CAFFEINE

Caffeine is the world's most widely used behaviorally active drug. More than 80 percent of adults in North America consume caffeine regularly. Average per capita caffeine intakes in the United States, Canada, Sweden, and the United Kingdom have been estimated at 211 milligrams, 238 milligrams, 425 milligrams, and 444 milligrams per day, respectively; the world's per capita caffeine consumption is about 70 milligrams per day. These dose levels are well within the range of caffeine doses that can alter human behavior: As little as 32 milligrams of caffeine, less than the amount of caffeine in most 12-ounce cola soft drinks, can improve vigilance performance and reaction time; and doses as low as 10 milligrams, less than the amount of caffeine in some chocolate bars, can alter self-reports of mood. These data suggest that a large number of people are daily consuming behaviorally active doses of caffeine.

Caffeine-containing foods and beverages are ubiquitously available in and widely accepted by most contemporary societies—yet dietary doses of caffeine can produce behavioral effects that share characteristics with prototypic drugs of abuse: physical dependence, self-administration, and Tolerance. Chronic administration of only 100 milligrams of caffeine per day, the amount of caffeine in a cup of coffee, can produce Physical Dependence, as evidenced by severe and pronounced withdrawal symptoms that can occur upon abrupt termination of daily caffeine. Under some circumstances, research volunteers reliably self-administer dietary doses of caffeine, even when they are not informed that caffeine is the drug under study; and some evidence indicates that daily use of caffeine produces tolerance to caffeine's behavioral and physiological effects.

CLASS AND CHEMICAL STRUCTURE

Caffeine is an Alkaloid that is often classified as a central nervous system stimulant. Caffeine is structurally related to xanthine, a purine molecule with two oxygen atoms (see Figure 1). Several important compounds, including caffeine, consist of the xanthine molecule with methyl groups attached. A methyl group consists of a carbon atom and three hydrogen atoms. These methylated xanthines, called methylxanthines, are differentiated by the number and location of methyl groups attached to the xanthine molecule. Caffeine is a 1, 3, 7-trimethylxanthine. The "tri" refers to the fact that caffeine has three methyl groups. The "1, 3, 7" refers to the position of the methyl groups on the purine molecule. Other important methylxanthines include theophylline, theobromine, and paraxanthine. All these methylxanthines are metabolites of caffeine. In addition, theophylline and theobromine are ingested directly in some foods and medications.

SALIENT FEATURES

Sources.

Coffee and Tea are the world's primary dietary sources of caffeine. Other sources include soft drinks, cocoa products, and medications. Caffeine is found in more than sixty species of plants. Coffee is derived from the beans (seeds) of several species of Coffea plants, and the leaves of Camellia sinensis plants are used in caffeine-containing teas. Chocolate comes from the seeds or beans of the caffeine-containing cocoa pods of Theobroma cacao trees. In developed countries, soft drinks, particularly Colas, provide another common source of dietary caffeine. Only a portion of the caffeine in soft drinks comes from the kola nut (Cola nitida ); most of the caffeine is added during manufacturing. Since the 1960s, a marked decrease in coffee consumption in the United States has been accompanied by a substantial increase in the consumption of soft drinks. Maté leaves (Ilex paraguayensis ), guarana seeds, and yoco bark are other sources of caffeine for a variety of cultures. Table 1 shows the amounts of caffeine found in common dietary and medicinal sources. As can be seen in the range of values for each source in this table, the caffeine content can vary widely depending on method of preparation or commercial brand.

Effects on Mood and Performance.

It has long been believed that caffeine stimulates mood and behavior, decreasing fatigue and increasing energy, alertness, and activity. Although caffeine's effects in experimental studies have sometimes been subtle and variable, dietary doses of caffeine have a variety of effects on mood and performance. Doses below 200 milligrams have been shown to improve vigilance and reaction time, increase tapping speed, postpone sleep, and produce reports of increased alertness, energy, motivation to work, desire to talk to people, self-confidence, and well-being. Higher doses can both improve or disrupt performance of complex tasks, increase physical endurance, work output, hand tremor, and reports of nervousness, jitteriness, restlessness, and anxiousness.

DISCOVERY

Caffeine, derived from natural caffeine-containing plants, has been consumed for centuries by various cultures. Consumption of tea was first documented in China in 350 a.d., although there is some evidence that the Chinese first consumed tea as early as the third century b.c. Coffee cultivation began around 600 a.d., probably in what is now Ethiopia.

Caffeine was first chemically isolated from coffee beans in 1820 in Germany. By 1865, caffeine had been identified in tea, maté (a drink made from the leaves of a South American holly), and kola nuts (the chestnut-sized seed of an African tree).

THERAPEUTIC USES

Caffeine is incorporated in a variety of over-the-counter preparations marketed as analgesic, stimulant, cold, decongestant, menstrual-pain, or appetite-suppression medications. As an ingredient in Analgesics (painkillers), caffeine is used widely in the treatment of ordinary types of headaches, although evidence for caffeine's analgesic effects is limited: Caffeine may only diminish headaches that result from caffeine withdrawal, but it is also combined with an ergot Alkaloid in the treatment of migraine. Caffeine may have some therapeutic effectiveness in its ability to constrict cerebral blood vessels. The use of caffeine as a central nervous system (CNS) stimulant does have an empirical basis, but there is little evidence that caffeine has appetite-suppressant effects.

Because of various effects of caffeine on the respiratory system, caffeine is used to treat asthma, chronic obstructive pulmonary disease, and neonatal apnea (transient cessation of breathing in newborns)—although other agents, including theophylline, are usually preferred for the treatment of asthma and chronic obstructive pulmonary disease.

Historically, caffeine has been used medically to treat overdoses with opioids and central depressants, but this use has decreased considerably with the development of alternative treatments.

ABUSE

Case reports have described individuals who consume large amounts of caffeine—exceeding one gram per day (1,000 milligrams). This excessive intake, observed particularly among psychiatric patients, drug and alcohol abusers, and anorectic patients, can produce a range of symptoms—muscle twitching, Anxiety, restlessness, nervousness, insomnia, rambling speech, tachycardia (rapid heartbeat), cardiac arrhythmia (irregular heartbeat), psychomotor agitation, and sensory disturbances including ringing in the ears and flashes of light.

The disorder characterized by excessive caffeine intake has been referred to as caffeinism. There is some suggestion that excessive caffeine consumption can be linked to psychoses and anxiety disorders. Substantial amounts of caffeine are also used by a small percentage of competitive athletes, despite specific sanctions against such use.

Abused drugs are reliably self-administered under a range of environmental circumstances by humans and most are also self-administered by laboratory animals. Caffeine has been self-injected by laboratory nonhuman primates and self-administered orally and intravenously by rats, but there has been considerable variability across subjects and across studies.

Human self-administration of caffeine has been variable, as well; however it is clear that human subjects will self-administer caffeine, either in capsules or in coffee, and even when they are not informed that caffeine is the drug under study. For example, heavy coffee drinkers given repeated choices between capsules containing 100 milligrams caffeine or placebo under double-blind conditions showed clear preference for the caffeine capsules and, on average, consumed between 500 and 1,300 milligrams of caffeine per day. Experimental studies with low to moderate caffeine consumers have found that between 30 and 60 percent of those subjects reliably choose caffeine over placebo in blind-choice tests. Subjects tend to show less caffeine preference as the caffeine dose increases from 100 to 600 milligrams, and some subjects reliably avoid caffeine doses of 400 to 600 milligrams.

TOLERANCE

Chronic caffeine exposure can produce a decreased responsiveness to many of caffeine's effects (i.e., tolerance). This has been observed in both nonhumans and humans. Research with nonhumans has clearly demonstrated that chronic caffeine administration can produce partial tolerance to various effects of caffeine and can produce complete tolerance to caffeine's stimulating effect on locomotor activity in rats. A number of studies also suggest that tolerance to caffeine develops in humans: Daily doses of 250 milligrams of caffeine can increase systolic and diastolic blood pressure, however tolerance quickly develops to these effects within four days. The stimulating effects of caffeine on urinary and salivary output also diminish with chronic caffeine exposure. Although tolerance appears to develop to some of the central nervous system effects of caffeine, this aspect of caffeine tolerance has not been well explored. Comparisons of the effects of caffeine between heavy and light caffeine consumers provide indirect evidence that repeated (regular) caffeine use diminishes the sleep-disturbing effects and alters the profile of self-reported mood effects. For example, 300 milligrams of caffeine may produce self-reports of jitteriness in people who normally abstain from caffeine but not in regular caffeine consumers. High chronic caffeine doses (900 mg per day) can eliminate the self-reported mood effects (tension, anxiety, nervousness and jitteriness) of 300 milligrams of caffeine given twice a day.

PHYSICAL DEPENDENCE

Evidence of physical dependence on caffeine is provided by the appearance of a withdrawal syndrome following abrupt termination of daily caffeine. Although there have been relatively few demonstrations of caffeine withdrawal in nonhumans, abrupt termination of chronic daily caffeine has been shown to clearly decrease locomotor behavior in rats. Considerably more is known about caffeine withdrawal in humans. Caffeine withdrawal is well documented in anecdotal case reports dating back to the 1800s and in experimental and survey studies from the 1930s to the present. Caffeine withdrawal is typically characterized by reports of headache, fatigue (e.g., reports of mental depression, weakness, lethargy, sleepiness, drowsiness, and decreased alertness), and possibly anxiousness. Descriptions of the withdrawal headache suggest that it develops gradually and can be throbbing and severe.

When caffeine withdrawal occurs, its intensity can vary from mild to severe. Anecdotal descriptions of severe withdrawal suggest that it can be incompatible with normal functioning and include flulike symptoms, fatigue, severe headache, nausea, and vomiting. In general, caffeine withdrawal begins twelve to twenty-four hours after terminating caffeine, peaks at twenty to forty-eight hours, and lasts from two to seven days. Caffeine withdrawal can occur following termination of caffeine doses as low as 100 milligrams per day, an amount equal to one strong cup of coffee, two strong cups of tea, or three soft drinks. Caffeine withdrawal effects can vary within an individual in that a given individual may not experience caffeine withdrawal during every period of caffeine abstinence. The severity of the withdrawal symptoms usually appears to be an increasing function of the maintenance dose of caffeine. Caffeine suppresses caffeine withdrawal symptoms in a dose-dependent manner, so that the magnitude of suppression increases as a function of the administered caffeine dose.

The data described above indicate that the large majority of the adult population in the United States is at risk for periodically experiencing significant disruption of mood and behavior when there are interruptions of daily caffeine consumption.

The nature and time course of effects of terminating daily caffeine consumption is illustrated in Figure 2, a recent experiment involving seven adult subjects. The subjects followed a caffeine-free diet throughout the study and received identically appearing capsules daily. Prior to the study, subjects had received 100 milligrams of caffeine daily for more than 100 days. Placebo capsules were substituted for caffeine without the subjects' knowledge, and subjects continued to receive placebo capsules for twelve days, after which caffeine administration was resumed. The top panel of the figure shows that substitution of placebo for caffeine produced statistically significant increases (asterisks) in the average ratings of headache during the first two days of placebo substitution. Headache ratings gradually decreased over the next twelve days and continued at low levels during the final caffeine condition. The bottom panel of the figure shows that substitution of placebo for caffeine produced similar time-limited increases in subjects' ratings of lethargy/fatigue/tired/sluggish.

ORGAN SYSTEMS

Caffeine affects the cardiovascular, respiratory, gastrointestinal and central nervous systems. Most notably, caffeine stimulates cardiac muscles, relaxes smooth muscles, produces diuresis by acting on the kidney, and stimulates the central nervous system. The potential of dietary doses of caffeine to stimulate the central nervous system is primarily inferred from caffeine's behavioral effects. Low to moderate caffeine doses can produce changes in mood (e.g., increased alertness) and performance (e.g., improvements in vigilance and reaction time). Higher doses produce reports of nervousness and anxiousness, measurable disturbances in sleep, and increases in tremor. Very high doses can produce convulsions.

Caffeine's cardiovascular effects are variable and depend on dose, route of administration, rate of administration, and history of caffeine consumption. Caffeine doses between 250 and 350 milligrams can produce small increases in blood pressure in caffeine-abstinent adults. Daily caffeine administration, however, produces tolerance to these cardiovascular effects within several days; thus comparable caffeine doses do not reliably affect blood pressure of regular caffeine consumers. High caffeine doses can produce a rapid heartbeat (tachycardia) and in rare cases irregularities in heartbeat (cardiac arrhythmia). Caffeine's effects on peripheral blood flow and vascular resistance are variable. In contrast, caffeine appears to increase cerebrovascular resistance and decrease cerebral blood flow.

