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.     

Mecamylamine blockade of both positive and negative effects of IV nicotine in human volunteers

The ganglionic blocker mecamylamine blocks the positive reinforcing effects of IV nicotine, but has been shown to increase cigarette smoking behavior under some conditions. The effects of mecamylamine on subjective and physiologic responses to IV nicotine were evaluated in seven healthy male volunteer cigarette smokers who provided informed consent and resided on a clinical pharmacology research unit. On four separate days, each subject was given a different oral dose of mecamylamine (placebo, 5, 10, or 20 mg). One hour later subjects received the first of four doses of IV nicotine (placebo, 0.75, 1.5, and 3.0 mg); the remaining injections were given at 1-h intervals. Both the positive effects following 0.75 mg and negative effects following 3.0 mg of nicotine were significantly reversed by mecamylamine. Thus, the mecamylamine-induced increase in smoking may be due both to competitive blockade of nicotinic receptors and nicotine's reversal of aversive effects.     

Mecamylamine acutely increases human intravenous nicotine self-administration

Previous studies of human cigarette smoking have shown that administration of the nicotinic acetylcholine receptor antagonist mecamylamine produces acute increases in smoking behavior. In contrast, studies of intravenous nicotine self-administration in animals typically show an immediate decrease in self-administration behavior following mecamylamine administration. To investigate whether this discrepancy might be due in part to the mode of nicotine self-administration (intravenous vs. cigarette smoke), we measured the rate of intravenous nicotine self-administration in tobacco-dependent human smokers. After being trained in a preliminary session to self-administer puff-sized bolus doses of nicotine, 16 subjects were exposed to two sessions (4 h duration) in which they could self-administer intravenous nicotine ad lib. Two hours prior to one session, subjects swallowed a capsule containing 10 mg mecamylamine, and before the other session they took a placebo capsule. Rates of responding for nicotine were assessed, as were subjective reports of withdrawal symptoms and plasma nicotine levels. There was a significantly higher rate of nicotine self-administration in the mecamylamine condition, and mecamylamine attenuated the reduction in craving over the session that occurred during nicotine self-administration. These results indicate that route of administration is not likely the major source of the discrepancy between findings from animal and human studies of nicotine administration. Instead, it is likely that the higher rates of nicotine self-administration induced by mecamylamine were due to an attenuation of the effects of nicotine (e.g., alleviation of withdrawal symptoms) in nicotine-dependent subjects. Thus, animal models of nicotine dependence may need to be employed in conjunction with self-administration procedures in order to duplicate the effects of mecamylamine observed in studies of human smokers.     

Effects of mecamylamine on human cigarette smoking and subjective ratings

Multiple measures of cigarette smoking, subjective effect and physiological effect were collected during 90-min test sessions in normal volunteers. Before sessions subjects received oral doses of mecamylamine (2.5, 5.0, 10, 20 mg) or placebo. Each dose and placebo was given three times in a randomized block sequence. Mecamylamine increased several measures of cigarette smoking, including number of cigarettes, number of puffs per cigarette, and expired air carbon monoxide level. Mecamylamine also produced modest, dose-related decreases in standing blood pressure and increases in standing heart rate. The subjective effects produced by mecamylamine were not characteristic of those of psychoactive drugs. Mecamylamine appears to have increased cigarette smoking by decreasing the effective dose level of nicotine available from cigarette smoking.     

Mecamylamine reduces some EEG effects of nicotine chewing gum in humans

Spontaneous EEG was recorded in nine cigarette smokers who had been abstinent from tobacco for 12 hr. Subjects were treated with a capsule containing either centrally acting nicotine blocker, mecamylamine (10 mg), or placebo. At each of three 60-min intervals after the capsule was ingested, the subjects chewed two pieces of gum containing a total of 0, 4 or 8 mg of nicotine. Nicotine and mecamylamine dose combinations were randomized across subjects. Two three-minute periods of spontaneous EEG were recorded before the capsule and before and after gum chewing from bipolar electrode montages at the following positions: Cz-T5, Cz-T6, Cz-F7 and Cz-F8. During one period the subjects relaxed with eyes closed, in the other period they performed a math task with eyes open. When the drugs were given individually, mecamylamine decreased beta power and nicotine gum (4 and 8 mg) increased alpha frequency. Mecamylamine pretreatment prevented the increase in alpha frequency caused by the 4 mg gum dose but not the 8 mg dose. Alpha power was increased by the 8 mg gum dose and that increase was prevented by mecamylamine. Self-reported ratings of the "strength" of the gum were significantly diminished by mecamylamine pretreatment. The data are consistent with the results of earlier studies which indicate that the effects of tobacco administration and withdrawal are mediated by central actions of nicotine.     

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.     

