Caffeine-related disorders

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 analeptic, 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 caffeinerelated 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 suffer from 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 listed below; 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 were 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 200 mg 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.

The prevalence of caffeine-related disorders in the United States is not known as of 2002.

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 caffeinism, 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.

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, 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., 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, 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, 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, A. J. Moreno. "Caffeine Enhances the Calcium-Dependent Cardiac Mitochondrial 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. (317) 637-9200.

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

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

Rebecca J. Frey, Ph.D.

Caffeine

Description

Caffeine is a drug that stimulates the central nervous system (CNS). Caffeine is found naturally in coffee, Kola seed kernels or nuts (Cola nidtida ), and a variety of teas. Other foods and beverages, such as chocolate and soft drinks, also contain caffeine, and the drug can be purchased in over-the-counter tablet and capsule form (No Doz, Overtime, Pep-Back, Quick-Pep, Caffedrine, and Vivarin). Some prescription pain relievers, medicines for migraine headaches, and antihistamines also contain caffeine.

General use

Caffeine makes people more alert, less drowsy, and improves coordination. It is sometimes included in athletes' diets to improve physical performance. In addition, one recent study found that older people who were given a cup of caffeinated coffee in the morning had fewer late-day memory problems than those who were given decaffeinated coffee. Combined with certain pain relievers or medicines for treating migraine headache , caffeine makes those drugs work more quickly and effectively. Caffeine alone can also help relieve headaches. Antihistamines are sometimes combined with caffeine to counteract the drowsiness caused by those drugs. Caffeine is also sometimes used to treat other conditions, including breathing problems in newborns and in young babies after surgery.

Preparations

Kola can be prepared in decoction or tincture form. To prepare a decoction, mix 1-2 tsp of powdered kola nut in a cup of water . After bringing the water to a boil, simmer the decoction on low heat for 10-15 minutes. Tinctures of kola nut can be purchased at many health food stores or mail order suppliers. A tincture is an herbal preparation made by diluting the herb in alcohol, glycerin, or vinegar. Dosage of kola tincture varies by formula and the symptoms or illness it is supposed to treat, but an average recommended dosage might be 1-4 ml three times daily. Powdered kola nut and kola tinctures should be stored in airtight containers away from direct light to maintain potency.

For over-the-counter caffeine preparations, adults and children age 12 years and older should take 100-200 mg no more than every 3-4 hours. In timed-release form, the dose is 200-250 mg once a day. Timed-release forms should not be taken less than 6 hours before bedtime. Caffeine pills or tablets are typically not recommended for children under 12 years of age.

Precautions

If caffeine is administered in a kola preparation, kola should always be obtained from a reputable source that observes stringent quality control procedures and industry-accepted good manufacturing practices. Consumers should look for the designations "U.S.P." (U.S. Pharmacopeia) or "NF" (National Formulary) on kola nut labeling. Herbal preparations prepared under USP or NF guidelines meet nationally recognized strength, quality, purity, packaging, and labeling standards as recommended by the United States Food and Drug Administration (FDA).

Avoid taking too much caffeine when it is being taken as an over-the-counter drug. Consider how much caffeine is being taken in from coffee, tea, chocolate, soft drinks, and other foods that contain caffeine. Check with a pharmacist or healthcare professional to find out how much caffeine is safe to use.

Caffeine cannot replace sleep and should not be used regularly to stay awake as the drug can lead to more serious sleep disorders , like insomnia .

People who use large amounts of caffeine over long periods build up a tolerance to it. When that happens, they have to use more and more caffeine to get the same effects. Heavy caffeine use can also lead to dependence. If an individual stops using caffeine abruptly, withdrawal symptoms may occur, including headache, fatigue , drowsiness, yawning, irritability, restlessness, vomiting , or runny nose. These symptoms can go on for as long as a week. In addition, caffeine dependence is not confined to the adult population. A study published in 2002 found that American teenagers have a high rate of caffeine dependence, partly because they consume large amounts of carbonated beverages that contain caffeine.