Moderate doses of caffeine can increase respiratory rate in caffeine-abstinent adults. Caffeine also relaxes the smooth muscles of the bronchi. Because of caffeine effects on respiration, it has been used to treat asthma, chronic obstructive pulmonary disease, and neonatal apnea (transient cessation of respiration in newborns).

Moderate doses of caffeine can act on the kidney to produce diuretic effects that diminish after chronic dosing. Caffeine has a variety of effects on the gastrointestinal system, particularly the stimulation of acid secretion. These effects can contribute to digestive upset and to ulcers of the gastrointestinal system.

Caffeine increases the concentration of free fatty acids in plasma and increases the basal metabolic rate.

TOXICITY

High doses of caffeine, typically doses above 300 milligrams, can produce restlessness, anxiousness, nervousness, excitement, flushed face, diuresis, gastrointestinal problems, and headache. Doses above 1,000 milligrams can produce rambling speech, muscle twitching, irregular heartbeat, rapid heartbeat, sleeping difficulties, ringing in the ears, motor disturbances, anxiety, vomiting, and convulsions. Adverse effects of high doses of caffeine have been referred to as caffeine intoxication, a condition recognized by the American Psychiatric Association. Extremely high doses of caffeine—between 5,000 and 10,000 mg—can produce convulsions and death.

Extremely high doses of caffeine, well above dietary amounts, have been shown to produce teratogenic effects (birth defects) in mammals. Although there is some evidence to the contrary, dietary doses of caffeine do not appear to affect the incidence of malformations or of low-birth-weight offspring. Although there has been some suggestion that caffeine consumption increases the incidence of benign fibrocystic disease and cancer of the pancreas, kidney, lower urinary tract, and breast, associations have not been clearly established between caffeine intake and any of these conditions. Similarly, dietary caffeine has been associated with little, if any, increase in the incidence of heart disease.

Controversies continue over the medical risks of caffeine. Although research has not definitively resolved all the controversies, health-care professionals must make recommendations regarding safe and appropriate use of caffeine. In a recent survey of physician specialists, more than 65 percent recommended reductions in caffeine in patients with arrhythmias, palpitations, tachycardia, esophagitis/hiatal hernia, fibrocystic disease, or ulcers, as well as in patients who are pregnant.

PHARMACOKINETICS

Absorption and Distribution.

Caffeine can be effectively administered orally, rectally, intramuscularly, or intravenously; however, it is usually administered orally. Orally consumed caffeine is rapidly and completely absorbed into the bloodstream through the gastrointestinal tract, producing effects in as little as fifteen minutes and reaching peak plasma levels within an hour. Food reduces the rate of absorption. Caffeine readily moves through all cells and tissue, largely by simple diffusion, and thus is distributed to all body organs, quickly reaching equilibrium between blood and all tissues, including brain. Caffeine crosses the placenta, and it passes into breast milk.

Metabolism and Excretion.

The bloodstream delivers caffeine to the liver, where it is converted to a variety of metabolites. Most of an ingested dose of caffeine is converted to paraxanthine and then to several other metabolites. A smaller proportion of caffeine is converted to theophylline and theobromine; both of those compounds are also further metabolized. Some of these metabolites may contribute to caffeine's physiologic and behavioral effects.

The amount of time required for the body of an adult to remove half of an ingested dose of caffeine (i.e., the half-life) is 3 to 7 hours. On average, about 95 percent of a dose of caffeine is excreted within 15 to 35 hours. Cigarette smoking produces a twofold increase in the rate at which caffeine is eliminated from the body. There is a twofold decrease in the caffeine elimination rate in women using oral contraceptive steroids and during the later stages of pregnancy. Newborn infants eliminate caffeine at markedly slower rates, requiring over 10 days to eliminate about 95 percent of a dose of caffeine. By 1 year of age, caffeine elimination rates increase substantially, exceeding those of adults; school-aged children eliminated caffeine twice as fast as adults.

MECHANISMS OF ACTION

Three mechanisms by which caffeine might exert its behavioral and physiological effects have been proposed: (1) blockade of receptors for adenosine; (2) inhibition of phosphodiesterase activity resulting in accumulation of cyclic nucleotides; and (3) translocation of intracellular calcium. Only one of these, however, the blockade of adenosine receptors, occurs at caffeine concentrations in plasma produced by dietary consumption of caffeine. Adenosine (an autacoid—or cell-activity modifier), found throughout the body, has a variety of effects that are often opposite to caffeine's effects—although caffeine is structurally very similar to adenosine. As a result, caffeine can bind to the receptor sites normally occupied by adenosine, thereby blocking adenosine binding, and preventing adenosine's normal activity. Thus, caffeine's ability to stimulate the central nervous system, and increase urine output and gastric secretions, may be due to the blockade of adenosine's normal tendency to depress the central nervous system and decrease urine output and gastric secretions. The methylxanthine metabolites of caffeine (including paraxanthine, theophylline, and theobromine) are also structurally similar to adenosine and block adenosine binding.

(See also: Addiction: Concepts and Definitions ; Tolerance and Physical Dependence )

BIBLIOGRAPHY

Dews, P.B. (Ed.) (1984). Caffeine. New York: Springer-Verlag.

Graham, D. M. (1978). Caffeine—Its identity, dietary sources, intake and biological effects. Nutrition Reviews, 36, 97-102.

Griffiths, R. R., & Woodson, P. P. (1988). Caffeine physical dependence: A review of human and laboratory animal studies. Psychopharmacology, 94, 437-51.

Griffiths, R. R., et al. (1990). Low-dose caffeine physical dependence in humans. Journal of Pharmacological and Experimental Therapy, 255, 1123-1132.

Hughes, J. R., Amori, G., & Hatsukami, K. D. (1988). A survey of physician advice about caffeine. Journal of Substance Abuse, 1, 67-70.

Rall, T. W. (1990). Drugs used in the treatment of asthma. In A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Spiller, G.A. (Ed.) (1984). The methylxanthine beverages and foods: Chemistry, consumption, and health effects. New York: Alan R. Liss.

Weiss, B., & Laties, V. G. (1962). Enhancement of human performance by caffeine and the amphetamines. Pharmacological Review, 14, 1-36.

Kenneth Silverman

Roland R. Griffiths

CAFFEINE

OFFICIAL NAMES: Caffeine

STREET NAMES: None

DRUG CLASSIFICATIONS: Not scheduled, stimulant

OVERVIEW

Doubtlessly the most widely used drug today, caffeine is consumed daily by 90% of the world's people. Evidence of its use exists as far back as the Stone Age, and today, children, teens, and adults everywhere ingest it in coffee, tea, and soft drinks.

Legend has it that the stimulant effect of the coffee bean was first noted by an Ethiopian shepherd guarding his flock, a thousand years ago. Sufi monks steeped the berries in hot water and found that the brew helped them stay awake for long nights of prayer. Meanwhile, written records show that, during the Tang dynasty, which lasted from the seventh to the tenth century, the Chinese were already steeping and consuming tea as a drink believed to lengthen life.

By the Middle Ages, coffee was a popular drink of Muslims. In fact, the word coffee is derived from the Arabic, qahweh (pronounced kahveh). It was the Turks, however, who controlled much of the world's trade in coffee by the Middle Ages. The Turkish Empire, attempting to expand into Europe, laid siege to Vienna in1683. The war failed, but the retreating Turks left behind 500 sacks of coffee beans, which an entrepreneur used to open the first coffeehouse in Vienna. Coffee use spread throughout Europe.

In 1675, King Charles II issued an order to close the coffeehouses that were already widespread throughout England, citing idleness as the chief complaint. Two days before the proclamation was to take effect, however, Charles backed down, fearing massive protests by coffee drinkers. Ironically, in the ensuing decades, the British came to prefer tea, probably due to the acquisition of its colony in India and the establishment of the tea trade there.

The social use of coffee then spread to America. By the eighteenth century, plantations devoted to the coffee plant were actively producing the bean in Indonesia and the West Indies.

Later, during the Vietnam War, coffee also played a part in the protest movement growing at home. Coffee bars flourished near military bases across the United States, where discussions flowed, along with the coffee, over strategies to aid war protestors.

Both health claims and controversies have followed caffeine through the centuries. By the 1960s, health concerns over coffee use were raised in the medical literature as well as the popular press. Research linked coffee consumption to medical conditions such as pancreatic cancer, breast lumps, and elevated levels of cholesterol.

In 1979, a Swiss company developed a distillation method to remove the caffeine from coffee, creating decaffeinated coffee. The Swiss water process proved popular among young urban professionals as it was considered to make a more "natural" product in comparison to the earlier method of making decaffeinated coffee, which used chemicals such as methylene chloride. The Swiss method also retained more of the flavorful oils residing in the coffee bean. Caffeine-free versions of colas soon followed.

Most follow-ups to earlier studies warning of the adverse effects of caffeine have failed to duplicate the initial findings, especially for the moderate use of caffeine. However, at the start of the new millennium, youth culture thrived on the excessive use of caffeine. New drinks were purposely formulated to contain large amounts of the mild stimulant, increasing the risk of possible adverse effects.

Critics of popular beverages such as Red Bull and Adrenaline Rush suggest that the high caffeine and sugar content pose a potential risk of dehydration for athletes, and that they could also pose a significant danger for adverse effects on the heart. In addition, these high caffeine drinks are used as mixer beverages for alcohol, a potentially dangerous combination.

Some body builders tout the combination of caffeine with the herbal stimulant ephedra as harmless, and suggest the combination helps turn fat into muscle. A study published in 2001 does support the claim that caffeine and ephedrine can boost results in laboratory attempts to mimic the tasks of competing athletes. However, ephedra, the herbal drug containing the chemical ephedrine, has been linked to several deaths.

In 1980, the Food and Drug Administration (FDA) proposed to remove caffeine from its Generally Recognized As Safe list. But the FDA concluded in 1992 that, after reviewing the scientific literature, no harm is posed by a person's intake of up to 100 mg per day. As of 2001, the FDA recognized caffeine as a substance that is a food additive with a provisional listing status.

CHEMICAL/ORGANIC COMPOSITION

Caffeine, the active substance responsible for the stimulant effect of the coffee plant's berry, is a methylxanthine, one of the family of stimulants present in more than 60 species of plants. The pure chemical forms white, bitter-tasting crystals, which were first isolated from coffee in 1820. Other family members are theophylline, found in tea leaves, and theobromine, found in the cacao pods that are ground to make chocolate. The most potent component in the coffee family by unit weight is theophylline, while theobromine, the weakest component by unit weight, stays in the body longer than does caffeine.

Caffeine is also a trimethylxanthine, which is made up of three methyl groups. Efforts by the liver to deactivate caffeine at first appear counterproductive. Liver enzymes usually detoxify potentially harmful chemicals obtained through food, or those naturally present in the body. But what is left after the liver initially removes a methyl from caffeine are theophylline and paraxanthine, both of which are still active. Only when the final methyl is stripped away is the chemical inert. This production of active metabolites is why the stimulant lasts a relatively long time. It is also why people with liver disease, or those who consume other drugs that engage the liver enzymes, cannot efficiently clear caffeine from their body. Impaired caffeine metabolism is also evident in women taking estrogen for birth control or who are at the high estrogen phase of their monthly cycle. Newborn babies whose livers are not yet fully developed also break down caffeine more slowly until the enzymes are fully activated.

The methylxanthine molecule is built on a foundation common to many biologic compounds, the xanthine double ring of carbons. The three methylxanthines, caffeine, theophylline, and theobromine, all block the action of the body's adenosine molecule, sending a signal that helps slow the chemical buildup inside cells. Because the methylxanthines closely resemble adenosine at the molecular level, they can occupy the molecular sites on cells that normally recognize, and react to, adenosine. Caffeine prevents the normal slowing action of adenosine at the cellular level, in both nerves and muscle.

Scientists working with cell and tissue preparations recognized that caffeine and the other methylxanthines can block an enzyme called phosphodiesterase. It seems now, however, that this action is carried out at caffeine doses that are much higher than what people normally

consume. A similar caveat goes for the supposed action of caffeine on calcium stores in muscle. It is an effect only evident at high doses.

Caffeine is present in coffee, tea, and chocolate. These plant-derived beverages and foods also contain the other methylxanthines, which some scientists say serve as defense chemicals for leaves and berries produced in climates where there is no winter to kill off chewing bugs. Tea contains mostly caffeine, with small amounts of theophylline and theobromine, but tea is a weaker plant extract than the stronger brew, coffee. Theobromine is the primary methylxanthine found in cocoa, which also contains a small amount of caffeine per cup. Caffeine content ranges from as little as 5 mg in a cup of hot cocoa to 300 mg in 6 oz (177 ml) of espresso. Colas have about 50 mg per 12 fl oz (355 ml).

