Effects of abstinence from tobacco: etiology, animal models, epidemiology, and significance: a subjective review.

This article updates a 1990 review of the effects of tobacco abstinence by reviewing (a) the etiology, (b) animal models, (c) the epidemiology, and (d) the clinical significance of tobacco abstinence effects. The author searched several databases to locate more than 3,500 citations on tobacco abstinence effects between 1990 and 2004. For brevity, the review does not evaluate these effects in regard to craving, hunger, or performance. Data collection and study conclusions were based on the author's subjective judgment. The most validated etiological model suggests that withdrawal is related to decreased dopaminergic activity, but how this relates to nicotine receptor changes is unclear. The two most validated animal models describe increases in intracranial self-stimulation thresholds or observable physical signs. Significant withdrawal symptoms occur in at least half of smokers when they try to quit. Withdrawal appears to produce clinically significant distress and impairment. Increases in depression after abstinence, but not other symptoms, prospectively predict relapse. In conclusion, the proposed neurobiological mechanisms by which withdrawal occurs leave several unanswered questions. Although animal models have been developed, how well they mimic withdrawal in humans is unclear. Tobacco withdrawal is common and can be distressing. Withdrawal-induced depression appears to undermine the smoker's ability to remain abstinent.     

Craving, withdrawal, and smoking urges on days immediately prior to smoking relapse.

Rates of smoking relapse remain high, despite the wide availability of cessation aids. Presumably factors such as craving, withdrawal symptoms, and smoking urges are key contributors to relapse, but empirical support for this presumption is not conclusive and is complicated by the high variability in symptoms across individuals and time, as well as by the lack of an absolute symptom threshold for response. Data were analyzed from 137 female smokers, aged 18-40 years, who completed 30 days of a protocol for a longitudinal smoking cessation trial. Subjects were assigned a quit date and followed regardless of subsequent smoking status. At baseline, subjects completed written measures of nicotine craving, withdrawal symptoms, and smoking urges. They also completed these measures daily for 30 days, beginning on their quit date, Scores were standardized within subjects and graphed to identify temporal symptom patterns. A total of 26 women quit smoking and 111 relapsed (at least one cigarette puff). The intensity of subjects' craving, withdrawal, and smoking urges Factors 1 and 2 peaked on the day of relapse by an average of 1.4, 1.1, 1.2, and 1.1 standard deviations, respectively, with symptoms rising during the previous 2-5 days and dropping precipitously over the 2 days subsequent to relapse. Additionally, women who relapsed had higher absolute (unstandardized) symptom scores on their quit day than those who were abstinent for 30 days. These findings imply that escalation of withdrawal symptoms, craving, and smoking urges during a quit attempt may contribute to smoking relapse. Frequent symptom monitoring might be clinically important for relapse prevention.     

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.     

A self-administered questionnaire to measure cigarette withdrawal symptoms: the Cigarette Withdrawal Scale.

Because few tobacco withdrawal scales have been submitted to appropriate validity analyses, we sought to develop and assess the validity of a new, self-administered scale measuring cigarette withdrawal symptoms. We generated the instrument content by conducting a qualitative survey of 404 smokers and ex-smokers. Then we tested 61 items on the Internet in 3,050 smokers and ex-smokers. Subsamples provided comprehensive retest data after 17 days (n = 1218) and smoking status after 41 days (n = 673). The study resulted in a 21-item, six-dimension scale labeled the Cigarette Withdrawal Scale (CWS-21). The six subscales cover the main components of nicotine or tobacco withdrawal in the Diagnostic and Statistical Manual of Mental Disorders and International Statistical Classification of Diseases and Related Health Problems and in qualitative data: Depression-anxiety, craving, irritability-impatience, appetite-weight gain, insomnia, and difficulty concentrating. The six scores had a satisfactory test-retest reliability (r = .60-.71) and a high internal consistency (Cronbach's alpha = .83-.96). The factor structure of the scale was robust in a bootstrap resampling procedure. In ex-smokers, all scores except appetite-weight gain and insomnia predicted relapse at 41-day follow-up. In recent ex-smokers who had quit smoking less than 14 days before baseline, all scores except appetite-weight gain decreased between baseline and the 17-day retest. In baseline ex-smokers who relapsed to smoking at the 17-day retest, appetite-weight gain decreased and craving increased between baseline and retest. CWS-21 is a reliable, valid, multidimensional measure of cigarette withdrawal symptoms that is sensitive to change over time and predicts relapse to smoking.     

