Studies on clinical features of nicotine dependence in comparison with those of alcohol and methamphetamine dependence using a two compartment model of drug dependence]

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol and methamphetamine dependence, using a two compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of six scoring items: subjective effects, tolerance, drug liking, social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (n = 68), alcohol (n = 62), or methamphetamine (n = 55). All subjects met DSM-IV diagnostic criteria for drug dependence. Nicotine produced a mild degree of drug liking and psychic withdrawal symptoms, but did not cause significant physical withdrawal symptoms, acute psychic or physical disorders or social disturbance. Alcohol and methamphetamine produced a moderate degree of drug liking and significant levels of withdrawal syndrome, acute disorders and social disturbance. Thus, in the present study, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".     

Genomewide linkage survey of nicotine dependence phenotypes

Background

A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses.

Methods

We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped in all subjects. The phenotypes analyzed were the Fagerström Test for Nicotine Dependence (FTND), a history of nicotine dependence, the number of symptoms of alcohol dependence (AlcSx), and a history of alcohol dependence. Genomewide linkage analyses were conducted with non-parametric and variance components methods.

Findings

For the bivariate variance component analysis of the continuous FTND and AlcSx scores, multipoint LOD scores were >4 in two genomic regions—an 11 cM region on chr7 (D7S2252–D7S691, empirical p = 0.0006) and an 8 cM region on chr18 flanking D18S63 (empirical p = 0.0007). These findings did not exceed a conservative estimate of study-wide significance. The remaining sets of findings had considerably smaller or less consistent peak signals. Notably, strong linkage signal at D4S1611 for AlcSx from a prior report (PMID 16534506) was not found when jointly analyzed with FTND.

Interpretation

Replication is required. However, chromosomes 7 and 18 may contain genetic loci relevant to the etiology of nicotine-related phenotypes.     

Heavy nicotine and alcohol use in alcohol dependence is associated with D2 dopamine receptor (DRD2) polymorphism

Cigarette smoking in those who are alcohol dependent is associated with higher morbidity and mortality. The A1 allele of the D2 dopamine receptor (DRD2) gene has been independently associated with alcohol and nicotine dependence. Whether this polymorphism is associated with nicotine dependence in those who are also alcohol dependent has not been investigated. Subjects were 84 (61 males; 23 females) Caucasian DSM IV diagnosed nicotine- and alcohol-dependent subjects sampled from consecutive admissions to a hospital alcohol detoxification ward. Data were obtained through standardised measures of nicotine and alcohol consumption and dependence severity. A1+ allelic (A1/A1 or A1/A2 genotype) compared to A1- allelic (A2/A2 genotype only) patients were characterised by higher levels of alcohol and cigarette consumption. A1+ allelic patients reported greater alcohol dependence severity, but not nicotine dependence severity. When the combined nicotine and alcohol dose was examined, A1+ allelic patients consumed significantly more of these drugs than their A1- allelic counterparts.     

Studies on clinical characteristics of nicotine dependence using a two compartment model of drug dependence]

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical characteristics of nicotine dependence with those associated with other drugs of abuse, using a two-compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of five scoring items: subjective effects, drug liking, withdrawal syndrome, acute psychic and acute physical disorders, and social disturbance. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (cigarette smoking) (n = 114), alcohol (n = 101), methamphetamine (n = 90), inhalants (n = 63), and benzodiazepines (n = 39). All subjects met the DSM-IV-TR criteria for drug dependence. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. The other four drugs produced more intensive degrees of withdrawal syndrome and acute psychic and physical symptoms, with more significant social disturbance than nicotine. The present study indicated that nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".     