The robusta strain of coffee plant cultivated in Indonesia and Africa contains about 2.2% caffeine, while the arabica variety, grown in Central and South America, contains half that concentration. The caffeine in tea was purified in 1827, and was initially given its own name of "theine," as chemists of the day thought it different from the caffeine in coffee.

The kola nut, source of some of the flavoring of cola drinks, also has a bit of caffeine. About 5% of the 35 mg in a standard 9.5 oz (280 ml) serving of cola is naturally present from the kola nuts. The caffeine in sodas is added by the manufacturer.

Caffeine is available by prescription as a solution of caffeine citrate. Caffeine is also an active ingredient in many headache medicines, both by prescription and sold over the counter, as well as in nonprescription aids and herbal preparations for alertness and dieting. Body builders may readily buy and use a "stack," a pill comprising of ephedra, caffeine, and aspirin. Often caffeine is added intentionally to the mixes in today's energy drinks. Many abused illegal drugs, as well as some drugs sold legally, contain caffeine, either for added effect, or as a "filler," used in powder form to cut the potency of street drugs.

INGESTION METHODS

The vast majority of caffeine is ingested in a beverage such as coffee, tea, or soda. Beyond beverages, caffeine is also consumed in snacks such as chocolate candy bars, or as a component in drug medications.

THERAPEUTIC USES

Caffeine is approved as a prescription drug for treating premature infants who are born before their lungs and brain are mature enough for automatic breathing. These babies may have a condition called apnea, in which they cease breathing, which could cause damage to the brain and other organs. Caffeine has been demonstrated to aid in keeping premature babies breathing regularly. But a study published in 2001 found that very-low-birth-weight preemies also failed to gain weight when treated for their apnea with caffeine. Apparently the caffeine raised the babies' metabolic rate, causing them to burn more calories.

Many headache medications also contain caffeine, which can increase the effectiveness of the other drugs that alleviate both tension and migraine headaches. People who get migraines can have their headaches controlled by pills that combine caffeine with aspirin or acetaminophen. A study in 2000 showed that the effect of caffeine also increases the effectiveness of ibuprofen.

A study in 1999 confirmed that rebound headaches will occur if regular caffeine users suddenly cease taking the stimulant. To cut down on heavy caffeine use, it was recommended that all forms of caffeine (including caffeine-containing medications) be temporarily eliminated.

In 1999, it was reported that caffeine combined with alcohol could prevent damage from strokes. However, the doses that provide the benefit are quite specific, and the treatment has to be given at a time quite close to the stroke. Another study casts doubt on these findings, and indeed suggests that caffeine cuts blood flow in the brain, an action that would be harmful in people suffering strokes. Then, a report published in 2001 concluded that caffeine could have adverse consequences for patients trying to recover from stroke. By slowing blood flow through the brain, caffeine could starve already struggling nerve cells.

A functional magnetic resonance imaging (fMRI) study of the brain can actually determine between the regular and the occasional coffee drinker. Caffeine consistently slows blood flow by 25% to the gray matter of the brain, which contains the cells, and by 20% to the white matter, which contains the connecting nerve fibers. Heavy users of caffeine show more blood flow in the gray matter in the front of the brain when they had abstained for 30 hours, compared to those who infrequently ingest caffeine. With fMRI, the doctor can look inside the brain and observe the phenomenon of caffeine withdrawal in action.

The therapeutic treatment of obesity with caffeine is another controversial area of interest. Many over-the-counter diet aids contain caffeine, but it has not yet been determined whether there is a medically safe way to use caffeine as a fat fighter. A 2000 study showed that a combination of herbal ephedra and caffeine lowered participants' body weight by both decreasing fat and decreasing the body mass index (BMI). Losses were 15 and 7 pounds for those taking the herbal supplement and a placebo, respectively.

Green tea with caffeine also seeks to weigh in as an herbal fat fighter. The thermogenic effect of tea is carried out at various control points in the adrenergic pathway. Caffeine, through the action of phosphodiesterase enzymes, indirectly boosts the adrenergic signals. However, there is no direct evidence that green tea successfully allows people to lose weight and keep it off.

USAGE TRENDS

Caffeine is widely used due to its relative safety as compared to other stimulants. In fact, in 2001 the U.S. military endorsed the usefulness of caffeine, recommending it as a safe and effective stimulant for its soldiers.

Scope and severity

Ninety-five percent of all caffeine is consumed in the form of tea and coffee. Following water, tea is the most popular beverage in the world. About 1.5 billion cups of coffee are consumed every day throughout the world.

Since water that is not boiled is unsafe to drink in many areas of the world, travelers are advised to drink coffee and tea instead. However, the diuretic effect of caffeine can cause dehydration.

Age, ethnic, and gender trends

The average daily consumption of caffeine for adults in the United States is about 210 mg. Coffee accounts for 60% of the total caffeine consumed in the United States, while soft drinks and tea each represent 16% of the total. In the United Kingdom, by comparison, caffeine intake is twice the American rate, and tea accounts for 72% of the British total. In Scandinavian countries, coffee is the preferred beverage. For instance, in Sweden, coffee makes up 85% of the total per capita of caffeine consumption. Finland is renowned for the practice of brewing particularly potent coffee, boiled and decanted directly from ground beans.

MENTAL EFFECTS

Within minutes of consumption, a caffeinated beverage will cause the drinker to feel more alert. Simple intellectual tasks are performed more readily, as are physical jobs that require endurance. However, while reaction time is shortened by caffeine, fine motor control suffers, perhaps due to the slight tremor that becomes more pronounced with higher doses of caffeine. The larger doses of caffeine, especially for people who do not use it regularly, cause headache and nervousness.

Caffeine decreases the duration of slow waves in the electroencephalogram (EEG) for about five hours after it is ingested. Taken near bedtime, caffeine will delay the time it takes for the consumer to fall asleep, and will reduce the depth and quality of sleep. Sleepers will also move more and waken more easily. These effects are evident with the amount of caffeine present in a cup or two of coffee, approximately 75–150 mg.

PHYSIOLOGICAL EFFECTS

Caffeine, by blocking the action of the body's adenosine, affects a wide variety of organs, as well as the brain, the gut, and basic metabolism. Theophylline works more actively on respiration and the heart. Caffeine is more active in the gut and in the central nervous system. Theobromine has very weak, if any, effect on the brain, but it retains the methylxanthine effect on the kidneys, increasing urination.

Caffeine dissolves easily in fats, so it encounters no barrier as it spreads in the body when taken by mouth. It rapidly crosses the mucosa of the stomach and soaks through the blood-brain barrier. In the bloodstream, the peak level of caffeine is achieved within half an hour. It takes four hours for the body to clear half a dose of the drug. This rate of metabolism of caffeine is slower in newborns and in women late in pregnancy. Smokers, though, rid caffeine more rapidly. Children also rid their bodies of caffeine more readily than adults.

Metabolic processes speed up appreciably under the influence of caffeine. Fatty acids are released into the blood, and a general increase in metabolism is evident as there is increased muscle activity, raised temperature, or both. More calcium is made available through caffeine's action in the muscles for contraction, but this effect is evident only at caffeine doses higher than people commonly use. Gut motility and secretion increase with a release of stomach acid and digestive enzymes. Urination is also stimulated; caffeine directly affects the kidneys, cutting into their ability to reabsorb electrolytes and water. For every cup of coffee or two to three cans of caffeinated soft drink consumed, about 5 mg of calcium is lost in the urine.

Breathing rate increases in response to caffeine. The effect on respiration occurs at the level of the brain stem's respiration control center. Theophylline has the most potent action of all the methylxanthines, affecting the smooth muscle of the bronchial tree in the lungs. This is why theophylline is a treatment for asthma. Doctors may recommend weak tea for their asthmatic patients with colds; this bronchodilating action of the theophylline in the tea will aid in clearing mucus.

Caffeine temporarily increases blood pressure, but the body readily compensates and adjusts back to its normal blood pressure. However, people with hypertension may have a more sensitive response to the drug, as caffeine may raise the blood pressure to a higher level in those with chronic high blood pressure.

For migraine patients, the effect of caffeine on the blood vessels around the brain is beneficial; it constricts both the inner and outer vessels, relieving pain. Also, because caffeine increases the acidity in the stomach, it speeds the absorption of pain medications.

Sports competitors recognize that caffeine can boost performance. Large amounts of caffeine release free fatty acids into the bloodstream, reserving the stores of glycogen in muscle for later use. Two to four cups of coffee contain the amount of caffeine that can enhance exercise performance in the average man weighing about 165 lb (75 kg), and it is two to three cups for a 130-lb (59 kg) woman. A down side to caffeine use during a sporting event is the need to urinate, caused by caffeine's diuretic effect on the kidneys.

Harmful side effects

Some people find that caffeine irritates their gastrointestinal tract. It is still unclear if the effect is from caffeine itself, or from another as-yet-undetermined substance that could be in coffee. Regardless, people with stomach ulcers or irritation may not find relief by switching from caffeinated to decaffeinated coffee.

Effects of caffeine on the heart can be considerable. Rapid or irregular heartbeats can result from ingesting large amounts of caffeine. People at risk for heart attacks might be ill advised to drink coffee or indulge in other sources of caffeine. Caffeine intake exceeding the amount found in five or more cups of drip coffee a day results in a statistically increased risk of cardiac arrest.

Frankly toxic effects, such as persistent insomnia and anxiety, only become evident when people drink more than eight or nine cups of coffee or tea a day. Convulsions and delirium can follow enormous doses, and a near-fatal dose can induce a state similar to that of a diabetic lacking insulin. Blood sugar surges, and ketones appear in the urine. The lowest recorded fatal dose of caffeine was 3200 mg, which was given by accident directly into the bloodstream. It takes the equivalent of 40 cups of coffee consumed by mouth in a short interval for caffeine to kill a person.

Long-term health effects

When studies in the 1980s raised concern about possible adverse effects, including miscarriage, birth defects, and infertility, doctors advised pregnant women to cut out caffeine entirely. Most of these studies have not been confirmed. Certainly, the amounts of caffeine used to cause birth defects in rodents exceed the usual amounts consumed by people. By the year 2000, doctors simply told women who were pregnant or planning pregnancy, to keep caffeine consumption within the bounds of a cup or two of coffee a day.

Most studies find that moderate use of caffeine does not impair fertility, risk miscarriage, or increase the chance of having a baby with birth defects. The March of Dimes has concluded that moderate caffeine is of low risk to pregnant and nursing women.

A study in the early 1990s compared more than 2,800 women who had recently given birth to 1,800 women diagnosed as infertile. Caffeine habits had little or no impact on the reported time it took to conceive in those who had given birth, and was not a risk factor in the infertile. A similar study in Denmark only pointed to smoking as a factor in delayed conception.

Babies born to women who consumed large amounts of caffeine during pregnancy might demonstrate delayed growth or delayed mental or physical development. However, caffeine consumption equivalent to about a cup and a half of coffee a day had no effect on a child's birth weight, length, and head circumference; nor did it have an effect on follow-up exams of the children at eight months of age and at seven years. In a study of 1,500 women, neither the motor skills nor the intelligence of these children was affected by their mother's caffeine consumption. Review of more than 20 studies since the 1980s show no evidence that caffeine causes either low birth weight babies, or early birth.

One study carried out between 1959 and 1966 found that very high levels of a caffeine metabolite is a marker for spontaneous abortion. Measured at 11 weeks gestation, the amount of the metabolite, paraxanthine, in blood serum was higher in women who had lost a pregnancy than in women in the control group. The risk of spontaneous abortion in women with the very highest level of paraxanthine was twice that than for the women with the lowest recorded levels. The levels were measured more than 30 years later, and the findings reported in 2000.

Caffeine can enter the milk of breastfeeding mothers. Babies younger than six months cannot metabolize caffeine as well as do adults. Mothers are advised, however, that up to three cups of coffee, or several cans of soda, can be consumed without passing caffeine on to their nursing infants.

The American Cancer Society states that there does not seem to be any relationship between caffeine and cancer. However, other adverse effects for women remain a concern, such as the possibility that large amounts of caffeine could contribute to osteoporosis (thinned and fragile bones), particularly in elderly women. As caffeine is a diuretic, which increases loss of fluids and electrolytes in the urine, it could rob the body of calcium. Nevertheless, a study published in 2001 concluded that the net effect of carbonated sodas on the body's calcium is negligible, and that the loss of calcium in urine due to carbonated drinks is too small to affect calcium balance.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

Caffeine cannot sober a drunk or save someone who is lethargic or unconscious from an overdose of a sedating drug. However, because caffeine lowers stomach pH, it can affect the absorption of other substances. Other drugs such as oral contraceptives, cimetidine, disulfiram, and alcohol can delay the body's ability to rid itself of caffeine.

