Rate of nicotine onset from nicotine replacement therapy and acute responses in smokers.

The subjective and reinforcing effects of drugs of abuse may depend partly on their rate of onset, with faster acting formulations typically producing stronger effects than slower ones. In this within-subjects study, we examined the acute effects of nicotine replacement therapy via nicotine nasal spray (fast delivery) vs. transdermal nicotine patch (slow delivery) on craving, withdrawal, cardiovascular responses, subjective ratings, and reinforcing effects of smoking. Smokers (N=30) not seeking treatment participated in three sessions, each after overnight smoking abstinence, involving 14-mg nicotine (Nicoderm) or placebo patch, followed 4 hr later by intermittent administration of nicotine (Nicotrol) or placebo nasal spray. Specifically, the three group comparisons were nicotine patch condition (with placebo spray), nicotine spray condition (with placebo patch), and placebo condition (placebo spray and patch). Nicotine patch and nicotine spray were never administered in the same session. Blood nicotine levels were similar between nicotine patch and nicotine spray conditions, by design. Heart rate and systolic blood pressure were higher following nicotine spray vs. the other conditions, as hypothesized. However, other than reductions in craving related to nicotine spray and patch at some points, no differences between conditions were observed in withdrawal, subjective effects of sprays and smoking, or smoking reinforcement assessed by a computer task. Thus, under these acute conditions, the speed of nicotine delivery from nasal spray vs. patch differentially affected cardiovascular responses and perhaps craving but did not influence withdrawal, subjective ratings, and smoking reinforcement.     

Association of retrospective early smoking experiences with prospective sensitivity to nicotine via nasal spray in nonsmokers

Greater sensitivity to early exposure to tobacco smoking may predict higher risk of becoming nicotine dependent. The most common measure of this sensitivity is the retrospective self-report Early Smoking Experiences (ESE) questionnaire. We examined the relationship between responses to the retrospective ESE and prospectively assessed sensitivity to nicotine via nasal spray in young adult nonsmokers (N = 58) with modest lifetime smoking experience (>0 but < or =10 lifetime uses). Nicotine spray (0 vs 10 microg/kg) was used due to ethical and practical concerns with administering tobacco smoke to nonsmokers. Responses to cigarette smoking on the retrospective ESE items of pleasant, unpleasant, nausea, relaxed, dizzy, and buzzed were compared with prospectively assessed nicotine spray effects (NSE) on the same responses. ESE responses were also compared with subjective spray ratings of nicotine reward (e.g., "liking") and perception (e.g., "feel the effects"), cardiovascular activity, and nicotine reinforcement via a nicotine spray choice procedure. Results showed that the retrospective ESE items of dizzy and buzzed were each associated with greater prospective NSE dizzy and buzzed responses to nasal spray nicotine. However, the other four ESE items were unrelated to the corresponding NSE items. Responses to some ESE items were also related to prospective nicotine spray reward and perception, but no ESE item was related to the cardiovascular or reinforcing effects of nicotine spray. These findings show that two of six retrospective ESE items, dizzy and buzzed, predicted the same prospectively assessed responses to acute nicotine via spray in young adult nonsmokers and may reflect a stable and reliable response to nicotine intake.     

The discriminative stimulus, subjective, cardiovascular, and reinforcing effects of nicotine as a function of light physical activity.

Smokers often experience the acute effects of cigarette smoking while they are engaged in the light physical activity of routine tasks. However, virtually all laboratory-based research on these effects is conducted under conditions of quiet rest and, thus, may not generalize to effects in the natural environment. We examined changes in the discriminative stimulus, subjective, cardiovascular, and reinforcing effects of nicotine in humans as a function of the level of concurrent physical activity. Men and women smokers (N = 17) were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo (0 microg/kg) at rest. Three sessions then followed, in which the generalization of discrimination was tested across a range of doses (0-20 microg/kg) while at rest or engaged in very light or light physical activity (15% and 30% of heart rate reserve, respectively) via bicycle ergometer. Generalization testing involved both two- and three-choice ("novel" option) quantitative procedures. Self-reported mood via the Profile of Mood States and visual analog scales, and cardiovascular measures of heart rate and blood pressure were obtained concurrent with discrimination responding. Nicotine reinforcement was assessed after the end of generalization testing using a choice procedure under the same rest or activity conditions. Results showed that physical activity did not significantly alter nicotine discrimination or reinforcement, as no interactions between activity and nicotine were observed. When activity and nicotine influenced the same subjective and cardiovascular responses, they acted in a generally additive fashion. These findings suggest that research on the acute effects of nicotine conducted under typical resting laboratory conditions generally are not altered by light physical activity and so may generalize to the effects of nicotine under conditions common in the natural environment.     

