Preliminary test of cigarette nicotine discrimination threshold in non-dependent versus dependent smokers.

BACKGROUND: Despite its potential for understanding tobacco dependence, behavioral discrimination of nicotine via smoking has not been formally examined as a function of nicotine dependence level. METHODS: Spectrum research cigarettes were used to compare non-dependent with dependent smokers on the lowest content of nicotine they could discriminate (i.e., "threshold"). Dependent (n=21; 16M, 5F) or non-dependent (n=7; 4M, 3F) smokers were tested on ability to discriminate between cigarettes with nicotine contents of 17, 11, 5, 2, and 1mg/g, one per session, from an "ultra-low" cigarette with 0.4mg/g (all had 9-10mg "tar"). All abstained from smoking overnight prior to sessions, and number of sessions was determined by the lowest nicotine content they could reliably discriminate from the ultra-low on >80% of trials (i.e., ≥5 of 6). Subjective perceptions and cigarette choice behavior were also assessed and related to discrimination behavior. RESULTS: Discrimination thresholds (and most perceptions) did not differ between dependent and non-dependent smokers, with median thresholds of 11mg/g for both subgroups. Yet, "liking" and puff choice for threshold cigarettes were greater in dependent but not non-dependent smokers, while cigarettes with nicotine contents below threshold did not support "liking" or choice in both groups. CONCLUSIONS: In sum, this preliminary study suggests threshold for discriminating nicotine via smoking may not vary by dependence level, and further study is needed to confirm that cigarettes unable to be discriminated are also not reinforcing.

Cross-validation of a new procedure for early screening of smoking cessation medications in humans.

Brief procedures for evaluating medication efficacy may reveal which candidate drugs warrant further testing in clinical trials and which do not. We previously carried out a study of smoking abstinence, involving the nicotine patch, and established the sensitivity of our procedure. In this study, we sought to cross-validate our earlier work by comparing short-term smoking abstinence due to varenicline (relative to placebo) in smokers with high intrinsic quit interest (n = 57) and those with low intrinsic quit interest (n = 67). All the subjects were randomly assigned to either abstinence reinforcement ($12/day) or no reinforcement. In a crossover design, all the subjects participated in two 3-week phases: ad libitum smoking (week 1), dose run-up of varenicline (1.0 mg b.i.d.) or placebo (week 2), and quit attempt on medication verified daily by carbon monoxide <5 ppm (week 3). As with the nicotine patch in the previous study, varenicline (relative to placebo) increased abstinence more effectively in those with high intrinsic quit interest than in those with low quit interest but did not affect abstinence due to reinforcement. These data confirm the feasibility of a brief, sensitive test of the efficacy of cessation medications in smokers with high quit interest.

Development of procedures for early screening of smoking cessation medications in humans.

Candidate medications for smoking cessation may be screened more efficiently if initial evaluations in humans combine the practical advantages of laboratory studies with the clinical validity of clinical trials, such as by increasing participants' "quit motivation" during brief testing. We manipulated "intrinsic" quit motivation by recruiting smokers who either did intend to quit soon ("treatment seekers," N = 47) or did not ("nonseekers," N = 93), and "extrinsic" quit motivation by providing or not providing reinforcement for abstinence ($12/day). All the subjects smoked as they would usually do during weeks 1 and 3, and tried to quit during weeks 2 and 4 using either a nicotine patch (21 mg) or a placebo patch, in accordance with the crossover design of the study. The nicotine patch increased abstinence in treatment seekers but not in nonseekers. Reinforcement had a main effect on abstinence but did not moderate the effects of the nicotine patch or treatment-seeking status. Intrinsic, but not extrinsic, quit motivation of participants may enhance the validity of brief tests of medication efficacy for smoking cessation.

The influence of alcohol pre-treatment on the discriminative stimulus, subjective, and relative reinforcing effects of nicotine.