Neuropsychological correlates of opioid dependence and withdrawal

Severity of opioid dependence, and performance on two successive runs of the Wisconsin Card Sorting Test (WCST), were assessed in 39 right-handed male and female methadone patients who had been randomly assigned to either a recently dosed (n=21) or 24 hr abstinent (n=18) condition. Results indicated that severity of opioid dependence was positively correlated with perseverative responses and errors on the second run of the WCST, p<.05. Further, controlling for the effect of dependence severity, patients in early methadone withdrawal made selectively more perseverative responses and errors than did recently dosed patients, p<.05, with no difference on nonperseverative errors. Findings were consistent with the hypothesis that opioid dependence, like alcoholism and cocaine addiction, is associated with disruption of executive cognitive functions mediated by the prefrontal cortex.     

High-dose nicotine patch therapy for smokers with a history of alcohol dependence: 36-week outcomes

This study reports findings from an investigation of the efficacy of high-dose nicotine patch (NP) therapy for heavy smokers with a history of alcohol dependence. One hundred thirty participants were randomly assigned to 42 or 21 mg of transdermal nicotine. Follow-up assessments were conducted at 4, 12, 24, and 36 weeks. Differences between dose conditions were nonsignificant, although, unexpectedly, outcomes favored participants in the 21-mg NP condition. Nicotine abstinence rates in the 21- and 42-mg NP conditions on Week 36 follow-up were 16.9% and 9.2%, respectively. Patch condition did not interact with severity of nicotine dependence. However, nicotine abstinence at follow-up was related to a longer length of alcohol abstinence. No evidence was found for better outcomes as a function of the percentage of baseline cotinine replaced by NPs. Future research should focus primarily on investigating ways to improve smoking quit rates for smokers in early alcohol recovery.     

Nicotine dependence, use of illegal drugs and psychiatric morbidity

The purpose of this study was to examine the association of smoking and nicotine dependence with psychiatric morbidity, controlling for the potential confounding effect of smoking on the relationship between the use of other substances and psychiatric morbidity. A sample of 290 adults were interviewed at a primary health centre (patients, 58%; patients' relatives, 34%; staff, 8%) to inquire about their tobacco, caffeine, alcohol, and illegal drug consumption. Psychiatric morbidity, defined by a score >6 on the General Health Questionnaire (GHQ-28), showed a strong direct association with nicotine dependence. The use of illegal drugs, but not of alcohol, was also strongly associated with psychiatric morbidity, after controlling for smoking. Both smoking and high nicotine dependence were also associated with use of caffeine, alcohol, cannabis and cocaine. High nicotine dependence may be considered as an expression of individual psychopathologic vulnerability. Tobacco may have a central facilitating role in the use of caffeine, alcohol, and illegal drug.     

Prevalence of DSM/ICD-defined nicotine dependence

This review compares nicotine dependence and the ability to stop smoking in smokers with no alcohol problems to smokers with current, past or lifetime (i.e., either current or past) alcohol problems. We searched computerized databases, meeting abstracts and made requests to listserves and grantees for comparisons of the above categories. We could not use meta-analyses and, thus, used consistency across studies to make conclusions. We located 17 articles on nicotine dependence, 12 on the ability to quit on a given attempt, 7 on lifetime quitting and 2 on quit attempts. Smokers with current and past alcohol problems were more nicotine dependent than smokers with no alcohol problems. Surprisingly, smokers with past problems were as able to quit on a given attempt as smokers with no problems. We hypothesize this may be because such smokers learned skills in resolving their alcohol problems that neutralized their increased nicotine dependence. Smokers with current or past alcohol problems appear to be less likely to quit in their lifetime. Given their equal ability to quit on a given attempt, this could be due to fewer quit attempts; however, whether this is actually so is unclear. Our results that smokers with past alcohol problems can quit as easily as those without alcohol problems suggest that smokers with past alcohol problems may respond to minimal treatments for smoking cessation.     