The role of impulsivity on smoking maintenance.

In order to better understand why those higher in impulsivity experience more difficulties during smoking abstinence, the current study examined the possible mechanisms contributing to cigarette smoking relapse. Fifty dependent cigarette smokers completed measures designed to assess craving, tobacco withdrawal severity, and negative affect during 48 hours of nicotine abstinence. Using a series of multilevel models (SAS Proc Mixed Procedure), significant impulsivity x time analyses revealed differences in craving, F(2, 96) = 3.74, p<.05, and anxiety, F(2, 96) = 3.23, p<.05. Simple slopes analyses indicated that heightened trait-impulsivity predicted greater increases in craving and anxiety during a 48-hour abstinence period. These findings suggest that smokers with higher levels of impulsivity may lack the ability to find an accessible and comparable substitute for cigarette smoking during a cessation attempt. This study also highlights the importance of considering individual differences when treating those who wish to quit smoking.     

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.     

Preliminary examination of tobacco withdrawal in adolescent smokers during smoking cessation treatment

Tobacco withdrawal symptoms have been shown to play a significant role in mediating relapse to smoking in adult smokers; however, few prospective studies have examined the course of tobacco withdrawal symptoms over time and their connection to lapse in adolescent smokers. Withdrawal symptoms were assessed weekly for 4 weeks in a sample of adolescent smokers participating in a pilot cessation intervention. Adolescent smokers experienced an exacerbation in overall withdrawal symptoms, particularly of cravings and restlessness, although symptoms were generally mild. The course of symptoms was different for boys and girls: Girls generally experienced a peak and subsequent decline in symptoms early in the establishment of abstinence, whereas boys experienced a constant level of symptoms that did not decline over the 4 weeks. Finally, withdrawal symptoms experienced on quit day were not related to lapse to smoking during the course of treatment for either boys or girls. These results suggest that although withdrawal symptoms may be uncomfortable, they may not be the most salient to a lapse to smoking for adolescent smokers attempting to quit. These findings have direct implications for the design and implementation of treatment of nicotine dependence in adolescent smokers.     

"Withdrawal symptoms" in adolescents: a comparison of former smokers and never-smokers.

Since the early 1980s, investigators have been reporting that adolescent smokers felt "dependent" on cigarettes and that adolescents trying to quit smoking experienced the same withdrawal symptoms observed in adult quitters, including restlessness, insomnia, increased appetite and weight gain, irritability or anger, depression, craving for cigarettes, and trouble concentrating. We hypothesized that most of these symptoms might be attributed to adolescence itself. To investigate this hypothesis, we examined the prevalence of these seven "adult" withdrawal symptoms in a population of adolescent former smokers and never-smokers. Participants were high school students in Houston, Texas, participating in a nested, group-randomized control group study designed to estimate the impact of a CD-ROM intervention for smoking prevention and cessation. We measured differences in symptoms frequency between never-smokers and former smokers, matched in a 2:1 ratio on sex and race/ethnicity, and differences in symptoms among former smokers as a function of time since final quit attempt and prior level of smoking. Only former heavy smokers have shown significantly higher prevalence of withdrawal symptoms compared with never-smokers. Of the seven symptoms assessed, only craving incrementally increased with the intensity of smoking. Overall the individual withdrawal symptoms did not effectively differentiate between 112 never-smokers and 34 former lighter smokers (persons who used to smoke less than "a few cigarettes on most days"). Withdrawal symptoms can reliably differentiate former heavy smokers from light smokers and never-smokers, among adolescents. Because most adolescents tend to be lighter smokers, future tobacco use and cessation studies should interpret adult withdrawal symptoms among adolescents with caution.     

