Addictions Case Study: Part 2 – Diagnostic Impressions

(Ksir, 2021)

Ksir, C. C. (2021-05-01). Drugs, Society, and Human Behavior, 18th Edition

Chapter 11

Caffeine

Caffeine: The World’s Most Common Psychostimulant

On a daily basis, more people use caffeine than any other psychoactive drug. Many use it regularly, and there is evidence for dependence and some evidence that regular use can interfere with the very activities people believe that it helps them with. It is now so domesticated that most modern kitchens contain a specialized device for extracting the chemical from plant products (a coffeemaker), but Western societies were not always so accepting of this drug.

Coffee

The legends surrounding the origin of coffee are at least geographically correct. The best one concerns an Ethiopian goatherd named Kaldi who couldn’t understand why his goats were bounding around the hillside so playfully. One day he followed them up the mountain and ate some of the red berries the goats were munching. “The results were amazing. Kaldi became a happy goatherd. Whenever his goats danced, he danced and whirled and leaped and rolled about on the ground.” Kaldi had taken the first human coffee trip! A holy man took in the scene, and “that night he danced with Kaldi and the goats.” Whatever the actual origin of human coffee use, the practice spread to Egypt and other Arabic countries by the 1400s, throughout the Middle East by the 1500s, and into Europe in the 1600s.

Coffeehouses began appearing in England (1650) and France (1671), and a new era began. Coffeehouses were all things to all people: a place to relax, to learn the news of the day, to seal bargains, and to plot. This last possibility made Charles II of England so nervous that he outlawed coffeehouses, labeling them “hotbeds of seditious talk and slanderous attacks upon persons in high stations.” In only 11 days the ruling was withdrawn, and the coffeehouses developed into the “penny universities” of the early 18th century. For a penny a cup people could listen to and learn from most of the great literary and political figures of the period. Women in England argued against the use of coffee in a 1674 pamphlet titled “The Women’s Petition Against Coffee, representing to public consideration the grand inconveniences accruing to their sex from the excessive use of the drying and enfeebling liquor.” The women claimed men used too much coffee, and as a result the men were as “unfruitful as those Desarts whence that unhappy Berry is said to be brought.” The women were really unhappy, and the pamphlet continued:

Our Countrymens pallates are become as Fanatical as their Brains; how else is’t possible they should Apostatize from the good old primitive way of Ale-drinking, to run a Whoreing after such variety of distructive Foreign Liquors, to trifle away their time, scald their Chops, and spend their Money, all for a little base, black, thick, nasty bitter stinking, nauseous Puddle water.1

Some men probably sat long hours in one of the many coffeehouses composing “The Men’s Answer to the Women’s Petition Against Coffee,” which said in part:

Why must innocent COFFEE be the object of your Spleen? That harmless and healing Liquor, which Indulgent Providence first sent amongst us. . . . Tis not this incomparable fettle Brain that shortens Natures standard, or makes us less Active in the Sports of Venus, and we wonder you should take these Exceptions.1

Across the Atlantic, coffee drinking increased in the English colonies, although tea was still preferred. Cheaper and more available than coffee, tea had everything, including, beginning in 1765, a 3-pence-a-pound tax on its importation.

The British Act that taxed tea helped fan the fire that lit the musket that fired the shot heard around the world. That story is better told in connection with tea, but the final outcome was that to be a tea drinker was to be a Tory, so coffee became the new country’s national drink.

Coffee use expanded as the West was won, and per-capita consumption increased steadily in the early 1900s. Some experts became worried about the increase, which some believed was caused by the widespread prohibition of alcohol.

But even after Prohibition went away, coffee consumption continued to rise. In 1946, annual per-capita coffee consumption reached an all-time high of 20 pounds. Americans now drink about half that much coffee per year. The wide variety of soft drinks, energy drinks, and bottled water have apparently replaced coffee as our most popular nonalcoholic beverages.

If the national drink is not as national as it once was, neither is it as simple. Kaldi and his friends were content to simply munch on the coffee beans or put them in hot water. Somewhere in the dark past, the Middle East discovered that roasting the green coffee bean improved the flavor, aroma, and color of the drink made from the bean. For years housewives, storekeepers, and coffeehouse owners bought the green bean, then roasted and ground it just before use. Commercial roasting started in 1790 in New York City, and the process gradually spread through the country. However, although the green bean can be stored indefinitely, the roasted bean deteriorates seriously within a month. Ground coffee can be maintained at its peak level in the home only for a week or two, and then only if it is in a closed container and refrigerated. Vacuum packing of ground coffee was introduced in 1900, a process that maintains the quality until the seal is broken.

Coffee growing spread worldwide when the Dutch began cultivation in the East Indies in 1696. Latin America had an ideal climate for coffee growing, and with the world’s greatest coffee-drinking nation just several thousand miles up the road, it became the world’s largest producer. Different varieties of the coffee tree and different growing and processing conditions provide many opportunities for varying the characteristics of coffee.

Although there are many bean-producing shrubs in the genus caffea, virtually all coffee is made from two species: caffea Arabica and caffea robusta. Arabica beans have a milder flavor, take longer to develop after planting, and require a near-tropical climate to grow properly. They are therefore more expensive and more desirable for most purposes. Robusta beans have a stronger and more bitter flavor and a higher caffeine content, and are used primarily in less-expensive blends and to make instant coffee. In some countries, such as Colombia, only Arabica beans are grown, whereas Brazil, the world’s largest coffee producer, produces both kinds. According to the U.S. Department of Agriculture (USDA.gov), in 2020 Brazil produced twice as much coffee as Vietnam, the second-biggest coffee growing country. Colombia and Indonesia were next, followed by Mexico and Central America. You can see that coffee is now grown in tropical climates around the globe. As for the over 3 billion pounds of coffee imported to the United States in 2020, Brazil supplied the most, followed by Colombia and Vietnam.