If taken too close to bedtime, caffeine can interfere with sleep. Even if it does not prevent a person from falling asleep, it may disturb sleep during the night.

The notion that caffeine helps people sober up after drinking too much alcohol is a myth. In fact, using caffeine and alcohol together is not a good idea. The combination can lead to an upset stomach, nausea , and vomiting.

Older people may be more sensitive to caffeine and thus more likely to have certain side effects, such as irritability, nervousness, anxiety , and sleep problems. Recent findings also suggest that people with insulin-dependent diabetes should monitor their caffeine intake. One study published in 2002 found that caffeine appears to decrease insulin sensitivity by about 15%.

Allergies

Anyone with allergies to foods, dyes, preservatives, or to the compounds aminophylline, dyphylline, oxtriphylline, theobromine, or theophylline should check with a physician before using caffeine. Anyone who has ever had an unusual reaction to caffeine should also check with a physician before using it again.

Pregnancy

Caffeine can pass from a pregnant woman's body into the developing fetus. Although there is no evidence that caffeine causes birth defects in people, it does cause such effects in laboratory animals given very large doses (equal to human doses of 12-24 cups of coffee a day). In humans, evidence exists that doses of more than 300 mg of caffeine a day (about the amount of caffeine in 2-3 cups of coffee) may cause miscarriage or problems with the baby's heart rhythm. Women who take more than 300 mg of caffeine a day during pregnancy are also more likely to have babies with low birth weights. Any woman who is pregnant or planning to become pregnant should check with her physician before using caffeine.

Breast-feeding

Caffeine passes into breast milk and can affect the nursing baby. Nursing babies whose mothers use 600 mg or more of caffeine a day may be irritable and have trouble sleeping. Women who are breast-feeding should check with their physicians before using caffeine.

Other medical conditions

Caffeine may cause problems for people with these medical conditions:

• peptic ulcer
• heart arrhythmias or palpitations
• heart disease or recent heart attack (within a few weeks)
• high blood pressure
• liver disease
• insomnia (trouble sleeping)
• anxiety or panic attacks
• agoraphobia (fear of being in open places)
• premenstrual syndrome (PMS)

Side effects

At recommended doses, caffeine can cause restlessness, irritability, nervousness, shakiness, headache, light-headedness, sleeplessness, nausea, vomiting, and upset stomach. At higher than recommended doses, caffeine can cause excitement, agitation, anxiety, confusion, a sensation of light flashing before the eyes, unusual sensitivity to touch, unusual sensitivity of other senses, ringing in the ears, frequent urination, muscle twitches or tremors , heart arrhythmias, rapid heartbeat, flushing, and convulsions.

Interactions

Using caffeine with certain other drugs may interfere with the effects of the drugs or cause unwanted—and possibly serious—side effects. Certain drugs interfere with the breakdown of caffeine in the body. These include oral contraceptives that contain estrogen, the antiarrhythmia drug mexiletine (Mexitil), the ulcer drug cimetidine (Tagamet), and the drug disulfiram (Antabuse), used to treat alcoholism .

Caffeine interferes with drugs that regulate heart rhythm, such as quinidine and propranolol (Inderal). Caffeine may also interfere with the body's absorption of iron . Anyone who takes iron supplements should take them at least an hour before or two hours after using caffeine.

Serious side effects are possible when caffeine is combined with certain drugs. For example, taking caffeine with the decongestant phenylpropanolamine can raise blood pressure. Very serious heart problems may occur if caffeine and monoamine oxidase inhibitors (MAO) are taken together. These drugs are used to treat Parkinson's disease, depression , and other psychiatric conditions. Consult with a pharmacist or physician about which drugs can interact with caffeine.

Because caffeine stimulates the nervous system, anyone taking other central nervous system stimulants should be careful about using caffeine.

Resources

BOOKS

Hoffman, David. The Complete Illustrated Herbal. New York: Barnes & Noble Books, 1999.