State-dependent learning effects with a combination of alcohol and nicotine

An experiment was carried out to investigate whether nicotine ingestion (via cigarette smoking) interacted with alcohol (vodka and tonic) in its effect on state-dependent learning (SDL) in humans. On Day 1 of the 2-day experiment 24 subjects were required to learn a simple route map previously found to be SDL sensitive with alcohol. All subjects ingested 0.66 g alcohol/kg body wt. and smoked two medium tar cigarettes (average nicotine content 1.4 mg). Twenty-four hours later, subjects attempted recall under one of the following drug states; (i) alcohol and nicotine (A+N); (ii) alcohol and smoking placebo (A+O); (iii) Nicotine and placebo drink (O+N); and (iv) no drugs (O+O). Highest recall scores were observed in the A+N subjects, with O+N and O+O subjects recalling the least. A+O subjects had intermediate recall performance. Thus the combination did produce a clear SDL effect, with alcohol possibly contributing the major influence.     

High prevalence of alexithymia in male patients with alcohol dependence

The personality trait of alexithymia was assessed in 100 male inpatients with alcohol dependence using the Schaling-Sifneos Personality Scale. The score indicative of alexithymia (below 50 points) was found in 78 patients, a prevalence which exceeds that found in psychosomatic subjects. Patients with alexithymia did not differ from non-alexithymics in regard to demographic factors and severity of alcohol dependence. They were younger and had a shorter duration of illness what may indicate that alexithymia is not a result of the dependence. Alcoholic patients with concomitant hypertension had greater alexithymic scores. It is hypothesized that psychological and biological features of alexithymic subjects may render them more vulnerable to alcohol and more prone to subsequent development of the dependence.     

Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence

Background

Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence.

Methods

Alcohol dependent subjects (n = 40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM).

Results

There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6–13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial.

Conclusions

Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.     

Alcohol use as a signal for sensitivity to nicotine dependence among recent onset smokers

Objective

This study evaluated the association between alcohol use, abuse and dependence and cigarette smoking to determine whether alcohol may signal greater sensitivity to nicotine dependence at very low levels of smoking.

Method

Data were drawn from five annual National Surveys on Drug Use and Health and included individuals age 12 to 21 who reported first exposure to smoking within the past two years and smoking at least once in the past month.

Results

Both alcohol abuse and alcohol dependence were associated with increased likelihood of symptoms that seem to tap tolerance for nicotine. These included items such as “the amount you smoke has increased”; “needing to smoke a lot more now in order to be satisfied”; and “smoking much more before starting to feel anything”. Alcohol dependence, but not abuse was associated with the remaining symptoms, “after not smoking for a while, needing to smoke to feel less restless and irritable”; “craving cigarettes after not smoking for a while”; and “worrying about running out of cigarettes”. All associations were not better accounted for by either alcohol use or amount smoked.

Conclusion

If causally associated, treatment of alcohol-use disorders may prevent or reduce the early emergence of nicotine dependence symptoms among new smokers, very early in the smoking uptake process. If instead alcohol disorders are a signal of sensitivity for nicotine dependence best accounted for by a third variable, then adolescents with alcohol dependence and/or abuse during early exposures to smoking represents an important subgroup that may benefit from interventions directly targeting this association.     

Symptoms of alcohol dependence and smoking initiation and persistence: A longitudinal study among US adults

Background

A large number of adults report symptoms of, but do not meet diagnostic criteria for, an alcohol use disorder. Yet, little is known about the relationship between symptoms of alcohol use disorders and the initiation and persistence of smoking. This study prospectively examines the relationship between having 1–2 symptoms of alcohol dependence (without abuse) and smoking initiation and persistence as well as nicotine dependence over a 3-year period among adults in the United States.

Methods

Data were drawn from Wave 1 (2001–2002) and Wave 2 (2004–2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. Relationships between Wave 1 symptoms of alcohol dependence, alcohol abuse, and alcohol dependence and initiation and persistence of cigarette smoking and nicotine dependence at Wave 2 were examined using logistic regression analyses. Analyses were adjusted for demographics, mood and anxiety disorders.

