The World of Caffeine (39 page)

Note:
A Japanese non-smoking man who was drinking alcohol with his coffee would probably feel the effects of caffeine about five times longer than would an Englishwoman who smoked cigarettes but did not drink or use oral contraceptives. If the man had liver damage, the difference could be even more dramatic. Remember this variability the next time you hear apparently contradictory reports from your friends about what caffeine does to them.

*Richard M.Gilbert,
Caffeine: The Most Popular Stimulant,
p. 62.

Caffeine and most other chemical compounds you ingest ultimately make their way to the liver, the body’s central blood purification factory. The bloodstream carries caffeine from the stomach and intestines, throughout the body, and, by means of the hepatic portal vein, through the liver. There it is metabolized, or converted into secondary products, called “metabolites,” which are finally excreted in the urine. More than 98 percent of the caffeine you consume is converted by the body in this way, leaving the remainder to pass through your system unchanged.

Caffeine’s biotransformation is complex, producing more than a dozen different metabolites. The study of these transformations in human beings has been impeded by the fact that the metabolic routes for caffeine demonstrate a remarkable variety among different species. This means that experiments with rats, mice, monkeys, and rabbits, for example, are of limited value in advancing our knowledge of what happens to caffeine in human beings. However, over the past two decades, sophisticated techniques for identifying the components of the caffeine molecule, distinguishing them from very similar compounds, and tracing the fate of caffeine in the body have revealed the human metabolic tree in considerable detail.

These extensive studies disclose that the liver accomplishes the biotransformation of caffeine in two primary ways:

• Caffeine, a trimethylxanthine, may be “demethylated” into dimethylxanthines and monomethylxanthines by being stripped of either one or two of its three methyl groups.
  
• Caffeine may be oxidized and converted to uric acids. This means that an oxygen atom is added to the caffeine molecule.
  

The first of these mechanisms predominates, with the result that the principal metabol ites of caffeine found in the bloodstream are the dimethylxanthines: paraxanthine, into which more than 70 percent of the caffeine is converted, theophylline, and theobromine. Paraxanthine is thus a sort of second incarnation of caffeine.

Although there are multiple alternative paths by which caffeine is metabolized in human beings, all of these pathways end in one or another uric acid derivative, which is then excreted in the urine. Complicating this picture is the fact that the profile of urinary metabolites, that is, the relative mix of the final metabolic products, exhibits marked variation among individuals, with differences observed as between children and adults, smokers and non-smokers, women who are taking oral contraceptives and those who are not.

An additional complicating factor is the fact that chemical metabolism can present cybernetic dynamics, which in this case means that the very process of metabolizing a methylxanthine can alter the speed at which additional amounts of methylxanthines will be metabolized. For example, it has been shown that the methylxanthine theobromine, a constituent of cacao and one of the primary metabolites of caffeine, is a metabolic inhibitor of theobromine itself, of theophylline, and possibly of caffeine as well. Studies reveal that daily intake of theobromine decreases the capacity to eliminate methylxanthines. This could mean, for example, that if you regularly eat chocolate, coffee or tea may keep you awake longer. Conversely, subjects on a methylxanthine-free diet for two weeks increased their capacity to eliminate theobromine. The fact that asthma patients being treated with theophylline need careful monitoring and frequent dosage adjustments is probably a result of these cybernetically governed variations in methylxanthine metabolism.

One of the challenges faced by researchers attempting to analyze any chemical compound’s health effects is the fact that a drug’s metabolites often have more significant effects than did the original drug itself. Scientists are still unsure as to what degree and in what respects caffeine’s metabolites are responsible for its effects, although most would agree that its methylxanthine products contribute to the physical and mental stimulation that is a hallmark of caffeine consumption.

Caffeine gets in and out of your body quickly. The same high solubility in water that facilitates its distribution throughout the body also expedites its clearance from the body. Because caffeine passes through the tissues so completely, it does not accumulate in any body organs. Because it is not readily soluble in fat, it cannot accumulate in body fat, where it might otherwise have been retained for weeks or even months, as are certain other psychotropic drugs such as marijuana. Because caffeine also demonstrates a relatively low level of binding to plasma proteins, its metabolism is not prolonged by the sequential process by which, in chemicals that are highly bound, additional amounts dissociate from the protein as the unbound fraction is excreted or metabolized, extending the active life of the drug in the body.

The degree to which a drug lingers in the body, its kinetic profile, is quantified by what physiologists call its “half-life,” the length of time needed for the body to eliminate one-half of any given amount of a chemical substance. For most animal species, including human beings, the mean elimination half-life of caffeine is from two to four hours, which means that more than 90 percent has been removed from the body in about twelve hours. However, the observed half-life can be influenced by several factors and therefore demonstrates considerable individual and group variation. For example, women metabolize caffeine about 25 percent faster than men. But if women are using oral contraceptives, their rate of caffeine metabolism is dramatically slowed. In addition, pregnancy results in a considerable increase the half-life with a concomitant increase in exposure by the fetus.
⁴
Because caffeine is metabolized in the liver, hepatic impairment will also slow caffeine’s metabolism. Newborn infants are dramatically less capable of metabolizing caffeine than are adults, probably because their livers are unable to produce the requisite enzymes, an incapacity that extends the drug’s half-life in them to eighty-five hours. Some studies suggest that many other factors, including the use of other drugs, can raise or lower the metabolic rate from the mean value. For example, cigarette smoking doubles the rate at which caffeine is eliminated, which means that smokers can drink more coffee and feel it less than nonsmokers. Drinking alcohol slows the elimination rate, which means that drinkers feel the caffeine in their coffee more than non-drinkers.
⁵
Research has even suggested that the rate of caffeine metabolism varies among the races, based on findings that Asians metabolize the drug more slowly than Caucasians.
⁶

Relative Half-Life of Caffeine

Adapted from
Drug Facts and Comparisons,
p. 928.

