The World of Caffeine (48 page)

In 1996, Hamza Hendawi, in an Associated Press article datelined San’a, Yemen, described how “from the finest private homes to the dusty streets…almost every man in Yemen chews khat.” He explains that government officials are concerned because a majority of the male population is stoned for at least part of every day. The bitter leaves are chewed slowly, forming a small ball that chewers roll around in their cheeks, as tobacco chewers do with snuff. In 2000, a bundle of six to ten branches sells for between fifty cents and fifty dollars, depending on its quality. A typical khat fix costs about three dollars, a staggering sum in a country with an average daily per capita income of about a dollar a day.

A common sight is men walking home from the market carrying bundles of khat. Khat chewing is often done at home during daily sessions that can bring together two dozen or more men from early afternoon until evening. However, taxi drivers, street vendors, and businessmen often chew it during the working day, and students chew it to keep awake at night while studying for exams. Ali Abdullah Saleh, the president of Yemen, a khat lover himself, still makes certain his troops receive their daily rations, as he did during their conflict with rebels in southern Yemen a few years ago.

In 2000, Donna Abu-nasr, in another Associated Press article datelined San’a, reports how increasing numbers of women are becoming regular khat users as well. After primping and scenting themselves for the occasion, they gather in their own version of afternoon tea, parties at which a light meal of sandwiches and desserts accompanies khat chewing and intoxication. Tea and soft drinks are frequently served to alleviate the dry mouth that is a side effect of Khat consumption.
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Khat nay-sayers include Mohammed Yehia al-Sharafi, a neuropsychiatry professor and head of Yemen’s University of Applied Sciences, who says that although small doses can reduce anxiety, regular use—and it
is
used with uncanny regularity —causes gastritis, inflammation of the gums, depression, poor appetite, and loss of sexual potency. Sharafi believes that most of khat’s attraction is the way it imbues its users with a sense of inspiration, a feeling of being full of important ideas that merit long, ebullient speeches. Khat’s proponents, who in addition to the president include many prominent citizens, see in the drug the encouragement of some of the same desirable social effects that coffee’s early proponents adduced. “Khat sessions remove all social divisions and bring together men from different walks of life,” comments Wad’ai, one of Yemen’s most respected judges and himself a devoted khat chewer. Besides, according to Wad’ai, “It is not addictive as people say. That is why we don’t need it when we are traveling outside Yemen.”

In a country in which khat cultivation consumes 75 percent of the irrigation water and occupies more than 80 percent of the arable land, an important goal of some factions in the government has been to decrease the production and use of khat. But an active trade has continued despite their attempts. Like the recurring efforts in many countries throughout the ages to ban caffeine-containing beverages, these measures enjoyed little success.

Ephedra

Ephedras are leafless desert bushes native to arid regions throughout the world. They are related to pine trees and bear tiny cones. Several species of genus
Ephedra
contain the drug ephedrine, a stimulant alkaloid that is used as a treatment for asthma. Since ancient times in China, the dry stems of
Ephedra vulgaris
have been boiled with water to make a pleasant-tasting, although some say bitter, stimulating tea. American ephedra, which grows throughout North America, is known as “Mormon tea,” because early Mormon settlers used it instead of caffeinated beverages, which are prohibited by their religion. Ma-huang, made from the more potent Chinese species
Ephedra sinica, Ephedra equisetina,
and
Ephedra intermedia,
has been a traditional medicine in China since well before the introduction of tea in that country. Until the development of synthetic ephedrine, the alkaloid extracted from these species was used in the West as the basis for nasal and bronchial remedies for relieving congestion and to treat low blood pressure.
⁵³
Today, extracts from these plants are common ingredients of herbal stimulants sold in health food stores. The FDA has recently warned about the dangers of the increasingly common use by the young of ephedra products as intoxicants and diet aids, especially when they are compounded with caffeine.

The plants are harvested in autumn, dried in the sun, and cut into pieces. When used as a powdered medicinal, the pieces are boiled in water, sometimes with honey, and then roasted until dry. It is still prescribed in China for typhoid, colds, coughing, and as a painkiller. Today, synthetic ephedrine and a closely related compound, pseudonorephedrine, are ingredients in dozens of prescription and over-the-counter allergy and cold medications.

Betel

“Betel” can refer to either of two unrelated plants, the areca palm, known as the “betel palm”
(Areca catechu),
or the betel pepper, known as the “pan plant”
(Piper betle)
. The “betel nut,” or seed of the areca palm, is wrapped in the so-called betel leaf of the betel pepper, and the two are chewed together as a stimulant throughout southern Asia and the East Indies. Many Western readers will be surprised to learn that chewing betel is a steady habit for about 10 percent of the world’s population.
⁵⁴

The areca palm, first described by Theophrastus (374–287 B.C.) in about 340 B.C., is cultivated in India, Sri Lanka, Thailand, Malaysia, and the Philippines. Its unbranched trunk can reach fifiy feet but is only about one and a half feet around, with a cluster of up to a dozen palm fronds sprouting from the top. The fruit, about the size of an egg, has a tough rind that contains a hard seed, or nut. The fruit is picked in the fall, before it is fully ripe, and is husked, boiled, and finally sun-dried until it turns dark brown or black.

