Home > Encyclopedia of Drugs, Alcohol, and Addictive Behavior > Caffeine

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)

KENNETH SILVERMAN

ROLAND R. GRIFFITHS