PERKINS NICOTINE - Sportsci



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NICOTINE: PHYSIOLOGY, EXERCISE, AND METABOLIC RATE

Kenneth A. Perkins, Ph.D.

Western Psychiatric Institute & Clinic, University of Pittsburgh

Preparation of this paper was supported by Grant DA-04174 from the National Institute on Drug Abuse.

Address all correspondence to:

Kenneth A. Perkins, Ph.D.

Western Psychiatric Institute & Clinic

3811 O'Hara Street

Pittsburgh, PA 15213

(412)624-1716

Nicotine is clearly the component of tobacco smoke which causes people to begin smoking on a regular basis and which makes it difficult for them to stop (7). There are a number of possible effects of nicotine which reinforce smoking behavior, including improvements in mood, such as decreasing feelings of stress, and maintaining alertness and concentration, which can help facilitate optimal performance on various lengthy cognitive and behavioral tasks (e.g. work duties). Another, less direct, effect of nicotine which may encourage smoking behavior is its influence on reducing body weight (3). Because of societal pressures to keep slim, this influence may induce some, especially female teens, to start smoking. Furthermore, the common experience of weight gain after stopping smoking, although averaging only 3-5 kg, may discourage smokers from trying to quit or encourage ex-smokers to return to smoking (3,7).

To explain nicotine's influence on weight, it is necessary to show that nicotine produces negative energy balance relative to nonsmokers. This can occur from decreases in eating, increases in energy expenditure (physical activity or metabolism), or both. There is surprisingly little evidence that smokers eat less than nonsmokers or that nicotine acutely suppresses appetite (3). Although eating does increase, perhaps temporarily, over the weeks following smoking cessation, this increase is usually not sufficient to explain all of the observed weight gain. Thus, to explain why smokers weigh less than nonsmokers despite eating the same and to account for all of their weight gain after quitting smoking, nicotine must influence energy expenditure by increasing activity or raising metabolic rate. The effects of nicotine on activity and metabolic rate will be described below, followed by a discussion of the possible mechanisms by which nicotine exerts its effects.

It should be emphasized that most studies with humans have not specifically examined the effects of nicotine itself but have usually manipulated exposure to tobacco smoke, which contains thousands of chemical compounds besides nicotine. Therefore, most of the research on the influence of nicotine in humans actually involves the effects of tobacco smoke and may not necessarily identify the impact of nicotine alone on activity or metabolic rate. So, this review will evaluate studies on the effects of tobacco smoking as well as the few studies on nicotine itself in order to try and understand how nicotine affects activity and metabolic rate.

Nicotine and Physical Activity

Animal studies have often shown that injections of small doses of nicotine can cause a short-term increase in locomotion (i.e. activity), while large doses initially cause decreased activity followed by a slight increase in activity (7). This increase in locomotion may become greater with repeated exposure to nicotine over days or weeks. Cessation of nicotine treatment can cause a brief decline in activity. Nevertheless, it has not been shown that this increased activity is a significant cause of reduced weight due to the nicotine treatment, even in studies which find no effect of nicotine on eating despite a reduction in weight. It is possible that the increased activity is very slight in terms of overall caloric expenditure, or that animals compensate for this increased activity by remaining less active during the rest of the day, resulting in no overall change in activity. Further research on the influence of nicotine on total physical activity in animals is necessary to answer these questions.

In any case, there is absolutely no evidence that smoking in humans is associated with an increase in physical activity or that stopping smoking leads to a decrease in activity. In fact, most research suggests the opposite, that smokers are less physically active and may become more active after stopping (8). It is unlikely that the increased activity after stopping is the direct result of nicotine withdrawal, and it may be due to ex-smokers wanting to actively counter the weight gain being experienced after stopping or perhaps to improve their overall health behavior.

One problem with most of these human studies is the use of self-report measures of physical activity, which may be subject to biases due to unreliable recall or social desirability. Studies of the effects of smoking on activity using more objective activity measures (e.g. observation, accelerometers) have not been published. Finally, there has been virtually no research on the short-term effects of nicotine intake or tobacco smoking on activity in humans, in contrast to the substantial animal literature.