Results

Symptoms of alcohol dependence were associated with smoking initiation at Wave 2. There was no association between symptoms of alcohol dependence and smoking persistence. Symptoms of alcohol dependence predicted incident and persistent nicotine dependence. Findings persisted after adjusting for demographic characteristics and mood/anxiety disorders.

Conclusions

Even 1–2 symptoms of alcohol dependence are associated with increased vulnerability to smoking initiation and onset and persistence of nicotine dependence at a similar strength as alcohol use disorders. Efforts at smoking cessation must address problematic alcohol use, even at the subclinical level, in order to improve efficacy.     

Alcohol dependence and the alcohol Stroop paradigm: evidence and issues

AIMS: Firstly to test alcohol abusers attentional bias towards alcohol-related stimuli. Secondly, to shed light onto other factors that may influence the alcohol Stroop effect by considering variables including mood status in the analyses. Finally, to examine severity of dependence on Stroop performance. DESIGN: Repeated measures with alcohol versus control group as the between participant factors and within participant factors were the reaction times to different types of stimuli. Standard multiple regression was used to determine predictors of Stroop performance. A repeated measures design was used with severity of dependence as the between participant factors and Stroop reaction times as the within participant factors. SETTING: South and East London, UK. PARTICIPANTS: Sixty-four alcoholics in treatment and 64 community controls from general practice participated in the study. MEASUREMENTS: Alcohol dependence severity was measured using the SADQ, mood was measured with the POMS-SF and a computerised emotional Stroop task was employed to measure attentional bias. FINDINGS: Regardless of demographic factors and mood status, alcoholics responded significantly slower to alcohol-related than neutral words when compared to controls. When severity of alcohol dependence was used as between participant factors, no significant differences were found with Stroop performance between high and low alcohol severity groups. CONCLUSIONS: Alcohol-related stimuli are distracting to heavy users of alcohol, independent of demographic, mood and dependence status. Findings offer insight into the development of alcohol dependence and the issues that surround the alcohol Stroop paradigm.     

CYP2E1*1D regulatory polymorphism: association with alcohol and nicotine dependence

OBJECTIVE: CYP2E1 bioactivates environmental protoxins and metabolizes alcohol. CYP2E1 is induced by alcohol and cigarette smoking and may contribute to metabolic tolerance in alcoholics. The CYP2E1*1D polymorphism has been associated with greater CYP2E1 inducibility. One objective was to determine the frequency of the variant allele in eight ethnic groups. Further, the Canadian Native Indian, South-east Asian Canadian and Caucasian Canadian groups were stratified by alcohol and nicotine dependence (as measured by DSM-IV criteria) to examine the potential association of CYP2E1*1D with drug dependence. RESULTS AND CONCLUSIONS: We found a significantly greater frequency of the CYP2E1*1D allele among Indo-Asian Canadians (0.31), Chinese Canadians (0.19), Taiwanese (0.20), Japanese Canadians (0.18), African Americans (0.13), African Canadians (0.10) and Canadian Native Indians (0.09) compared to Caucasian Canadians (0.02). Although the power of the association study was low among some subgroups, the CYP2E1*1D genotype (subjects with at least one variant allele) was associated with alcohol as well as nicotine dependence. Specifically, Canadian Native Indians dependent on nicotine alone or alcohol alone exhibited significantly greater CYP2E1*1D frequencies compared to non-drug dependent controls, while the variant frequency among Southeast Asians dependent on nicotine was greater than their non-drug dependent counterparts. We also found that CYP2E1*1D genotype was associated with significantly greater 3-hydroxycotinine per cigarette in African Americans. The variable frequency of CYP2E1*1D among ethnic groups suggests a greater risk for diseases putatively related to CYP2E1 in some non-Caucasian ethnic groups. The association of CYP2E1*1D with alcohol and nicotine dependence suggests that CYP2E1 may contribute to the development of these dependencies.     

