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The metabolic effects of nicotine have been implicated in the relation between smoking and lower body weight. This study examined whether the nicotine-induced increase in the metabolic rate observed at rest is also present during physical activity. We compared the energy expenditure of 10 male smokers receiving nicotine (15 micrograms per kilogram of body weight) with that of 10 male smokers receiving placebo on two occasions, each including a period of rest and a period of exercise on a modified bicycle ergometer at workloads designed to simulate and standardize light daily activity. All had abstained from cigarette smoking the night before the study. The excess energy expenditure attributable to nicotine was more than twice as great during exercise (difference between groups, 0.51 kJ per kilogram per hour, or 12.1 percent of the metabolic rate at rest; P less than 0.001) than during rest (0.23 kJ per kilogram per hour, or 5.3 percent of the metabolic rate at rest; P less than 0.05). In contrast, the expenditure was not affected by placebo during exercise or rest in the smokers or in a comparison group of 10 non-smokers, indicating that smoking status has no long-term metabolic effect in the absence of short-term nicotine intake. We conclude that the relatively small metabolic effect of nicotine when the subject is at rest is enhanced during light exercise. Our data also suggest that the weight gain that often follows smoking cessation may be influenced not only by nicotine intake but also by the level of physical activity a smoker typically engages in while smoking.

Nicotine and alcohol are often consumed concurrently by smokers. Each drug alone produces significant subjective and cardiovascular responses, but the effects of the two drugs in combination have rarely been examined. Smokers who were moderate alcohol drinkers (n = 18, 9 males and 9 females) participated in four sessions, involving acute administration of nicotine/placebo and alcohol/no alcohol. Subjects abstained overnight from tobacco and alcohol prior to each session. Nicotine (20 micrograms/kg per presentation) or placebo was administered by measured-dose nasal spray every 30 min for 2 h following consumption of diet tonic water with or without alcohol (0.5 g/kg). Subjective (visual analog scales, Profile of Mood States, Addiction Research Center Inventory) and cardiovascular (heart rate, systolic and diastolic blood pressure) responses were assessed after each nicotine/placebo administration. Nicotine increased head rush, dizzy, and most stimulant effects (i.e. jittery, tension, and arousal and decreased fatigue and relaxed), while alcohol increased intoxication, head rush, dizzy, and jittery, with no other stimulant effects. Nicotine and alcohol generally produced additive subjective and cardiovascular effects when consumed together, although nicotine attenuated sedating and intoxicating effects of alcohol alone. Furthermore, there were several interaction effects on subjective measures involving gender. Nicotine plus alcohol tended to attenuate some subjective effects due to one drug or the other alone in men but enhanced the effects of either alone in women. These findings indicate that nicotine and alcohol generally have additive subjective and cardiovascular effects, but that men and women differentially respond on some subjective measures to the combination of alcohol and nicotine.

Discriminative stimulus effects of nicotine were evaluated in humans using formal behavioral drug discrimination procedures. Male and female smokers (n = 9 each) were trained on day 1 to reliably discriminate 0 versus 12 micrograms/kg nicotine administered by measured-dose nasal spray. All subjects were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 2, 4, 8, and 12 micrograms/kg (approximately 0-0.8 mg for typical subject) was then examined on day 2. Nicotine-appropriate responding was linearly related to dose, and subjects were able to distinguish the smallest dose (2 micrograms/kg) from placebo. Although there were no differences between males and females in behavioral discrimination, subjective effects were correlated with nicotine discrimination in females but not in males. These findings indicate that humans are able to discriminate among low doses of nicotine per se, that males and females may differ in the stimuli used to discriminate nicotine, and that drug discrimination procedures may be more sensitive than traditional subjective effects measures in distinguishing among low doses of nicotine.

The inverse relationship between smoking and body weight may be due in part to nicotine's effects on reducing hunger and eating. Male smokers and nonsmokers (n = 10 each), abstinent overnight from smoking and food, participated in four sessions, involving consumption of a liquid caloric load or water followed by nicotine (15 micrograms/kg) or placebo via nasal spray every 20 min for 2 h. Hunger and satiety ("fullness") ratings were obtained prior to each dose presentation. At the end of the two sessions involving the caloric load (simulating breakfast), subjects were also presented with typical lunch/snack food items varying in sweet taste and fat content for ad lib consumption. Results indicated that, for both smokers and nonsmokers, the hunger-reducing effects of nicotine occurred only following caloric load consumption, and there was no effect of nicotine on hunger afer water consumption. Smokers unexpectedly reported greater satiation than nonsmokers following the caloric load regardless of nicotine or placebo condition. Nicotine also resulted in less caloric intake during the meal, and the decrease was not specific to consumption of sweet, high-fat foods. These results indicate that nicotine reduces appetite, possibly helping to explain the influence of smoking on body weight.

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The effects of short-term nasal spray nicotine replacement in suppressing desire to smoke and ad libitum cigarette smoking behavior were evaluated in male and female smokers. In study I, 10 male and 10 female smokers received intermittent doses of 0, 7.5, 15, and 30 micrograms/kg nicotine by way of measured-dose nasal spray, with each dose on a separate day. Self-reported desire to smoke was significantly suppressed by each nicotine dose compared with placebo, but there were no significant differences among nicotine doses or between men and women. In study II, eight male and eight female smokers received 0, 15, and 30 micrograms/kg nicotine intermittently and were allowed to smoke their preferred brands of cigarettes ad libitum. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latency to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attributable to 15 micrograms/kg tended to be greater in men than in women. However, plasma nicotine concentrations were significantly higher after 15 and 30 micrograms/kg versus placebo, suggesting only partial compensation in smoking behavior with short-term nasal nicotine replacement. These findings support the idea that short-term nicotine replacement decreases smoking desire and behavior, but the findings indicate that smoking behavior is partly influenced by factors other than nicotine regulation.