Does nicotine do what we think it does? A meta-analytic review of the subjective effects of nicotine in nasal spray and intravenous studies with smokers and nonsmokers.

We conducted a meta-analysis of placebo-controlled laboratory studies of the subjective effects of nicotine. A total of 15 studies (11 with nasal spray, four with intravenous administration) with smokers and six studies (all with nasal spray) with never-smokers were included. Studies of other routes of administration (e.g., smoked tobacco) were not included because of insufficient numbers of available effect sizes. Meta-analysis results indicated that nicotine increased vigor for smokers but increased fatigue for never-smokers. Nicotine increased head rush for both smokers and never-smokers. In studies of smokers only, nicotine also increased ratings of drug high and drug liking. Contrary to expectations, nicotine decreased relaxation and increased tension/jitteriness for both smokers and never-smokers. Dose-response relationships were most clearly observed for head rush and drug high. Considerable variability was found across studies for a given nicotine dose and route of administration. Implications of the current findings about the role of subjective effects in nicotine reinforcement and self-administration are discussed along with commentary on methodological issues and recommendations for future studies.     

Real-time craving and mood assessments before and after smoking.

This study explored some quandaries concerning craving and mood as motivators to smoke. Craving and negative mood have long been associated with day-to-day smoking as two of the primary motivational forces behind the maintenance of the behavior, as well as significant barriers in smokers' attempts to quit. Craving remains a clinically relevant phenomenon, with most smokers describing craving as a troublesome problem when quitting. Smokers' self-reports of negative mood, as an antecedent for smoking, are so robustly reported that many models of nicotine dependence have incorporated a critical role for negative mood in maintaining smoking behavior. However, several naturalistic studies that collected mood ratings with hand held computers from smokers in real time, just before smoking a cigarette, have provided scant evidence that negative mood plays a major role in motivation to smoke. No study to date has examined craving and mood data as a consequence of smoking, that is, collecting the same data immediately after smoking. This study used personal digital assistants (PDAs) to collect craving and mood data immediately before smoking, immediately after smoking, and at random times of day. Nontreatment seeking smokers (N = 72) carried a PDA for an average of 10 days while they recorded their smoking behavior. Results showed that craving and negative mood ratings were lowest immediately after smoking compared with immediately before smoking and at random times of day. These findings suggest that smokers may be at least partially motivated to smoke to lower their craving and improve their mood states.     

Correspondence of Interactive Voice Response (IVR) reports of nicotine withdrawal, craving, and negative mood with questionnaire ratings.

This study focuses on comparing reports of nicotine withdrawal, craving, and depressive symptoms obtained using an Interactive Voice Response (IVR) system and several questionnaires. As part of a smoking cessation trial, daily reports of withdrawal, craving, and negative mood were collected using an IVR system for 7 days after participants attempted to quit smoking, and several pencil and paper questionnaires (i.e., the Minnesota Nicotine Withdrawal Scale, the Questionnaire on Smoking Urges, and the Center for Epidemiological Studies-Depression) were completed a week after the target quit date. The sample was composed of 378 daily smokers. Moderate to high correlations were found between the research questionnaires obtained at the end of the week and the corresponding daily IVR reports of nicotine withdrawal, craving, and depressive symptoms. However, the sample size decreased on each day of IVR reporting due to attrition. Thus, an appealing aspect of daily assessment using an IVR system is that it can provide additional data that are not obtained with paper and pencil assessments given once per week, but it will be important for future studies to concentrate on improving adherence with the IVR system in this population.     

The relationship between cigarette use, nicotine dependence, and craving in laboratory volunteers.