The stimulating ingredient in betel nuts is the alkaloid arecoline, a drug used by veterinarians as a worming agent. (This is not the same as “black catechu,” an extract for dyeing and tanning, which, confusingly enough, is taken from the wood of the areca palm.)

For more than two thousand years the natives of the regions where the “betel palm” grows have used this combination drug.
⁵⁵
Betel chewing was recorded in China by the fourth century, where the nut, then as now, was known under its Malay name,
“pinang
.
”
Travelers to the Far East have long noted the habit among the natives. Marco Polo in the thirteenth century and Ibn Batuta in the fourteenth century described how betel was consumed together with the areca nut and lime and noted its intoxicating effects. Polo tells us:

As we have seen, Bacon mentions the drug in 1627 in
Sylva Sylvarum,
describing how it is chewed with lime, in a list of intoxicants that includes opium, tobacco, and coffee. In the first quarter of the twentieth century, Lewin, who did extensive field research into psychoactive botanicals, observed:

Those who enjoy betel prepare to chew the dried pieces of the nut of the areca palm by wrapping it in the fresh leaf of the betel pepper smeared with a lime paste and perhaps flavored with cloves, tamarind, or other spices. The use of the betel pepper leaf and lime increases salivation and helps to bring out the active alkaloids of the areca nut. When the betel nuts and leaves are chewed, a large amount of red saliva is pro duced, which temporarily colors the gums and lips. However, the practice does not stain the teeth black, as has sometimes been claimed, an error arising from the fact that some of the chewers deliberately stain their teeth black for cosmetic effect or have poor nutrition and dental hygiene.

Yohimbé

Yohimbé is the bark of an African tree
(Corynanthe yohimbe)
containing a crystalline alkaloid stimulant called “yohimbine.” The bark has an acrid, spicy flavor and has been used for centuries in central Africa as an aphrodisiac. In the United States, yohimbé bark is occasionally available at herb stores and can be brewed into an invigorating tea for use as an aphrodisiac. Some say it causes tingling feelings up and down the spine.

Some scientists say that yohimbine stimulates sexual arousal by irritating the urinary tract, as do cantharides found in powdered blister beetles (a folk medicine administered to male livestock to encourage breeding that is sometimes called “Spanish fly” when used by people).
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Others say that its aphrodisiac reputation is simply the result of the power of suggestion, because the stimulating powers of yohimbé are produced only when it is consumed in toxic doses. Still a third faction suggests that there must be other, unknown active constituents in yohimbé bark, because yohimbine alone does not seem to produce the same effects as the bark extract.

Yohimbine, perhaps the main active constituent in yohimbé bark, is an alpha-2 adrenergic antagonist. Alpha-2 autoreceptors act as a kind of thermostat to regulate adrenergic activity. Some of the noradrenaline released by a neuron
returns to its alpha-2 autoreceptor, which then reduces the amount of noradrenaline it secretes. This cybernetic control mechanism is similar to a thermostat, which registers the temperature and reduces the amount of heat produced when the air warms up. Unlike simple agonists, which universally activate receptors, yohimbine, by blocking the alpha-2 autoreceptors, actually induces an amplification of noradrenergic activity.

Yohimbine is an ingredient in some folk medicines sold around the world to treat impotence, as increased adrenergic activity seems to help stimulate sexual function. Yohimbine is contraindicated in people with high blood pressure, heart problems, or problems with anxiety, all of which can be exacerbated by increased adrenergic activity. It should never be combined with any other stimulant or any monoamine oxidase (MAO) inhibitor.

Caffeine and, before caffeine was identified, coffee, tea, and chocolate, have been said to cause, exacerbate, palliate, or cure an enormous variety of diseases and have also been said to confer marvelous benefits, including increases in both intellectual and physical capacities. If, like the great majority of people in the world, you use caffeine regularly, you are faced with a complex, confusing, and often apparently contradictory cacophony of traditional and contemporary claims about its effects on human health. In former centuries, caffeine lovers had no guidance but the often fanciful discourses of the medical men of their time. We are fortunate that, in the last half of the twentieth century, a explosion of general medical knowledge and a large number of controlled experiments have shed scientific light on many of caffeine’s effects. It has been often and truly said that caffeine is the most studied drug in history. Yet, because of its nearly universal use, the variety of its modes of consumption, its presence in and effects on nearly all bodily systems, and its occurrence in chemically complex foods and beverages, together with the complexity of the social and psychological factors that shape its use, caffeine may also be one of the least adequately understood. Despite tremendous scientific scrutiny, many central health questions about caffeine remain unanswered or even unaddressed.