Alcohol intake may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining why alcohol increases tobacco smoking. In this study, cigarette smokers were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo. Three sessions then followed, in which the generalization of nicotine discrimination was tested across a range of doses (0--20 microg/kg) following pre-treatment with 0, 0.4, and 0.8 g/kg alcohol p.o. Intermittent 'topping' doses of alcohol maintained a steady breath alcohol level (BAL) throughout testing. Generalization testing involved both two- and three-choice ('novel' option) procedures. A visual discrimination task was also conducted to determine the specificity of effects of alcohol. Subjective and cardiovascular measures were obtained concurrent with discrimination responding. The relative reinforcing effects of nicotine were assessed after the end of generalization testing using a choice procedure. Alcohol pre-treatment had no significant effects on nicotine discrimination or self-administration behavior. Alcohol and nicotine each influenced selected subjective responses and heart rate, but virtually no interactions between the drugs were observed. Within the limitations of this study, these results do not support the notion that alcohol acutely alters nicotine's discriminative stimulus, subjective, or relative reinforcing effects at these low nicotine doses. Acute effects of alcohol on smoking behavior may be due to alterations in other effects of nicotine intake or in non-nicotine effects of tobacco smoking.

Quitting cigarette smoking produces minimal loss of chronic tolerance to nicotine.

RATIONALE: Long-term exposure to nicotine is associated with chronic tolerance to its acute effects, adaptation that may lead to tobacco dependence. The time course for loss of this tolerance after cessation of exposure is not known in humans but could relate to risk of smoking relapse. OBJECTIVES: We examined changes in responses to nicotine as a function of days, weeks, or years of smoking cessation in formerly dependent smokers to determine at what point sensitivity to nicotine is reinstated (i.e., loss of tolerance). METHODS: Acute subjective, cardiovascular, performance, and reinforcing (self-administration) effects of nicotine nasal spray (0-20 microg/kg) were assessed prospectively in men and women smokers before and then day-by-day (study 1) or 3 weeks (study 2) after stopping smoking. A smoking resumption period (study 1) and a group of non-quitting smokers (study 2) were included to control for the passage of time. These effects were also compared cross-sectionally between those who had quit for 1-4 years and those who had for 6-19 years in a separate sample of long-time ex-smokers to determine whether lengthier abstinence causes greater loss of tolerance (study 3). RESULTS: No clear loss of tolerance was observed on any measure in studies 1 or 2, suggesting that chronic tolerance is fully maintained for at least weeks after quitting smoking. Sensitivity to nicotine's effects was also not different as a function of years quit in study 3. CONCLUSIONS: Chronic tolerance to nicotine is not lost within several weeks of quitting smoking and may not change even after years of abstinence from tobacco use.

The characteristics of women smokers concerned about postcessation weight gain.

Concern about weight gain after quitting smoking is common among women, however, little is known about the characteristics of women concerned about this weight gain. We characterized concerns about smoking and weight, smoking behaviors and eating attitudes among weight-concerned women smokers. Women (N= 219) were participants in a larger trial comparing different approaches to treating postcessation weight gain concerns, and endorsed considerable concern about postcessation weight gain. Women completed assessments of smoking behavior, nicotine dependence and eating attitudes prior to beginning treatment. Although weight-concerned women smokers expected to gain 16.5 lb after quitting, most were willing to tolerate a weight gain of only 5 lb. A substantial number expressed unwillingness to gain any weight at all. However, weight-concerned women did not have elevated nicotine dependency or aberrant eating attitudes. Thus, although weight-concerned women smokers expected to gain large amounts of weight after quitting, they expressed a willingness to tolerate only minimal weight gain. The discrepancy between expected and tolerable weight gain may undermine efforts to quit smoking in this group of women.

Cognitive-behavioral therapy to reduce weight concerns improves smoking cessation outcome in weight-concerned women.

Women smokers concerned about weight gain (N = 219) were randomly assigned to 1 of 3 adjunct treatments accompanying group smoking cessation counseling: (a) behavioral weight control to prevent weight gain (weight control); (b) cognitive-behavioral therapy (CBT) to directly reduce weight concern, in which dieting was discouraged; and (c) standard counseling alone (standard), in which weight gain was not explicitly addressed. Ten sessions were conducted over 7 weeks, and no medication was provided. Continuous abstinence was significantly higher at posttreatment and at 6 and 12 months of follow-up for CBT (56%, 28%, and 21%, respectively), but not for weight control (44%, 18%, and 13%, respectively), relative to standard (31%, 12%, and 9%, respectively). However, weight control, and to a lesser extent CBT, was associated with attenuation of negative mood after quitting. Prequit body mass index, but not change in weight or in weight concerns postquit, predicted cessation outcome at 1 year. In sum, CBT to reduce weight concerns, but not behavioral weight control counseling to prevent weight gain, improves smoking cessation outcome in weight-concerned women.

