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1 From the Department of Human Nutrition, Centre for Advanced Food Studies, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark.
2 Supported by a grant from Fertin Pharma A/S, Vejle, Denmark. 3 Address reprint requests to A Astrup, Department of Human Nutrition, Centre for Advanced Food Studies, The Royal Veterinary and Agricultural University, 30 Rolighedsvej, 1958 Frederiksberg C, Denmark. E-mail: ast{at}kvl.dk.
ABSTRACT
Background: Nicotine replacement therapy limits weight gain after smoking cessation. This finding is partly attributable to the thermogenic effect of nicotine, which may be enhanced by caffeine.
Objective: We assessed the acute thermogenic effects of chewing gum containing different doses of nicotine and caffeine.
Design: This randomized, double-blind, placebo-controlled, crossover study included 12 healthy, normal-weight men (aged 18–45 y). Energy expenditure was measured with indirect calorimetry before and 2.5 h after subjects chewed each of 7 different types of gum containing the following doses of nicotine/caffeine: 0/0, 1/0, 2/0, 1/50, 2/50, 1/100, and 2/100 mg/mg.
Results: The thermogenic responses (increases over the response to placebo) were 3.7%, 4.9%, 7.9%, 6.3%, 8.5%, and 9.8%, respectively, for the gums containing 1/0, 2/0, 1/50, 2/50, 1/100, and 2/100 mg nicotine/mg caffeine (P < 0.05 for all). Adding caffeine to 1 and 2 mg nicotine significantly enhanced the thermogenic response, but changing the caffeine dose (from 50 to 100 mg) did not change the thermogenic effect. None of the combinations changed the respiratory quotient compared with placebo, which indicates that glucose and fat oxidation rates were increased to a similar extent. Side effects occurred only with 2 mg nicotine.
Conclusions: One milligram of nicotine has a pronounced thermogenic effect, which can be increased by 100% by adding 100 mg caffeine. Increasing the nicotine dose to 2 mg does not increase the thermogenic effect but produces side effects in most subjects. Caffeine may be useful in preventing weight gain after smoking cessation if its thermogenic effect can be used to enhance nicotine’s effect on long-term energy balance.
Key Words: Nicotine • caffeine • fatty acid oxidation • carbohydrate oxidation • energy expenditure • respiratory quotient • smoking cessation • weight management • weight control • cigarette smoking
INTRODUCTION
Cigarette smoking is recognized as one of the most important preventable causes of premature death, mainly because it increases the risk of heart disease, diabetes, lung cancer, respiratory disorders, and other illnesses (1, 2). Although the negative health consequences caused by cigarette smoking are well established, 20–35% of people in affluent countries still smoke (3). As many as 40% of smokers would like to quit smoking, but continue the habit. One of the most important barriers to giving up smoking is the tendency to gain weight after quitting; thus, the weight control associated with smoking reinforces the decision to continue smoking (4, 5). A large proportion of smokers, particularly women, admit that they continue to smoke to control body weight (2, 5).
Anorectic properties and increased energy expenditure (EE) produced by nicotine are thought to be the factors responsible for the lower average body weight of smokers compared with nonsmokers (6). Weight gain after smoking cessation results from the withdrawal of nicotine and the subsequent reduction in metabolic rate, altered food preferences, or the consumption of food as a substitute for the psychological effects of tobacco (2, 7, 8). Modest weight gains after smoking cessation are largely unavoidable for most smokers, and a substantial proportion of people who quit smoking gain > 5% of their body weight (9). Nicotine gum has been shown to relieve withdrawal symptoms and double success rates compared with placebos in trials on smoking cessation (10); nicotine gum also diminished weight gain after smoking cessation (11). The use of nicotine gum is therefore an accepted strategy for alleviating withdrawal symptoms and preventing weight gain in the vulnerable period after smoking cessation (11). Dale et al (7) showed that 100% nicotine replacement does not completely prevent weight gain. Consequently, there is a need to develop improved strategies for managing the problem of weight gain after smoking cessation. Because the health risks associated with nicotine use are clearly much less than those linked to cigarette smoking, even in individuals with cardiovascular disease and during pregnancy (12), nicotine replacement therapy may remain a component of improved strategies for preventing weight gain after smoking cessation.
We and other investigators have shown that the thermogenic effect of sympathomimetic compounds such as ephedrine can be potentiated by methylxanthines (13), and that a combination of ephedrine and caffeine is superior to ephedrine monotherapy in producing weight loss in obese subjects (14). Although a combination of ephedrine and caffeine does not seem to have a place in the prevention of weight gain after smoking cessation (15), a combination of nicotine and caffeine has not been considered previously. Caffeine has marked thermogenic properties in man (16, 17), and from a pharmacodynamic standpoint it is likely that nicotine and caffeine possess additive thermogenic effects.