Medical Economics Corporation. The PDR for Herbal Medicines. Montvale, NJ: Medical Economics Corporation, 1998.

PERIODICALS

Bernstein, G. A., M. E. Carroll, P. D. Thuras, et al. "Caffeine Dependence in Teenagers." Drug and Alcohol Dependence 66 (March 2002): 1-6.

Keijzers, G. B., B. E. De Galan, et al. "Caffeine Can Decrease Insulin Sensitivity in Humans." Diabetes Care 25 (February 2002): 399-400.

Maughan, R. "The Athlete's Diet: Nutritional Goals and Dietary Strategies." Proceedings of the Nutrition Society 61 (February 2002): 87-96.

Ryan L., C. Hatfield, and M. Hostetter. "Caffeine Reduces Time-of-Day Effects on Memory Performance in Older Adults." Psychological Science 13 (January 2002): 68-71.

ORGANIZATIONS

Office of Dietary Supplements. National Institutes of Health. Building 31, Room 1B25, 31 Center Drive, MSC 2086, Bethesda, MD 20892-2086. (301) 435-2920. Fax: (301) 480-1845. http://odp.od.nih.gov/ods/ (Includes on-line access to International Bibliographic Information on Dietary Supplements (IBIDS), a database of published, international scientific literature on dietary supplements and botanicals).

Paula Ford-Martin

Rebecca J. Frey, PhD

Caffeine

Definition

Caffeine is a drug that stimulates the central nervous system.

Purpose

Caffeine makes people more alert, less drowsy, and improves coordination. Combined with certain pain relievers or medicines for treating migraine headache, caffeine makes those drugs work more quickly and effectively. Caffeine alone can also help relieve headaches. Antihistamines are sometimes combined with caffeine to counteract the drowsiness that those drugs cause. Caffeine is also sometimes used to treat other conditions, including breathing problems in newborns and in young babies after surgery.

Description

Caffeine is found naturally in coffee, tea, and chocolate. Colas and some other soft drinks contain it. Caffeine also comes in tablet and capsule forms and can be bought without a prescription. Over-the-counter caffeine brands include No Doz, Overtime, Pep-Back, Quick-Pep, Caffedrine, and Vivarin. Some pain relievers, medicines for migraine headaches, and antihistamines also contain caffeine.

Recommended dosage

Adults and children age 12 years and over

100-200 mg no more than every 3-4 hours. In timed-release form, the dose is 200-250 mg once a day. Timed-release forms should not be taken less than six hours before bedtime.

Children under 12 years

Not recommended.

Other considerations

People should avoid taking much caffeine when it is being used as an over-the-counter drug and should consider how much caffeine is being taken in from coffee, tea, chocolate, soft drinks, and other foods that contain caffeine. A pharmacist or physician should be consulted to find out how much caffeine is safe to use.

Precautions

Caffeine cannot replace sleep and should not be used regularly to stay awake as the drug can lead to more serious sleep disorders, such as insomnia.

People who use large amounts of caffeine over long periods build up a tolerance to it. When this happens, they have to use more and more caffeine to get the same effects. Heavy caffeine use can also lead to dependence. If the person then stops using caffeine abruptly, withdrawal symptoms may occur. These can include throbbing headaches, fatigue, drowsiness, yawning, irritability, restlessness, vomiting, or runny nose. These symptoms can go on for as long as a week if caffeine is avoided. Then the symptoms usually disappear. As of 2004, caffeine withdrawal has been officially recognized as a disorder classification manual.

If taken too close to bedtime, caffeine can interfere with sleep. Even if it does not prevent a person from falling asleep, it may disturb sleep during the night.

The notion that caffeine helps people sober up after drinking too much alcohol is a myth. In fact, using caffeine and alcohol together is not a good idea. The combination can lead to an upset stomach, nausea, and vomiting.

Older people may be more sensitive to caffeine and thus more likely to have certain side effects, such as irritability, nervousness, anxiety, and sleep problems.

Special conditions

Caffeine may cause problems for people with certain medical conditions or who are taking certain medicines.

