Smoking quit success genotype score predicts quit success and distinct patterns of developmental involvement with common addictive substances.

Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts. We report data that validate a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances. In a cessation study, v1.0 genotype scores predicted ability to quit with P=0.00056 and area under receiver-operating characteristic curve 0.66. About 43% vs 13% quit in the upper vs lower genotype score terciles. Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use. Higher v1.0 scores were associated with (a) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence (P=0.0004) and (b) lower probabilities of membership in a class that reported escalating use (P=0.001). These results indicate that: (a) we have identified genetic predictors of smoking cessation success, (b) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and (c) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts.

Platelet monoamine oxidase, smoking cessation, and tobacco withdrawal symptoms.

Previous studies have found that constituents in tobacco inhibit both forms of the enzyme monoamine oxidase (MAO-A and MAO-B). This enzyme is important in the breakdown of the amine neurotransmitters, including dopamine, which is thought to mediate the reinforcing effects of nicotine and contribute to tobacco dependence. To further examine the relationship between cigarette smoking, smoking cessation and MAO, we measured platelet MAO-B activity in 16 smokers before and after being switched to smoking denicotinized cigarettes; in a subset of six subjects who subsequently quit-smoking, MAO-B activity was also measured at 1 and 4 weeks following cessation. Smoking cessation treatment was provided in an open-label format, and included nicotine skin patch treatment in conjunction with oral mecamylamine (a nicotinic antagonist) and neostigmine (a peripherally acting acetylcholinesterase inhibitor, administered to counteract constipation experienced from mecamylamine). Results showed that smoking behavior, indexed by expired air carbon monoxide levels, was negatively correlated with platelet MAO-B activity prior to smoking cessation. Moreover, MAO-B activity significantly increased by approximately 100% at 4 weeks after quitting smoking. However, little or no recovery occurred within the first week of abstinence, suggesting that the constituents in tobacco responsible for MAO inhibition may have half-lives of several days. Thus, if relapse to smoking is due in part to withdrawal from the MAO-inhibiting effects of tobacco, this effect likely occurs more than 1 week after quitting. Additionally, low baseline MAO-B activity significantly predicted the intensity of withdrawal symptoms reported upon switching to the denicotinized cigarettes as well as after smoking cessation. These results support the view that MAO inhibition from non-nicotine constituents in cigarette smoke is relevant to tobacco dependence and that continued investigation of the potential use of MAO inhibitors in smoking cessation treatment is warranted.

Individual differences in smoking reward from de-nicotinized cigarettes.

Most studies of cigarette smoking and smoking cessation have focused on the psychopharmacological effects of nicotine; relatively few have explored the role of sensory aspects of cigarette smoke. Sensory aspects of cigarette smoke play a role in the maintenance of smoking behavior, and may be particularly important for certain smokers. This paper presents the results of a pooled analysis of nine studies conducted in our laboratory, in order to explore the influence of demographic and smoking-related variables on ratings of de-nicotinized as compared to nicotine-containing cigarettes. A major finding of this analysis is that ratings of smoking derived from de-nicotinized, but not nicotine-containing, cigarettes appear to vary with level of tobacco dependence, suggesting that sensory factors may be more important to highly dependent, as compared to less-dependent, smokers. The implications of these findings for smoking cessation treatment and for future research are discussed.

Acute effects of nicotine and mecamylamine on tobacco withdrawal symptoms, cigarette reward and ad lib smoking.

Separate and combined effects of nicotine and the nicotinic antagonist mecamylamine were studied in 32 healthy volunteer smokers after overnight abstinence from smoking. Subjects participated in three sessions (3 h each), during which they wore skin patches delivering either 0 mg/24 h, 21 mg/24 h or 42 mg/24 h nicotine. Thirty-two subjects were randomly assigned to two groups receiving oral mecamylamine hydrochloride (10 mg) vs. placebo capsules. Two and one-half hours after drug administration, subjects were allowed to smoke ad lib, rating the cigarettes for rewarding and aversive effects. Transdermal nicotine produced a dose-related reduction in the subjective rewarding qualities of smoking. Nicotine also reduced craving for cigarettes and this effect was attenuated, but not eliminated, by mecamylamine. Mecamylamine blocked the discriminability of high vs. low nicotine puffs of smoke, and increased nicotine intake substantially during the ad lib smoking period. Some of the psychophysiological effects of each drug (elevation in blood pressure from nicotine, sedation and decreased blood pressure from mecamylamine) were offset by the other drug. The results supported the hypothesis that nicotine replacement can alleviate tobacco withdrawal symptoms even in the presence of an antagonist such as mecamylamine. Mecamylamine did not precipitate withdrawal beyond the level associated with overnight cigarette deprivation, suggesting its effects were primarily due to offsetting the action of concurrently administered nicotine as opposed to blocking endogenous cholinergic transmission.