Assessing the senok,sory role of nicotine in cigarette smoking

Thirty-two subjects were tested in five double-blind sessions (16 subjects in the morning following overnight smoking abstention, and 16 in the afternoon following ad-lib smoking). In each session, subjects smoked one of five experimental (EX) cigarettes having the following FTC nicotine/‘tar’ yields in mg: 0.08/8.5, 0.17/9.1, 0.37/9.8, 0.48/9.8, and 0.74/10.4. In a sixth session, subjects smoked a 0.71/8.6 commercial ‘light’ (CL) cigarette that was their usual brand. Before and after smoking, subjects subjectively rated their desire to smoke a cigarette of their usual brand and had blood smaples drawn. Following smoking subjects rated the cigarette on a variety of sensory dimensions; they also rated smoking satisfaction. Analysis of variance indicated that nicotine played an important sensory role for a variety of dimensions related to cigarette taste and sensory impact but not perceived draw. Principal-components analyses indicated that sensory factors were at least as important as nicotine pharmacology (indirectly indexed by the preto post-smoking rise in blood nicotine concentration) when considering smoking’s overall effects on satisfaction, product acceptance, and reduction in desire to smoke. A preliminary version of these data was presented at the International Symposium on Nicotine. The Effects of Nicotine on Biological Systems II, Montreal, July 21–24, 1994. The authors thank Drs. Brad Ingebrethsen, Deborah Pritchard, and two anonymous reviewers for comments on earlier drafts.     

A system for administering quantified doses of tobacco smoke to human subjects: plasma nicotine and filter pad validation

A new, automated system for administering quantified doses of cigarette smoke to human subjects is described and results of two studies demonstrating the reliability and validity of the system are presented. To overcome the large variability in nicotine and tar delivery associated with previous means of controlling smoke delivery, an automated quantified smoke delivery system was constructed. The system increases the precision and reliability of the smoke and nicotine dose delivered to human subjects. The quantified smoke delivery system was found to deliver doses of nicotine with a substantially greater degree of precision than procedures typically used in previous laboratory studies of smoking behavior.     

Mecamylamine does not precipitate withdrawal in cigarette smokers

Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine’s effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers’ subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Cigarette desirability and nicotine preference in smokers

We conducted two experiments to explore the role of nicotine in the maintenance of cigarette smoking behavior. In Experiment 1 we determined that, compared to 0 or 2 mg injections, an injection of 4 mg nicotine base into the filter of non-nicotine cigarettes significantly increased their desirability. In Experiment 2, to determine how nicotine-seeking varied across a wide range of cigarette deprivation, we studied nicotine preference under three cigarette deprivation conditions: overnight abstinence, 30 min deprivation, and immediately after smoking (satiation condition). Nicotine preference was assessed by allowing subjects to freely adjust the nicotine concentration of each puff using a smoke mixing device. Nicotine preference was greatest after overnight deprivation. Least after satiation, and intermediate after 30 min deprivation. However, nicotine seeking increased as a function of cigarette deprivation despite the fact that higher nicotine puffs were rated as harsher, stronger and less desirable than lower nicotine puffs. The results of both experiments suggest an inverted-U relationship between nicotine content and desirability.     

Mecamylamine does not precipitate withdrawal in cigarette smokers

Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine’s effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers’ subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation. Received: 20 April 1996/Final version: 3 June 1996     

Can cigarette size and nicotine content influence smoking and puffing rates?

The stimuli controlling the rate at which people smoke cigarettes have not been clearly defined. On the hypothesis that smoking is basically nicotine-seeking behavior. nicotine available to the subject was experimentally manipulated through controlling cigarette size and nicotine content. In Experiment I, subjects given their own cigarettes in whole, half, quarter, and eighth lengths, increased the number of cigarettes smoked and number of puffs to compensate for reductions in size. Satisfaction was directly related to cigarette length. In Experiment II, subjects given special cigarettes delivering 0.2 or 2.0 mg nicotine/cigarette smoked significantly more of the low than of the high nicotine cigarettes and took significantly more puffs. As in Experiment I, significantly more quarter length than full length cigarettes were smoked, but total number of puffs did not differe. These results support the hypothesis that nicotine controls smoking behavior.     

Self-administration of intravenous nicotine in male and female cigarette smokers.