ALLERGIES. Anyone with allergies to foods, dyes, preservatives, or to the compounds aminophylline, dyphylline, oxtriphylline, theobromine, or theophylline should check with a physician before using caffeine. Anyone who has ever had an unusual reaction to caffeine should also check with a physician before using it again.

PREGNANCY. Caffeine can pass from a pregnant woman's body into the developing fetus. Although there is no evidence that caffeine causes birth defects in people, it does cause such effects in laboratory animals given very large doses (equal to human doses of 12-24 cups of coffee a day). In humans, evidence exists that doses of more than 300 mg of caffeine a day (about the amount of caffeine in 2-3 cups of coffee) may cause miscarriage or problems with the baby's heart rhythm. Women who take more than 300 mg of caffeine a day during pregnancy are also more likely to have babies with low birth weights. Any woman who is pregnant or planning to become pregnant should check with her physician before using caffeine.

BREASTFEEDING. Caffeine passes into breast milk and can affect the nursing baby. Nursing babies whose mothers use 600 mg or more of caffeine a day may be irritable and have trouble sleeping. Women who are breastfeeding should check with their physicians before using caffeine.

OTHER MEDICAL CONDITIONS. Caffeine may cause problems for people with these medical conditions:

• peptic ulcer
• heart arrhythmias or palpitations
• heart disease or recent heart attack (within a few weeks)
• high blood pressure
• liver disease
• insomnia (trouble sleeping)
• anxiety or panic attacks
• agoraphobia (fear of being in open places)
• premenstrual syndrome (PMS)

USE OF CERTAIN MEDICINES. Using caffeine with certain other drugs may interfere with the effects of the drugs or cause unwanted—and possibly serious—side effects.

Side effects

At recommended doses, caffeine can cause rest-lessness, irritability, nervousness, shakiness, headache, lightheadedness, sleeplessness, nausea, vomiting, and upset stomach. At higher than recommended doses, caffeine can cause excitement, agitation, anxiety, confusion, a sensation of light flashing before the eyes, unusual sensitivity to touch, unusual sensitivity of other senses, ringing in the ears, frequent urination, muscle twitches or tremors, heart arrhythmias, rapid heartbeat, flushing, and convulsions. High caffeine consumption can lead to benign breast disease, which also can increase risk of breast cancer.

Interactions

Certain drugs interfere with the breakdown of caffeine in the body. These include oral contraceptives that contain estrogen, the antiarrhythmia drug mexiletine (Mexitil), the ulcer drug cimetidine (Tagamet), and the drug disulfiram (Antabuse), used to treat alcoholism.

Caffeine interferes with drugs that regulate heart rhythm, such as quinidine and propranolol (Inderal). Caffeine may also interfere with the body's absorption of iron. Anyone who takes iron supplements should take them at least an hour before or two hours after using caffeine.

KEY TERMS

Arrhythmia— Abnormal heart rhythm.

Central nervous system— The brain and spinal cord.

Fetus— A developing baby inside the womb.

Palpitation— Rapid, forceful, throbbing, or fluttering heartbeat.

Withdrawal symptoms— A group of physical or mental symptoms that may occur when a person suddenly stops using a drug to which he or she has become dependent.

Serious side effects are possible when caffeine is combined with certain drugs. For example, taking caffeine with the decongestant phenylpropanolamine can raise blood pressure. And serious heart problems may occur if caffeine and monoamine oxidase inhibitors (MAO) are taken together. These drugs are used to treat Parkinson's disease, depression, and other psychiatric conditions. A pharmacist or physician should be consulted about which drugs can interact with caffeine.

Because caffeine stimulates the nervous system, anyone taking other central nervous system (CNS) stimulants should be careful about using caffeine. Those trying to withdraw from caffeine are advised to do reduce their consumption slowly over time by substituting decaffeinated or non-caffeinated products for some of the caffeinated products.

Resources

PERIODICALS

"Caffeine Withdrawal Recognized as Disorder." Ascribe Health News Service September 29, 2004.