The aim of this study was therefore to assess the acute thermogenic effects of different chewing gums containing nicotine and caffeine, separately and in combination, and to compare their effects with those of placebo chewing gum in healthy, normal-weight men.
SUBJECTS AND METHODS
Subjects
We recruited 12 healthy, lean men aged 18–45 y, with body mass index (BMI; in kg/m2) values of 18.5–25. All the subjects were students at the Royal Veterinary and Agricultural University in Frederiksberg. Six were smokers and 6 were nonsmokers. For inclusion in the smoker group, smoking ≥ 15 cigarettes/d for ≥ 1 y was required, whereas the nonsmokers reported never having smoked on a regular basis (ie, daily). All subjects denied serious current health problems or medication use or any history of substance abuse. Body weight was measured by using a digital scale accurate to 0.01 kg (Lindeltronic 8000S; Lindells, Malmo, Sweden) and height was measured to the nearest 0.001 m. Subject characteristics are shown in Table 1. Subjects were fully informed about the study and gave their written informed consent. The Municipal Ethical Committee of Copenhagen and Frederiksberg approved the study in accordance with the Helsinki II Declaration. Subjects received 3500 DKr (500 Euro) on completion of all the tests.
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TABLE 1 . Characteristics of the subjects1
Study design
The study was a randomized, double-blind, crossover, placebo-controlled trial that tested 7 different chewing gums. Each subject underwent seven 3-h sessions in a within-subject design. Assignment of the order of the different gums was randomized and all subjects received each treatment once. To ensure that all the nicotine and caffeine were extracted from the gum, subjects were asked to maintain a chewing frequency of 1 chew/s (60 Hz). The subjects chewed each piece of gum for 25 min (Figure 1) to ensure a high absorption fraction of the test compounds; chewing for 20 min results in the release of 53–72% of the nicotine (18). The subjects were told that chewing the gum might lead to jaw muscle ache, gassy stomach, hiccups, and increased heart rate.
FIGURE 1. . Protocol for each test day: the first piece of gum was given 30 min after the test started and the second piece was given after an additional 60 min. The subjects chewed each piece of gum for 25 min. The meal was consumed after the final (sixth) measurement (185 min after the test started).
Procedures
Subjects were instructed to abstain from alcohol and physical activity and to drink approximately the same amounts of caffeine in the 2 d before each test day. They arrived at the laboratory on the morning of each test day at 0800 in the postabsorptive state, having refrained from smoking since 2200 the preceding evening. Body weight, height, and electrical impedance were measured. Subjects first rested for 10 min to become habituated to the apparatus and then rested for an additional 30 min while baseline basal metabolic rates were measured with a ventilated hood system (time 0 to 30 min; Figure 1). They rested supine, but sleeping was not permitted. To avoid any influence of physical activity on EE, no movement or change in position was allowed. Subjects completed questionnaires every 15 min from just before the first piece of gum was given until after the meal was consumed. The meal was served after the 6 measurements of EE were completed (at time 180 min) and the subjects could eat ad libitum until comfortably full. The exact time, amount of time spent on eating the meal, and amount of water consumed (maximum of 200 mL) on the first test day were noted and repeated on the subsequent test days. Only 2 pieces of gum were given on each test day (Figure 1). From 1–3 subjects were tested on any single day. A washout period of ≥ 2 d elapsed between test days for each subject.
Energy expenditure and respiratory quotient
EE was measured by using open-circuit indirect calorimetry (Meijnhardt BV, Bunnik, Netherlands). The rates of carbon dioxide production (mL/min;
RESULTS
Energy expenditure
There was a marked overall treatment effect on the thermogenic response to the gum (P < 0.001) (Figure 2 and Table 2), which was also influenced by the covariates resting EE (P < 0.001) and body weight (P < 0.001). Thermogenic response was significantly affected by both nicotine (P < 0.001) and caffeine (P < 0.001), and there was also an interaction between nicotine and caffeine (P < 0.05). The responses were not influenced by smoking status. The thermogenic responses (increases over response to placebo) were 3.7%, 4.9%, 7.9%, 6.3%, 8.5%, and 9.8%, respectively, for the gums containing 1/0, 2/0, 1/50, 2/50, 1/100, and 2/100 mg nicotine/mg caffeine (P < 0.05 for all). The thermogenic responses were higher after 1 mg nicotine (P < 0.001) and 2 mg nicotine (P < 0.001) than after 0 mg nicotine. There was also a greater thermogenic effect of 50 mg caffeine (P < 0.05) and 100 mg caffeine (P < 0.01) compared with 0 mg caffeine. However, there was no significant difference between 1 mg nicotine and 2 mg nicotine (P > 0.05) and no significant difference between 50 mg caffeine and 100 mg caffeine (P > 0.05). Adding caffeine to either 1 or 2 mg nicotine significantly enhanced the thermogenic response, but there was no significant difference between the thermogenic effects of adding 50 or 100 mg caffeine to nicotine.