Reinforcing effects of nicotine as a function of smoking status.

The authors compared acute nicotine self-administration among 4 groups varying in current or past dependence: dependent smokers, nondependent smokers, ex-smokers who had quit at least 1 year ago, and nonsmokers. Nicotine (0 vs. 12 microg/kg/8 sprays) available by nasal spray was self-administered with a choice procedure. Self-administration also was related to participant characteristics (sex, alcohol and caffeine intake, sensation-seeking score) and to subjective responses to initial nicotine spray exposure. Nicotine self-administration was similar between dependent and nondependent smokers but was greater in those groups than in ex-smokers and nonsmokers, who did not differ from each other. Self-administration was unrelated to most other participant characteristics. In nonsmokers, self-administration was related directly to pleasurable effects but inversely to aversive effects. Few effects were related to self-administration in the other groups.

Subjective responses to nicotine in smokers may be associated with responses to caffeine and to alcohol.

Sensitivity in responses to one drug may relate to sensitivity to other drugs, suggesting broad individual differences in characteristic responsivity across drugs. Data from two separate studies of smokers were reanalyzed to examine associations between acute subjective and cardiovascular effects of nicotine vs. caffeine and between nicotine vs. alcohol. Typical intakes of cigarettes, alcohol, and caffeine were included as covariates when they were correlated with the responses of interest. Significant associations between nicotine and caffeine were seen for most of the subjective measures and for blood pressure responses. Fewer significant associations were observed between nicotine and alcohol. Responses associated between nicotine and both of the other drugs tended to reflect psychomotor stimulation. These results suggest that smokers who are more responsive to some of nicotine's subjective and blood pressure effects are also more sensitive to the same effects of caffeine and, to a lesser extent, of alcohol.

Smoking cessation in women. Special considerations.

Women may be at relatively greater risk of smoking-related diseases than men but tend to have less success than men in quitting smoking. The failure of most outcome studies to report results by gender and the lack of statistical power for detecting significant gender differences currently do not allow for many firm conclusions to be drawn about smoking cessation rates in women, but several trends warrant attention and further study. First, the difference in cessation rates for women versus men may be even greater in trials of nicotine replacement therapies (NRT). This suggests that women benefit less from NRT relative to men, although this difference may depend on the particular form of NRT (e.g. inhaler versus gum). On the other hand, some non-NRT medications may reverse the poorer outcome of women, producing quit rates in women comparable with those in men. Gender differences in outcome, as well as overall success rates, with NRT and some of the non-NRT medications appear to be enhanced when treatment includes substantial behavioural counselling. However, while several of the non-NRT medications may be particularly appropriate to consider for treating women trying to quit smoking, adverse effects may limit widespread use of some of these drugs, such as clonidine and naltrexone. Thus, even if the gender differences in outcome with NRT versus non-NRT drugs are confirmed in further research, such findings do not necessarily justify limiting NRT use in women, because such treatment is clearly effective and is likely to be safer and more readily available than non-NRT medications. Nevertheless, study of the mechanisms by which some non-NRT drugs are effective in women may aid our understanding of factors that are more influential in smoking behaviour in women than in men. Secondly, smoking cessation treatment for women must address several other issues that often emerge, and these are most likely to require behavioural counselling that is tailored to these problems. These issues include concern about bodyweight gain, restrictions on medication use in pregnant smokers, variability in mood and withdrawal as a function of menstrual cycle phase, harnessing social support to foster abstinence, and the possibility that smoking-associated environmental cues may be more influential in smoking behaviour in women than men. Greater attention to gender differences in clinical trial outcomes and to addressing concerns of women smokers may aid in the development of substantially improved smoking cessation interventions for women.

Threshold doses for nicotine discrimination in smokers and non-smokers.