Dose, duration and pattern of nicotine administration as determinants of behavioral dependence in rats

Rationale Relatively little is known about the role of dose, duration, and pattern of nicotine exposure in the development of dependence. Disruption of learned behavior during antagonist-precipitated withdrawal can be a sensitive, quantitative measure of behavioral dependence. Objectives The present study sought to determine whether behavioral dependence upon nicotine could be induced in rats and, if so, what exposure conditions were essential for inducing it. Our primary focus was on whether continuous exposure over several days was necessary to produce dependence. Methods Male Sprague–Dawley rats were trained to lever press under fixed-ratio 10 schedules of food reinforcement during daily, 15-min experimental sessions. Nicotine was then administered s.c. via osmotic minipumps that delivered various nicotine dosage regimens, some including 24-h nicotine-free periods, to manipulate pattern of exposure. The presence of dependence was tested with challenges with the nicotinic acetylcholine receptor antagonist, mecamylamine, or during spontaneous withdrawal. Results After 7 days of 3, 6, and 12 mg kg⁻¹ day⁻¹ nicotine administration, response rates were significantly reduced in nicotinized, but not in saline-treated rats following mecamylamine challenges. Subsequent studies demonstrated that 4 days, but not 3 days, of cumulative 3 mg kg⁻¹ day⁻¹ nicotine administration was sufficient to induce dependence. The induction of dependence could be prevented by imposing a nicotine-free period between the first and second days during these 4-day regimens but not at other times. Conclusion Behavioral dependence upon nicotine can be induced in the rat, and its induction is dependent upon its cumulative duration and pattern of exposure suggesting that tobacco dependencies could be controlled by similar determinants.     

Double-blind clinical trial of sertraline treatment for alcohol dependence

Clinical studies that have evaluated serotonergic medications to reduce alcohol consumption have yielded conflicting results. These studies primarily treated patients with alcohol dependence, excluding those with a current depressive disorder, in an effort to differentiate any medication effects directly on drinking from those on mood. Yet despite the exclusion of current depression, a group of alcohol-dependent patients who are not depressed can be highly heterogeneous. For example, this subgroup can include those with a lifetime depressive disorder. If these patients were more sensitive to serotonergic medications than patients without a lifetime depressive disorder, medication effects in a subgroup of patients who were not depressed could be obscured. Thus, the purpose of this study was to examine the efficacy of sertraline for treating alcohol dependence in patient groups that were differentiated by the presence or absence of lifetime depression. This study examined the effectiveness of sertraline (200 mg/day) or placebo for 14 weeks in 100 alcohol-dependent subjects with (N = 53) or without (N = 47) a lifetime diagnosis of comorbid depression. Sertraline treatment seemed to provide an advantage in reducing drinking in alcohol-dependent patients without lifetime depression, illustrated best with a measure of drinking frequency during treatment. However, sertraline was no better than placebo in patients with a diagnosis of lifetime comorbid depression, and current depression did not change the results. Treatment with selective serotonin reuptake inhibitors may be useful in alcohol-dependent patients who are not depressed. Subtyping those with alcohol dependence on the basis of the absence versus the presence of a lifetime depressive disorder may help to resolve conflicting findings in the literature on the treatment of alcohol dependence with serotonergic medications.     

Eysenck's personality and tobacco/nicotine dependence in male ever-smokers in Japan