FIGURE 2. . Mean (± SD) energy expenditure measured in normal-weight men by using indirect calorimetry in the fasting state, during and after chewing 7 different gums containing nicotine, caffeine, or both (n = 12 for all gums except n = 10 for gum containing 2 mg nicotine and 100 mg caffeine). Baseline resting energy expenditure was 5.93 ± 0.56 kJ/min.
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TABLE 2 . Thermogenic effect (change in area under the curve) of nicotine and caffeine in 12 healthy, normal-weight men who chewed 7 different gums containing nicotine, caffeine, or both1
Substrate oxidation
In Figure 3, the effect of treatment on RQ is shown. There was no significant interaction between nicotine and caffeine in the effect of treatment on RQ. Caffeine had a significant treatment effect on RQ (P < 0.05) but nicotine did not when the 2 treatments were analyzed separately by ANOVA. The post-dose RQ was influenced by the covariates baseline RQ (P < 0.001), body weight (P < 0.01), and EE (P < 0.05) according to analysis of covariance. The effects on substrate oxidation are shown in Figure 4.
FIGURE 3. . Mean respiratory quotient (RQ) calculated from energy expenditure measured with indirect calorimetry in normal-weight men in the fasting state, during and after chewing 7 different gums containing nicotine, caffeine, or both (n = 12 for all gums except n = 10 for gum containing 2 mg nicotine and 100 mg caffeine). Left panel: Changes from baseline in mean RQ. Right panel: Mean (± SD) RQ; caffeine had a significant treatment effect (P < 0.05), but nicotine did not, and there was no interaction between nicotine and caffeine on the basis of analysis of variance.
FIGURE 4. . Substrate oxidation after normal-weight men in the fasting state chewed 7 different gums containing nicotine, caffeine, or both (n = 12 for all gums except n = 10 for gum containing 2 mg nicotine and 100 mg caffeine). Mean (± SD) integrated area under the curve above baseline for oxidation of carbohydrate (top) or fat (bottom). There was no significant interaction between nicotine and caffeine treatment, but caffeine had significant treatment effects on fat and carbohydrate oxidation (P = 0.039).
Side effects
No side effects were reported with the placebo gum or the gums that contained 1 mg nicotine with 0, 50, or 100 mg caffeine. Side effects were only reported with the gums that contained 2 mg nicotine. The side effects were headache, unpleasant taste in the mouth, dizziness, vision problems, and nausea (Table 3). The unpleasant taste and sore throat were the only side effects reported with gums containing 2 mg nicotine with either 0 or 50 mg caffeine, and these effects occurred predominantly among nonsmokers. Four of the nonsmokers reported that they felt nauseous and had a sore throat after chewing the gum containing 2 mg nicotine. Two of these subjects had to discontinue the strongest dose (2 mg nicotine and 100 mg caffeine) because of side effects. These side effects also occurred with 2 mg nicotine and 50 mg caffeine, but the side effects were not as pronounced as with 2 mg nicotine and 100 mg caffeine, and all 12 subjects completed this dose. We found that the gums containing different concentrations of nicotine and caffeine were perceived as most unpleasant 5 min after subjects started to chew, and the unpleasant taste abated considerably after 10–15 min.
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TABLE 3 . Observed side effects in all 12 subjects1
DISCUSSION
The present study confirms previous findings of thermogenic effects of both nicotine and caffeine in human subjects (16, 17, 21–23). It further shows the existence of only a weak dose-response relation within the tested dose range of both compounds. This is in agreement with the findings of Collins et al (24), who reported that smoking cigarettes containing 0.80 and 1.74 mg nicotine increased RMR by 5.2% and 6.9%, respectively. It is evident that it is easier to achieve a greater thermogenic response by adding 50 mg caffeine to 1 mg nicotine (+4.2%) than by increasing the nicotine dose from 1 to 2 mg, which only had a modest effect (+1.2%) on thermogenesis. Moreover, little additional increase in thermogenesis was obtained by increasing the caffeine dose from 50 to 100 mg independent of the nicotine dose (Table 2). Quantitatively, a much greater effect on the thermogenic response was achieved by adding caffeine to nicotine, independent of dose. For example, adding 100 mg caffeine to nicotine doubled the thermogenic response compared with placebo. This finding is in agreement with the results of Collins et al (23), who studied the effect of smoking cigarettes together with the ingestion of 200 mg caffeine and found a supra-additive thermogenic effect which was similar in smokers and nonsmokers.