Electronic nicotine delivery systems: a research agenda

Electronic nicotine delivery systems (ENDS, also called electronic cigarettes or e-cigarettes) are marketed to deliver nicotine and sometimes other substances by inhalation. Some tobacco smokers report that they used ENDS as a smoking cessation aid. Whether sold as tobacco products or drug delivery devices, these products need to be regulated, and thus far, across countries and states, there has been a wide range of regulatory responses ranging from no regulation to complete bans. The empirical basis for these regulatory decisions is uncertain, and more research on ENDS must be conducted in order to ensure that the decisions of regulators, health care providers and consumers are based on science. However, there is a dearth of scientific research on these products, including safety, abuse liability and efficacy for smoking cessation. The authors, who cover a broad range of scientific expertise, from basic science to public health, suggest research priorities for non-clinical, clinical and public health studies. They conclude that the first priority is to characterize the safety profile of these products, including in long-term users. If these products are demonstrated to be safe, their efficacy as smoking cessation aids should then be tested in appropriately designed trials. Until these studies are conducted, continued marketing constitutes an uncontrolled experiment and the primary outcome measure, poorly assessed, is user health. Potentially, this research effort, contributing to the safety and efficacy of new smoking cessation devices and to the withdrawal of dangerous products, could save many lives.     

Menstrual cycle phase effects on nicotine withdrawal and cigarette craving: a review.

Evidence suggests that women are less likely to quit smoking than are men. This may reflect differences in nicotine dependence and, more specifically perhaps, nicotine withdrawal and craving. However, there is conflicting research on gender differences on the experience of withdrawal and craving. Menstrual cycle effects may moderate this relationship. Given hormonal changes during the menstrual cycle, abstinence-related symptoms such as withdrawal and craving may vary as a function of menstrual phase as well. This qualitative review summarizes the modest but expanding body of research in this area. One of the challenges inherent in interpreting this literature is the difficulty in distinguishing withdrawal symptomatology from premenstrual symptomatology. Methodological variation, including limited sample size and possible selection bias, in which several studies finding null effects excluded women with severe premenstrual dysphoric disorder, may explain some of the inconsistent findings across studies. Nonetheless, some of the 13 studies included in this review found heightened experiences of withdrawal or craving within the latter days of the menstrual cycle (i.e., the luteal phase). Further research is necessary to replicate these findings, but they may suggest the need for focused cessation treatment during the luteal phase or quit attempts that are well timed relative to specific menstrual phases.     

Clinical laboratory evaluation of potential reduced exposure products for smokers.

Smoking-related cancer and other disease account for more than 400,000 U.S. deaths annually. Smoking cessation reduces smoking-related disease rates, but relapse rates are high. Thus, interest in reducing the harm of continued smoking is growing. Potential reduced exposure products (PREPs) are marketed to reduce smokers' exposure to smoke toxicants such as carbon monoxide (CO) and carcinogens and may be harm reduction tools. New PREPs are proliferating, but past experience with "low-yield" cigarettes that failed to reduce smokers' toxicant exposure suggests that comprehensive evaluation is necessary to predict if these new products are likely to alter the harm caused by smoking. The purpose of the study was to develop clinical laboratory methods for PREP evaluation. Smokers (N = 35) completed four, 5-day conditions that differed by product used: Advance, Eclipse, own brand cigarettes, or no cigarettes. Carcinogen (as assessed by one nitrosamine and one polycyclic aromatic hydrocarbon biomarker) and nicotine exposure were assessed via thrice-weekly urine sampling. Withdrawal symptoms were measured daily, and smoking behavior was assessed on the first and last day of each condition. Relative to own brand, Advance reduced exposure to the nitrosamine NNK and CO, and Eclipse reduced exposure to nicotine and the nitrosamine NNK, increased exposure to CO, and resulted in larger, longer, and more frequent puffs. No smoking reduced exposure to the nitrosamine NNK, CO, and nicotine, whereas withdrawal was elevated (all p values <.05). Clinical laboratory evaluation of PREPs for smokers is valuable for measuring users' smoke toxicant exposure, withdrawal, and smoking behavior and should be incorporated into a comprehensive PREP evaluation strategy.     