In summary, there is no evidence that tobacco smoking or nicotine intake increases physical activity or that stopping smoking decreases activity in humans, even though some animal studies suggest that nicotine may do so.

Nicotine and Metabolic Rate

Given that nicotine does not appear to decrease eating or increase activity in humans, essentially the only remaining explanation for lower body weight in smokers compared to nonsmokers is an increase in metabolic rate. The influence of nicotine or tobacco smoking on metabolic rate has been studied over chronic as well as acute time courses. Chronic effects here refer to differences between regular smokers and never smokers or to changes which occur over weeks or months after changing smoking habits (i.e. quitting or relapsing back to smoking). Acute effects here refer to changes which occur soon after nicotine intake during the smoking of a cigarette (usually within minutes).

Chronic Metabolic Effects of Nicotine

Since resting metabolic rate accounts for about two-thirds of total daily caloric expenditure in sedentary adults, even a small chronic effect of nicotine on metabolic rate could substantially lower body weight in the absence of any change in eating or physical activity. Very few studies have examined the chronic effects of nicotine or tobacco smoke inhalation on metabolic rate in animals. A series of four studies investigated the chronic effects of tobacco smoke exposure or nicotine injections in hamsters and rats (10). Results generally showed modest increases due to several weeks of smoke exposure, but this effect was not statistically significant. There was no apparent long-term effect of the nicotine injections. There have been no other published controlled studies on chronic effect of nicotine on metabolic rate in animals. However, just as in human studies, other animal studies have shown that nicotine reduces body weight without influencing eating or physical activity, leaving a metabolic effect of nicotine as the only obvious remaining cause of the reduced weight.

In the human literature, chronic effects of smoking on metabolic rate have been examined by comparing resting metabolic rate (RMR) between smokers and nonsmokers. Most of these studies involved rather small sample sizes, and they often failed to verify that smokers did not smoke right before RMR assessment. This is an important problem since smoking just before assessment would not allow researchers to determine if increased RMR in smokers was a chronic effect of smoking or was due instead to acute effects of having just smoked (see acute effects below). Nevertheless, just as with the findings from the few animal studies, the vast majority of studies comparing RMR between smokers and nonsmokers have found no significant differences (4).

Chronic influences of nicotine or smoking on metabolic rate have also been determined by examining the change in metabolic rate before and after stopping smoking. The first such study found a significant decrease in a small group of male smokers who quit for at least 4 weeks. Most subsequent studies, however, found no significant decrease in metabolic rate following smoking cessation (4). On the other hand, one recent study reported a significant 12-16% decrease in metabolic rate in females who quit smoking for at least 1 month (2). Metabolic rate returned to the same level it had been prior to quitting in those who relapsed back to smoking but remained reduced in those who stayed quit. There was no significant change in metabolic rate across months in comparison groups of smokers who never quit and nonsmokers. Thus, there may be a chronic decline in metabolic rate after smoking cessation, although most of the studies in this area and the comparisons between smokers and nonsmokers do not support a significant chronic effect of smoking.

Acute Metabolic Effects of Nicotine

Nicotine intake by tobacco smoking occurs very rapidly, as nicotine reaches the arterial circulation within seconds of taking a puff. Nicotine is also cleared relatively quickly from the body, such that the time required to remove half of the drug from the body (i.e., half-life) is approximately 2 hrs. Therefore, nicotine is a fast-acting drug with many acute effects, one of which appears to be a brief increase in metabolic rate.

As with animal research on chronic effects, there has been very little study of acute metabolic effects of smoking or nicotine in animals. In the only study published in detail, a modest dose of nicotine presented by intravenous infusion produced a significant 9% increase in oxygen consumption, a key component in determining metabolic rate. Acute exposure to tobacco smoke produced a smaller but still significant 6% increase.