Data from epidemiological studies suggest that individual differences in cigarettes per day (CPD) and duration of smoking account for only a small portion of the variance in Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) nicotine dependence. However, DSM-IV may be an insensitive measure of nicotine dependence; other measures might better reflect the true nature of the relationship between use and dependence. This paper describes the relationship between cigarettes per day (CPD) and years smoking and the severity of nicotine dependence as measured by the Nicotine Dependence Syndrome Scale (NDSS). Furthermore, we assessed the validity of individual differences in nicotine dependence by determining whether they related to cue-evoked craving during abstinence. Data were pooled from five laboratory studies of 489 regular (i.e., 15+ CPD) smokers. In contrast to previously reported data demonstrating a relatively strong relationship between CPD and dependence in chippers (Shiffman & Sayette, 2005), CPD and years smoking accounted for a statistically significant, but small (<6%), portion of the variance in nicotine dependence in daily smokers. Individual differences in both CPD and years smoking had little or no relationship with craving. However, the magnitude of craving was significantly related to the degree of nicotine dependence even after controlling for use variables and excluding craving-related items on the NDSS. These data suggest that among moderate to heavy daily smokers, meaningful individual differences in nicotine dependence are observed independent of differences in current daily cigarette consumption and duration of smoking. Further research into the sources of this variance is critical to understanding the process of and risk for nicotine dependence.     

Cotinine levels in relation to smoking behavior and addiction in young adolescent smokers.

The goal of this study was to identify associations among self-reported nicotine exposure, nicotine addiction, and actual nicotine intake as measured by salivary cotinine levels in adolescent smokers. A total of 170 adolescent smokers with a mean age of 15 years were recruited from seven northern Californian public high schools. Data were collected on smoking behaviors, addiction, craving, and withdrawal. Nicotine dependence was assessed using a modified teen Fagerstr?m Tolerance Questionnaire (mtFTQ), a modified Nicotine Dependence Syndrome Scale (mNDSS), and a simple self-rating. Withdrawal was assessed using the Minnesota Withdrawal Questionnaire, and craving was assessed using a survey created by the authors. Salivary cotinine levels were collected from and analysed in participants who self-identified as smokers; data from the 54 participants who smoked in the past 4 days and whose salivary cotinine levels were greater than 0.1 ng/ml were used in the analysis. Among this group of adolescent smokers, the mean number of cigarettes smoked per day was 3.51 (SD = 3.44) and the mean level of salivary cotinine was 44.1 ng/ml (Mdn = 24.2). Even at this low level of nicotine exposure, cotinine was highly correlated with measures of nicotine dependence such as the mtFTQ (r = 0.497, p = .001), NDSS (r = 0.439, p = .002), timing of craving in the morning (r = -0.601, p = .000), and self-rated addiction (r = 0.562, p = .000). Most interesting, cotinine levels reached a plateau at around 4-5 cigarettes/day.     

Nicotine lozenges for the treatment of smokeless tobacco use.

Nicotine lozenges have been shown to increase tobacco abstinence rates in cigarette smokers, but they have not been evaluated in smokeless tobacco (ST) users. We conducted an open-label, one-arm, phase II clinical trial to evaluate the efficacy of the 4-mg nicotine lozenge for the treatment of withdrawal and craving associated with tobacco abstinence among ST users. Eligible subjects received 4-mg nicotine lozenges for 6 weeks followed by a 6-week taper. Subjects completed daily tobacco withdrawal diaries, and data on lozenge use, adverse events, and lozenge acceptability were collected. Urine anabasine was collected at 3 and 6 months for biochemical confirmation of self-reported tobacco abstinence. Participants were 30 ST users with a mean age of 35.4 years (SD=6.5) using an average of 4.2 cans or pouches (SD=3.2) of ST per week for a mean of 15.1 years (SD=6.5). Among subjects continuously tobacco abstinent for the first 2 weeks, no significant increases in composite withdrawal symptoms were observed, compared with baseline symptoms, whereas craving decreased significantly. Biochemically confirmed 7-day point-prevalence tobacco abstinence was 53% (95% CI=34%-72%) at 12 weeks (end of treatment) and 47% (95% CI=28%-66%) at 6 months. Few adverse events attributable to the nicotine lozenge occurred, and the lozenge was perceived as helpful in assisting subjects quit ST. The use of the 4-mg nicotine lozenge appears promising for the clinical treatment of withdrawal symptoms and craving associated with tobacco abstinence in ST users. Future phase III clinical trials investigating the efficacy of nicotine lozenges are warranted.     