RATIONALE: Tobacco use during initial experimentation often involves modest nicotine exposure, escalating to larger doses and more frequent exposure with the onset of tobacco dependence. Threshold doses for nicotine discrimination therefore may differ between naive and experienced tobacco users. OBJECTIVES: We determined the lowest (threshold) dose of nasal spray nicotine that smokers and non-smokers could reliably discriminate from placebo spray. METHODS: Male and female smokers (n=18) and non-smokers (n=17) were initially trained to discriminate 20 microg/kg from placebo before proceeding to threshold determination sessions, which involved discrimination of progressively lower doses below 20 microg/kg ("descending order" subgroup) or higher doses above 1 microg/kg ("ascending order" subgroup). Threshold was determined by the lowest dose reliably discriminated from placebo (correct on > or =80% of testing trials) and by failure to discriminate the next lowest dose. RESULTS: Threshold doses for nicotine discrimination were low and not different between smokers and non-smokers (median thresholds of 3 versus 2 microg/kg and approximate blood levels of 2.6 versus 1.6 ng/ml, respectively). Thresholds were similar between descending and ascending order subgroups. Several subjective responses differentiated threshold dose from the dose just below threshold, particularly in non-smokers. CONCLUSIONS: Threshold doses for nasal spray nicotine discrimination in humans are low, well below the typical nicotine delivery of most cigarette brands, and may not change after long-term smoking exposure.

Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli.

Although nicotine intake clearly reinforces cigarette smoking behavior, non-nicotine smoke stimuli may become conditioned reinforcers of smoking. In Study 1, we compared the acute subjective and reinforcing effects of cigarette smoking in men and women under two conditions: blockade of visual and olfactory/taste smoke stimuli vs. no blockade. Subjective hedonic ratings of 'like puffs' and 'satisfying', but not 'strength', 'high in nicotine', or CO boost, were significantly reduced under the blockade vs. no blockade conditions. During subsequent ad lib puffing, significantly fewer puffs were self-administered under the blockade condition, particularly among women. In Study 2, we examined the influences of these stimuli separately and found that olfactory/taste stimuli, but not visual stimuli, reduced hedonic ratings and puff self-administration in women but not in men. In Study 3, procedures similar to those in Study 1 were used to examine whether this sex difference in responses to conditioned stimuli generalizes to a non-drug consummatory behavior, eating (pizza). However, hedonic ratings and ad lib consumption of pizza were substantially reduced in both men and women following blockade of visual and olfactory/taste food stimuli. These results indicate that the presumably conditioned stimuli of olfactory/taste from cigarette smoke may influence subjective hedonic ratings and reinforcement from smoking more in women than in men. However, this sex difference may not generalize beyond smoking or other drug reinforcement.

The discriminative stimulus and reinforcing effects of nicotine in humans following nicotine pretreatment.

Smokers often report that the first cigarette of the day is the most rewarding, and subsequent smoking is less rewarding. Reduction in smoking enjoyment later in the day may be related to acute tolerance to the discriminative stimulus effects of nicotine. We examined changes in nicotine discrimination behaviour in humans as a function of acute nicotine pretreatment. Male and female dependent smokers (n = 15) were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo (0 microg/kg) without nicotine pretreatment. They then were tested on generalization of discrimination across a range of spray doses from 0-20 microg/kg following pretreatment with placebo, moderate dose (14-21 mg) or high dose (28-42 mg) transdermal nicotine. Generalization testing involved both two- and three-response ('novel' option) quantitative procedures. Subjects also engaged in a self-administration phase at the end of each session, involving choices between nicotine (20 microg/kg) and placebo spray. Nicotine pretreatment significantly attenuated nicotine-appropriate responding at higher nicotine spray doses, suggesting acute tolerance, but only in women. Similar results were seen for subjective 'head rush', suggesting this effect may be related to discrimination behaviour in women. However, nicotine pretreatment also increased novel-appropriate responding, especially in men, following intermediate generalization doses, suggesting qualitatively different stimulus effects. Although differences were not significant, nicotine self-administration tended to be inversely associated with nicotine pretreatment dose in men but not in women. These results only modestly support the notion of acute tolerance to the discriminative stimulus effects of nicotine, and even then only in women and not in men.

Dissociation of nicotine tolerance from tobacco dependence in humans.