A number of human studies have examined the acute effects of tobacco smoking and, more recently, nicotine intake by other means (nicotine nasal spray). Most of these studies have employed procedures standard in metabolic research. These procedures usually require that subjects be tested in the early morning after overnight abstinence from food, smoking, coffee, etc., and without having exerted themselves. Aside from exercise studies, metabolic research is also usually done with subjects remaining very still but awake. This is done to minimize any extraneous influences on metabolic rate so that the effect of interest, in this case an acute increase due to tobacco smoking or nicotine intake, can be assessed more easily.

By and large, human studies have found acute increases in metabolic rate very comparable to the results of the animal study reported above. The range of increase observed is generally about 2-10% above resting baseline (4). This increase usually lasts only about 20 minutes or so after smoking a cigarette, probably because many of the biochemical effects of nicotine are similarly brief (see Mechanisms, below). Nevertheless, because smokers tend to smoke one cigarette about every 30 minutes, these brief metabolic increases may occur throughout most of the day. It is likely that the variability in the magnitude of increase is due to poor control by researchers over the amount of nicotine smokers take in when smoking.

It is well known that smokers may smoke in very different ways, from each other and even from themselves at different times. For example, some smokers may tend to inhale intensely and frequently, extracting a lot of nicotine from each cigarette, while others may puff casually and infrequently, obtaining only small amounts of nicotine from each cigarette. Controlling nicotine intake from tobacco smoking is extremely difficult, even after instructing smokers on how long and how often they may inhale (7).

Research using methods of nicotine administration other than smoking have typically produced more reliable acute increases in metabolic rate. For example, one research group has found in three separate studies that the same dose of nicotine from a nasal spray (equal to the average cigarette yield) produces a significant 5-7% increase in metabolic rate for 20 min after nicotine intake (4).

Whatever the precise magnitude of the acute metabolic increase due to smoking, these studies suggest that it has only a small effect that by itself may be too trivial to explain much of the weight difference due to smoking. A consistent 5-7% increase in metabolic rate throughout waking hours would account for only about a 1-kg change in weight over a 4-month period of time, while many studies show that ex-smokers gain about 1 kg in the first month after quitting (8). However, it is important to remember that the acute metabolic studies mentioned previously examined the influence of smoking or nicotine only while subjects were at quiet rest after overnight fasting. Yet, in the natural environment, smokers very often smoke while they are doing a variety of activities (e.g. work tasks, light recreational activities, eating) which themselves can acutely influence metabolic rate. It is the effects of smoking under these more typical conditions which may identify the actual magnitude of the influence of smoking and nicotine on metabolic rate in most smokers.

Most people, including smokers, spend most of their time involved in low-intensity, casual physical activity such as occupational duties, household chores, and sedentary recreation. This spontaneous minor activity can account for as much as 20% of total daily expenditure.

Importantly, as shown in Figure 1, the acute metabolic effects of nicotine intake (by nasal spray) appear to be twice as great under conditions of casual physical activity compared with quiet rest (5). This finding has been replicated in subsequent studies of male and female smokers with nicotine nasal spray. Studies examining whether the metabolic effects of tobacco smoking may be similarly enhanced during activity have not been published. However, one well-designed study found a relatively large metabolic effect of smoking (10%, almost twice typical effect at rest) over a 24-hour period in subjects residing in a calorimetry chamber, which allowed them to engage in casual spontaneous activities while smoking (1).

A few studies have examined whether increasing the intensity of the activity similarly increases the metabolic effect of smoking or nicotine (4). Results were not completely clear, although one study found greater enhancement in the acute metabolic effect of nasal spray nicotine with increased intensity of activity in male smokers, while female smokers experienced a smaller effect at the highest intensity of activity. In any case, the enhanced metabolic effect of nicotine or smoking suggests that this effect may be more important in accounting for weight changes due to smoking than previously assumed based on the studies of effects at quiet rest.

Aside from casual physical activity, smokers also often smoke after eating. Consuming calories itself causes a gradual increase in metabolic rate, as the body burns calories in order to absorb and digest the food just eaten. A number of studies have therefore examined the metabolic influence of nicotine or smoking just after eating a meal. These studies have generally found a smaller metabolic effect under this condition compared with quiet, fasting rest (4,6). Effects of smoking or nicotine in conjunction with other conditions have not been reported. Finally, there do not seem to be any significant individual differences in metabolic effects of smoking or nicotine, such as differences between male and female smokers (aside from the possibly reduced effect during high-intensity activity in females).