Caffeine is like the air. You don’t see it and usually hardly notice it, but it’s there all the same, and it becomes part of you in a critical metabolic exchange that involves every cell in your body. Considering that the sensorium and biomass of the human race is virtually awash in caffeine, and has been besotted so for hundreds of years, and that an overwhelming majority of people in almost every nation, including young and old, healthy and infirm, rich and poor, has made the regular use of this psychoactive stimulant more popular than the habitual use of any other drug, what do we really know of caffeine? What do we know of what it is doing for us, doing to us, even doing to our unborn children? The answer, as should become clear after reviewing the very impressive record of studies presented in the following chapters and the appendices, and evaluating both the findings and limitations of this research, is, “not nearly as much as we need to know.”

The lack of adequate information about caffeine’s health effects is evident in the disagreements that exist among experts. For example, the FDA, as recently as the late 1980s, reaffirmed its earlier position that medical evidence demonstrated no adverse health consequences from caffeine in soft drinks, and the National Academy of Sciences’ National Research Council and the U.S. Surgeon General’s office agreed that no risk to health had been shown for moderate caffeine intake. In contrast, many researchers, adducing the complexity of caffeine’s effects on the human body and the many aspects of these effects that have received limited research attention, argue that such a “clean bill of health” is not fully justified.

The
acute
administration of caffeine under experimental conditions in which the subject has no tolerance to caffeine has been correlated with certain unmistakable physiological responses, including temporary increases in blood pressure, catecholamine levels, rennin activity, cortisol, free fatty acid levels, urine output, and gastric secretions. In contrast,
regular
caffeine consumption does not continue producing elevation in any of these levels. Nor does chronic caffeine ingestion elevate cholesterol or glucose levels. Older people using caffeine regularly demonstrate no change in blood pressure or heart
rate, and even continuous heavy use does not increase the risk of developing high blood pressure. The most recent studies contradict earlier findings of a positive correlation between caffeine and heart attacks, kidney and bladder cancers, pancreatic cancer, anxiety, fibrocystic breast disease, and hyperlipidemia. Less clear is the evidence concerning the link between maternal caffeine consumption and the health of the newborn.
¹

Many beneficial effects of caffeine are well established, and others may be coming to light. Caffeine is a powerful bronchodilator in asthma patients and provides possible protection against the adverse pulmonary effects of smoking.
²
It also increases the length of time that chronic, stable angina patients can walk without feeling pain. Some researchers think that caffeine is effective as a therapy for neonatal apnea and could be effective as a topical treatment of atopic dermatitis.
³
It has long been recognized as an analgesic adjuvant, or enhancer of pain medications. Caffeine is also useful in averting acute hypotension (a sudden drop in blood pressure), such as that which sometimes occurs after breakfast, especially in the elderly; people experiencing this problem are advised to consume about 200–250 mg of caffeine, or about two cups of coffee, each day.
⁴

The difficulties of interpreting health care studies are suggested by a juxtaposition of two articles that were published in 1983 in the
New England Journal of Medicine
. One study asserted that arrhythmias are induced in susceptible patients with about two cups of coffee or the equivalent amount of caffeine. The other challenged the significance of this conclusion, stating, “What is not yet appreciated is that ventricular premature beats are innocuous in the overwhelming majority of persons. They no more augur sudden death than a sneeze portends pneumonia.”
^5
,
6

Coffee and tea contain so many different pharmacologically active substances that there is no easy way to isolate the effects of caffeine from those of the other substances they contain. It has even been found that the method of preparation as well as the amount consumed alters the ultimate effects on human health, especially the effects on the cardiovascular system.