"High Caffeine Intake May Increase Risk of Benign Breast Disease." Womenós Health Weekly September 16, 2004: 32.

Caffeine

Definition

Caffeine is a drug that stimulates the central nervous system.

Description

Caffeine is found naturally in coffee, tea, and chocolate. Colas and some other soft drinks contain it. Caffeine also comes in tablet and capsule forms and can be bought without a prescription. Over-the-counter caffeine brands include No Doz, Overtime, Pep-Back, Quick-Pep, Caffedrine, and Vivarin. Some pain relievers, medicines for migraine headaches, and antihistamines also contain caffeine.

General use

Caffeine makes people more alert, less drowsy, and improves coordination. Combined with certain pain relievers or medicines for treating migraine headache , caffeine makes those drugs work more quickly and effectively. Caffeine alone can also help relieve headaches. Antihistamines are sometimes combined with caffeine to counteract the drowsiness that those drugs cause. Caffeine is also sometimes used to treat other conditions, including breathing problems in newborns and in young babies after surgery.

Precautions

Caffeine cannot replace sleep and should not be used regularly for staying awake as the drug can lead to serious sleep disorders , like insomnia.

People who use large amounts of caffeine over long periods build up a tolerance to it. When that happens, they have to use more and more caffeine to get the same effects. Heavy caffeine use can also lead to dependence. If the person then stops using caffeine abruptly, withdrawal symptoms may occur. These can include throbbing headaches, fatigue, drowsiness, yawning, irritability, restlessness, vomiting , or runny nose. These symptoms can go on for as long as a week if caffeine is avoided. Then the symptoms usually disappear.

If taken too close to bedtime, caffeine can interfere with sleep. Even if it does not prevent a person from falling asleep, it may disturb sleep during the night.

The notion that caffeine helps people sober up after drinking too much alcohol is a myth. In fact, using caffeine and alcohol together is not a good idea. The combination can lead to an upset stomach, nausea , and vomiting.

Older people may be more sensitive to caffeine and thus more likely to have certain side effects, such as irritability, nervousness, anxiety , and sleep problems.

Children under the age of 12 should normally avoid caffeine.

Side effects

Although caffeine is used to treat headaches, regular consumption of large quantities of caffeine containing beverages can cause severe headaches.

Excess use of caffeine by children leads to decreased nighttime sleep, but increased daytime sleep.

Interactions

Certain drugs interfere with the breakdown of caffeine in the body. These include oral contraceptives that contain estrogen, the antiarrhythmia drug mexiletine (Mexitil), and the ulcer drug cimetidine (Tagamet).

Caffeine interferes with drugs that regulate heart rhythm, such as quinidine and propranolol (Inderal). Caffeine may also interfere with the body's absorption of iron. Anyone who takes iron supplements should take them at least an hour before or two hours after using caffeine.

Serious side effects are possible when caffeine is combined with certain drugs. For example, taking caffeine with the decongestant phenylpropanolamine can raise blood pressure. Very serious heart problems may occur if caffeine and monoamine oxidase (MAO) inhibitors are taken together. These drugs are used to treat Parkinson's disease, depression, and other psychiatric conditions. People who use these drugs should consult a pharmacist or physician about which drugs can interact with caffeine.

Because caffeine stimulates the nervous system, anyone taking other central nervous system (CNS) stimulants should be careful about using caffeine.

Parental concerns

Moderate amounts of caffeine are not normally associated with adverse effects. As a rule, a daily intake of 300 milligrams should not present a problem. The following list gives the estimated amount of caffeine in common foods, but actual concentrations may be higher or lower.

• coffee, 115 mg
• black tea, 40 mg
• cola and other soft drinks, 18 mg
• chocolate milk, 5 mg
• milk chocolate (1 ounce) 6 mg

KEY TERMS

Arrhythmia —Any deviation from a normal heart beat.

