TTFC response classification, TTFC was predictive of salivary and plasma cotinine levels. In three independent samples of smokers, Heatherton and colleagues (Heatherton et al., 1989) found that salivary and plasma cotinine levels increased as TTFC decreased, with categorical scoring of TTFC explaining slightly more variance in cotinine levels (vs. dichotomous scoring of TTFC). Similarly, the same investigators (Heatherton et al., 1991) found that when using the dichotomous FTQ scoring, cotinine levels were highest among smokers reporting a TTFC ≤30 minutes (vs. >30 minutes) of waking. When using the categorical HSI/FTND scoring, cotinine levels were highest among smokers reporting a TTFC within 5 minutes of waking, and decreased with each later category of TTFC, although cotinine levels were not significantly different between those with a TTFC of 31–60 minutes vs. 61+ minutes.

More recent studies (Figueiredo et al., 2007; Fu, Fernández, et al., 2011; Fu, Martinez-Sanchez, et al., 2011; Muhammad-Kah, Hayden, Liang, Frost-Pineda, & Sarkar, 2011; Muscat, Chen, et al., 2009; Muscat, Liu, Stellman, & Richie, 2012; Muscat, Stellman, Caraballo, & Richie, 2009) have examined TTFC’s ability to predict cotinine among various populations, using different cotinine collection techniques and scoring methods for TTFC, in the absence of and after controlling for confounding variables. For example, in contrast to the typical dichotomous scoring of TTFC as either within or after 30 minutes of waking, a study by Figueiredo and colleagues (Figueiredo et al., 2007) examined the relationship of TTFC with cotinine using dichotomies of “within 5 minutes of waking” and “after 5 minutes of waking.” Despite this difference in scoring, smokers who reported a TTFC within 5 minutes of waking had significantly higher levels of cotinine than those who reported a TTFC >5 minutes of waking. Regardless of how these studies categorized TTFC, which smoking history variables or other confounds were controlled for in analyses (e.g., Fu and colleagues (Fu, Martinez-Sanchez, et al., 2011) controlled for gender and cigarettes smoked in past 24 hours, while Muscat and colleagues (Muscat, Stellman, et al., 2009) controlled for cigarettes per day), or the collection method of cotinine (e.g., saliva, plasma, urine), all of these studies have found that earlier categories of TTFC correspond to the greatest levels of cotinine. More detail on the specific outcomes of these studies is available in Table 1.

Table 1:

Summary of studies providing evidence for TTFC as an indicator of nicotine dependence.

Author(s) & Year Sample Size(s) Nicotine Dependence Outcome Main Finding
Baker et al. (2007) Multiple Studies Quit status, rate of relapse TTFC significant predictor of early and late abstinence outcomes, latency to first lapse following a cessation attempt, and “lapse-relapse interval”; associations across studies were fairly dose-dependent
Borland et al. (2010) 4,974 – 6,116 Quit status, quit attempts TTFC independent predictor of making quit attempt and maintaining quit status; earlier TTFC related to decreased likelihood of making and sustaining a quit attempt
Branstetter & Muscat (2013b) 220 Serum cotinine Adolescents’ TTFC dose-dependently predictive of serum cotinine levels, even after controlling for CPD, having a family member who smokes, and time since last cigarette smoked; adolescents reporting TTFC ≤5 min had greatest serum cotinine levels
Figueiredo et al. (2007) 401 Salivary cotinine Smokers reporting TTFC ≤5 min had higher salivary cotinine levels than those with TTFC >5 min
Fu et al. (2011a) 278 Salivary cotinine Inverse association between salivary cotinine and TTFC categories
Fu et al. (2011b) 210 Salivary cotinine Inverse association between salivary cotinine levels and TTFC categories even when adjusting for gender and 24-hr cigarette consumption
Heatherton et al. (1989) 30–736 Serum nicotine & cotinine, CO Nicotine, cotinine, and CO all increased with earlier TTFC although differences were not significant between 31–60 and 61+ TTFC groups
Heatherton et al. (1991) 254 Salivary cotinine, CO For the FTQ, ≤30 min TTFC had greater CO and cotinine than >30 min; For HSI, shorter TTFC associated with greater CO and cotinine, except not significant between 31–60 and 61+ TTFC groups
Kabat & Wynder (1987) 5,264 Quit status Among ever-smokers, lifetime quit rates increased as TTFC increased; lowest quit rates found among TTFC ≤15 min
Kozlowski et al. (1981) 56 Quit status Smokers abstinent at 6 mo. follow-up had later TTFC than those who had not quit or relapsed. TTFC was best predictor of abstinence, even over CPD and other confounds
Li et al. (2010)* 3,863 Quit attempts Later TTFC predictive of making a quit attempt, but TTFC was not related to maintaining abstinence
Mercincavage et al. (2013) 1,167 Quit status Adolescents with TTFC >30 min twice as likely to report being quit at cessation program follow-up even after accounting for baseline CPD, age, gender, treatment condition, quitting motivation, and quitting confidence
Muhummad-Kah et al. (2011) 3,585 CO, COHb, serum cotinine TTFC a significant predictor of COHb independent of CPD; no specific breakdown by TTFC categories
Muscat et al. (2009a) 252 Plasma and urinary cotinine Even after adjusting for CPD, shorter TTFC associated with greater cotinine levels though not significant between 31–60 and 61+min TTFC groups
Prokhorov et al. (2000) 131 Salivary cotinine TTFC inversely related to adolescent salivary cotinine: adolescents with TTFC ≤30 min had greatest cotinine levels, followed by TTFC between 30 min and noon, and lowest levels in those reporting TTFC in afternoon or evening
Sweitzer et al. (2012) 56 Rate of relapse TTFC predictor of time to first lapse: TTFC ≤30 min associated with greater likelihood of lapse, even controlling for CPD and craving
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Although the majority of the previously mentioned studies have examined the relation between TTFC and cotinine among adult smokers, two studies have evaluated these associations among adolescent populations. Prokhorov et al. (Prokhorov et al., 2000) modified the FTQ for use with adolescent smokers (i.e., mFTQ) by classifying TTFC into three categories: “within the first 30 minutes of waking”, “between 30 minutes of waking and noon”, and “after noon.” Using these categories, adolescent TTFC was significantly inversely correlated with salivary cotinine levels, with the greatest concentrations in those reporting smoking within the first 30 minutes of waking, followed by those who smoked between 30 minutes of waking and noon, and the lowest salivary cotinine concentrations in those who reported a TTFC in the afternoon or evening.