Although nicotine is the main addictive chemical in tobacco, there have been few studies of pure nicotine self-administration in humans. The goal of this study was to test the parameters of an intravenous (IV) nicotine self-administration model using nicotine doses presumed to be within the range of those of average intake from cigarette smoking. Six male and four female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. In each experimental session, subjects were randomly assigned to one of the three doses of nicotine (0.1, 0.4, or 0.7 mg). The lowest nicotine dose, 0.1 mg, was chosen to be approximately half the amount of nicotine inhaled from one puff of a cigarette. During each experimental session, subjects first sampled the assigned nicotine dose and placebo and then had the opportunity to choose between nicotine and placebo for a total of six choices over a 90-min period. Out of six options, the average (SEM) number of nicotine choices were 3.0 (0.48) for 0.1 mg, 4.7 (0.48) for 0.4 mg and 4.5 (0.46) for 0.7 mg, indicating a significant effect of nicotine dose on nicotine choice. Both the 0.4 and 0.7, but not the 0.1 mg, nicotine doses were preferred to placebo. These higher doses also produced increases in heart rate, blood pressure, and ratings of drug liking and high. Overall, these findings indicate that smokers chose both the 0.4 and the 0.7 mg nicotine doses over placebo. Our model may be useful in the evaluation of the effects of both behavioral and pharmacological manipulations on nicotine self-administration in humans.     

New lower nicotine cigarettes can produce compensatory smoking and increased carbon monoxide exposure

Potential reduced exposure products (PREPs) are marketed as a means to reduce exposure to tobacco toxicants. Quest cigarettes, a new type of PREP, use genetically modified tobacco to provide a nicotine step-down approach, and are available as 0.6, 0.3 and 0.05 mg nicotine cigarettes. However, these cigarettes deliver equivalent levels of tar (10 mg). Prior research on low nicotine cigarettes suggests smokers will compensate for lower nicotine delivery by increasing their puffing behavior to extract more nicotine. This study tested the hypothesis that compensatory smoking will occur with this PREP as nicotine levels decrease, increasing exposure to tobacco toxins. Fifty smokers completed a within-subject human laboratory study investigating the effect of cigarette nicotine level on smoking behavior. Cigarette nicotine level was double-blinded and order of presentation counter-balanced. Breath carbon monoxide (CO) boost was used as a biomarker of smoke exposure; total puff volume to assess smoking behavior. Total puff volume was greatest for the 0.05 mg nicotine cigarette and CO boost was moderately greater after smoking the 0.3 and 0.05 mg cigarettes compared to the 0.6 mg nicotine cigarette. These data provide novel behavioral and biochemical evidence of compensatory smoking when smoking lower nicotine cigarettes. Although marketed as a PREP, increases in CO boost suggest this product can potentially be a harm-increasing product.     

Blockade of nicotine self-administration with nicotinic antagonists in rats

The reinforcing properties of a variety of drugs abused by humans have been investigated using the technique of intravenous self-administration in the rat. To examine the effect of nicotine dose on nicotine self-administration, Wistar rats were allowed to self-administer various doses of nicotine using a within-subjects Latin square design. An inverted U-shaped dose response curve was obtained, with the highest rates of responding at the 0.03 mg/kg/inf dose. With 1-h daily nicotine self-administration sessions, rats did not appear dependent on nicotine 24 h later, as indicated by the absence of somatic signs of withdrawal after subcutaneous injection of a nicotinic acetylcholine receptor antagonist, mecamylamine (0.57 mg/kg). In another set of studies, pretreatment with subcutaneous mecamylamine or dihydro-beta-erythroidine, two nicotinic acetylcholine receptor antagonists, resulted in significant dose-dependent reductions in nicotine self-administration, at two nicotine doses (0.03 and 0.06 mg/kg/inf). These results indicate that nicotine is an effective reinforcer in Wistar rats under the present parameters, and that these reinforcing effects are mediated by activation of nicotinic acetylcholine receptors.     

High-dose transdermal nicotine and naltrexone: effects on nicotine withdrawal, urges, smoking, and effects of smoking

Although treatment with transdermal nicotine replacement (TNR) has improved smoking abstinence rates, higher doses of TNR could improve effects on urge to smoke, nicotine withdrawal, and reinforcement from smoking, and naltrexone might further reduce reinforcement and urges. A laboratory investigation with 134 smokers using a 3 x 2 parallel-group design evaluated the effects of TNR (42-mg, 21-mg, or 0-mg patch) as crossed with a single dose of naltrexone (50 mg) versus placebo on urge to smoke, withdrawal, and responses to an opportunity to smoke (intake, subjective effects) after 10 hr of deprivation. Urge and withdrawal were assessed both prior to and after cigarette cue exposure. Only 42 mg TNR, not 21 mg, prevented urge to smoke, heart rate change, and cue-elicited increase in withdrawal. Both 21 and 42 mg TNR blocked cue-elicited drop in heart rate and arterial pressure. Naltrexone reduced cue-elicited withdrawal symptoms but not urges to smoke or deprivation-induced withdrawal prior to cue exposure. Neither medication significantly affected carbon monoxide intake or subjective effects of smoking except that 42 mg TNR resulted in lower subjective physiological activation. No interaction effects were found, and no results differed by gender. Results suggest that starting smokers with 42 mg TNR may increase comfort during initial abstinence, but limited support is seen for naltrexone during smoking abstinence.     