These metabolic findings help us to understand the strong social association between cigarettes and coffee. We picture the writer at his word processor, drinking big mugs of strong coffee as he puffs away at an endless sequence of smokes. We also imagine the typical coffeehouse habitué, gesticulating in a cloud of smoke as he converses with his fellow coffee drinkers. These images make sense. Heavy smokers, to achieve the same stimulating effects, would have to drink far more coffee than non-smokers. See
part 5
of this book, “Caffeine and Health,” for a full discussion of how heavy caffeine use may delay or prevent some of the serious lung complications that can result from smoking, which would constitute an additional strong bond between the two.

The metabolic profile of caffeine may also help to account for the common attempt to use caffeine to combat the effects of alcohol. It is true that the degree of alcohol intoxication is a function of the alcohol level in the blood, a level that cannot be altered by caffeine. However, caffeine, because it is felt more persistently by those who are drinking alcohol, may in fact have a more sustained stimulating effect and in this way help the drinker dissipate the grogginess that is associated with excess boozing.
⁷

The French essayist Michel de Montaigne (1533–92) did not trust physicians because he thought that each person, knowing himself best, is the best judge of the conditions conducive to his own health. Today nearly everyone agrees that good medical doctors and their expert care are indispensable for well-being. Nevertheless, even our quick review of the variability and complexity of caffeine’s metabolism suggests that, whatever the general profile of its behavioral and physical effects, each person must consider his own personal and medical history in order to understand how caffeine might affect him.

Most caffeine advocates and many caffeine opponents agree that caffeine helps to keep a person awake, increases energy, improves mood, and enhances the ability to think clearly In an effort to discover how and to what degree caffeine does these and other things, scientists have investigated it more extensively than any other drug in history. Central to the long-standing debate over health concerns about the use of coffee and tea was the question of how these drinks do what they do, that is, what caffeine’s mechanism of action in the human body is. The Russo-Swiss scientist Gustav von Bunge, a late-nineteenth-century professor at Basel University, who originated the concept of the hematogen in 1885, authored a precursor of contemporary theories. Bunge hypothesized that an unconscious longing of the body to increase its stores of xanthine, a substance present in small quantities in all tissues, was satisfied by caffeine, because of their chemical similarity.
⁸
Although this explanatory mechanism is fanciful by today’s scientific standards, it does recognize caffeine’s membership in the xanthine family and attempts to tie its action to the functions of related compounds naturally occurring in the body.

In approaching the question of how caffeine works, scientists today are confronted with the complex circumstance that the drug produces an effect, and in certain instances more than one effect, on the cardiovascular, respiratory, renal, and central and peripheral nervous systems. Partly as a consequence of this complexity, no one has identified caffeine’s mechanism of action with any certainty. Particularly unclear are the sources of its psychostimulant and cardiovascular effects.

A good way to begin our inquiry into the possible mechanisms underlying caffeine’s effects is to briefly consider the ways other stimulants, such as amphetamine and cocaine, have been understood to operate.

Stimulants seem to work in one of two ways, as agonists or antagonists. Agonists are substances that aid drug or bodily processes by increasing or decreasing the production or effectiveness of hormones or neurotransmitters that, through the modulation of neuromediators, cause nerve cells to fire more frequently and more energetically. Antagonists, or agents that work to reduce the action of drug or bodily processes, augment or diminish the uptake of neurotransmitters that, had they been allowed to reach their uptake sites, would have caused the nerve cells to fire more or less frequently or energetically. In rough laymen’s terms, the stimulants in the first group help you generate or utilize a charge of energy, while those in the second group delay the dampening or dissipation of whatever energy is already circulating.

Amphetamine and methamphetamine work in the first of the ways described above. Amphetamines are essentially artificial adrenaline, and, when they circulate in the bloodstream, all the effects of increased adrenaline production are experienced. Amphetamine exerts most of its central nervous system (CNS) effects by releasing nitrogen-containing organic compounds,
or amines, from their storage sites in the nerve terminals. Its analeptic, or alerting, effect and a component of its muscle-stimulating action are thought to be mediated by the release of the hormone norepinephrine by the brain. Other components of motor stimulation and the stimulating effects of amphetamine are probably caused by the release of the neurotransmitter dopamine.

Cocaine works in the second way. Where amphetamine stimulates increased production of a neurotransmitter such as dopamine, cocaine achieves many reinforcing effects by inhibiting the uptake of dopamine by the neurons. Both mechanisms result in increased concentrations of dopamine at the synapses, or junctures connecting the neurons.

Although the use of stimulants in both categories can be self-reinforcing, only stimulants that depend for their effects on the first mechanism tend to produce tolerance and physical dependence, two major clinical manifestations of addiction. Stimulants that depend for their effects on the second mechanism tend to remain effective at or near the original dose, and, although they may produce psychical habituation, that is, a strong mental craving, they do not create a true physical dependence or metabolic tolerance characterized by somatic, or bodily, withdrawal symptoms.

Modern investigations into the pharmacology of caffeine are both intricate and inconclusive. Although techniques have become dramatically more sophisticated in the past few decades and researchers have applied tremendous energies and considerable resources to unraveling the tangled skein of caffeine’s course of action in the human body, the results are not only difficult for a layman to understand but are ambiguous and tentative at best, even when considered by the experts. Three theories have successively enjoyed favor in the last two decades, and two of these three have already been discredited. The fate of the third remains undecided.