The effects of smoking deprivation and nicotine administration on emotional reactivity.

Although converging lines of evidence suggest that nicotine and mood are related at a fundamental biological level, this link has not been reliably demonstrated in laboratory studies. In this study, startle probe methodology was used to examine the effects of nicotine administration and deprivation on emotional processes associated with motivation. Smokers (N = 115) completed four laboratory sessions crossing deprivation (12-hr deprived vs. nondeprived) with nicotine spray (active vs. placebo). Participants viewed affective pictures (positive, negative, neutral) and pictures involving cigarette cues, while startle probes were administered. Deprivation decreased startle responding to cigarette cues, suggesting an activation of appetitive processes. Nicotine administration suppressed overall startle responding during deprivation. In addition, during deprivation, random exposure to negative stimuli over two blocks of trials resulted in decreased adaptation of the startle response, suggesting that some sensitization to negative emotional cues may take place during nicotine withdrawal. These effects are consistent with formulations of addiction, stressing that withdrawal may both increase the reinforcement salience of smoking stimuli and decrease habituation to negative emotional stimuli.     

Nicotine delivery, cardiovascular profile, and subjective effects of an oral tobacco product for smokers.

The tobacco industry markets potential reduced exposure products (PREPs) to smokers, including oral products that are intended to be used in situations where cigarettes cannot. For example, Ariva, marketed by Star Scientific, is a tablet made from compressed tobacco powder and is intended for "adult smokers in situations where they cannot or choose not to smoke." No objective data are available regarding Ariva's effects in smokers, including its nicotine delivery, cardiovascular profile, or subjective effects. In this single-session, clinical laboratory study, 10 overnight-abstinent cigarette smokers were administered one Ariva tablet, followed 90 min later by two Ariva tablets, followed 90 min later by three Ariva tablets. Participants allowed each dose to dissolve in their mouths according to package instructions. Blood was sampled, heart rate monitored, and subjective effects assessed regularly. Ariva delivered nicotine in a dose-dependent manner; mean (SD) nicotine levels increased from 2.4 ng/ml (0.9) at baseline, to 3.4 ng/ml (1.4) 45 min post-1 tablet, 7.3 ng/ml (4.0) 45 min post-2 tablets, and 9.7 ng/ml (4.4) 45 min post-3 tablets. Heart rate increased after tablet administration, independent of dose. The tablets also significantly decreased subjective ratings of craving and urge, and increased ratings of nausea. Based on this short-term laboratory evaluation, Ariva exposes users to nicotine and may suppress some symptoms of tobacco abstinence, though its nausea-inducing characteristics may limit initial acceptability.     

Transdermal nicotine use in postmenopausal women: does the treatment efficacy differ in women using and not using hormone replacement therapy?

This study of postmenopausal female smokers (N = 94) asked: During short-term smoking abstinence, do the beneficial effects of transdermal nicotine replacement therapy (NRT) on acute symptomatology (i.e., withdrawal, cigarette craving, smoking urges, mood, depressive symptoms, motor speed, and reaction time) differ in women who use and do not use hormone replacement therapy (HRT)? Participants were recruited according to HRT and non-HRT use (self-selecting), then randomized within strata to active nicotine or placebo nicotine patch. After 1 baseline week of smoking, participants quit smoking for 2 weeks. Women received cessation counseling and were monitored for abstinence. Dependent measures were collected during five clinic visits. Two-way analysis of covariance (ANCOVA) were run on change scores for dependent variables, with nicotine patch group (active/placebo) and HRT group (HRT/non-HRT) as independent variables and age as a covariate. No interactions were found between HRT and patch condition, but both showed specific effects. During the first abstinent week, women on active nicotine patch (compared with placebo) experienced less severe withdrawal, greater reductions in cigarette cravings, and lower (more favorable) Factor 1 scores on the Questionnaire of Smoking Urges. During the second abstinent week, women using HRT (compared with the non-HRT group) exhibited better mood (Profile of Mood States scores) and less depression (Beck Depression Inventory scores). These results suggest the following: First, the efficacy of transdermal nicotine replacement is not adversely modified by women's HRT use; second, ovarian hormones might influence women's responses to smoking cessation, and thus should be considered in developing effective strategies for women to quit smoking.     

