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.

Although nicotine and caffeine have separately been shown to acutely increase subjective arousal, their combined effects are unclear. Furthermore, their effects during casual physical activity, the condition under which individuals usually experience nicotine and caffeine, are unknown. Smokers who were regular coffee drinkers (n = 19, 9 males, 10 females) participated in eight morning sessions, involving nicotine/placebo, caffeine/no caffeine, and rest/physical activity (i.e. 2 x 2 x 2 within-subjects design). Nicotine (15 micrograms/kg) or placebo was given via measured-dose nasal spray intermittently after consumption of decaf coffee with or without added caffeine (5 mg/kg), followed by subjective [Profile of Mood States (POMS), Stress-Arousal Checklist, visual analog scales] and cardiovascular (heart rate, blood pressure) measures. Casual physical activity was standardized by low-intensity bicycle riding while sitting comfortably. Results indicated significant subjective and cardiovascular effects of nicotine and caffeine individually, with the combination of nicotine and caffeine generally producing additive or greater than additive effects for each measure. However, activity mediated some of the subjective effects of nicotine, as nicotine appeared to be "stimulating" during rest but not during activity. There were no differences between males and females. These findings suggest that nicotine per se and caffeine generally have additive subjective and cardiovascular effects, and that nicotine may influence subjective stimulation differentially depending on whether a smoker is resting or engaged in casual activity.

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The thermogenic effects of nicotine and caffeine during physical activity compared with rest were examined in male and female smokers (n = 10 each). During eight sessions, nicotine (15 micrograms/kg) or placebo was given via measured-dose nasal spray intermittently after consumption of decaffeinated coffee with or without added caffeine (5 mg/kg), followed by assessment of energy expenditure by indirect calorimetry while subjects engaged in standardized, low-intensity cycle ergometer riding (activity) or remained at quiet rest. Results indicated significant thermogenic effects of nicotine and caffeine individually, with the combination of nicotine and caffeine producing additive effects. Expenditure attributable to nicotine, caffeine, or their combination was significantly enhanced during activity compared with rest, but only for males and not females. Plasma nicotine concentrations were influenced by activity and caffeine, but these pharmacokinetic changes did not appear to explain the differences in expenditure. These findings suggest a sex difference in thermogenic effects of nicotine and caffeine during casual physical activity and potentially explain some of the apparent individual variability in expenditure due to tobacco smoking.