Effects of smoking different doses of nicotine on human aggressive behavior

A new methodology was employed to study the effects of drugs on human aggressive behavior in a laboratory situation. The effects of not smoking, smoking a low nicotine dose (0.42 mg/cigarette), and smoking a high nicotine dose (2.19 mg/cigarette) on human nonaggressive and aggressive responding was determined. A nonaggressive response, which resulted in the accumulation of money, was continuously available to the subject. Two different aggressive responses were also available: the ostensible subtraction of money from, and the ostensible presentation of a 1-s blast of white noise to a (fictitious) person. Aggressive responding was elicited by subtracting money from the research subjects, which was attributed to a fictitious person paired with the research subject randomly each day. Nicotine, administered with experimental cigarettes, produced dose-dependent decreases in both types of aggressive responding elicited by low or high frequency subtractions of money attributed to another person. Generally, the more aggressive response option, i.e., subtraction of money from another person, decreased more following nicotine administration. Smoking the same doses of nicotine increased nonaggressive monetary reinforced responding. This indicates that the suppressant effect of nicotine on aggressive responding was not due to a nonspecific depressant action.Portions of these data have been previously reported at a regional meeting of the International Society for Research on Aggression held in Boston, MA, in August, 1981.     

Effects of a nicotine-enriched cigarette on nicotine titration,daily cigarette consumption,and levels of carbon monoxide,cotinine, and nicotine

To test whether cigarettes with low tar, low carbon monoxide, and medium nicotine yield produce less dangerous effects than cigarettes low in tar and CO but high in nicotine, 12 subjects were recruited to smoke nicotine-enriched cigarettes. The subjects smoked three types of cigarettes in the three experimental conditions: (1) their own brand; (2) cigarettes with 4.8 mg tar, 4.0mg CO, and 0.5 mg nicotine; (3) cigarettes with 5.8 mg tar, 4.1 mg CO, and 1.1 mg nicotine. Subjects monitored their daily consumption for 12 weeks; 4 weeks for each condition. During laboratory visits, the subjects smoked a cigarette while their heart rate and carbon monoxide in expired air were measured pre- and post-smoking. A blood sample was drawn and analyzed for nicotine and cotinine in each experimental condition. No significant differences in daily cigarette consumption were found, although a trend (P<0.07) in the direction of fewer nicotine-enriched cigarettes per day was found. Levels of CO varied significantly among the three conditions: The subjects' own brands yielded the highest level, while the nicotine-enriched cigarette yielded the lowest level. No differences were found for nicotine or cotinine levels. A second purpose of the experiment was to record the degree of nicotine titration displayed by individual smokers, tar and CO levels remained constant in the experimental cigarettes. No general titration effect was observed, although for daily consumption it approached significance. When the subjects' nicotine dependence, measured with a tolerance questionnaire, was taken into acount, a correlation with daily consumption was found (r=77, P<0.005). A cigarette with low tar and CO, but medium to high nicotine yield, would seem to produce less hazardous effects and is worthy of further investigation. The controversial question of whether smokers titrate for nicotine is a function of the individual's nicotine dependence.     

Comparative effects of tobacco smoking and nasal nicotine

OBJECTIVE: Compare the electroencephalographic (EEG) and cardiovascular effects of tobacco smoking and nasal nicotine in the same subjects. METHODS: Eleven volunteer smokers were studied after >10 h of overnight tobacco deprivation. Quantitative EEG was used to measure brain electrical changes produced by four different treatments. Each subject smoked a low (0.08 mg) and average nicotine (1 mg) yield cigarette on one test day and received placebo and nicotine nasal spray (0.5 mg/spray) on a second day in a counterbalanced design. EEG activity was measured from 16 scalp electrodes and analyzed as delta, theta, alpha (1), alpha (2), beta (1), and beta (2) frequency bands. Heart rate (HR), blood pressure (BP), and plasma venous nicotine concentrations (VNC) were monitored during both sessions. EEG data from all 16 channels at each of six frequencies were compared over 10 min using repeated measures ANOVA analysis. Changes in HR, BP, and VNC from baseline were compared using ANOVA followed by post hoc Scheffe's test. RESULTS: Smoking an average nicotine delivery cigarette resulted in highly significant decreases in alpha (1) activity, significant increases in alpha (2) activity, and significant increases in both HR and VNC compared to all other conditions. CONCLUSION: When smokers are allowed to pace themselves, cigarette smoking is far more effective than nasal nicotine in activating the EEG and increasing HR and VNC. This lack of equivalent physiological effects may explain the low success rate when nicotine nasal spray is used by those trying to quit smoking.