Central nervous system —Part of the nervous system consisting of the brain, cranial nerves, and spinal cord. The brain is the center of higher processes, such as thought and emotion and is responsible for the coordination and control of bodily activities and the interpretation of information from the senses. The cranial nerves and spinal cord link the brain to the peripheral nervous system, that is the nerves present in the rest of body.

Withdrawal symptoms —A group of physical and/or mental symptoms that may occur when a person suddenly stops using a drug or other substance upon which he or she has become dependent.

Resources

BOOKS

Beers, Mark H., and Robert Berkow, eds. The Merck Manual, 2nd home ed. West Point, PA: Merck & Co., 2004.

Mcevoy, Gerald, et al. AHFS Drug Information 2004. Bethesda, MD: American Society of Healthsystems Pharmacists, 2004.

Siberry, George K., and Robert Iannone, eds. The Harriet Lane Handbook, 15th ed. Philadelphia: Mosby Publishing, 2000.

PERIODICALS

Hering-Hanit, R., and N. Gadoth. "Caffeine-induced headache in children and adolescents." Cephalalgia 23, no. 5 (June 2003): 332–5.

Pollak Charles P., and David Bright. "Caffeine consumption and weekly sleep patterns in U.S. seventh, eighth, and ninth graders." Pediatrics 111, no. 1 (January 2003): 42–6.

Steer, P. A., and D. J. Henderson-Smart. "Caffeine versus theophylline for apnea in preterm infants." Cochrane Database of Systematic Review 2 (2000): CD000273.

ORGANIZATIONS

Baylor College of Medicine USDA/ARS Children's Nutrition Research Center. 1100 Bates Street, Houston, TX 77030.

University of Minnesota Extension Service. Office of the Director, 240 Coffey Hall, 1420 Eckles Ave. St. Paul, MN 55108–6068.

WEB SITES

"Caffeine." Center for the Evaluation of Risks to Human Reproduction. Available online at <http://cerhr.niehs.nih.gov/genpub/topics/caffeine-ccae.html> (accessed October 16, 2004).

"Questions and Answers about Caffeine and Health." International Food Information Council. Available online at <www.ific.org/publications/qa/caffqa.cfm> (accessed October 16, 2004).

Nancy Ross-Flanigan Samuel Uretsky, PharmD

Caffeine

Caffeine belongs to the family of heterocyclic compounds known as purines. It has the systematic name 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione; it is also known as 1,3,7-trimethylxanthine, and 1,3,7-trimethyl-2,6-dioxopurine. Caffeine can be classified as an alkaloid , a term used for substances produced as end products of nitrogen metabolism in some plants. The chemical formula is C₈H₁₀N₄O₂. Caffeine has a molar mass of 194.19 grams (6.85 ounces). It is soluble in water and in many organic solvents, and it appears in pure form as white crystals. Caffeine can be prepared by extraction from natural sources or by synthesis from uric acid.

More than sixty plants, including those that give us coffee, tea, cola, and cacao, produce caffeine from the purine xanthine. Whereas caffeine is a natural constituent in coffee, tea, chocolate, and some cola drinks, it is added to consumer products such as soft drinks, diet pills, and analgesics . Caffeine is said to be the most widely used drug in the world, and more than 100 million people in the United States consume caffeine each day. It has pharmacological uses: as a cardiac and respiratory stimulant and as an agent that promotes kidney diuresis. A therapeutic dose of caffeine is about the same as the amount found in an average cup of coffee, between 100 and 200 milligrams (0.0071 ounces). Decaffeinated coffee can be prepared through extraction with a solvent (such as methylene chloride), water extraction, or steam extraction.

Caffeine enters the bloodstream about ten minutes after its ingestion and stays in the body for up to twelve hours. Like other alkaloids, caffeine has powerful physiological effects on humans and animals. It stimulates heart muscle and relaxes certain structures that contain smooth muscle, including the coronary arteries and the bronchi. It is a diuretic. Theophylline and theobromine, two other plant alkaloid derivatives of xanthine, have physiological effects similar to those of caffeine.