A more recent study by Branstetter and Muscat (Branstetter & Muscat, 2013) used nationally representative data from the 2007–2008 and 2009–2010 National Health and Nutrition Examination Survey to examine the association of TTFC with adolescent serum cotinine levels. Similar to studies of salivary cotinine, adolescents’ TTFC was a significant predictor of serum cotinine levels. Adolescents who reported smoking within the first five minutes of waking had the greatest serum cotinine levels, followed by decreases in cotinine levels with each increasing classification of TTFC. This dose-dependent relationship persisted even after controlling for number of cigarettes smoked per day, having a family member who smokes, and time since last cigarette smoked.

In summary, TTFC is a robust predictor of cotinine among adolescent and adult smokers, independent of sampling (e.g., urine vs saliva vs. blood) and categorization method, as well as other covariates like cigarettes per day. Studies which evaluated the direction of this relationship generally found that earlier TTFC categories were associated with the highest cotinine levels, while later categories were associated with lower cotinine levels.

In addition to validating TTFC as a measure of tobacco exposure through its association with cotinine, several studies (Heatherton et al., 1991, 1989; Muhammad-Kah et al., 2011) also examined the relation between TTFC and carbon monoxide (CO) and carboxyhemoglobin (COHb).

Discussion

Implications

This review sought to gather and synthesize the body of literature characterizing TTFC as an indicator of nicotine dependence. Of the sixteen articles examining the relation between TTFC and these outcomes, all found that an earlier TTFC was related to several indices of greater severity of nicotine dependence, such as greater difficulty quitting smoking cigarettes and maintaining abstinence, and greater levels of cotinine, carbon monoxide, and carboxyhemoglobin.

In studies of cessation outcomes, earlier TTFC predicted greater likelihood of relapse and inability to quit, irrespective of TTFC scoring method (e.g., dichotomous or categorical). The relationship of TTFC with cessation outcomes was found in both adult and teen smoking populations, and in many studies remained even after controlling for other factors such as smoking frequently. The convergence of results across all studies examining the relationship of TTFC with cessation outcomes suggests that earlier TTFC is a robust indicator of more severe nicotine dependence.

Clinicians and researchers may consider assessing smokers’ TTFC prior to a cessation attempt in order to assign additional resources (e.g., greater dosage of nicotine replacement therapy, combined behavior and pharmacotherapy treatment) to smokers with an earlier TTFC to increase chance of success. Clinicians currently define nicotine dependence according to extensive criteria in defined in the Diagnostic and Statistical Manual (e.g. Tobacco use disorder). However, this approach is limited in that smokers are diagnosed as either dependent or not dependent, and thus who do not meet enough criteria to qualify as “dependent” may be miscategorized. TUD may consequently not assign misclassified individuals to appropriate resources during cessation attempts. Given TTFC’s strong associations with cessation outcomes, use of this item to screen for or diagnose dependence may be more appropriate and useful prior to a cessation attempt. Few studies have compared TTFC and Tobacco Use Disorders in the same patients. One study, however, found little correlation of Tobacco Use Disorder with TTFC (Hughes et al., 2004). Moreover, given these results, researchers may consider balancing intervention groups by TTFC to ensure equal numbers of early vs. later morning smokers in each group or results such include measures of TTFC as a covariate for analyses.