Pilot study on lower nitrosamine smokeless tobacco products compared with medicinal nicotine.

Smokeless tobacco (ST) products have the potential to be used as a harm reduction method for cigarette smokers. These products can deliver significantly less toxicants than cigarettes, although they are not toxicant free nor harmless. It is important to examine potential health risks and benefits of these products. These two small pilot studies examined the effects of two different ST products (Exalt and Ariva) compared with medicinal nicotine, another potential harm reduction product. Dependent, healthy adult cigarette smokers, who were motivated to quit smoking, underwent 1 week of baseline smoking measurement. They were then asked to quit smoking and were randomly assigned to use either an ST product or a medicinal nicotine lozenge (MNL, Commit) for 2 weeks, then crossed over to use the other product for 2 weeks. In the last week, following the sampling phase, subjects could choose the product they wished to use. Assessments were made repeatedly during baseline cigarette use and throughout the 5 weeks of treatment. Outcome measures included biomarkers for tobacco exposure and subjective, physiological, and behavioral responses. Tobacco-specific carcinogen uptake was greater from Exalt than from the MNL, and was comparable between the MNL and Ariva. Physiological effects and subjective effects on withdrawal and craving were comparable among Exalt, Ariva, and the MNL. Ariva was preferred over the MNL, which was preferred over Exalt. With the exception of medicinal nicotine products, low-nitrosamine ST products have the greatest potential to result in reduced toxicant exposure compared with other combustible reduced exposure products and have promise for reducing individual risk for disease. However, the population effect of marketing of such products as reduced exposure/reduced risk is unknown. The need for further research in this area and regulation of tobacco products is evident.     

Tobacco craving predicts lapse to smoking among adolescent smokers in cessation treatment.

Previous research indicates that tobacco craving predicts relapse to smoking among adult smokers attempting to quit. We hypothesized a similar relationship between craving and lapse (any smoking following a period of abstinence) among adolescent smokers during the treatment phase of a clinical trial. A visit was considered a lapse visit if the participant reported smoking or had a carbon monoxide level of 7 ppm or greater subsequent to an abstinent visit. A total of 34 participants (mean age = 14.9 years [SD = 1.3]; mean cigarettes/day = 18.0 [SD = 7.6]; mean Fagerstr?m Test for Nicotine Dependence score = 6.8 [SD = 1.34]; 65% female), were included in the present analysis of 167 treatment visits. Logistic regression analyses showed a positive relationship between degree of craving, measured by the Questionnaire on Smoking Urges, and lapse during smoking cessation treatment (p = .013). Additionally, linear regression analyses demonstrated a strong positive association between cigarettes smoked per day and craving scores (p<.001). Taken together with other data, these findings suggest that degree of craving might influence tobacco abstinence for adolescent smokers. Thus monitoring and addressing craving appears useful to increase the success of adolescent smoking cessation.     

Is Swedish snus associated with smoking initiation or smoking cessation?

Nicotine replacement therapies (NRT) are an effective treatment for tobacco dependence, yet most smokers do not quit or remain abstinent. We investigated whether Swedish snus (snuff) use was associated with smoking cessation among males participating in a large population based twin study in Sweden. Snus use was associated with smoking cessation but not initiation. Given that snus delivers comparable nicotine concentrations but carries lesser cancer risk than cigarettes, snus may be a widely used, non-medical form of NRT. Evaluation of the efficacy of snus for smoking cessation should be evaluated in randomised clinical trials.     

