The World of Caffeine

by Weinberg, Bennett Alan, Bealer, Bonnie K.

  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

  Subject Half-Life (in hours)

  Healthy adults 3 to 7.5 (mean, 3.5)

  Pregnant women <18

  Preterm infants 65 to 100

  Term infants 82

  3- to 4.5-month-olds 14.4

  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.

  Mechanism of Action: Caffeine Kicks In

  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 t
he 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.

  The three major theories that have been recently adduced to explain the mechanism of action of caffeine and the other methylxanthines are:

  Calcium mobility theory or the translocation of intracellular calcium;

  Phosphodiesterase inhibition theory, or the mediation by increased accumulation of cyclic adenosine monophosphate (cAMP) due to inhibition of phosphodiesterase; and

  Adenosine blockade theory, or the competitive blockade of adenosine receptors.

  Calcium Mobility Theory

  Inotropic agents are drugs that increase the force of cardiac muscle contraction, thereby tending to increase cardiac output. The most important group of inotropic agents includes digitalis, found in the foxglove plant, which has been used to stimulate the heart muscle in cardiac arrest for hundreds of years. There are several classes of inotropic agents with different mechanisms of action. One type of inotropic agent is caffeine and related methylxanthines, such as theophylline.

  Inotropic agents can influence the body’s response to neurotransmitters through affecting the output of neuromediators such as cyclic adenosine 3-, 5-monophosphate, which indirectly increases the influx of calcium ions into the cells, and thereby increases the force of contraction of the heart muscles. An increase in intracellular calcium increases the force of contraction, since intracellular calcium ions are responsible for initiating the shortening of muscle cells.

  It now appears that caffeine achieves these effects only at toxic dose levels, from ten to a hundred times greater than those normally consumed in coffee, tea, or soft drinks. Consequently it is virtually impossible that calcium translocation is important in explaining the general effects of dietary caffeine.

  Phosphodiesterase Inhibition: The cAMP Cycle of Energy Release

  The human body stores energy in the muscles in the form of sugars called “glycogens.” When you need a burst of energy, for example, when you are exercising or when you have delayed eating, glycogen is quickly released and burned as fuel. In the late 1950s, researchers discovered that a hormone called cyclic adenosine monophosphate, or “cAMP,” which mediates the actions of many neurotransmitters and hormones in the nervous system, played a central role in the regulation of glycogen metabolism. It was demonstrated that, by increasing the persistence of cAMP, through a relatively complex process involving the inhibition of another hormone, phosphodiesterase, caffeine prolongs or intensifies the effect of adrenaline and thus enhances the ability of your body to burn glycogen. This mechanism was widely advanced as the mechanism of caffeine’s stimulating action in the body.

  However, the effect of caffeine on cAMP is modest, even at concentrations well above typical plasma concentrations in humans. In fact, in order to achieve blood levels of caffeine equal to those in the studies supporting this hypothesis, a 200-pound man would have to drink fifty cups of coffee in a few minutes. Thus, as with the intracellular calcium hypothesis, the mechanism of phosphodiasterase inhibition appears to be of limited importance in explaining the effects of caffeine observed at the levels attained by its ordinary consumption.

  Adenosine Blockade: The Newest Theory on the Block

  If a neurotransmitter or neuromodulator is to achieve any effect, it must reach the sites designed to accomplish its uptake into the human nervous system. Any substance that blocks this uptake prevents or reduces the effects of the neurotransmitter or neuromodulator it is blocking.

  Adenosine is a neuromodulator with mood-depressing, hypnotic (sleep-inducing), and anticonvulsant properties and tends to induce hypotension (low blood pressure), bradycardia (slowed heartbeat), and vasodilatation. It also decreases urination and gastric secretion. Adenosine decreases the rate of spontaneous nerve cell firing and depresses evoked nerve cell potentials in the brain by inhibiting the release of other neurotransmitters that control the excitability, or responsiveness, of central neurons. The newest theory about caffeine’s mechanism of action is that it acts as a competitive antagonist of adenosine; that is, it achieves most of its stimulant effects by blocking the uptake of, and thereby the actions of, adenosine.

  To put matters simply, there are only so many receptors where adenosine can “plug itself in” to the nervous system, the way a key fits into a lock. Caffeine counterfeits the key. By doing so, caffeine blocks many of adenosine’s receptors, and thus prevents the body from being affected by adenosine’s depressing and hypnotic effects. The result, according to this theory, which arose in the early 1970s, is that when we ingest caffeine we are unable to become tired or sleepy as we would otherwise have done. This theory holds that caffeine, by inhibiting the actions of adenosine, produces a whole slew of effects which are opposite adenosine’s. Such a mechanism would account, for example, for caffeine’s ability to increase respiration, urination, and gastric secretion.9

  The ultimate evaluation of this theory of caffeine’s mechanism of action is complicated by the variety of adenosine receptors and their differing roles in different tissues. However, because, with typical dietary doses of caffeine, blood levels of caffeine are believed to be too low to appreciably affect the non-adenosine mechanisms of action, adenosine antagonism appears to be the primary mechanism for caffeine’s effects. It is not known if these other mechanisms may mediate some of the clinical effects produced when caffeine blood levels are unusually elevated, as may occur in cases of caffeine intoxication. A possible shortcoming of the adenosine blockade theory is that, even though it appears that the blockade of these receptors by caffeine has an important role in its pharmacology, caffeine’s complex effects on behavior may not be fully explicable in terms of this blockade alone.10 For example, alertness is informed by many neurotransmitter systems, only one of which is the noradrenalin system. Because chronic caffeine use effects changes in a number of other neurotransmitters, including norepinephrine, dopamine, serotonin, acetylcholine, GABA, and the glutamate systems in the brain, it remains for future researchers to determine what part if any these changes play in the behavioral effects associated with caffeine’s use.

  The very latest findings suggest that the adenosine story may actually tie caffeine’s mechanism of action to that of other stimulants, such as amphetamines and cocaine, after all. In an unpublished study, Bridgette Garrett and Roland Griffiths maintain that caffeine enhances dopaminergic activity, “presumably by competitive antagonism of adenosine receptors that are co-localized an
d functionally interact with dopamine receptors. Thus caffeine, as a competitive antagonist at adenosine receptors, may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors, thus stimulating dopaminergic activity.”11 If true, this means that caffeine, like amphetamine or cocaine, produces increased synaptic concentrations of dopamine, an explanation consistent with findings that caffeine’s behavioral effects are similar to those of these classic dopaminergically mediated stimulants.

  Paradoxes and Problems and Unanswered Questions

  A major paradox that arises when we attempt to understand caffeine’s primary effects in terms of its role as an adenosine antagonist, or reuptake inhibitor, is that, were this its only operative mechanism, we would have trouble explaining the development of tolerance and physical dependence. Obviously tolerance, or increasing “resistance” to the drug, which requires caffeine users to progressively augment their dose in order to maintain its stimulant effects, is generally experienced by regular coffee drinkers; and dependence, as defined by the occurrence of withdrawal symptoms upon abrupt cessation of use, seems fairly common as well, and both tolerance and dependence have been well established in the literature.