The World of Caffeine (40 page)

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.
  

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.

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.

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.
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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.
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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 and 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.”
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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.

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.

However, the observation that caffeine produces increases of 10 to 20 percent in the number of brain adenosine receptors has prompted speculation that this increase may be the mechanism underlying withdrawal symptoms. The notion here is that the body is not completely fooled by the invasion of caffeine as an adenosine impostor and creates new receptor sites as compensation. When caffeine intake is reduced or eliminated, these extra sites combine with the original sites to uptake a greater amount of adenosine than is normal, with the result that adenosine’s effects, including sleepiness and depression, are multiplied. Thus, this explanation would help account for many of the withdrawal symptoms produced by the abrupt reduction or cessation of caffeine use.

Unfortunately, there remain some inconsistencies that lead scientists to believe that this explanation is at best incomplete, for it cannot adequately serve to explain the development of tolerance. Tolerance to caffeine can increase to the point where it cannot be overcome by any dose, that is, where it becomes insurmountable, failing to duplicate its former effects in the user
regardless of how high a dose is ingested, and there is no easy way to understand how the adenosine blockade theory could be consistent with insurmountable tolerances. In addition, as we have observed in our discussion of cocaine, there is no clear precedent of a competitive antagonist, such as caffeine, losing its potency after chronic administration. And, in fact, caffeine seems to retain its full potency as an adenosine antagonist, even in cases where an insurmountable tolerance to caffeine’s stimulant effects has clearly been achieved. Finally, there seems to be no theoretical basis for expecting that an increase in the number of receptor sites should produce tolerance to the antagonist.

To put it simply, if caffeine’s mechanism of action is explicable in terms of a competitive blockade of adenosine, we might expect withdrawal symptoms upon cessation of use, but we would still lack any explanation for the development of tolerance. Problems like these make it clear how far science still has to go if it is to reveal the secrets of caffeine. Exactly what it does and exactly how it does what it does are still largely unknown. Fortunately, it is possible to assess the effects of caffeine on human health by means of studies that are independent of a detailed knowledge of its underlying mechanisms.

Few of us in Western countries today chew the leaves, bark, fruit, or nuts of caffeine-containing plants. We get our caffeine and other methylxanthines from drinks, foods, and pills. In the United States, about 70 percent of our caffeine is found in coffee beans, about 14 percent is found in tea leaves, more than 12 percent is in the form of the crystal caffeine, nearly 3 percent is found in cacao beans, and the remaining fraction from all other sources, including cola nut, maté, and guarana. Chocolate owes some of its stimulating power to the methylxanthine theobromine, and tea contains a small amount of theophylline. The caffeine in cola drinks is not derived from cola nuts, but is a superadded extract from coffee or tea. Caffeine is found in some over-thecounter medications, such as alertness aids and aspirin compounds, and in prescription medications, such as narcotic painkillers, as an adjuvant to their analgesic power.

In
Appendix B
are a number of charts listing various dietary and medicinal sources, with the amount of caffeine, theobromine, or theophylline found in each.

A figure that is passed around, from one research paper or newspaper article to the next, is that a cup of coffee contains an average of 100 mg of caffeine. This sounds simple and straightforward and suggests that it is fairly easy to determine how much caffeine we are taking in when we have a cup of coffee. Unfortunately, when we scrutinize this figure, many uncertainties arise.

One problem is, exactly how much liquid is in a “cup of coffee”? A big mug or large paper cup, filled to the brim, may be 10 ounces or even 12 ounces or more. If not filled to the brim, a small cup may hold as little as 4 ounces. Amounts often quoted for cups are 5 ounces or 6 ounces, and the cup itself as a standard liquid measure is 8 ounces. So when we speak of a cup, we may be speaking of 4, 5, 6, 8, 10, 12 ounces or more. Another problem is, how much caffeine is in the coffee, ounce for ounce? This number will vary widely with such variables as method of preparation, type of coffee bean, method of roasting, and amount of coffee used.

The result of multiplying these two uncertainties produces a remarkably wide range for what might constitute the “correct” value for the amount of caffeine in a “cup” of coffee. A small cup of weak instant coffee might have as little as 50 mg. A large cup of infused coffee steeped for a long time with a lot of robusta beans might have 350 mg. Admittedly these are extreme values, but we believe that doses in the range of 100 to 250 mg are common. According to the Food and Drug Administration, a 5-ounce cup of coffee contains 40 to 180 mg of caffeine. Similar problems beset an evaluation of how much caffeine is found in a cup of tea.

Studies profiling the caffeine content of coffee and tea as actually served to restaurant customers or consumed at home are rare. One 1988 Canadian study, published in
Food and Chemical Toxicology,
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surveyed almost seventy “preparation sites,” and found considerable differences from place to place and even between one day and the next at the same place. A review of the caffeine content of coffee brewed in almost sixty homes showed levels ranging from about 20 mg to nearly 150 mg per cup, more than a sevenfold variation. Coffee tested in eleven restaurants exhibited similar differences. Further, “decaf” served at restaurants sometimes had substantial amounts of caffeine. Finally, there were large variations in the caffeine content among the seventeen brands of instant coffee, even when prepared under controlled laboratory conditions.