No side effects were reported with the gum containing 1 mg nicotine, and none occurred when 50 or 100 mg caffeine was added. In contrast, 2 mg nicotine produced side effects in most of the subjects and in all nonsmokers. In this study, the thermogenic response to 1 mg nicotine was markedly enhanced by the addition of caffeine without producing any acute side effects. The thermogenic effect of some of the combinations was 8–10% above baseline, which is similar to that of the most promising sympathomimetic compounds and ß3 agonists (25). If the additive thermogenic effect of caffeine and nicotine can be translated into a corresponding enhancement of nicotine’s effect on long-term energy balance, it may be useful in the prevention of weight gain after smoking cessation.
The potentiation of nicotine’s thermogenic effect by caffeine probably results from the 2 compounds’ different mechanisms of action. Nicotine increases sympathetic activity with greater release of norepinephrine from the nerve endings and subsequently enhanced stimulation of ß-adrenoceptors in the thermogenic target tissues. Caffeine acts by amplifying the post-receptor signal via antagonism of the effect of adenosine and inhibition of cyclic AMP (26). We showed previously that the thermogenic effect of caffeine (200 mg, 3 times/d) does not translate into weight loss when it is given in conjunction with an energy-restricted diet (14). However, the thermogenic effect of caffeine is markedly potentiated by another sympathomimetic agent, ephedrine (13), which also produces weight loss in clinical trials (14). Although caffeine monotherapy does not produce weight loss, the combination of ephedrine and caffeine produces significantly greater weight loss than does ephedrine alone (14). On the basis of this and the present results, it is likely that the addition of caffeine to nicotine may improve the ability of nicotine gum to prevent weight gain after smoking cessation.
The thermogenic effect of chewing gum is composed of different components. First, chewing is a thermogenic process per se because of the muscle activity involved. Levine and Baukol (27) found that chewing gum at a frequency of 100 Hz increased EE from 58 to 70 kcal/h, which corresponded to a 19% increase in RMR. To put this into perspective, they found that standing was associated with an increase in RMR of only 11%. In our study, the placebo gum produced an increase in RMR of 4 kcal/h, corresponding to a 5% increase in RMR, which was consistent with our lower chewing frequency of 60 Hz. The chewing gum containing 1 mg nicotine and 100 mg caffeine further increased the mean RMR above that with the placebo gum by 8.5%, so that the total mean increase above RMR would be 14%. Although this figure cannot be extrapolated to a 24-h period, we observed that the thermogenic effect of nicotine in combination with caffeine was still present > 1 h after the second chewing gum was finished. If this thermogenic effect is maintained throughout 75% of the waking hours, with no other change in energy balance, a yearly loss of > 5 kg body fat could be anticipated (28). Perkins et al (21) studied the effect on EE of 1 mg nicotine during rest and during light exercise and found that the thermogenic response induced by nicotine during physical activity was more than twice that during rest (12.1% and 5.3%, respectively). It is therefore likely that the effect of nicotine on EE may be even greater under free-living conditions. In addition, any anorectic effect of nicotine with caffeine may contribute to the prevention of increased energy intake after smoking cessation. To prevent a positive energy balance after smoking cessation and to limit the use of nicotine, nicotine-free, calorie-free gum could be used instead of some of the chewing gum containing nicotine and caffeine.
In most smoking-cessation studies, gum containing 2 mg nicotine has been used. Several studies showed a dose-response relation between nicotine use and prevention of weight gain (11, 29). Doherty et al (11) compared weight gain after smoking cessation during treatment with placebo or gum containing 2 or 4 mg nicotine. They found that weight gain was 3.7 kg in the placebo group, 2.1 kg in the 2-mg nicotine group, and 1.7 kg in the 4-mg nicotine group. Using large amounts of nicotine gum was also associated with lower weight gain according to another report (30). Because nicotine induces insulin resistance, which increases the risk of cardiovascular disease, it may be advantageous to achieve the same effect on energy balance with the use of lower doses of nicotine. This may be possible with the use of 1 mg nicotine and 100 mg caffeine. Much higher doses of caffeine were found to induce slight insulin resistance during acute exposure (31), but tolerance to this effect develops with repeated daily use (14).
In conclusion, we found that 1 mg nicotine has a pronounced thermogenic effect, which is increased by 100% when it is combined with 100 mg caffeine. Increasing the nicotine dose from 1 to 2 mg did not increase the thermogenic effect but produced side effects in most subjects. If the thermogenic effect of adding caffeine can be translated into a corresponding enhancement of nicotine’s effect on long-term energy balance, it may be useful in the prevention of weight gain after smoking cessation.
ACKNOWLEDGMENTS
All authors contributed equally to the study design, data collection, data analysis, and writing of the manuscript. AJ and ST had no financial or personal interest in Fertin Pharma A/S. AA may benefit financially from a nicotine- and caffeine-containing gum marketed by Fertin Pharma A/S, Vejle, Denmark.
REFERENCES