TREATMENT AND REHABILITATION

Legally, caffeine is not regulated as a dangerously addictive substance. Yet, withdrawal from caffeine is documented as a recognized set of symptoms in the medical literature. Many people who regularly consume caffeine and then suddenly stop will experience headache, irritability, muscle aches, and lethargy, including impaired concentration.

As with any active agent that produces a withdrawal syndrome, the common-sense approach is to gradually wean oneself from caffeine in order to minimize any symptoms. Those wishing to decrease their use should taper off slowly and perhaps substitute cups of caffeinated drinks with decaffeinated varieties or other caffeine-free beverages.

The extent to which people suffer withdrawal from caffeine use remains controversial. However, a study reported that 11,000 subjects were interviewed about their daily consumption of caffeine, among a host of other questions about lifestyle. Only 11% reported withdrawal symptoms from stopping caffeine intake, and only 3% said their symptoms interfered with daily living. Notably, that figure breaks down differently for the genders: 5.5% of women, but only 0.9% of men, reported symptoms from stopping caffeine intake that affected daily activities. Nevertheless, the study concluded that caffeine withdrawal remains a well-documented phenomenon. A major symptom of abrupt cessation of caffeine use is a headache of moderate to severe intensity that generally begins within 18 hours of the last dose. It peaks at about three to six hours of onset. The feeling is of fullness in the head that continues to a diffuse, throbbing pain, and is worsened by physical activity. Sadness and mild nausea are also reported by a quarter of those who show the withdrawal headache. Those who chronically consume 500 to 600 mg of caffeine per day are more likely to experience withdrawal if they suddenly cease their habit.

PERSONAL AND SOCIAL CONSEQUENCES

A caffeine roundtable discussion by experts concluded that there is no evidence that caffeine is linked to the socially damaging behaviors that characterize drugs of abuse.

LEGAL CONSEQUENCES

There are no legal consequences since caffeine is not a scheduled substance.

Legal history

In 1909, the federal government seized a shipment of Coca-Cola syrup, citing the added caffeine as a poisonous and deleterious substance. In 1959, caffeine was listed in the Code of Federal Regulations as generally recognized as safe, when used in cola type drinks at a level set at 0.02%, based on industry standards at that time. In 1997, the FDA required labeling of the caffeine content of foods and drinks.

Federal guidelines, regulations, and penalties

The FDA allows soft drink manufacturers to add caffeine to a limit of 72 mg per 12-ounce (355 ml) serving. Coffee and tea, containing caffeine naturally rather than as an additive, are not regulated for caffeine content.

See also Ephedra; Herbal drugs

RESOURCES

Books

Braun, Stephen. Buzz. New York: Oxford University Press, 1996.

Pendergrast, Mark. Uncommon Grounds. New York: Basic Books, 1999.

Periodicals

Bell, Douglas. "Effect of Caffeine and Ephedrine Ingestion on Anaerobic Exercise and Performance." Medicine and Science in Sports and Exercise 33 (August 2001): 1399-1403.

Cordes, Helen. "Generation Wired." The Nation (April 27,1998) On-line edition. <http://past.thenation.com/1998/980427.htm>.

Sparano, Nicole. "Is the Combination of Ibuprofen Plus Caffeine Effective for the Treatment of Tension-type Headache?" Journal of Family Practice 50 (January 2001): 312-319.

Other

Center for the Evaluation of Risks to Human Reproduction Web site. <http://cerhr.niehs.nih.gov/genpub/topics/caffeine-ccae.html>.

Cohen, Elizabeth. "Energy Drinks Pack a Punch, But Is It Too Much?" CNN.com. <http://www.cnn.com/2001/HEALTH/diet.fitness/05/29/energy.drinks.02/>. May 29, 2001 (January 30,2002).

Organizations

American College of Sports Medicine, 401 Michigan Street, Indianapolis, IN, USA, 46202-3233, (317) 637-9200, (317) 634-7817, mkeckhaver@acsm.org, <http://www.acsm.org>.

National Headache Foundation, 428 W. St. James Place, 2nd Floor, Chicago, IL, USA, 60614-2750, (888) 643-5552, (773) 525-7357, (888) 643-5552, info@headaches.org, <http://www.headaches.org>.

Roberta L. Friedman, Ph.D.

Caffeine

What Kind of Drug Is It?

Caffeine is a natural stimulant. A stimulant is a substance that increases the activity of a living organism or one of its parts. Caffeine was named after the shrubby coffee plant, which is native to the eastern African nation of Ethiopia. Although coffee is an ancient drink, it was not until 1821 that German chemist Friedlieb Ferdinand Runge finally isolated caffeine from the coffee bean.

Chemically speaking, caffeine is a bitter white alkaloid. Its chemical formula is C₈H₁₀N₄O₂, and it is found especially in coffee and tea. Caffeine is considered both a drug and a psychoactive substance. Such substances alter the user's mental state or change behavior.

As a mild stimulant, it is often used medicinally to treat certain kinds of headache pain. Caffeine consumption speeds up the rate at which chemical reactions occur in the body. By increasing the heart and breathing rates, it helps more oxygen get to the brain. It also acts as a diuretic (pronounced die-er-EH-tik), a substance that reduces bodily fluids by increasing the production of urine.

Overview

Caffeine is said to be consumed on a regular basis by up to 90 percent of the world's people. Humankind's fascination with caffeine dates back to prehistoric times. Andrew Weil and Winifred Rosen retold the story of coffee's accidental discovery in From Chocolate to Morphine. "Legend has it that coffee was first discovered long ago by Ethiopian nomads [or wanderers] who noticed that their domestic animals became frisky" after eating the red fruit of a certain shrub. "When people tried eating the seeds," continued the authors, "they got frisky, too, and eventually they learned to make a flavorful drink from the roasted seeds." By the fifteenth century, just as the Middle Ages (c. 500–c. 1500) were coming to a close, coffee had become a popular drink in the Arab world.

Official Drug Name: Caffeine

Also Known As: None

Drug Classifications: Not scheduled; stimulant

Thousands of years earlier, the Chinese were already steeping and drinking tea as a beverage believed to lengthen life.

A Chinese myth about the discovery of tea dates back more than 4,000 years. According to the tale, a Chinese emperor brewed the first cup of tea after a mysterious leaf fell into the water his servant had boiled for him. The leaf, so the story goes, was from a wild tea tree.

The Road from Picking to Profits

Centuries of war, land-grabbing, oceanic explorations, and trading led to the arrival of coffee and tea in Europe by the 1500s. Coffee use spread throughout the continent and then to America. In the eighteenth century, coffee plantations were actively producing the bean in Indonesia and the West Indies.

Since then, caffeine has been credited with transforming the United States and countries in Europe from agricultural nations to industrial nations. This change has made "the modern world

possible," wrote T. R. Reidin National Geographic in 2005. "Boiling water to make coffee or tea helped decrease the incidence of disease among workers in crowded cities. And the caffeine in their systems kept them from falling asleep over the machinery."

Coffee farming in the South American nation of Colombiais done the old-fashioned way, noted Ruth Morris in Life in 2005. The process "still relies on strained back muscles, wooden tools, and traditional methods" such as mule power "that haven't changed much since coffee was first produced here in the early 1800s." After observing coffee farmers firsthand, Morris explained: "It's a long way from these Colombian hills to 'Skim latte, no foam, please."'

What Is It Made Of?

Caffeine, the active substance responsible for the stimulant effect of the coffee plant's berry, is a xanthine. Xanthines are compounds made of the elements carbon, hydrogen, nitrogen, and oxygen. Some xanthines occur in the blood, urine, and muscle tissue of animals; others are found in certain plants.

The caffeine xanthine is one of the family of stimulants present in more than sixty different species of plants. The pure chemical is a yellowish-white, bitter crystal. Other xanthines related to caffeine include theophylline and theobromine. The pods of cacao beans (better known in the United States as cocoa beans) are ground to make chocolate.

How Is It Taken?

The vast majority of caffeine is ingested in a beverage such as coffee, tea, or soft drinks. Beyond beverages, caffeine is also consumed in snacks such as chocolate candy bars. Pain relievers, including aspirin, acetaminophen, and ibuprofen, may contain some caffeine. The stimulant effects of the caffeine allow the pain relievers to act more quickly.

Caffeine is also found in nonprescription aids and herbal preparations for alertness and dieting. Pure caffeine in tablet form is available over-the-counter in substances such as No-Doz and Vivarin. The caffeine in these tablets has the same effect as the caffeine found in coffee or tea—it is just more concentrated. Many abused illegal drugs contain caffeine, either for added effect or as a "filler," used in powder form to cut the strength of street drugs.

Crazy for Coffee

How much do you know about coffee? Ruth Morris' article "America's Bottomless Cup" in Life magazine and the Web site www.coffeekids.org offer many interesting facts about growing, producing, and drinking coffee. For example, did you know that:

• It takes 4,000 coffee beans to produce one pound of coffee; that is more beans than the average coffee tree yields in a year.
• Americans consume 3 billion pounds of coffee each year.
• Worldwide coffee consumption is estimated at 11 billion pounds per year.
• The average coffee farm in the poverty-stricken nation of Colombia makes about $1,900 each year.
• The female Colombian farm workers who pick out flawed coffee beans—by hand—from enormous troughs of beans make only $5 per day.
• In the coffee-growing regions of Mexico, Guatemala, Nicaragua, and Costa Rica, most coffee farmers earn just a few pennies per pound for their harvest.

CNN medical correspondent Dr. Sanjay Gupta told interviewer Daryn Kagan that people need to be more informed about the "hidden" caffeine content in the foods they eat. "Half a cup of … coffee ice cream from Häagen-Dazs has actually more caffeine than a Coke," remarked Gupta. "Most people are surprised by that." Another example cited by Gupta involved carbonated soft drinks. Ounce for ounce, Sunkist orange soda—a beverage not often thought of as a high source of caffeine—has nearly the same caffeine content as a Coke.

Many people think that dark-colored soft drinks contain caffeine and the light-colored ones do not. However, many popular root beers contain no caffeine while the light-colored Mountain Dew contains more caffeine than a regular Coke. Some manufacturers now offer their popular products in caffeine-free versions as well. If in doubt, check the ingredients on the can or bottle. It will note if the beverage contains caffeine or not.

MSNBC.com reported in 2004 that "in North America, 80 percent to 90 percent of adults drink caffeine regularly." Each day in the United States, the average person consumes about 280 milligrams of caffeine, which equals roughly a mug or two of coffee or three to five cans of soft drinks.

How Much Caffeine Is in That?

Ever wonder how much caffeine is in a certain product? Various Web sites list the caffeine content of many of the most popular products containing caffeine. Among those Web sites are: American Beverage Association <http://www.ameribev.org/health/caffeinecontent.asp> and Center for Science in the Public Interest <http://cspinet.org/new/cafchart.htm>. Here are some examples of popular products and their caffeine content:

Soft Drinks

• 12 oz. A&W Root Beer: 0 mg
• 12 oz. Coca-Cola: 34 mg
• 12 oz. Diet Coke: 45 mg
• 12 oz. Mountain Dew: 55 mg
• 12 oz. Sunkist Orange: 42 mg

Energy Drinks

• 12 oz. Red Bull: 115 mg

Coffee, Tea, Hot Chocolate

• 8 oz. coffee (brewed): 80-135 mg
• 8 oz. decaffeinated coffee (brewed): 3-5 mg
• 8 oz. tea (brewed): 40-60 mg
• 8 oz. iced tea: 15-40 mg (depending on brand)
• 8 oz. hot chocolate: 5-14 mg

Candy Bars

• 1.5 oz. milk chocolate bar: 10 mg
• 1.5 oz. dark chocolate bar: 31 mg

Over-the-Counter Pills

• 1 tablet No-Doz: 100 mg
• 1 tablet Excedrin: 65 mg
• 1 tablet Midol: 32.4 mg

Are There Any Medical Reasons for Taking This Substance?

Many headache medications contain caffeine, which helps speed up the action of analgesics. Because caffeine cuts blood flow in the brain, it should not be used by people at risk for or recovering from a stroke. By slowing blood flow through the brain, caffeine could starve already struggling nerve cells. Rumors of caffeine's effectiveness and safety as a weight loss agent have persisted for years, but they have never been medically proven.