Caffeine acts as a stimulant of the central nervous system (CNS) through several proposed mechanisms. The most important seems to be its interference with the ability of the neurotransmitter adenosine to bind to its nerve cell receptor . Also, caffeine inhibits the enzyme cyclic nucleotide phosphodiesterase, which breaks down intracellular cyclic adenosine monophosphate (cAMP), another messenger involved in the transmission of nerve signals from hormones originating outside the central nervous system

such as epinephrine and glucagon—hormones that initiate the "fight or flight" response in animals. Other proposed mechanisms have to do with effects on CNS intracellular calcium ion concentrations.

Caffeine is moderately habit-forming, but because caffeine users can usually control its use, it is not listed as an addicting stimulant by the American Psychiatric Association. Caffeine is not regarded as being harmful to the average healthy adult. In fact there are beneficial effects to be derived from moderate caffeine intake (about three cups of coffee per day). It relieves tiredness, improves thought processes, increases alertness, and enhances physical performance. It may be used to treat respiratory depression and, because it constricts blood vessels in the brain, is often an ingredient in headache remedies. There is some evidence that caffeine may help to mitigate symptoms of migraine headache and lower the risk of gallstones. Some studies show that caffeine may protect against Parkinson's disease, perhaps by inhibiting the depletion of the neurotransmitter dopamine in brain cells.

There may be some adverse effects due to excessive caffeine intake, such as restlessness, headaches, heart palpitations, heartburn, and insomnia. Some individuals may have a toxic reaction to it. Ingestion by pregnant women and nursing mothers may have adverse effects on fetuses and babies; caffeine crosses the placenta and gets into breast milk. Caffeine has a wide margin of safety. A lethal dose for most people would be the amount of caffeine found in about one hundred cups of coffee.

Some investigations into caffeine-related health issues are inconclusive. Studies have shown no correlation between caffeine intake and increased risk of osteoporosis or increased risk of spontaneous abortion. There is no conclusive evidence linking caffeine intake (as coffee) with bladder, pancreatic, breast, or colon cancer. There is also no conclusive evidence that moderate caffeine intake contributes to heart disease or heart arrhythmias; however, one study has shown that relatively high coffee consumption elevates blood levels of homocysteine (an amino acid)—a situation that may contribute to heart attack or Alzheimer's disease. There is continuing controversy over whether heavy caffeine intake increases blood pressure, a woman's risk of developing breast lumps, or the incidence of miscarriage.

see also Dopamine; Epinephrine; Stimulants.

Sharron W. Smith

Bibliography

"Coffee: How Much Is Too Much?" (2001). Consumer Reports (May): 64–65.

Other Resources

Merck Index, 12th edition. CD-ROM Version 12:1. (1996). London: Chapman and Hall.

Caffeine Archive. Available from <http://www.caffeinearchive.com>.

caffeine is a methylxanthine present in tea and coffee, and therefore probably is the most common drug, regularly taken, in the world. Three very similar compounds — all in this same group of alkaloids — are present in common beverages, namely caffeine, theophylline, and theobromine. The first two are found mainly in tea and coffee, and the third in cocoa. Cola beans, used in the manufacture of well-known soft drinks, also contain caffeine. The three compounds differ very little from each other: simply the number and disposition of methyl groups about the xanthine nucleus is variable. Weight for weight, the caffeine content of coffee beans (0.7–1.5%) and tea leaves (2–3%) is similar, but generally a coffee infusion is stronger than that used for tea. Thus the dose of alkaloid per usual portion of tea or coffee is very similar, namely 50–150 mg, depending on taste.

Infusions made from the leaves of Camellia sinensis (i.e. tea) have been consumed in the East for almost two millenia, and the practice reached Europe in the sixteenth century. The demand grew, and plantations were started in the Indian subcontinent. The British remain the most constant tea drinkers, with an average annual consumption of 4.5 kg, equivalent to a daily caffeine intake of 300 mg. In Japan tea is made from powdered green leaves. An elaborate tea ceremony is sometimes performed in which the tea maker performs a series of ritualized procedures in a very precise way. The green tea served at these ceremonies is usually bitter in taste.