Additional confounding factors plaguing research into coffee’s effects are well summarized by Silvio Garattini, researcher and editor of
Caffeine, Coffee, and Health,
who comments that although there are many epidemiological studies on the health effects of caffeine and coffee, their probative value is limited by the high correlation between smoking or alcohol consumption and coffee drinking. That is, it is often almost impossible to isolate the effects arising from coffee from those arising instead from smoking or alcohol. Garattini points out that it is also difficult to come up with a universal definition of coffee consumption, because of the differences between types of coffee beans, different methods of roasting, and the varying ways of preparing coffee even in the same population. To make the situation worse, nondrinkers of coffee may also differ from coffee drinkers in their other dietary habits or aspects of their lifestyle, and in the disposition to different diseases.
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Individual differences in sensitivity to caffeine, differences that are often traced to inherited variations in the rate of caffeine metabolism, are another source of confusion. Few studies have been done pertaining to these differences. Although it seems likely that caffeine sensitivity, like most other quantifiable natural variables, should follow a normal bell curve of distribution, and therefore exhibit a range of values, some investigators recognize in some people a qualitatively different response than is observed in the general population. Anecdotal accounts of these unusual reactions suggest a peculiar sensitivity that goes beyond the range of normal distribution. Drug discrimination studies provide evidence for wide individual differences in sensitivity to caffeine and document that some people can detect remarkably small amounts of the drug. As reported in the
Handbook of Experimental Pharmacology,
in a chapter by Griffiths and Mumford, the lowest dose detected by research subjects ranged from 1.8 to 178 mg, with about 70 percent of them detecting 56 mg or less and about 35 percent detecting 18 mg or less.
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Other scientists have purportedly identified more unusual reactions. For example, researcher S.S.Hayreh, in a 1973 study, gives an account of his own extreme sensitivity to caffeine, which he describes as manifested in “dizziness, weakness, and tremors, lasting two hours, and my pulse-rate went very high,”
⁹
effects he claims are experienced by many others. The significance of such observations remains uncertain, as researcher Jack James explains: “It is not clear whether these reactions represent pronounced, normal responses to a large caffeine dose, or whether the subject’s reactions denote a peculiar sensitivity to the drug.”
¹⁰

An example of the equivocal and uncertain effects of caffeine is the current debate over whether caffeine is implicated in stimulating the symptoms of attention deficit disorder (ADD) or whether it is a possible cure for ADD or both. In other words, no one yet knows if it causes, relieves, or does not effect a given set of symptoms, an uncertainty reminiscent of the humoral debates of the sixteenth and seventeenth centuries as to whether coffee was “wet” or “dry” or “hot” or “cold” or all of these things at once.

Despite the daunting array of cautionary and compromising considerations, it is difficult not to acknowledge the concordant and apparently probative conclusions of certain large-scale, well-designed studies. For example, a study of more than twelve thousand men and women with high blood pressure and high cholesterol levels, the first large-scale prospective study of caffeine and all causes of death, concluded that there was no “relationship between coronary heart disease events or total mortality and coffee consumption”
¹¹
in this high-risk group. The same result—that is, an absence of any relation between caffeine consumption and all or any causes of death— was found by a 1990 study of forty-five thousand men, published in the
NEJM,
¹²
and also by the Framingham study,
¹³
the Evans County study (1960–69),
¹⁴
and the Gothenburg, Sweden, study.
¹⁵

When evaluating the probative significance of these studies and the others referenced in this section, consider that any study demonstrating that there is no link between coffee and a given disease entity probably excludes any link with caffeine as well; while a study that demonstrates a link with coffee leaves open the question of whether caffeine or some other agent in coffee is responsible for the outcome.

The inquiry into the cardiovascular effects of caffeine is more than a century old, and clinical studies in human subjects have proliferated since the 1970s. It is now well established that the administration of caffeine to people without a history of its use produces both a transient mild pressor effect, or increase in blood pressure, and a biphasic effect on heart rate—that is, lower doses slow, and higher doses quicken, the heartbeat. Yet, despite such acute effects on people who haven’t used caffeine recently, virtually all studies reveal
no long-term effect on the heart of any kind from caffeine
.

How can this be? The development of a tolerance to caffeine, which is to say, a resistance to its effects, probably explains the disparity between the apparent acute, or immediate, effects of caffeine consumption on non-caffeine users and the absence of harmful consequences in long-term users. As the tolerance to the cardiovascular effects of caffeine develops, the impact initially observed quickly declines or even disappears. The one category of risk that has not been extensively considered is the long-term cardiovascular effects of occasional coffee drinking in people without a tolerance. This means that you may be safer drinking coffee every day than you would be doing so once or twice a week. Another area requiring investigation is the interaction between stress and caffeine consumption on long-term blood pressure levels. Extrapolating from the results of studies on caffeine and heart attacks, it appears, however, that even the combination of caffeine and stress will rarely have any clinical impact.
¹⁶

Increased blood pressure is a cause of congestive heart failure and a major cause of death. An increase in either systolic pressure, which is the pressure associated with the contraction of the heart muscle, or diastolic pressure, which is associated with its relaxation, can be dangerous, but an elevated diastolic pressure, or lower number given in a blood pressure reading, is the more critical. Conversely, lowered blood pressure is associated with a lowered incidence of congestive heart failure and other cardiovascular diseases. It is therefore of significant interest to note that a 1989 Norwegian study of thirty thousand middle-aged men and women demonstrated that drinking more than one cup of coffee a day is positively correlated with a
reduction
in both systolic and diastolic blood pressure. In other words, people who drink a cup of coffee every day tend to have lower blood pressure than people who do not.
¹⁷