Breathing rates increase in response to caffeine. Theophylline has an especially strong effect on respiration, affecting the smooth muscle of the bronchial tree in the lungs. This is why theophylline is sometimes used as a treatment for asthma. Doctors may recommend weak tea for their asthmatic patients with colds, as the tea will aid in clearing mucus from the respiratory tract.

Usage Trends

Ninety-five percent of all caffeine is consumed in the form of tea and coffee. In the United States and Scandinavian countries, coffee is the main source of total caffeine consumption. In the United Kingdom, tea accounts for about three-quarters of the total caffeine intake. Following water, tea is the most popular beverage in the world.

"People generally take caffeine in forms so diluted as to make it highly unlikely that excessive doses—more than 300 or 400 milligrams at a sitting—will be ingested," noted Edward M. Brecher in The Consumers Union Report on Licit and Illicit Drugs. "People have also developed the custom of drinking coffee and tea after a meal," he added, offering "further protection for the stomach lining."

From Beans and Leaves to Power Drinks

Both health claims and controversies have followed caffeine through the centuries. Studies warning of the harmful effects of caffeine began surfacing in the 1960s. By the early 2000s, though, most follow-ups to those studies failed to duplicate the initial findings. Around the same time, youth culture began to thrive on the excessive use of caffeine. New drinks such as Red Bull, Jolt, and Adrenaline Rush purposely contained large amounts of the stimulant.

Although moderate use of caffeine has been deemed safe by medical researchers, the "power drinks" of the twenty-first century increased the risk of possible negative effects on users. While doing research in London, Reid interviewed several young users of Red Bull. "I've had eight.… I'm flying," reported one. Another compared drinking two tins of the energy drink to "drinking a pint of speed."

Critics of popular beverages such as Red Bull and Adrenaline Rush suggest that the caffeine content, along with the massive doses of sugar in each can, pose a significant health risk. These drinks do provide users with an energy boost. But some researchers think they also increase the chance of dehydration among athletes and all-night dancers. The high sugar content of the drinks impairs the body's ability to replenish fluids lost through sweat.

Energy drinks are also used as mixers for alcoholic drinks. The combination of the two can cause heart damage. In addition, "people who ingest a lot of caffeine, a stimulant, along with a lot of alcohol … won't realize how drunk they really are," warned Elizabeth Cohen on the CNN.com/HEALTH Web site. This could lead people to believe they are capable of driving when they really are not.

Effects on the Body

"The reasons for the attraction" to caffeine, wrote Jennie Kim in The Hoya, "lie in the short-term effects … often referred to as a caffeine 'lift."' Within about fifteen minutes of consumption, a caffeinated beverage will cause the drinker to feel more alert. But, according to Reid, "the instant surge is mostly placebo"—the belief that the substance will produce a desired effect in the user, even if the substance itself is not capable of producing that effect. Reid added: "[C]affeine's effects don't peak for up to an hour after it hits the bloodstream."

Caffeine Consumption

Many people throughout the world consume caffeine every day. Caffeine is found in coffee, tea, soft drinks, chocolate, and even over-the-counter drugs, among other products. Here are more facts about this popular natural stimulant.

• Medical experts recommend that the caffeine intake for children be limited to 100 milligrams daily.
• The average daily consumption of caffeine for adults in the United States is about 280 milligrams.
• Approximately 600 milligrams of caffeine have the same stimulating effect as 20 milligrams of amphetamines (am-FETT-uh-meens). (Prescription-only stimulant drugs, amphetamines increase mental alertness, reduce appetite, and help keep users awake.)
• About 1.5 billion cups of coffee are consumed every day throughout the world.
• Most of the caffeine in soft drinks is added by the manufacturers. The kola nut, the source of some of the flavoring of cola drinks, has only a bit of caffeine, providing about 5 percent of the total amount in a standard serving.

Whether it takes fifteen minutes or sixty minutes after consumption for a "caffeine buzz" to kick in, the stimulant effects of this substance are very real. Simple intellectual tasks are performed more readily, as are physical jobs that require endurance. However, fine motor movements may become more difficult to carry out, perhaps due to the slight hand tremors

that become more pronounced with higher doses of caffeine. Larger doses of caffeine, especially in people who do not use it regularly, typically cause headache and nervousness.

The effects of caffeine last for about five hours after it is ingested. Taken near bedtime, caffeine will delay the time it takes for the user to fall asleep. It will also reduce the depth and quality of sleep. These effects are evident with the amount of caffeine present in a cup or two of coffee, approximately 80 to 250 milligrams. People who have consumed caffeine shortly before trying to sleep tend to move around in bed more and wake up more easily than sleepers who have not consumed caffeine prior to bedtime.

More Harmful Side Effects

After being taken by mouth, caffeine dissolves easily in body fats. It does not encounter any barrier as it spreads throughout the body, so it rapidly crosses the mucosa (the mucus membrane) of the stomach and soaks through the blood-brain barrier. Caffeine affects the brain, the digestive system, heart and breathing rates, and the kidneys. When consumed in very large amounts, it can cause users to experience an increase in muscle activity, a rise in body temperature, a decrease in appetite, and problems sleeping.

In addition to increased heartbeat and rate of respiration, stomach acid production rises, sometimes causing indigestion. Urination is also stimulated. Caffeine directly affects the kidneys, cutting their ability to reabsorb electrolytes and water. For every single cup of coffee or two to three cans of caffeinated soft drink consumed, about five milligrams of calcium, an important electrolyte, are lost in the urine.

Caffeine temporarily increases blood pressure. In healthy users, the body is able to compensate for this increase and adjust back to its normal blood pressure rate. However, people with hypertension or who are at high risk for heart attacks may have a more sensitive response to the drug and are advised to minimize their caffeine intake. Even in people without heart disease, the effects of caffeine on the heart can be considerable. Rapid or irregular heartbeats can result from ingesting the substance in very large amounts.

For migraine headache sufferers, the effect of caffeine on the blood vessels around the brain is beneficial. It constricts both the inner and outer vessels, relieving pain. Also, because caffeine-containing drinks such as coffee increase the acidity in the stomach, they speed the absorption of pain medications. Some people, however, find that caffeine irritates their stomachs and intestinal tracts. It is still unclear if the effect is from the caffeine itself, or from another asyet-undetermined substance that could be in coffee. Large amounts of caffeine may also contribute to osteoporosis, particularly in elderly women.

Caffeine Can Be Toxic

Toxic or poisonous effects, such as persistent insomnia and anxiety, only become evident when people drink more than eight or nine cups of coffee or tea a day. Insomnia is when someone has difficulty falling asleep or an inability to sleep. Anxiety is a feeling of being extremely overwhelmed, restless, fearful, and worried.

Convulsions and delirium can follow enormous doses. Morris noted that the amount of caffeine in forty-nine eight-ounce cups of coffee can actually be fatal to a human being if consumed by mouth in a short period of time. That works out to about 4,000 to 6,600 milligrams of caffeine in a sitting.

Dangers can occur when caffeine-containing beverages are mixed with caffeine tablets such as No-Doz or Vivarin, both of which are sold without a prescription at drugstores. These tablets have high concentrations of caffeine in them. Taking them at higher than recommended doses, especially along with coffee, tea, or other caffeinated drinks, can cause toxic results.

Women and Caffeine, 1969

In 1969, Dr. Avram Goldstein and Dr. Sophia Kaizer, both of the Stanford University School of Medicine, decided to examine why so many people drink coffee. They focused their study on the coffee-drinking habits of 239 young women.

The women were asked a series of questions. A full 60 percent of them claimed that they drank their first cup of coffee in the morning "because they needed it." Heavier users reported symptoms of withdrawal when they skipped their morning coffee. These symptoms ranged from "headache" and "irritability" to an "inability to work effectively."

The next phase of the experiment produced interesting results. Some of the women agreed to brew and drink nine unmarked vials of coffee—one each morning over the course of nine days. Three of the vials contained no caffeine, three contained 150 milligrams of caffeine, and three contained 300 milligrams of caffeine. Each day, the group was asked to record their moods every half hour for two hours after drinking whatever vial they brewed that day. None of them knew who was drinking what each morning.

The Goldstein–Kaizer study is credited with proving that caffeine is indeed a mind-affecting drug. Heavy coffee drinkers reported feeling nervous, sluggish, and irritable on the mornings they drank the caffeine-free coffee. Among light coffee drinkers, jittery feelings and stomach problems plagued them on mornings when they drank the highly caffeinated coffee.

The results of the Goldstein–Kaizer study were first published in the July 8, 1969, issue of Clinical Pharmacology and Therapeutics. The information was adapted by Edward M. Brecher for use in The Consumers Union Report on Licit and Illicit Drugs, 1972.

Babies born to women who consume extremely large amounts of caffeine during pregnancy have demonstrated delayed growth and problems with mental or physical development. As of 2005, doctors were advising pregnant women to keep their caffeine consumption within the bounds of a cup or two of coffee per day to ensure the good health of their babies. Pregnant women who have miscarried in the past are advised to avoid caffeine totally.

Reactions with Other Drugs or Substances

Caffeine cannot sober up someone who is drunk or save someone who is overdosing on a sedative. It can, however, alter the rate of absorption in the digestive system. Consuming caffeine in combination with drugs such as oral contraceptives and alcohol can delay the body's ability to rid itself of the caffeine.

Treatment for Habitual Users

Legally, caffeine is not regulated as a dangerously addictive substance. Yet, withdrawal from caffeine is documented in medical literature as a recognized set of symptoms. Physical and psychological dependence on coffee, for instance, tends to occur at rates of five or more cups per day. Many people who regularly consume caffeine and then suddenly stop will experience headaches, irritability, muscle aches, extreme tiredness, and impaired concentration.

A major symptom of quitting caffeine abruptly is a moderate to severe headache that generally begins within eighteen hours of the last dose. The feeling has been described as a fullness in the head that turns into a throbbing pain and is worsened by physical activity. Sadness and mild nausea are also reported by a quarter of those individuals who get the withdrawal headache. Those who chronically consume 500 to 600 mg of caffeine per day are more likely to experience withdrawal if they suddenly cease their habit. MSNBC.com reported that 13 percent of coffee addicts "were sick enough to lose time at work" when the source of their caffeine was taken away. Withdrawal symptoms can last as long as nine days.

In "Decreasing Your Caffeine Intake," registered dietician Karen Schroeder advises users who want to cut back on their caffeine intake to do so gradually. "Decreasing over a period of time" rather than going "cold turkey" may help minimize the symptoms of withdrawal. For starters, Schroeder suggests "mixing half regular and half decaffeinated coffee" or brewing tea "for a shorter time," since "a one-minute brew contains about half of the caffeine that a three-minute brew contains."

Consequences

As of 2005, there was no evidence that caffeine use alone was linked to the socially damaging behaviors that characterize drugs of abuse. Kim noted, however, that students who consume large amounts of caffeine to "enhance mental capacity" should be cautioned. Excessive caffeine consumption may actually bring on "symptoms unfavorable to studying, such as restlessness, anxiety, and heart palpitations. The student may struggle and would have better study habits without the caffeine."

The Law

There are no legal consequences for caffeine sale, use, or possession, since caffeine is not a scheduled substance. In 1997, the U.S. Food and Drug Administration (FDA) required labeling of the caffeine content of foods and drinks. Soft drink manufacturers are allowed to add a maximum of 6 milligrams of caffeine per ounce of beverage, which adds up to a limit of 72 milligrams per 12-ounce serving. Coffee and tea, containing caffeine naturally rather than as an additive, are not regulated for caffeine content.

For More Information

Books

Braun, Stephen. Buzz: The Science and Lore of Alcohol and Caffeine. New York: Oxford University Press, 1996.

Brecher, Edward M., and others. The Consumers Union Report on Licit and Illicit Drugs. Boston: Little Brown & Co., 1972.

Gahlinger, Paul M. Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse. Las Vegas, NV: Sagebrush Press, 2001.

Kuhn, Cynthia, Scott Swartzwelder, Wilkie Wilson, and others. Buzzed: The Straight Facts about the Most Used and Abused Drugs from Alcohol to Ecstasy, 2nd ed. New York: W.W. Norton, 2003.

Pendergrast, Mark. Uncommon Grounds. New York: Basic Books, 1999.

Weil, Andrew, and Winifred Rosen. From Chocolate to Morphine. New York: Houghton Mifflin, 1993, rev. 2004.

Weinberg, Bennett Alan, and Bonnie K. Bealer. The World of Caffeine: The Science and Culture of the World's Most Popular Drug. New York: Routledge, 2001.