Coffee cultivation began in the Yemen in the ninth century, the beans being obtained from a bush, Coffea arabica, and they were introduced into Europe alongside tea in the sixteenth century. The major source of coffee is now in the state of Sao Paulo, Brazil. Coffee is supposed to have been discovered by an Ethiopian holy man whose goats had eaten the berries, allowing them to frisk all night long. It was claimed that coffee ‘quickens the spirits and makes the heart lightsome’ and is ‘good against the dropsy’, but a distinguished professor of medicine at Cambridge around 1900 claimed coffee caused tremors and agitation. Explanations for all these claims can be made, particularly when allowance is made for ‘dose’. However, assuming the effects are due to caffeine, tea drinkers as well as coffee drinkers will benefit, or suffer, alike. While lethargy and irritability often result from withdrawal in drinkers, it is doubtful whether true caffeine dependency exists.

The pharmacological effects of caffeine are widespread and various. By inhibition of certain enzymes, it allows an increase in the concentration of the ‘second messenger’, cyclic AMP, within cells, enhancing in turn the systems which this activates. Since caffeine penetrates the blood–brain barrier it is assumed that the central stimulant effects that enhance alertness and counteract feelings of fatigue, are due to this action. Caffeine also acts on the kidneys as a mild diuretic; this combined with its stimulant actions on heart muscle provide good evidence for the claim that it is ‘good for the dropsy’, both by strengthening the force of the heart beat and by removing accumulated body fluid.

Alan W. Cuthbert

caffeine , odorless, slightly bitter alkaloid found in coffee , tea , kola nuts (see cola ), ilex plants (the source of the Latin American drink maté ), and, in small amounts, in cocoa (see cacao ). It can also be prepared synthetically from uric acid . While relatively harmless, it is the most commonly used mind-altering drug in the world. When used in moderation, caffeine acts as a mild stimulant to the nervous system, blocking the neurotransmitter adenosine and resulting in a feeling of well-being and alertness. It increases the heart rate, blood pressure, and urination and stimulates secretion of stomach acids; excessive intake can result in restlessness, insomnia, and heart irregularities. The effects of caffeine vary from person to person, as people excrete it at different rates. Physical dependence and unpleasant symptoms upon withdrawal (headache, fatigue, depression) are common in regular caffeine users.

Bibliography: See B. A Weinberg and B. K. Bealer, The World of Caffeine (2001).

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 An alkaloid (chemically trimethylxanthine) found in coffee and tea (when it is sometimes called theine). It raises blood pressure, stimulates the kidneys, and temporarily averts fatigue and tiredness, so has a stimulant action. It can also be a cause of insomnia in some people, and decaffeinated coffee and tea are commonly available.

Coffee beans contain about 1% caffeine, and the beverage contains about 70 mg/100 mL. Tea contains 1.5–2.5% caffeine, about 50–60 mg/100 mL of the beverage. Cola drinks contain 12–18 mg/100 mL, and some energy drinks may contain more.

See also coffee, decaffeinated; theobromine; xanthine.

caffeine (C₈H₁₀N₄O₂) White, bitter substance that occurs in coffee, tea and other substances, such as cocoa and ilex plants. It acts as a mild, harmless stimulant and diuretic, although an excessive dose can cause insomnia and delirium.

caf·feine / kaˈfēn; ˈkafˌēn/ • n. the alkaloid crystalline compound C₈H₁₀N₄O₂, found esp. in tea and coffee plants. It is a stimulant of the central nervous system.

caffeine (kaf-een) n. an alkaloid drug, present in coffee and tea, that has a stimulant action on the central nervous system and is a weak diuretic. It is included in some analgesic preparations.

caffeine (chem.) alkaloid found in the coffee and tea plants. XIX. — F. caféine, f. café COFFEE; see -INE 5.

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