In summary, there is little clear evidence of a chronic effect of smoking or nicotine on metabolic rate, but acute studies generally show significant, if small and brief, metabolic increases after intake of smoking or nicotine. Research on the acute metabolic influence of nicotine under more natural conditions suggests that smoking or nicotine can increase metabolic rate to varying degrees depending on what else the smoker is doing when smoking. This also suggests that different smokers may experience different amounts of total metabolic rate increase (and therefore body weight decrease) depending on their typical pattern of smoking throughout the day. Smokers who smoke mostly while busy with various activities may experience a relatively large overall metabolic increase, while smokers who smoke mostly after meals or during quiet rest may experience a smaller increase.

Mechanisms Explaining Acute Metabolic Effects of Smoking or Nicotine

As noted previously, nicotine is a relatively fast-acting drug with many brief biochemical effects (7). One of its most prominent acute effects is sympathetic stimulation, which involves increased circulating catecholamines (norepinephrine and epinephrine). Norepinephrine enhances free fatty acid (FFA) activity and lipolysis, which have been observed following nicotine administration in animals and smoking in humans.

Repeated nicotine intake resulting in repeated increases in FFA activity and lipolysis also helps explain why nicotine selectively decreases fat stores in animals and reduces total body fat in humans. Epinephrine could increase metabolic rate by increasing glucose utilization. The increase in these catecholamines after smoking lasts for about 20 min or more, which accounts for the time course of the acute metabolic increase after smoking. Nicotine also influences numerous other neurochemicals, including acetylcholine, dopamine, cortisol, sertonin, and many others, which could be involved in the metabolic effects of nicotine. Notably, increased dopamine is a likely cause of the acute increases in physical activity observed in animals following nicotine intake.

Explanations for the enhanced effect of nicotine during casual physical activity and the reduced effect of nicotine following a meal are not so clear. The most likely, and simplest, explanation is that these conditions alter the speed with which nicotine is metabolized and removed from the body (i.e., pharmacokinetics). Physical activity causes blood flow to be shunted toward muscles involved in the activity and away from the liver and kidneys, the organs responsible for most drug metabolism. If less blood containing nicotine flows through these organs, then less nicotine is metabolized and removed from the circulation, resulting in larger amounts remaining in the circulation. Larger amounts of nicotine in the circulation may produce larger metabolic effects. Physical activity has also been shown to slow the metabolism of several other drugs (9). In contrast, eating a meal causes blood flow to be shunted away from muscles and toward the gut, liver, and kidneys, which would increase the rate of nicotine metabolism and decrease the amount remaining in the circulation. A smaller amount of nicotine would produce smaller acute metabolic effects. It is also possible that the biochemical changes due to nicotine are themselves influenced by activity or a meal. For example, cocaine has been shown to produce greater than expected increases in catecholamines during physical activity in animals. A similar effect of nicotine could explain the enhanced metabolic effect of nicotine during physical activity.

It is quite clear that nicotine is primarily responsible for the body weight changes due to changes in tobacco smoking. It also seems clear that the acute metabolic effects of smoking are predominantly due to the actions of nicotine. However, there may be some metabolic contribution from other constituents of tobacco smoke, such as carbon monoxide and carbon dioxide, and from the actual behavior of inhaling and exhaling (4). Carbon dioxide and the microscopic particles which make up smoke may each stimulate increases in respiration rate, which would increase oxygen consumption and metabolic rate. A few studies have found that simply instructing subjects to "puff" on an object such as a straw very briefly increases metabolic rate.

In summary, it is likely that nicotine acutely increases metabolic rate by the actions of catecholamines on free fatty acid activity, lipolysis, and glucose utilization, although other biochemical changes due to nicotine may also be involved. Little research has specifically examined the cause of the enhanced metabolic effect of nicotine during casual physical activity or the reduced effect following a meal, but the most likely explanation is that each condition alters the clearance of nicotine from the circulation such that greater amounts of nicotine remain during activity and lesser amounts of nicotine remain after a meal.