Periodicals

Kim, Jennie. "The Buzz on Caffeine." The Hoya (February 8, 2000).

Morris, Ruth. "America's Bottomless Cup." Life (January 14, 2005): pp. 4-9.

Reid, T. R. "Caffeine." National Geographic (January, 2005): pp. 3-33.

Sparano, Nicole. "Is the Combination of Ibuprofen Plus Caffeine Effective for the Treatment of Tension-type Headache?" Journal of Family Practice (January, 2001): pp. 312-319.

Web Sites

"Coffee Kids." Coffee Kids: Grounds for Hope.http://www.coffeekids.org/ (accessed June 30, 2005).

Cohen, Elizabeth. "Energy Drinks Pack a Punch, But Is It Too Much?" CNN.com/HEALTH, May 29, 2001. http://archives.cnn.com/2001/HEALTH/diet.fitness/05/29/energy.drinks.02/index.html (accessed June 30, 2005).

Kagan, Daryn. "Dr. Sanjay Gupta: Caffeine Hidden in Many Foods." CNN.com/HEALTH, June 27, 2003. http://www.cnn.com/2003/HEALTH/diet.fitness/06/27/otsc.gupta/index.html (accessed June 30, 2005).

Schroeder, Karen. "Decreasing Your Caffeine Intake." St. John Health.http://www.stjohn.org/healthinfolib/ (accessed June 30, 2005).

"Tea and Caffeine." Holy Mountain Trading Company.http://www.holymtn.com/tea/caffeine.htm (accessed June 30, 2005).

"Too Much Caffeine." Information for Health Professionals: Medsafe Prescriber Update Articles, August 1999. http://www.medsafe.govt.nz/profs/PUarticles/caffeine.htm (accessed June 30, 2005).

"Yes, You Really Do Need That Coffee." MSNBC.com, September 30, 2004. http://www.msnbc.msn.com/id/6140162/ (accessed June 30, 2005).

See also: Amphetamines; Ephedra; Herbal Drugs

CHAPTER 9
CAFFEINE

As Americans sit down to their morning cups of coffee or tea or drink a cola, few think about the fact that they are taking a drug. A drug is any substance that affects the mood or the state and function of the body. According to this definition, the caffeine in many of our favorite beverages is a drug.

SOURCES OF CAFFEINE

Caffeine occurs naturally in the seeds, leaves, or fruits of more than sixty-three plant species throughout the world. The primary sources available in the United States, however, are coffee, tea, cacao (cocoa), and kola (cola) plants. These are grown and produced in tropical locations and shipped all over the world. Two other plants, maté and guarana, are primarily grown and consumed in South America as yerba maté and guarana bars and drinks (soda drinks or brewed hot drinks).

Table 9.1 lists the four major sources of caffeine, the parts of the plants that are consumed, and the locations in which the plants are grown. Of the three species of coffee, coffea arabica L. accounts for about three-quarters of all coffee consumption. Spices and other substances, such as vanilla and chocolate, can be added to make flavored coffees.

The three major tea types (green, oolong, and black) all come from the same species of plant; differences in flavor and color are a result of how the tea leaves are processed. For green tea, the leaves are steamed and dried. For oolong tea, the steamed leaves are partly fermented before they are dried. And for black tea, the steamed leaves are completely fermented before they are dried. As with coffee, spices and other flavorings can also be added to vary the taste of tea.

There are many products on the market today that are called "teas" even though they do not contain tea leaves. Virtually any beverage prepared by steeping substances in hot or boiling water is popularly called a tea. Herbal teas do not contain tea leaves or caffeine.

Varying Amounts of Caffeine

Not all plants contain equal concentrations of caffeine. Different methods of processing and brewing can also affect the amount of caffeine per cup or glass of a beverage. When calculating the amount of caffeine per cup or glass, a person must keep in mind the size of the cup or glass, and whether he or she dilutes coffee or tea with another substance, such as milk.

Of caffeinated drinks, coffee contains the highest concentration of caffeine. (See Table 9.2.) The way it is prepared, however, can change the amount of caffeine it contains. In general, coffee made in a drip-style coffee maker is highest in caffeine content. A six-ounce cup of coffee made by the drip method contains between 110-150 milligrams (mg) of caffeine; percolated coffee contains 64-124 mg of caffeine; and instant coffee contains 40-108 mg. Tea has significantly less caffeine than coffee, but the longer it is allowed to steep, the higher the caffeine concentration. A one-minute brew for a six-ounce cup of tea contains between thirty-five and forty-six mg of caffeine; a three-minute brew contains twenty to forty-six mg of caffeine. A hot cocoa mix typically contains six mg of caffeine. Both cocoa and cola drinks generally have lower levels of caffeine ounce per ounce than tea and coffee. However, cocoa contains large amounts of theobromine, a chemical related to caffeine that has the same stimulating effect.

Consumers should be aware that many popular over-the-counter (OTC, or nonprescription) medications contain caffeine. Caffeine is used in some OTC and prescription pain relievers because some studies have shown that caffeine increases their effectiveness. Caffeine is also a major ingredient in most preparations to help individuals stay awake and in OTC weight-control products.

HOW MUCH CAFFEINE DO WE CONSUME?

Table 3.2 in Chapter 3 shows the per capita consumption of beverages: milk, tea, coffee, bottled water, carbonated soft drinks, fruit juices and fruit drinks, canned iced tea, and vegetable juices. Consumption of carbonated soft drinks generally rose between 1966 and the early 1990s and then leveled off somewhat. Most carbonated soft drinks contain caffeine. Coffee consumption was relatively stable from 1966 through 1976, dropped sharply in 1977, and has stayed somewhat consistent since then with the lowest level of consumption in the mid-1990s. In 2003 coffee consumption was 24.3 gallons per person.

Tea consumption rose somewhat steadily from 1966 through the mid-1970s, somewhat stabilized until 1990, and then rose sharply in the early-to-mid-1990s to somewhat stabilize again. In the mid-1990s, when coffee consumption was down somewhat, tea consumption was up somewhat. In 2003 tea consumption was 7.6 gallons per person.

The average daily intake of caffeine among consumers in the United States is about 280 mg, which is equal to about three cups of coffee or about seven twelve-ounce glasses of a cola beverage (L. M. Juliano and R. R. Griffiths, "A Critical Review of Caffeine Withdrawal: Empirical Validation of Symptoms and Signs, Incidence, Severity, and Associated Features," Psychopharmacology, vol. 176, 2004).

Results of a study published in 2001 (Janet Brown et al., "Misclassification of Exposure: Coffee as a Surrogate for Caffeine Intake," American Journal of Epidemiology, no. 153) show that the four main sources of caffeine for people aged thirty to seventy-five living in southern Ontario, Canada, were brewed coffee, instant coffee, regular tea, and cola soft drinks. Brewed coffee was the main source of caffeine, while tea and cola soft drinks ranked second or third, depending on age. Cola drinks ranked second for those aged thirty to forty-four, and tea ranked second for those aged forty-five to seventy-five. Men had a higher caffeine intake than women, and those aged forty-five to fifty-nine had a higher caffeine intake than younger persons.

Results of a study on beverage caffeine intake in U.S. consumers (C. A. Knight et al., Food and Chemical Toxicology, vol. 42, no. 12, December 2004) were some-what consistent with the Ontario study. Research results revealed that children and young adults up to age twenty-four consumed most of their caffeine in carbonated soft drinks. Consumption of coffee generally did not begin until age fifteen, but children as young as one year old consumed tea. People ages twenty-five and older consumed most of their caffeine in coffee, with carbonated soft drinks a second choice, and tea in third place. When people reached fifty years of age or so, tea became their second-largest source of caffeine, with carbonated soft drinks their third. This "switch" between tea and soft drinks remained throughout the rest of their lives.

The Ontario study also showed that caffeine intake is usually underestimated because people often report only their coffee intake and omit caffeine from other sources. The results of this study showed an average intake of caffeine for subgroups of these Ontario residents to range from a low of 288 mg per day for women ages thirty to forty-four to a high of 426 mg per day for men ages forty-five to fifty-nine.

Coffee remains the major source of caffeine for adults. According to the National Coffee Association's 2003 National Coffee Drinking Trends survey, 51% of the adult population drinks coffee everyday, representing 108.3 million coffee drinkers. Another 28% of the population, or 58.3 million adults, drinks coffee occasionally.

Only a small percentage of eighteen-to-twenty-four-year-olds consumed coffee in 2003—just 7% as estimated by the National Coffee Association. High levels of unemployment are correlated with lower levels of coffee drinking; this age group had the highest level of unemployment of all adults in 2003.

PHYSICAL EFFECTS OF CAFFEINE

Caffeine is classified as a stimulant because it increases the activity of the cardiovascular system, digestive system, and sympathetic nervous system (that which generally mobilizes the body for greater activity), and produces a sense of alertness in the brain. It also has a mild diuretic effect, eliminating water from the body by increasing urination. In moderate amounts, it can increase the ability to work longer and concentrate better. Too much caffeine, however, can produce nervousness, anxiety, irritability, and sleeplessness.

Because it gives athletes quicker reaction and longer endurance times, caffeine is a drug for which Olympic competitors are tested. If more than a small to moderate amount of caffeine (the amount in a few cups of coffee) is found in the blood, an athlete can be disqualified from the Olympic Games and other international competitions.

Many caffeine-producing plants also contain related stimulants known as methylxanthines, two of which are theophylline and theobromine. Theophylline is used in prescription drugs to treat chronic lung diseases such as asthma and emphysema. Theobromine is a weaker stimulant than caffeine, but it is more abundant in cocoa beans than is caffeine. Part of the stimulating effect of chocolate and cocoa is probably due to theobromine.

The fact that caffeine increases alertness has led to the myth that a strong cup of coffee will help to sober up someone who is drunk, but caffeine does not counteract the effects of alcohol.

How Caffeine Is Metabolized

In its pure state, caffeine is a bitter white powder that looks something like cornstarch. It is a member of the purine family of compounds. When purines are broken down in the body, they form a chemical called xanthine. The liver converts xanthine to uric acid, a metabolic waste product.

Caffeine dissolves in water, and it is rapidly and completely absorbed into the blood after ingestion. It takes from four to twelve hours to be eliminated completely from the body. Therefore, drinking coffee, tea, or caffeine-containing soft drinks several times a day can result in a large amount of caffeine in the body.

Two other purines, adenine and guanine, play a major role in human genetics and cell function. One of their by-products, adenosine, participates in the supply of energy to cells and helps regulate body processes such as the transmission of signals by nerves. In addition, adenosine can

• Promote sleepiness.
• Dilate blood vessels.
• Reduce the contractions of the stomach and intestines.
• Prevent seizures.
• Slow the reaction to stress.
• Lower the heart rate, blood pressure, and body temperature.

To perform these functions, adenosine inhibits the release of neurotransmitters (chemicals that carry messages from one nerve cell to another) by binding to specific receptors on a cell's surface. The structure of caffeine and its by-products is chemically similar to that of adenosine, which allows caffeine to bind to the same receptor sites, blocking adenosine and preventing it from taking effect. The effects of caffeine are the result of this blocking of the "slowing" effects of adenosine and explain why ingesting large amounts of caffeine may result in the "caffeine jitters."

IS CAFFEINE ADDICTIVE?

The question of whether caffeine is addictive has been debated for decades. Some medical experts believe it is mildly addictive because it fits the criteria for addiction: dependence and tolerance. In "Clinical Pharmacology of Caffeine" (Annual Review of Medicine, 1990), Neal L. Benowitz observed, "Minor criteria for addiction liability include the development of tolerance, physical dependence, and recurrent intense desire for the drug, all of which are characteristic of regular caffeine consumers. Thus, there is a group of coffee drinkers who appear to be addicted to caffeine, although the extent of caffeine addiction in the population is unknown."

While caffeine is both psychoactive (mood altering) and addictive, it is not intoxicating. No one gets drunk or "high" on caffeine, although it can produce anxiety and sleeplessness.

However, results of a 1999 study, "Are We Dependent upon Coffee and Caffeine? A Review on Human and Animal Data" (Neuroscience and Biobehavioral Reviews), show that complete tolerance to many of the effects of caffeine on the central nervous system does not occur. Additionally, average daily doses of caffeine do not act on brain structures related to reward, motivation, and addiction as do "hard" drugs such as cocaine and amphetamines.

HEALTH EFFECTS

One major side effect of consuming large quantities of coffee, tea, soft drinks, and chocolate is a nervous feeling or jitters. In general, the more caffeine that is consumed, the more likely the person is to suffer these side effects. For some people, however, even a minor amount of caffeine can disrupt their sleeping patterns, cause their hands to shake, or create anxiety.