Chronic functional tolerance to nicotine generally is believed to be associated with processes responsible for tobacco dependence. The dose-related effects of nicotine (0-20 microg/kg by nasal spray) on subjective, cardiovascular, and performance responses were compared among four groups varying in current or past dependence: dependent smokers (21 cigarettes per day for 20 years; n = 45), nondependent smokers (three cigarettes per day for 14 years; n = 12), former dependent smokers (mean of 7 years quit after smoking 25 cigarettes per day for 19 years; n = 17), and life-long nonsmokers (n = 19). Chronic tolerance was determined by a shift to the right, or flattening, of the dose-response curve relative to the curve for nonsmokers. Responses were corrected for plasma nicotine concentration to rule out dispositional tolerance. Chronic tolerance was observed for most subjective responses, but little or none for cardiovascular and performance effects. Tolerance was substantial and virtually identical between dependent and nondependent smokers, whereas tolerance of former smokers was intermediate between nonsmokers and dependent smokers. Identical chronic tolerance between dependent and nondependent smokers indicates that tolerance is not a linear function of smoking exposure and does not require presence of dependence. Thus, the wide variability in daily smoking rate among smokers cannot be attributed to differences in tolerance and must involve other processes of adaptation to nicotine. The modest reversal of tolerance in long-time former smokers suggests that such tolerance reversal is either limited or extremely slow after extended abstinence, despite loss of dependence. These results suggest there is no close link between nicotine tolerance and dependence and question the utility of tolerance as one of the criteria for defining dependence.

Cue dependency of nicotine self-administration and smoking.

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Greater sensitivity to subjective effects of nicotine in nonsmokers high in sensation seeking.

The personality characteristic of sensation seeking is associated with risk of smoking, perhaps because of greater initial sensitivity to nicotine. Young healthy nonsmokers (N = 37) were administered 0, 10, and 20 microg/kg nicotine by nasal spray in 3 separate sessions, and subjective responses were assessed. Sensation-Seeking Scale (SSS) scores were then correlated with these responses. A comparison group of smokers (N = 55) was included to determine whether sensation seeking was associated specifically with initial sensitivity to nicotine or with general sensitivity regardless of past nicotine exposure. SSS subscales, particularly Experience Seeking and Disinhibition, were correlated with subjective responses to nicotine in nonsmokers but generally not in smokers. These findings indicate that sensation seeking is associated with greater initial sensitivity to nicotine's subjective effects and may provide directions for further study of individual-differences characteristics that predispose people to the risk of becoming smokers.

Sex differences in the acute effects of cigarette smoking on the reinforcing value of alcohol.

Alcohol consumption acutely increases smoking behavior, but the reverse relationship, the acute effects of smoking on alcohol intake, largely has been ignored. We examined whether smoking acutely increases the reinforcing value of alcohol, first in the absence of recent alcohol intake and then following an alcohol pre-load. Healthy, social-drinking smokers (n = 11 men, 14 women) engaged in a computerized task involving concurrent schedules of reinforcement for beer (FR10, 3 oz (90 ml) per reinforcement) or money (FR5 to FR30, $0.20 per reinforcement) during two sessions, one following day-long ad lib smoking and the other following overnight smoking abstinence. During each session, subjects performed the task in two sets of trials, one before and one after consumption of an alcohol pre-load, with 60 min between sets. To standardize the alcohol pre-load, all subjects were led to believe that they had earned 9 oz (270 ml) of beer after the first trial set, which they then consumed before the second set of trials. Compared to responding during the abstinent session, responding for alcohol during the smoking session was no different before the alcohol pre-load (trial set one) but was significantly greater following the alcohol pre-load (trial set two), although only in men and not women. Subjective sedation after the alcohol pre-load was attenuated during the smoking session in both men and women, but attenuated sedation due to smoking was related to subsequent alcohol-reinforced responding only in men. Additional research is needed to determine the extent to which these effects in men are pharmacological in nature or are conditioned responses to smoking or to consuming a preferred alcoholic beverage.

Relapse and maintenance issues for smoking cessation.

This article reviews short-term (6 months) and longer term (12-24 months) maintenance of cessation and relapse in adult smokers and the factors and treatments that affect these outcomes. MedLine and PsycLIT searches were done for research published in English between 1988 and 1998 meeting a defined set of criteria. Intensive intervention, telephone counseling, and use of pharmacotherapy were found to improve outcomes; however, compared with public health approaches, they reach relatively few smokers. Brief interventions during medical visits are cost-effective and could potentially reach most smokers but are not consistently delivered. Predictors of relapse include slips, younger age, nicotine dependence, low self-efficacy, weight concerns, and previous quit attempts. Potential areas for research, recommendations for longer follow-up assessments, and standard definitions for slip, relapse, and long-term maintenance are discussed.