Dissociating nicotine and nonnicotine components of cigarette smoking.

To dissociate the sensorimotor aspects of cigarette smoking from the pharmacologic effects of nicotine, smokers rated the subjective effects of nicotine-containing or denicotinized cigarettes, and intravenous (IV) nicotine or saline infusions. Three groups of participants (n=20 per group) received either: (1) continuous nicotine, (2) pulsed nicotine, or (3) saline. Each group was exposed to an IV condition once while smoking a denicotinized cigarette and once while not smoking, in a 3x2 mixed design. A fourth group (n=20) received saline while smoking their usual brand of cigarette. The dose and rate of nicotine administration were individualized based on previous measures of ad lib smoke intake. Denicotinized cigarette smoke significantly reduced craving and was rated significantly more satisfying and rewarding than the no-smoking conditions. IV nicotine reduced craving for cigarettes, and increased ratings of lightheadedness and dizziness. However, no significant satisfaction or reward was reported after IV nicotine. The combination of IV nicotine and denicotinized cigarette smoke produced effects similar to those of smoking the usual brand of cigarette. The results suggest that sensorimotor factors are critical in mediating the immediate subjective response to smoking, and that the immediate subjective effects of nicotine administered in doses obtained from cigarette smoking are subtle. Thus, addressing smokers' needs for both for the sensorimotor aspects of smoking as well as for the direct CNS effects of nicotine may be critical in enhancing smoking cessation treatment outcome.

Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction.

An understanding of drug addiction requires knowledge of the effective drug concentrations to which receptors in the nervous system are exposed. It has often been thought that smoking of abused substances such as nicotine or cocaine produces much higher drug concentrations in the arterial blood than those achieved following any other route of administration. However, to date no studies have sampled arterial blood following cigarette smoking with the rapidity necessary to evaluate this hypothesis. We measured arterial plasma nicotine concentrations in samples collected every 5 s from 13 cigarette smokers during cigarette smoking and during administration of nicotine by intravenous injections. Our results show that, for both routes of administration, concentrations of nicotine in arterial blood were more than 10 times lower than expected. Thus, the delivery of nicotine into arterial blood is substantially slower than would be predicted if nicotine were absorbed as rapidly as has generally been assumed. A plausible explanation of these results is that lung uptake of nicotine considerably slows the entry of nicotine into the systemic circulation, as has been shown for other amines. These results have significant implications for theories of addiction to nicotine as well as other drugs such as cocaine that may be subject to binding by lung tissue.

Naltrexone blockade of nicotine effects in cigarette smokers.

RATIONALE: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. OBJECTIVE: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. METHODS: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. RESULTS: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. CONCLUSIONS: The blockade of nicotine's effects by naltrexone supports a role for opioid mechanisms in cigarette smoking.

Blockade of smoking satisfaction using the peripheral nicotinic antagonist trimethaphan.

The present study was conducted to investigate the role of peripheral nicotinic receptors in mediating the rewarding effects of cigarette smoking. Twelve cigarette smokers rated cigarettes after intravenous infusion of the short-acting peripheral nicotinic receptor antagonist trimethaphan and after placebo (saline) infusions. Subjects were blinded to the infusion and cigarette conditions. Cigarette conditions included subjects' usual brand of cigarette, denicotinized tobacco cigarettes, and nicotine-injected cigarettes that had a tar delivery equal to that of the denicotinized cigarettes but with an enhanced nicotine delivery equal to that of subjects' usual brands. The latter cigarettes were rated as extremely harsh due to the high nicotine/tar ratio. Trimethaphan significantly attenuated the airway sensations associated with nicotine, and eliminated the difference in smoking satisfaction between the usual brand of cigarette and the other two cigarettes. These findings suggest that nicotinic receptors on peripheral nerve endings in the respiratory tract modulate smoking satisfaction and may be important in the maintenance of cigarette addiction.

Nicotine-mecamylamine treatment for smoking cessation: the role of pre-cessation therapy.