To examine the relationship between Eysenck's personality traits and tobacco/nicotine dependence in a male population, a random sample of 200 male ever-smokers aged 35 or older from a community in Japan were interviewed using the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), which yielded ICD-10, DSM-III-R and DSM-IV diagnoses of tobacco/nicotine dependence. They were also asked to complete the Fagerstrom Tobacco Questionnaire (FTQ) and the short-form Eysenck Personality Questionnaire-Revised. A total of 136 subjects completed both the interview and the questionnaire. Neuroticism scores were significantly higher in those who had lifetime diagnosis of tobacco/nicotine dependence according to ICD-10, DSM-IV, or FTQ criteria than nondependent ever-smokers (p < 0.05). Lie scores were significantly lower in DSM-III-R or DSM-IV tobacco/nicotine dependence than in nondependent ever-smokers (p < 0.05). Multiple logistic regression indicated that neuroticism was significantly associated with a higher risk of ICD-10 tobacco/nicotine dependence (p < 0.05), after controlling for age, education, employment status and smoking behaviors; lie score was significantly associated with a lower risk of DSM-III-R tobacco/nicotine dependence (p < 0.05). It is suggested that neuroticism is associated with a higher risk of tobacco/nicotine dependence in male Japanese ever-smokers. A nonconforming and rebellious attitude or reporting bias represented by higher lie score may be associated with lower rates of tobacco/nicotine dependence.     

Modelling the contribution of negative affect,outcome expectancies and metacognitions to cigarette use and nicotine dependence

BackgroundBoth positive smoking outcome expectancies and metacognitions about smoking have been found to be positively associated with cigarette use and nicotine dependence. The goal of this study was to test a model including nicotine dependence and number of daily cigarettes as dependent variables, anxiety and depression as independent variables, and smoking outcome expectancies and metacognitions about smoking as mediators between the independents and dependents.MethodsThe sample consisted of 524 self-declared smokers who scored 3 or above on the Fagerstrom Test for Nicotine Dependence (FTND: Uysal et al., 2004).ResultsAnxiety was not associated with either cigarette use or nicotine dependence but was positively associated with all mediators with the exception of stimulation state enhancement and social facilitation. Depression, on the other hand, was found to be positively associated with nicotine dependence (and very weakly to cigarette use) but was not associated with either smoking outcome expectancies or metacognitions about smoking. Only one smoking outcome expectancy (negative affect reduction) was found to be positively associated with nicotine dependence but not cigarette use. Furthermore one smoking outcome expectancy (negative social impression) was found to be positively associated with cigarette use (but not to nicotine dependence). All metacognitions about smoking were found to be positively associated with nicotine dependence. Moreover, negative metacognitions about uncontrollability were found to be positively associated with cigarette use.ConclusionsMetacognitions about smoking appear to be a stronger mediator than smoking outcome expectancies in the relationship between negative affect and cigarette use/nicotine dependence. The implications of these findings are discussed.     

The relationship between nicotine dependence scores and biomarkers of exposure in adult cigarette smokers

Background: Tobacco dependence is a multidimensional phenomenon. The Fagerström Test for Nicotine Dependence (FTND) is a widely administered six-item questionnaire used as a measure of nicotine dependence. It has been suggested that this test may not represent the entire spectrum of factors related to dependence. Also the relationship of this test with biomarkers of exposure to cigarette smoke has not been extensively studied. Methods: Data from a multi-center, cross-sectional, ambulatory study of US adult smokers (the Total Exposure Study, TES) was analyzed. The FTND score and a number of additional questions related to smoking behavior, from an adult smoker questionnaire (ASQ) completed by 3585 adult smokers in the TES were analyzed. The 24-h urine nicotine equivalents, serum cotinine and blood carboxyhemoglobin were measured as biomarkers of exposure (BOE) to nicotine and carbon monoxide. Cigarette butts returned were collected during the 24-h urine collection period. Results: The FTND showed moderate correlations with BOE, while selected questions from ASQ although statistically significant, had weaker correlations. FTND scores showed substantially weaker correlations without the question about cigarettes smoked per day (CPD). CPD and time to first cigarette (TTFC) had the most impact on BOE. Conclusion: Additional questions from ASQ did not appear to contribute towards refining the FTND test. The correlation of the FTND scores with nicotine and carbon monoxide seems to be primarily driven by CPD. CPD and TTFC were the most important factors correlating with exposure.