Conclusions

Nearly all studies examining TTFC’s association with biomarkers of cigarette exposure found that regardless of the biomarker used (e.g., cotinine, carboxyhemoglobin, carbon monoxide), exposure levels were inversely associated with TTFC. The consistency of these results affirms that TTFC is a behavioral indicator of tobacco exposure. In situations where it is not feasible to assess tobacco use through biomarkers, it may be sufficient to instead assess smokers’ TTFC. Given that adolescents and young adults typically smoke with less regularity and frequency than adult smokers, the results of adolescent studies (Branstetter & Muscat, 2013; Prokhorov et al., 2000) assessing TTFC’s relationship with tobacco exposure taken together with findings of adult studies highlight the ability of TTFC to predict levels of tobacco exposure independent of cigarette smoking frequency. These findings suggest that TTFC may capture smoking intensity (e.g., how deeply a smoker inhales when smoking) although to date studies have not examined TTFC with measures of smoking topography.

Research is needed to elucidate the mechanisms by which TTFC is related to nicotine dependence. It has been suggested that individuals who delay smoking the first cigarette of the day may be more sensitive to the subjective effects of smoking (e.g., feeling buzzed, nauseous) earlier in the morning. Studies (Pillitteri, Kozlowski, Sweeney, & Heatherton, 1997) examining individual differences in subjective responses to smoking the first cigarette of the day found that participants who smoked more cigarettes per day or who had smoked for a greater number of years were less sensitive to, yet reported greater liking of, these subjective effects. Another study (Toll, Schepis, O’Malley, McKee, & Krishnan-Sarin, 2007) evaluated the mechanisms responsible for TTFC’s ability to predict relapse following a cessation attempt by examining how craving reduction, withdrawal relief, and changes in affect resulting from smoking the first cigarette of the day were related to relapse rates following immediate treatment with bupropion and at a 3-month follow-up. Smokers who experienced greater craving reduction after smoking the first cigarette of the day were more likely to relapse both by the end of treatment and at the 3-month follow-up. Although these studies did not specifically examine the relation of these outcomes with the length of time to the first cigarette of the day, results suggest that reduced sensitivity to and greater subjective reactivity after overnight abstinence may be a potential mechanism for why some smokers may be able to tolerate an earlier TTFC than those who delay smoking the first cigarette of the day.

Given that an earlier TTFC has been associated with higher scores on measures of automaticity, (Baker et al., 2007) it has been hypothesized that individuals with an earlier TTFC may engage in patterns of heavy, uninterrupted smoking patterns. If true, this pattern of heavy smoking might explain why studies have found higher concentrations of biomarkers of nicotine and tobacco exposure among smokers with an earlier TTFC. However, the only study(Grainge, Shahab, Hammond, O’Connor, & McNeill, 2009) to date that has examined the relationship of TTFC with smoking behaviors throughout the day instead found that individuals with an earlier TTFC smoked their first cigarette of the day less intensively than the cigarettes smoked subsequently throughout the day. As such, there is a great need to further explore the relationship of TTFC with measures of smoking topography.

The genetic contribution to nicotine dependence remains incompletely understood and remains an avenue of further research. In particular the role of genetic variability in explaining differences in TTFC has not been explored. One study found that the CYP2A6-driven nicotine metabolite ratio did not predict TTFC in adolescent smokers (Berlin, Gasior, & Moolchan, 2007).

Finally, longitudinal studies are needed to examine the relation of TTFC with smoking trajectory. The data presented throughout this review indicate that TTFC demonstrates similar relations with negative outcomes associated with nicotine dependence and Tobacco Use Disorders among both adolescent and adult smokers. Thus, it is possible that TTFC may be a unifying or common factor throughout the various developmental stages of nicotine dependence. Longitudinal studies of adolescent smokers transitioning to smoking during adulthood would help to determine if TTFC is a stable predictor of dependence throughout the lifespan, or if its relationships with these outcomes change as smokers transition from experimentation with cigarettes to later dependence. These types of studies may be more challenging than those conducted in adult populations. Adolescents are increasingly using multiple tobacco products. While the relationship between TTFC and cigarette use has been well characterized, it is unknown if TTFC predict the same outcomes in young users of other nicotine-containing tobacco products such as little cigars, hookah and electronic cigarettes or in dual and poly-use of these substances.

Acknowledgements

This work was supported by the National Institute on Drug Abuse, National Institutes of Health (R01 DA026815), and National Institutes on Minority Health and Health Disparities, National Institutes of Health (R01 MD013338).

This work was supported by the National Institutes of Health (P50 DA036107, R01 DA026815, and R01 MD013338).

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