Effects of smoking abstinence, smoking cues and nicotine replacement in smokers with schizophrenia and controls.

The mechanisms underlying the low smoking cessation rates among smokers with schizophrenia (SS) are unknown. In this laboratory study, we compared the responses of 21 SS and 21 non-psychiatric controls (CS) to manipulations of 5-hour smoking abstinence, transdermal nicotine replacement (0 mg, 21 mg and 42 mg), and in vivo smoking cues. Results indicate that SS were more sensitive than CS to the effects of acute abstinence on carbon monoxide (CO) boost, but not more sensitive to the effects of abstinence on urge levels or withdrawal symptoms. SS and CS did not differ in urge response to in vivo smoking cues, but SS were less consistent in their reactions. These findings suggest that heightened sensitivity to the effects of abstinence on smoke intake may partially account for the low cessation rates experienced by SS, but other potential mechanisms should be explored using behavioral laboratory models.     

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.     

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.     

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.     

Impulsivity and smoking relapse.

Previous research has shown that elevated trait-impulsivity heightens the risk for initiating tobacco use and indicates that nicotine may be disproportionately rewarding for more impulsive persons. However, the influence of impulsivity on the ability to maintain nicotine abstinence has not been studied. The present study tested the hypothesis that a higher level of trait-impulsivity would predict a more rapid relapse to smoking following 48 hr of nicotine abstinence. Participants were euthymic, regular smokers (N=45), with a history of at least one major depressive episode, who participated in a paid smoking cessation study with biological challenge (tryptophan depletion). Treatment involved a 1-day skills training workshop followed by 48 hr of bioverified abstinence and weekly follow-up for 1 month. Regression analyses indicated that elevated impulsivity predicted shorter time to relapse following the workshop after controlling for treatment condition, baseline nicotine dependence, and age (beta=-.39, R(2) change=.147, p=.011). Greater impulsivity predicted more rapid relapse to smoking, which mediational analyses indicated could not be explained by positive affect, negative affect, or craving. Findings suggest a need to identify alternative mechanisms to explain impulsive smokers' increased difficulty in maintaining abstinence and to develop targeted treatments that address the special needs of smokers high in impulsivity.     

The nicotine dependence syndrome scale: a multidimensional measure of nicotine dependence.

We report the development of a new multidimensional questionnaire to measure nicotine dependence, based on Edwards's syndromal conceptualization of dependence. We present three studies. In study 1, we administered the Nicotine Dependence Syndrome Scale (NDSS) to 317 smokers in a smoking cessation study. Factor analysis of the NDSS revealed five factors: Drive (craving and withdrawal, and subjective compulsion to smoke), priority (preference for smoking over other reinforcers), tolerance (reduced sensitivity to the effects of smoking), continuity (regularity of smoking rate), and stereotypy (invariance of smoking). A single overall score based on the first principal component, NDSS-T, was retained as a single core measure of dependence. The NDSS showed promising psychometric properties: NDSS-T and factor scores showed strong associations with dependence-relevant measures, even when we controlled for scores on the Fagerstr?m Tolerance Questionnaire (FTQ); and the NDSS predicted urges when smoking, withdrawal in acute abstinence, and outcome in cessation. The five factor scores showed differential patterns of correlations with external validators, supporting the multidimensionality of the measure. In study 2, we revised the NDSS to expand some subscales and administered it to 802 smokers in a cessation study. The same five factors were extracted, the internal reliability of some subscales was improved, and the factor scores again showed associations with dependence-relevant validators, which were largely maintained when we controlled for FTQ scores. In study 3, with 91 smokers in a cessation trial, we established that the test-retest reliability of the subscales was adequate. Thus, the NDSS presents a valid multidimensional assessment of nicotine dependence that may expand on current measures.