The physical effects of caffeine in the body are fairly well understood, but studies attempting to link caffeine to different diseases have been inconclusive. For example, scientists know that caffeine stimulates the central nervous system, resulting in increased alertness and mood elevation. However, for persons in good general health, studies have not shown any link between drinking coffee or tea and suffering from a nervous disorder, other than the temporary side effects discussed above.

Caffeine does raise blood pressure. Some people develop a tolerance to this effect, and the blood pressure soon returns to its normal level. However, some do not develop this tolerance. Caffeine causes a persistent rise in blood pressure among some regular consumers, even when their daily intake is moderate (W. R. Lovall et al., "Blood Pressure Response to Caffeine Shows Incomplete Tolerance after Short-Term Regular Consumption," Hypertension, vol. 43, no. 4, April 2004). In "Critical Review of Dietary Caffeine and Blood Pressure: A Relationship That Should Be Taken More Seriously," J. E. James contends that caffeine use could account for 14% of coronary heart disease deaths and 20% of stroke deaths (Psychosomatic Medicine, vol. 66, no. 1, January-February 2004).

Coffee has also been suspected of increasing cholesterol levels in the blood, but research data are some-what contradictory. Results from a Norwegian study found that drinking filtered coffee was not associated with high cholesterol levels, but that consumption of boiled coffee promoted increased plasma concentration of cholesterol and was thus associated with an elevated risk for cardiovascular disease (T. Ranheim and B. Halvorsen, "Coffee Consumption and Human Health—Beneficial or Detrimental?" Molecular Nutrition and Food Research, vol. 49, no. 3, March 2005). In contrast, P. Happonen et al. determined that brewing method does not make a difference, and concluded from their data that heavy coffee consumption increases the short-term risk of heart attack and death ("Coffee Drinking Is Dose-Dependently Related to the Risk of Acute Coronary Events in Middle-Aged Men," Journal of Nutrition, vol. 134, no. 9, September 2004). Moreover, results of a Nigerian study conducted by A. J. Onuegbu and E. O. Agbedana suggest that shortterm consumption of coffee may increase the total serum cholesterol and LDL (bad) cholesterol levels ("The Effects of Coffee Consumption on Serum Lipids and Lipoprotein in Healthy Individuals," African Journal of Medicine and Medical Sciences, vol. 30, no. 1-2, March–June 2001).

Caffeine Overdose

It is possible to overdose on caffeine. Symptoms of an overdose include hyperventilation (rapid, deep breathing), rapid heartbeat, atrial heart fibrillation (twitching; beating unevenly), convulsions, and imbalances in the body's levels of potassium, sugar, and other blood chemicals. The overdose amount differs from person to person and depends on body weight, metabolic rate, and usual intake of caffeine (tolerance).

Fatal caffeine overdoses are very rare, but they can occur. Most are either suicide attempts or accidental overuse of caffeine tablets. An average-sized adult would have to consume about 5,000 milligrams (five grams) of caffeine—about fifty cups of normal-strength coffee—to get a fatal dose, and the cups would have to be drunk in rapid succession. In children, because of their smaller body mass and differences in metabolizing caffeine, a much smaller dose could be lethal.

Is There a Link to Cancer?

Results of studies to determine the links (if any) between caffeine and various types of cancer have been contradictory. For every study that gives evidence of a possible link, another study finds no evidence of a link. Results of laboratory studies have shown that caffeine can change the cells of bacteria, plants, insects, and humans in the laboratory, but results of epidemiological studies have not shown that caffeine causes cancerous cell development in generally healthy people. In a 1997 report (Nutrition and the Prevention of Cancer: A Global Perspective), the American Institute of Cancer Research in Washington, D.C., and the World Cancer Fund in London stated that "most evidence suggests that regular consumption of coffee and/or tea has no significant relationship with the risk of cancer of any site."

Results of a 2005 Harvard study, which used large data sets from the Nurses' Health Study (women) and the Health Professionals' Follow-up Study (men), support the findings reported in the previous paragraph, in that consumption of caffeinated coffee or tea, or caffeine from other sources, was not associated with the incidence of colon or rectal cancer. Conversely, regular consumption of decaffeinated coffee was associated with a reduced incidence of rectal cancer (K. B. Michels et al., "Coffee, Tea, and Caffeine Consumption and Incidence of Colon and Rectal Cancer," Journal of the National Cancer Institute, vol. 97, no. 4, February 2005).

Caffeine and Pregnancy

While heavy caffeine use has been suspected of contributing to miscarriages, some studies have given conflicting results and failed to establish a definite link (L. B. Signorello and J. K. McLaughlin, "Maternal Caffeine Consumption and Spontaneous Abortion: A Review of

the Epidemiologic Evidence," Epidemiology, vol. 15, no. 2, March 2004).

The U.S. Food and Drug Administration (FDA) advises pregnant women to limit or eliminate their intake of caffeine. The substances that an expectant mother eats or drinks can be passed through the bloodstream to her unborn baby, and a mother who drinks large amounts of caffeine may produce a baby who shows signs of caffeine jitters. Nursing mothers can also pass caffeine to their babies through breast milk, leading to sleep disruptions and irritability.

Interactions with Other Drugs

Caffeine may also interact with prescription and OTC drugs. In some cases, a drug may have side effects similar to those of caffeine, so even a small amount of coffee, tea, or cola may cause jitteriness or disturb sleep. In other cases, caffeine may reduce or heighten the effectiveness of medications. In addition, alcohol and tobacco affect the metabolism of caffeine in the body, causing it either to leave the body more rapidly or to remain in the bloodstream for a longer time. (See Table 9.3.) People who drink a lot of caffeinated beverages should discuss with their doctors the effects caffeine might have on any medications they are taking.

Possible Health Benefits

Caffeine's bronchodilator effect of opening the air-ways can be beneficial to people suffering from acute bronchial asthma. Caffeine acts as an analgesic (pain killer) and, when combined with ibuprofen, can bring faster and longer lasting relief from tension headaches. It is often prescribed for migraine headaches. Drinking two cups of coffee before breakfast has helped individuals suffering from dizziness and other effects caused by abnormally low blood pressure.

DECAFFEINATION

People who are sensitive to caffeine or those who want to moderate their caffeine intake can still enjoy their favorite beverages in decaffeinated forms. Decaffeination removes almost all the caffeine (about 97%) from coffee or tea. There are three common methods of decaffeination.

• The direct method uses methylene chloride, which dissolves caffeine, to remove caffeine from green coffee beans and moist tea leaves. Then a further process removes the methylene chloride from the product.
• The water method uses water to dissolve the caffeine from steamed coffee beans or tea leaves. Then the caffeine is removed from the water by using methylene chloride, and the decaffeinated water is added back to the coffee or tea to enhance flavor. The beans or leaves are steamed again to remove any methylene chloride remaining.
• The carbon dioxide method, which is the newest, uses carbon dioxide to remove caffeine. This process leaves in more flavor than the other two methods.

Methylene chloride, in its inhaled form, is known to cause cancer in laboratory animals. When methylene chloride is diluted in their drinking water, however, the laboratory animals do not develop cancer. The FDA has analyzed decaffeinated coffee made through the direct method and found that so little methylene chloride is left in the final product that any risk of it causing cancer is remote. The amount of methylene chloride in the finished product is less than that found in the air on a smoggy day.

Some people find that decaffeinated coffee lacks some of the flavor of regular coffee. Using fresh-ground or flavored decaffeinated coffee beans may help brew a better-tasting pot of coffee. Using half regular coffee and half decaffeinated coffee can also help cut down caffeine intake, as can simply drinking fewer caffeineladen drinks per day. Hot chocolate, hot apple cider, and herbal teas make good low-caffeine or caffeine-free substitutes for those wanting to limit their caffeine intake.

What Do They Do with the Caffeine They Take Out?

The caffeine removed from coffee and tea is a useful by-product. It can be used in medications or added to soft drinks to increase their caffeine content. Some is processed into theophylline, which is used in medications for asthma and emphysema.

Caffeine-Related Disorders

Definition

Description

Causes and symptoms

Demographics

Diagnosis

Treatments

Prognosis

Prevention

Resources

Definition

Caffeine is a white, bitter crystalline alkaloid derived from coffee or tea. It belongs to a class of compounds called xanthines, its chemical formula being 1,3,7-trimethylxanthine. Caffeine is classified together with cocaine and amphetamines as an ana-leptic, or central nervous system stimulant. Coffee is the most abundant source of caffeine, although caffeine is also found in tea, cocoa, and cola beverages as well as in over-the-counter and prescription medications for pain relief.

In the clinician’s handbook for diagnosing mental disorders (the Diagnostic and Statistical Manual of Mental Disorders, known as the DSM-IV-TR), caffeine-related disorders are classified under the rubric of substance-related disorders. DSM-IV-TR specifies four caffeine-related disorders: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified. A fifth, caffeine withdrawal, is listed under the heading of “Criteria Sets and Axes Provided for Further Study.”

Caffeine-related disorders are often unrecognized for a number of reasons:

• Caffeine has a “low profile” as a drug of abuse. Consumption of drinks containing caffeine is unregulated by law and is nearly universal in the United States; one well-known textbook of pharmacology refers to caffeine as “the most widely used psychoactive drug in the world.” In many countries, coffee is a social lubricant as well as a stimulant; the “coffee break” is a common office ritual, and many people find it difficult to imagine eating a meal in a fine restaurant without having coffee at some point during the meal. It is estimated that 10-12 billion pounds of coffee are consumed worldwide each year.
• People often underestimate the amount of caffeine they consume on a daily basis because they think of caffeine only in connection with coffee as a beverage. Tea, cocoa, and some types of soft drink, including root beer and orange soda as well as cola beverages, also contain significant amounts of caffeine. In one British case study, a teenager who was hospitalized with muscle weakness, nausea, vomiting, diarrhea, and weight loss was found to have caffeine intoxication caused by drinking 8 liters (about 2 gallons) of cola on a daily basis for the previous two years. She had been consuming over a gram of caffeine per day. Chocolate bars and coffee-flavored yogurt or ice cream are additional sources of measurable amounts of caffeine.
• Caffeine has some legitimate medical uses in athletic training and in the relief of tension-type headaches. It is available in over-the-counter (OTC) preparations containing aspirin or acetaminophen for pain relief as well as in such OTC stimulants as NoDoz and Vivarin.
• Caffeine is less likely to produce the same degree of physical or psychological dependence as other drugs of abuse. Few coffee or tea drinkers report loss of control over caffeine intake, or significant difficulty in reducing or stopping consumption of beverages and food items containing caffeine.
• The symptoms of caffeine intoxication are easy to confuse with those of an anxiety disorder.

The DSM-TR-IV states that it is unclear as of 2000 whether the tolerance, withdrawal symptoms, and “some aspects of dependence on caffeine” seen in some people who drink large amounts of coffee “are associated with clinically significant impairment that meets the criteria for Substance Abuse or Substance Dependence.” On the other hand, a research team at Johns Hopkins regards caffeine as a model drug for understanding substance abuse and dependence. The team maintains that 9%-30% of caffeine consumers in the United States may be caffeine-dependent according to DSM criteria for substance dependency.

Description

Pharmacological aspects of caffeine

An outline of the effects of caffeine on the central nervous system (CNS) and other organ systems of the body may be helpful in understanding its potential for physical dependence. When a person drinks a beverage containing caffeine (or eats coffee-flavored ice cream), the caffeine is absorbed from the digestive tract without being broken down. It is rapidly distributed throughout the tissues of the body by means of the bloodstream. If a pregnant woman drinks a cup of coffee or tea, the caffeine in the drink will cross the placental barrier and enter the baby’s bloodstream.

When the caffeine reaches the brain , it increases the secretion of norepinephrine, a neurotransmitter that is associated with the so-called fight or flight stress response. The rise in norepinephrine levels and the increased activity of the neurons, or nerve cells, in many other areas of the brain helps to explain why the symptoms of caffeine intoxication resemble the symptoms of a panic attack.

The effects of caffeine are thought to occur as a result of competitive antagonism at adenosine receptors. Adenosine is a water-soluble compound of adenine and ribose; it functions to modulate the activities of nerve cells and produces a mild sedative effect when it activates certain types of adenosine receptors. Caffeine competes with adenosine to bind at these receptors and counteracts the sedative effects of the adenosine. If the person stops drinking coffee, the adenosine has no competition for activating its usual receptors and may produce a sedative effect that is experienced as fatigue or drowsiness.