The nicotinic antagonist mecamylamine was evaluated in a randomized smoking cessation trial. Four groups of participants (n = 20 per group) received nicotine plus mecamylamine, nicotine alone, mecamylamine alone, or no drug for 4 weeks before cessation. After the quit-smoking date, all subjects received nicotine plus mecamylamine treatment for 6 weeks. Nicotine skin patches (21 mg/24 hr) and mecamylamine capsules (2.5-5.0 mg twice per day) were used. Precessation mecamylamine significantly prolonged the duration of continuous smoking abstinence; abstinence rates at the end of treatment were 47.5% with mecamylamine and 27.5% without mecamylamine. Nicotine + mecamylamine reduced ad lib smoking, smoking satisfaction, and craving more than either drug alone. Moreover, the orthostatic decrease in blood pressure caused by mecamylamine was offset by nicotine. Mecamylamine before smoking cessation may be an effective adjunct to nicotine patch therapy.

Smoking behavior on the first day of a quit attempt predicts long-term abstinence.

BACKGROUND: The nicotine patch has been widely used for smoking cessation, but not all smokers quit using the patch. Knowing which smokers are likely to succeed with the nicotine patch may improve the efficiency of nicotine patch use. OBJECTIVE: To identify predictors of smoking abstinence using baseline characteristics, smoking behavior, and withdrawal symptoms. METHODS: Using 2 randomized clinical trials of pharmacologic treatment, brief counseling, and quit date formats in the outpatient research clinic setting, predictors of smoking cessation were derived in 1 sample (n = 159), then prospectively validated in an independent sample (n = 48). Subjects smoked 1 pack of cigarettes per day or more and were motivated to quit smoking. Self-report of abstinence at 6 months verified by exhaled carbon monoxide of 8 ppm or less was used. RESULTS: Abstinence at 6 months was 24% in the derivation set and 25% in the validation set. Using logistic regression, a model containing quit date abstinence (odds ratio, 10.6; 95% confidence interval [CI], 2.9-38.7) and baseline nicotine dependence (odds ratio, 0.75; 95% CI, 0.6-1.0 per unit increase in Fagerstrom score) provided the optimal predictive ability and was validated in the independent set. Quit date abstinence improved the likelihood of 6-month abstinence by 4.1 over baseline (95% CI, 2.6-6.4) for low-nicotine-dependent smokers and 1.2 (95% CI, 0.6-2.2) for high-nicotine-dependent smokers. Quit date smoking altered the likelihood of 6-month abstinence by 0.2 (95% CI, 0.0-0.8) for low-dependent smokers and 0.1 for high-dependent smokers (95% CI, 0.0-0.6). CONCLUSIONS: Abstinence on the quit date and low-nicotine dependence improve the likelihood of smoking abstinence at 6 months. Smoking on the quit date may be an indication for postponing the cessation attempt or adjusting the therapy for smoking cessation.

Dissociating the nicotine and airway sensory effects of smoking.

This study examined the subjective and cardiovascular effects of two of the components of cigarette smoking when given separately: nicotine and airway sensations. Using a within-subjects design, six healthy volunteer smokers, age 18-45 years, who smoked at least 20 cigarettes per day were given six conditions in a randomized, counterbalanced order. The effects of IV nicotine, IV saline, and denicotinized cigarettes were compared to a standard 1-mg cigarette. The standard cigarette produced more of a calming effect and more irritability reduction than either the nicotine or airway sensations alone. The denicotinized cigarette was similar to the standard cigarette condition, except the cigarette condition was associated with higher feelings of "exhilaration." Many of the positive subjective effects from a denicotinized cigarette were comparable to that of a standard cigarette. These data support the hypothesis that replacement of the sensory cues of smoking with "airway sensory replacement" may be useful for smoking cessation.

Airway sensory replacement combined with nicotine replacement for smoking cessation. A randomized, placebo-controlled trial using a citric acid inhaler.