Implications of Metabolic Effects of Nicotine

The research described in this review indicates that smoking, and in particular nicotine, acutely increases metabolic rate. Although this research generally did not demonstrate a chronic effect of nicotine on metabolic rate, it is important to recognize that stopping smoking would remove the metabolic influence of the repeated, brief exposures to nicotine normally occurring with each cigarette. Removal of this repeated acute influence most likely contributes to the weight-increasing effect of stopping smoking.

A topic of considerable interest in clinical research concerns the best way to prevent this weight gain after smoking cessation. Dieting has not been very successful and, for a number of reasons, may actually interfere with an ex-smoker's ability to maintain smoking abstinence (3). This outcome leaves increased physical activity as the primary alternative strategy for minimizing weight gain after cessation. Because many people, smokers or nonsmokers, quit formal exercise programs within several months of starting them, it may be wiser to encourage ex-smokers to engage in low-intensity physical activity to increase their caloric expenditure and minimize weight gain. Research on exercise adherence has often shown better compliance with such programs, suggesting that ex-smokers may be more likely to keep weight off. Furthermore, because the metabolic effect of smoking is relatively small, replacing this caloric expenditure does not need to involve substantial amounts of activity. It has been estimated that walking an average of 1-2 miles per day would be sufficient to completely replace the "lost" expenditure from stopping smoking and attenuate weight gain (4).

Finally, a great deal of epidemiological research indicates that increased weight carries with it increased risk of chronic diseases. However, there is no question that the weight gain experienced by most ex-smokers is trivial in terms of health risk, especially when compared to the very substantially increased health risk due to continued smoking. Thus, maintaining smoking cessation, regardless of resulting weight gain, should still be the primary goal of health professionals treating ex-smokers (8).

References

1. Hofstetter, A., Y. Schutz, E. Jequier, and J. Wahren. Increased 24-hour energy expenditure in cigarette smokers. N. Engl. J. Med. 314:79-82,1986.

2. Moffatt, R.J. and S.G. Owens. Cessation from cigarette smoking: changes in body weight, body composition, resting metabolism and energy consumption. Metabol. 40:465-470,1991.

3. Perkins, K.A. Weight gain following smoking cessation. J. Consult. Clin. Psychol., in press.

4. Perkins, K.A. Metabolic effects of cigarette smoking. J. Appl. Physiol. 72:401-409, 1992.

5. Perkins, K.A., L.H. Epstein, B.L. Marks, R.L. Stiller, and R.G. Jacob. The effects of nicotine on energy expenditure during light physical activity. N. Engl. J. Med. 320:898-903,1989.

6. Perkins, K.A., L.H. Epstein, R.L. Stiller, J.E. Sexton, M.H. Fernstrom, R.G. Jacob, and R.D. Solberg. Metabolic effects of nicotine following consumption of a meal in smokers and nonsmokers. Am. J. Clin. Nutr. 52:228-233,1990.

7. U.S. Department of Health and Human Services. The health consequences of smoking: nicotine addiction. Washington DC: U.S. Government Printing Office, 1988.

8. U.S. Department of Health and Human Services. The health benefits of smoking cessation. Washington DC: U.S. Government Printing Office, 1990.

9. von Baak, M.A. Influence of exercise on the pharmacokinetics of drugs. Clin. Pharmacokinet. 19:32-43,1990.

10. Wager-Srdar, S.A., Levine, A.S., Morley, J.E., Hoidal, J.R., & Niewoehner, D.E. (1984) Effects of cigarette smoke and nicotine on feeding and energy. Pharmacol. Biochem. Behav. 32:389-395.

Figure Caption

Figure 1. Mean energy expenditure during baseline activity or baseline rest and periods 1-3 during activity and rest sessions for smokers receiving 15 ug/kg nicotine (filled circles), smokers receiving placebo (open circles), and nonsmokers receiving placebo (open squares). Nicotine or placebo presented prior to each period. Reprinted by permission of the New England Journal of Medicine.

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