Caffeine content of food items and OTC preparations

The caffeine content of various food items and medications is as follows:

• brewed coffee, 8-oz cup: 135-150 mg
• instant coffee, 8-oz cup: 95 mg.
• powdered cappuccino beverage, 8-oz cup: 45-60 mg
• tea brewed from leaves or bag, 8-oz cup: 50 mg
• iced tea from mix, 8-oz glass: 25-45 mg
• Snapple iced tea, 8-oz glass: 21 mg
• Mountain Dew, 8-oz glass: 38 mg
• Dr. Pepper, 8-oz. glass: 28 mg
• diet cola, 8-oz glass: 31 mg
• root beer, 8-oz glass: 16 mg
• coffee ice cream, 8-oz serving: 60-85 mg
• coffee yogurt, 8-oz serving: 45 mg.
• dark chocolate candy bar, 1.5 oz: 31 mg
• NoDoz, regular strength, 1 tablet: 100 mg
• NoDoz, maximum strength, 1 tablet: 200 mg
• Excedrin, 2 tablets: 130 mg

Caffeine can produce a range of physical symptoms following ingestion of as little as 100 mg, although amounts of 250 mg or higher are usually needed to produce symptoms that meet the criteria of caffeine intoxication.

Caffeine intoxication

To meet DSM-IV-TR criteria for caffeine intoxication, a person must develop five or more of the twelve symptoms identified, the symptoms must cause significant distress or impair the person’s social or occupational functioning; and the symptoms must not be caused by a medical disorder or better accounted for by an anxiety disorder or other mental disorder.

Because people develop tolerance to caffeine fairly quickly with habitual use, caffeine intoxication is most likely to occur in those who consume caffeine infrequently or who have recently increased their intake significantly.

Caffeine-induced anxiety and sleep disorders

DSM-IV-TR criteria for caffeine-induced anxiety and sleep disorders specify that the symptoms of anxiety and insomnia respectively must be more severe than the symptoms associated with caffeine intoxication. In addition, the anxiety or insomnia must be severe enough to require separate clinical attention.

Causes and symptoms

Causes

The immediate cause of caffeine intoxication and other caffeine-related disorders is consumption of an amount of caffeine sufficient to produce the symptoms specified by DSM-IV-TR as criteria for the disorder. The precise amount of caffeine necessary to produce symptoms varies from person to person depending on body size and degree of tolerance to caffeine. Tolerance of the stimulating effects of caffeine builds up rapidly in humans; mild withdrawal symptoms have been reported in persons who were drinking as little as one to two cups of coffee per day.

Some people may find it easier than others to consume large doses of caffeine because they are insensitive to its taste. Caffeine tastes bitter to most adults, which may serve to limit their consumption of coffee and other caffeinated beverages. Slightly more than 30% of the American population, however, has an inherited inability to taste caffeine.

Symptoms

The symptoms of caffeine intoxication include:

• restlessness
• nervousness
• excitement
• insomnia
• flushed face
• diuresis (increased urinary output)
• gastrointestinal disturbance
• muscle twitching
• talking or thinking in a rambling manner
• tachycardia (speeded-up heartbeat) or disturbances of heart rhythm.
• periods of inexhaustibility
• psychomotor agitation

People have reported ringing in the ears or seeing flashes of light at doses of caffeine above 250 mg. Profuse sweating and diarrhea have also been reported. Doses of caffeine higher than 10 g may produce respiratory failure, seizures, and eventually death.

Side effects and complications

High short-term consumption of caffeine can produce or worsen gastrointestinal problems, occasionally leading to peptic ulcers or hematemesis (vomiting blood).

In addition to the symptoms produced by high short-term doses, long-term consumption of caffeine has been associated with fertility problems and with bone loss in women leading to osteoporosis in old age. Some studies have found that pregnant women who consume more than 150 mg per day of caffeine have an increased risk of miscarriage and low birth weight babies, but the findings are complicated by the fact that most women who drink large amounts of coffee during pregnancy are also heavy smokers. Some researchers believe that long-term consumption of caffeine is implicated in cardiovascular diseases, but acknowledge that further research is required.

On the other hand, moderate doses of caffeine improve athletic performance as well as alertness. Caffeine in small doses can relieve tension headaches, and one study found that a combination of ibuprofen and caffeine was more effective in relieving tension headaches than either ibuprofen alone or a placebo. Coffee consumption also appears to lower the risk of alcoholic and nonalcoholic cirrhosis of the liver.

Drug interactions

Caffeine is often combined with aspirin or acetaminophen in over-the-counter and prescription analgesics (pain relievers). It can also be combined with ibuprofen. On the other hand, certain groups of drugs should not be combined with caffeine or taken with beverages containing caffeine. Oral contraceptives, cimetidine (Tagamet), mexiletine (Mexitil), and disulfiram (Antabuse) interfere with the breakdown of caffeine in the body. Caffeine interferes with the body’s absorption of iron, and with drugs that regulate heart rhythm, including quinidine and propranolol (Inderal). Caffeine may produce serious side effects when taken together with monoamine oxidase inhibitors or with certain decongestant medications.

Combinations of ephedra and caffeine have been used in weight-loss programs because they produce greater weight loss than can be achieved by caloric restriction alone. Major studies are underway as of 2001 at Harvard and Vanderbilt to determine the safety of these regimens.

Practitioners of homeopathy have traditionally advised patients not to drink beverages containing caffeine in the belief that caffeine “antidotes” homeopathic remedies. Contemporary homeopaths disagree on the antidoting effects of caffeine, observing that homeopathy is used widely and effectively in Europe and that Europeans tend to drink strong espresso coffee more frequently than Americans.

Demographics

The general population of the United States has a high level of caffeine consumption, with an average intake of 200mg per day. About 85% of the population uses caffeine in any given year. Among adults in the United States, about 30% consume 500 mg or more each day. These figures are lower, however, than the figures for Sweden, the United Kingdom, and other parts of Europe, where the average daily consumption of caffeine is 400 mg or higher. In developing countries, the average consumption of caffeine is much lower— about 50 mg per day.

In the United States, levels of caffeine consumption among all races and ethnic groups are related to age, with usage beginning in the late teens and rising until the early 30s. Caffeine consumption tapers off in adults over 40 and decreases in adults over 65. Caffeine intake is higher among males than among females in North America.

Diagnosis

Diagnosis of a caffeine-related disorder is usually based on the patient’s recent history, a physical examination, or laboratory analysis of body fluids. In addition to medical evidence, the examiner will rule out other mental disorders, particularly manic episodes, generalized anxiety disorder, panic disorder, amphetamine intoxication, or withdrawal from sedatives, tranquilizers, sleep medications, or nicotine . All of these disorders or syndromes may produce symptoms resembling those of caffeine intoxication. In most cases the temporal relationship of the symptoms to high levels of caffeine intake establishes the diagnosis.

In some cases, the examiner may consider the possibility of depression during the differential diagnosis, as many people with depression and eating disorders self-medicate with caffeine.

Treatments

Treatment of caffeine-related disorders involves lowering consumption levels or abstaining from beverages containing caffeine. Some people experience mild withdrawal symptoms that include headaches, irritability, and occasionally nausea, but these usually resolve quickly.

Caffeine consumption has the advantage of having relatively weak (compared to alcohol or cigarettes) social reinforcement, in the sense that one can easily choose a noncaffeinated or decaffeinated beverage in a restaurant or at a party without attracting comment. Thus physical dependence on caffeine is less complicated by the social factors that reinforce nicotine and other drug habits.

Prognosis

With the exception of acute episodes of caffein-ism, people recover from caffeine intoxication without great difficulty.

Prevention

Prevention of caffeine-related disorders requires awareness of the caffeine content of caffeinated beverages, OTC drugs, and other sources of caffeine; monitoring one’s daily intake; and substituting decaffeinated coffee, tea, or soft drinks for the caffeinated versions of these beverages.

KEY TERMS

Adenosine —A compound that serves to modulate the activities of nerve cells (neurons) and to produce a mild sedative effect when it activates certain types of adenosine receptors. Caffeine is thought to produce its stimulating effect by competing with adenosine for activation of these receptors.

Analeptic —A substance that acts as a stimulant of the central nervous system. Caffeine is classified as an analeptic.

Caffeinism —A disorder caused by ingesting very high doses of caffeine (10g or more per day) and characterized by seizures and respiratory failure.

Dependence —The adaptation of neurons and other physical processes to the use of a drug, followed by withdrawal symptoms when the drug is removed; physiological and/or psychological addiction.

Hematemesis —Vomiting blood. Hematemesis is a symptom that sometimes occurs with gastrointestinal ulcers made worse by high levels of caffeine consumption.

Norepinephrine —A catecholamine neurotransmitter that acts to constrict blood vessels, raise blood pressure, and dilate the bronchi of the respiratory system. Caffeine increases the secretion of norepinephrine.

Reinforcement —A term that refers to the ability of a drug or substance to produce effects that will make the user want to take it again.

Tolerance —Progressive decrease in the effectiveness of a drug with long-term use.

Withdrawal —Symptoms experienced by a person who has become physically dependent on a drug, experienced when the drug use is discontinued.

Xanthine —A class of crystalline nitrogenous compounds that includes caffeine, which is 1,3,7-trimethylxanthine.

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revised. Washington, DC: American Psychiatric Association, 2000.

“Anxiety Due to a Physical Disorder or a Substance.” Section 15, Chapter 187. In The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Murray, Michael, ND, and Joseph Pizzorno, ND. Encyclopedia of Natural Medicine. Rocklin, CA: Prima Publishing, 1991.

O’Brien, Charles P. “Drug Addiction and Drug Abuse.” Chapter 24 in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, edited by J. G. Hardman and L. E. Limbird. 9th edition. New York and St. Louis, MO: McGraw-Hill, 1996.

Pelletier, Kenneth R., MD. “Naturopathic Medicine.” Chapter 7, in The Best Alternative Medicine. New York: Simon & Schuster, 2002.

PERIODICALS

Breslin, P. A. S., C. D. Tharp, and D. R. Reed. “Selective Taste Blindness to Caffeine and Sucrose Octa Acetate: Novel Bimodal Taste Distributions Unrelated to PROP and PTC.” American Journal of Human Genetics 69 (October 2001): 507.

“Caffeine Toxicity from Cola Consumption.” Internal Medicine Journal 31 (2001): 317–318.

Corrao, G. “Coffee, Caffeine, and the Risk of Liver Cirrhosis.” Annals of Epidemiology 11 (October 2001): 458–465.

De Valck, E., and R. Cluydts. “Slow-Release Caffeine as a Countermeasure to Driver Sleepiness Induced by Partial Sleep Deprivation.” Journal of Sleep Research 10 (September 2001): 203–209.

Diamond, S., T. K. Balm, and F. G. Freitag. “Ibuprofen Plus Caffeine in the Treatment of Tension-Type Headache.” Clinical Pharmacology and Therapeutics 68 (2000): 312–319.

Griffiths, R. R., and A. L. Chausmer. “Caffeine as a Model Drug of Dependence: Recent Developments in Understanding Caffeine Withdrawal, the Caffeine Dependence Syndrome, and Caffeine Negative Reinforcement.” Nihon Shinkei Seishin Yakurigaku Zasshi 20 (November 2000): 223–231.

MacFadyen, L., D. Eadie, and T. McGowan. “Community Pharmacists’ Experience of Over-the-Counter Medicine Misuse in Scotland.” Journal of Research in Social Health 121 (September 2001): 185–192.

Preboth, Monica. “Effect of Caffeine on Exercise Performance.” American Family Physician 61 (May 2000): 628.

Rapurl, P. B., J. C. Gallagher, H. K. Kinyarnu, and others. “Caffeine Intake Increases the Rate of Bone Loss in Elderly Women and Interacts with Vitamin D Receptor Genotypes.” American Journal of Clinical Nutrition 74 (2001): 694–700.

Rumpler, William, James Seale, Beverly Clevidence, and others. “Oolong Tea Increases Metabolic Rate and Fat Oxidation in Men.” Journal of Nutrition 131 (November 2001): 2848–2852.

Sardao, V. A., P. J. Oliveira, and A. J. Moreno. “Caffeine Enhances the Calcium-Dependent Cardiac Mitochon-drial Permeability Transition: Relevance for Caffeine Toxicity.” Toxicology and Applied Pharmacology 179 (February 2002): 50–56.

ORGANIZATIONS

American College of Sports Medicine. P. O. Box 1440, Indianapolis, IN 46206-1440. Telephone: (317) 637-9200.

American Dietetic Association. Telephone: (800) 877-1600. <www.eatright.org>.

Center for Science in the Public Interest (CSPI). <www.cspinet.org>.

Rebecca J. Frey, Ph.D.