STUDY OBJECTIVE: This study was conducted to determine if the combination of airway sensory replacement and nicotine replacement improves 10-week smoking abstinence rates over nicotine replacement alone. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Outpatient research clinic. PARTICIPANTS: One hundred healthy volunteers who smoked at least one pack of cigarettes per day and desired to quit smoking. INTERVENTIONS: Subjects received either citric acid (n = 41) or lactose placebo (n = 59) inhalers to cope with smoking urges for 10 weeks. All subjects received self-help materials and nicotine patches for 6 weeks. Return visits were at weeks 1, 4, 6, and 10. Abstinence was defined as zero cigarettes smoked since the quit date verified by exhaled carbon monoxide < or = 8 ppm at all return visits. Inhaler effects were measured by a standardized questionnaire. MEASUREMENTS AND RESULTS: The primary outcome of continuous abstinence at the end of the 10-week treatment period was 19.5% (95% confidence interval [CI] = 7.4 to 31.6%) for the citric acid group vs 6.8% (95% CI = 0.4 to 13.2%) for the lactose group (p = 0.05). Relief from craving and short-term abstinence increased as airway sensations from the inhaler also increased. Abstinence at 10 weeks for subjects receiving strong airway sensations from the inhalers was 33.3% (95% CI = 14.5 to 52.1%). At 6 months, there was no difference in abstinence between the treatment groups (0% vs 5.1%, p = 0.20). CONCLUSIONS: When combined with the nicotine patch, the citric acid inhaler improved 10-week smoking abstinence over lactose inhaler. The combination of airway sensory replacement and nicotine replacement may prove beneficial for smoking cessation.

Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone.

OBJECTIVE: To evaluate concurrent administration of mecamylamine (nicotine antagonist) with nicotine skin patch treatment for smoking cessation. METHODS: This was a randomized, double-blind, placebo-controlled trial. Forty-eight healthy smokers who smoked at least one pack per day were studied at an outpatient smoking cessation research clinic. The subjects ranged in age from 20 to 40 years. Intervention with the nicotine skin patch (6 to 8 weeks) plus oral mecamylamine (2.5 to 5 mg twice a day for 5 weeks) was compared to nicotine patch plus placebo. Mecamylamine treatment began 2 weeks before smoking cessation. The primary outcome was continuous abstinence through 7 weeks after cessation (1 week after treatment), confirmed by expired air carbon monoxide measurements. Secondary measures included point abstinence at 7 weeks, continuous abstinence at 6- and 12-month follow-up, and self-reported withdrawal symptoms. RESULTS: The continuous abstinence rate at 7 weeks was three times higher in the mecamylamine condition: 50% versus 16.7%, p = 0.015. Point abstinence at 7 weeks was 58% for mecamylamine versus 29% for placebo, p = 0.044. At follow-up, continuous abstinence remained higher for mecamylamine: 37.5% versus 12.5% at 6 months (p = 0.046) and 37.5% versus 4.2% at 12 months (p = 0.004). Mecamylamine also significantly reduced craving for cigarettes, negative affect, and appetite. CONCLUSIONS: Agonist-antagonist therapy, consisting of the nicotine patch with oral mecamylamine, may substantially improve current smoking cessation treatment.

Inhalation of vapor from black pepper extract reduces smoking withdrawal symptoms.

Previous studies have suggested that sensory cues associated with cigarette smoking can suppress certain smoking withdrawal symptoms, including craving for cigarettes. In this study we investigated the subjective effects of a cigarette substitute delivering a vapor of black pepper essential oil. Forty-eight cigarette smokers participated in a 3-h session conducted after overnight deprivation from smoking. Subjects were randomly assigned to one of three conditions: one group of smokers puffed on a device that delivered a vapor from essential oil of black pepper; a second group puffed on the device with a mint/menthol cartridge, and a third group used a device containing an empty cartridge. Subjects puffed and inhaled ad libitum from the device throughout the session during which no smoking was allowed. Reported craving for cigarettes was significantly reduced in the pepper condition relative to each of the two control conditions. In addition, negative affect and somatic symptoms of anxiety were alleviated in the pepper condition relative to the unflavored placebo. The intensity of sensations in the chest was also significantly higher for the pepper condition. These results support the view that respiratory tract sensations are important in alleviating smoking withdrawal symptoms. Cigarette substitutes delivering pepper constituents may prove useful in smoking cessation treatment.

Nicotine skin patch treatment increases abstinence, decreases withdrawal symptoms, and attenuates rewarding effects of smoking.

A variety of studies have shown that nicotine skin patches are effective in promoting smoking cessation. This study replicated this effect, in addition, nicotine skin patches were found to decrease a variety of withdrawal effects, including craving for cigarettes, negative affect, hypoarousal, and increased appetite. This study also assessed the depressive symptoms shown by smokers before and after they quit smoking. Control subjects showed a significant increase in depressive symptoms after smoking cessation, whereas the subjects given the nicotine skin patch were not as affected. If the subjects slipped and smoked a cigarette during the time they were wearing the patch, they were asked to rate the effects of that cigarette. These "slip" cigarettes were rated significantly lower in satisfaction and good taste by subjects in the nicotine patch group than by controls. The nicotine skin patch may improve smoking cessation rates both by reducing nicotine withdrawal effects and by reducing the reward of slips back to smoking. This latter effect may prove to be effective in preventing slips from turning into relapses.