Smokers' expectancies for nicotine replacement therapy vs. cigarettes.

Smokers (N=188) recruited from the local community completed a questionnaire that measured expected outcomes of using cigarettes, nicotine gum, nicotine patch, and nicotine nasal spray. Expectancy questions relating to negative affect, craving, weight, and health risks were derived from the Smoking Consequences Questionnaire-Adult. As predicted, smokers held much greater expectancies that cigarettes help control negative affect, craving, and weight relative to nicotine replacement therapy (NRT). All NRT products were expected to cause fewer health risks than cigarette smoking. As predicted, smokers held strong negative affect reduction expectancies for cigarette smoking. For NRT, although still relatively low, craving reduction was the strongest expectancy. Individuals who had experience using the nicotine patch had greater positive expectancies for NRT. Greater positive expectancies for NRT were correlated with more immediate plans to quit smoking. In summary, cigarette smokers' positive expectancies about cigarettes do not appear to generalize to NRT products, which may limit their use and effectiveness.     

A sensitization-homeostasis model of nicotine craving, withdrawal, and tolerance: integrating the clinical and basic science literature.

Recent reports suggest that nicotine withdrawal symptoms are common among adolescents after a few weeks of intermittent tobacco use. No current model of nicotine dependence had predicted the rapid development of symptoms of dependence and withdrawal before the development of tolerance. We present a model that integrates neuroscience with clinical observations regarding how nicotine dependence develops, progresses, and resolves in humans. The central tenet of this sensitization-homeostasis model is that nicotine's dependence liability derives from its ability to stimulate neural pathways responsible for the suppression of craving. As a result of sensitization, the craving suppression produced by nicotine is magnified to superphysiological levels. The overinhibition of neurons responsible for craving initiates compensatory homeostatic measures that stimulate the craving pathways and result in craving when nicotine is absent. Separate homeostatic mechanisms are responsible for craving, withdrawal, and tolerance. The sensitization-homeostasis model is unique in its attribution of dependence to craving suppression, its attention to the temporal relationships among clinical features of nicotine dependence, and its extensive integration of clinical observations and basic science. It provides a framework for theory-based research.     

Nicotine decreases attentional bias to negative-affect-related Stroop words among smokers

The present study examined the hypothesis that nicotine is associated with reduced attentional bias to affective and smoking-related stimuli in a modified Stroop task. A total of 56 habitual smokers were each tested on 4 days with 14 mg nicotine patches and placebo patches, counterbalanced, as a within-subjects factor in a double-blind design. A modified Stroop using negative-affect words, smoking words, color words, and neutral words was presented via computer in blocked format. As predicted, nicotine, relative to placebo, was associated with decreased attentional bias to negative words. Nicotine speeded performance during smoking-word and color-word blocks to the same degree as during neutral words and thus appeared to also have a nonspecific performance-enhancing effect. In an exploratory analysis, nicotine-attention effects occurred only in the initial presentation of pairs of blocked word pages. Nicotine also was associated with improved mood. The results are discussed in terms of affect-attention and smoking literatures.     

Brain indices of nicotine's effects on attentional bias to smoking and emotional pictures and to task-relevant targets.

Aversive and smoking-related stimuli are related to smoking urges and relapse and can be potent distractors of selective attention. It has been suggested that the beneficial effect of nicotine replacement therapy may be mediated partly by the ability of nicotine to reduce distraction by such stimuli and thereby to facilitate attention to task-relevant stimuli. The present study tested the hypothesis that nicotine reduces distraction by aversive and smoking-related stimuli as indexed by the parietal P3b brain response to a task-relevant target digit. We assessed the effect of nicotine on distraction by emotionally negative, positive, neutral, and smoking-related pictures immediately preceding target digits during a rapid visual information processing task in 16 smokers in a double-blind, counterbalanced, within-subjects design. The study included two experimental sessions. After overnight smoking deprivation (12+ hr), active nicotine patches were applied to participants during one of the sessions and placebo patches were applied during the other session. Nicotine enhanced P3b responses associated with target digits immediately subsequent to negative emotional pictures bilaterally and subsequent to smoking-related pictures only in the right hemisphere. No effects of nicotine were observed for P3bs subsequent to positive and neutral distractor pictures. Another measure of attention, contingent negative variation amplitude in anticipation of the target digits also was increased by nicotine, especially in the left hemisphere and at posterior sites. Together, these findings suggest that nicotine reduces the distraction by emotionally negative and smoking-related stimuli and promotes attention to task-related stimuli by modulating somewhat lateralized and task-specific neural networks.     