Role of nicotine dose and sensory cues in the regulation of smoke intake.

We investigated the role of nicotine dose and sensory cues in the regulation of ad lib smoke intake. The smoking behavior of 12 adult male smokers was assessed in three conditions, presenting either high-nicotine cigarette smoke (high nicotine, high sensory), diluted cigarette smoke (low nicotine, low sensory), or an aerosol containing cigarette smoke constituents suspended in solution, which was low in nicotine, yet high in sensory impact. Subjects showed marked compensatory increases in smoking with the dilute smoke conditions, whereas they puffed and inhaled the aerosol to a similar extent as the high-nicotine cigarette. Thus, subjects regulated their smoking behavior to equate sensory intensity rather than nicotine intake. Moreover, the aerosol and high-nicotine cigarette conditions lowered craving to a greater degree than the dilute smoke condition. Other mood indices, such as arousal and negative affect, were more effectively relieved by the high-nicotine dose condition. These results highlight the importance of sensory cues in the regulation of smoke intake and modulation of craving and suggest the clinical application of techniques for providing relief of cigarette craving during smoking cessation.

Clinical evaluation of a citric acid inhaler for smoking cessation.

In this study, we evaluated the efficacy of a hand-held inhaler as an adjunct to a smoking cessation behavioral program. The inhaler delivered a citric acid aerosol with tobacco smoke flavor. Seventy-four smokers were recruited for a 3-week smoking cessation trial. During the first 12 days of the cessation period, smokers used the citric acid aerosol inhaler instead of a cigarette whenever the urge to smoke occurred. The citric acid inhaler significantly reduced CO levels and enhanced rates of smoking abstinence for those with higher than average (34.2 ppm) baseline end-expired carbon monoxide (CO) levels. Craving for cigarettes and negative affect were also alleviated by the citric acid aerosol. These results suggest that the citric acid aerosol may promote successful smoking reduction or cessation in a subgroup of smokers and relieves withdrawal symptoms such as craving for cigarettes, a symptom difficult to treat with currently available nicotine replacement techniques.

Psychophysiological interactions between caffeine and nicotine.

The interactive effects of caffeine and nicotine were studied in twelve subjects. Mood and physiologic responses to the pharmacologic components nicotine and caffeine were measured, while controlling for the sensory/behavioral aspects of smoking and coffee drinking. Two experimental sessions presented a caffeine x nicotine design, with caffeinated or decaffeinated coffee followed at thirty-minute intervals by controlled inhalations of nicotine and nonnicotine smoke. Results showed that there was a significant interactive effect of caffeine and nicotine on subjective arousal such that nicotine decreased arousal only in the presence of caffeine. These findings extend previous work showing interactive effects of caffeine and self-titrated doses of cigarette smoke in affecting subjective arousal. The effects of nicotine on subjective arousal may, therefore, depend not only on nicotine dose, but also on the presence of caffeine. Heart rate was increased by nicotine and both systolic and diastolic blood pressures were elevated by caffeine. Caffeine also potentiated the increase in diastolic blood pressure resulting from smoke inhalations, but this occurred irrespective of nicotine dose.

Transdermal nicotine facilitates smoking cessation.

The efficacy of a transdermal nicotine patch in facilitation of smoking cessation was evaluated in a randomized double-blind trial. Sixty-five smokers who were highly dependent on cigarettes participated in the study, which included a behavioral smoking-cessation program. The rates of continuous abstinence were significantly higher in the nicotine group both initially (55% versus 34%) and at 3 weeks (18% versus 6%). Certain smoking withdrawal symptoms, including negative affect and hypoarousal, were effectively relieved by the nicotine patch. There was a trend toward a reduction in cigarette craving, whereas hunger and habit withdrawal symptoms were not affected. The main side effect associated with the nicotine patch was skin irritation. These findings suggest that a nicotine skin patch may be a useful aid to smoking cessation; however, the combination of other techniques with nicotine replacement may provide a more effective treatment for symptoms such as craving for cigarettes.