Factorial and convergent validity of nicotine dependence measures in adolescents: toward a multidimensional approach.

The present study investigated the possibility of forming a multidimensional scale for the measurement of nicotine dependence among adolescents, based on the modified Fagerstr?m Tolerance Questionnaire (mFTQ) and the Hooked on Nicotine Checklist (HONC). A survey was conducted among 33 Dutch secondary schools, resulting in 2,041 smokers who completed the questionnaire. Motivation to quit and number of quit attempts were assessed and used as convergent construct variables for the construct of nicotine dependence. The findings show that combining the items of the mFTQ and the HONC results in three distinct dimensions: behavioral aspects of nicotine dependence, craving, and nervousness during abstinence. We examined this new multidimensional model in a second sample using confirmatory factor analysis. The new multidimensional measure fitted the data satisfactorily and showed good psychometric properties. Results of this study support the notion that nicotine dependence among adolescents is multidimensional.     

The reinforcing effects of nicotine and stimulant medication in the everyday lives of adult smokers with ADHD: A preliminary examination.

Whereas the smoking prevalence rates in the general population are declining, rates among people diagnosed with attention-deficit/hyperactivity disorder (ADHD) continue to be elevated. Previous research has shown that nicotine may improve attention and mood, suggesting that nicotine may help ameliorate the attentional and emotional problems associated with ADHD. The present study examined the effects of nicotine with and without stimulant medication on ADHD symptoms, moods, and arousal in the everyday lives of smokers with ADHD. A total of 10 smokers with ADHD who were being treated with stimulant medication were asked to abstain from smoking while participating in the study. Participants underwent four conditions in randomized order: (a) Nicotine patch+stimulant medication, (b) nicotine patch only, (c) placebo patch+stimulant medication, and (d) placebo patch only. Each condition continued for 2 days, during which self-reports of ADHD symptoms and moods were obtained using electronic diaries. Lightweight ambulatory monitors recorded cardiovascular activity at each diary entry. Smoking abstinence was verified by expired carbon monoxide and salivary cotinine analysis. Results showed that nicotine patches and stimulant medication alone and in combination reduced difficulty concentrating and core ADHD symptoms compared with placebo patch only. Borderline improvement in impatience and self-control was seen with nicotine patch administration primarily on day 1. Nicotine patches also tended to elevate systolic and diastolic blood pressure compared with placebo patch during day 2. The findings suggest that smokers with ADHD experience nicotine-related reductions in ADHD symptoms during their everyday lives.     

Nicotine, cotinine, withdrawal, and craving patterns during smoking and nicotine nasal spray use: results from a pilot study with African American men.

Nicotine intake via smoking is highly variable. Individualized dosing of nicotine replacement therapy (NRT) may improve product efficacy, but a better understanding of the within-day and within-subject relationships between smoking, NRT use, nicotine and cotinine concentrations in blood, and cravings and withdrawal symptoms is needed to inform dosing algorithms. A pilot study was undertaken to collect data on these relationships and to assess the feasibility of the methods needed for this type of research, including a sophisticated statistical modeling technique (a two-part mixed-effects model with correlated random effects that accounts for clumping at zero). Because nicotine metabolism varies by gender and race, the sample was homogeneous with respect to these characteristics. In a within-subjects study, 27 African American adult male smokers carried a computerized cigarette dispenser for 1 week, capturing the time each cigarette was smoked. Subjects then entered an inpatient setting for 1 day of scheduled smoking (matched to data from the cigarette dispenser to create an ecologically valid schedule) and 4 days of ad libitum nicotine nasal spray use, while tobacco abstinent. Eight times per day, at 2-hour intervals, blood was drawn and ratings of cigarette cravings and withdrawal symptoms were obtained. On average, subjects used less than half of the manufacturer's recommended minimum daily dose of nicotine nasal spray. Large differences in nicotine and cotinine levels were observed between individuals. When predicting nicotine, cotinine, withdrawal, and cravings, we observed significant interactions between route of nicotine intake and a variety of independent variables.     

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).