Beginning in the early 1970s, health-conscious Americans began to drink more decaffeinated coffee and less regular coffee. There are several ways of removing caffeine from the coffee bean. In the process used by most American companies, the unroasted beans are soaked in an organic solvent, raising concerns about residues of the solvent remaining in the coffee. The most widely used solvent has been methylene chloride, and studies have shown that high doses of that solvent can cause cancer in laboratory mice. In 1985, the FDA banned the use of methylene chloride in hair sprays, which can be inhaled during use, but allowed the solvent to be used in decaffeination as long as residues did not exceed 10 parts per million. Because the solvent residue evaporates during roasting, decaffeinated coffees contain considerably lower amounts than that, so the assumption is that the risk is minimal. The Swiss water process, which is not used on a large commercial scale in the United States, removes more of the coffee’s flavor. The caffeine that is taken out of the coffee is used mostly in soft drinks. One of the largest decaffeinating companies is owned by Coca-Cola.

Today’s supermarket shelves are filled with an amazing variety of products derived from this simple bean—pure Colombian, French roast, decaf, half-caf, flavored coffees, instants, mixes, and even cold coffee beverages. The competition for the consumer’s coffee dollar has never been greater, it seems. And Americans are lining up in record numbers at espresso bars to buy cappuccinos, lattes, and other exotic-sounding mixtures of strong coffee, milk, and flavorings. The number of these specialty coffee shops increased from fewer than 200 in 1989 to about 35,000 in 2019.3 They are found in small towns, in shopping malls, and on practically every corner in cities.

Tea

Tea and coffee are not like day and night, but their differences are reflected in the legends surrounding their origins. The bouncing goatherd of Arabia suggests that coffee is a boisterous, blue-collar drink. Tea is a different story: much softer, quieter, more delicate. According to one legend, Daruma, the founder of Zen Buddhism, fell asleep one day while meditating. Resolving that it would never happen again, he cut off both eyelids. From the spot where his eyelids touched the earth grew a new plant. From its leaves a brew could be made that would keep a person awake. Appropriately, the tea tree, Thea sinensis (now classed as Camellia sinensis), is an evergreen, and sinensis is the Latin word for “Chinese.”

The first report of tea that seems reliable is in a Chinese manuscript from around AD 350, when it was primarily seen as a medicinal plant. The nonmedical use of tea is suggested by an AD 780 book on the cultivation of tea, but the real proof that it was in wide use in China is that a tax was levied on it in the same year. Before this time, Buddhist monks had carried the cultivation and use of tea to Japan.

Europe had to wait eight centuries to savor the herb that was “good for tumors or abscesses that come from the head, or for ailments of the bladder . . . it quenches thirst. It lessens the desire for sleep. It gladdens and cheers the heart.” The first European record of tea, in 1559, says, “One or two cups of this decoction taken on an empty stomach removes fever, headache, stomachache, pain in the side or in the joints. . . . ” Fifty years later, in 1610, the Dutch delivered the first tea to the continent of Europe.

An event that occurred 10 years before had tremendous impact on the history of the world and on present patterns of drug use. In 1600, the English East India Company was formed, and Queen Elizabeth gave the company a monopoly on everything from the east coast of Africa across the Pacific to the west coast of South America. The English East India Company concentrated on importing spices, so the first tea was taken to England by the Dutch. As the market for tea increased, the English East India Company expanded its imports of tea from China. Coffee had arrived first, so most tea was sold in coffeehouses. Even as tea’s use as a popular social drink expanded in Europe, there were some prophets of doom. A 1635 publication by a physician claimed that, at the very least, using tea would speed the death of those over 40 years old. The use of tea was not slowed, however, and by 1657 tea was being sold to the public in England. This was no more than 10 years after the English had developed the present word for it: tea. Although spelled tea, it was pronounced tay until the 19th century. Before this period the Chinese name ch’a had been used, anglicized to either chia or chaw.

With the patrons of taverns off at coffeehouses living it up with tea, coffee, and chocolate, tax revenues from alcoholic beverages declined. To offset this loss, coffeehouses were licensed, and a tax of eight pence was levied on each gallon of tea and chocolate sold. Britain banned Dutch imports of tea in 1669, which gave the English East India Company a monopoly. Profit from the China tea trade colonized India, brought about the Opium Wars between China and Britain, and induced the English to switch from coffee to tea. In the last half of the 18th century, the East India Company conducted a “Drink Tea” campaign unlike anything ever seen. Advertising, low cost on tea, and high taxes on alcohol made Britain a nation of tea drinkers.

That same profit motive led to the American Revolution. Because the English East India Company had a monopoly on importing tea to England and thence to the American colonies, the British government imposed high duties on tea when it was taken from warehouses and offered for sale. But, as frequently happens, when taxes went up, smuggling increased. Eventually, more smuggled tea than legal tea was being consumed in Britain. The drop in legal tea sales filled the tea warehouses and put the East India Company in financial trouble.

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The American colonies, ever loyal to the king, had become big tea drinkers, which helped the king and the East India Company stay solvent. The Stamp Act of 1765, which included a tax on tea, changed everything. Even though the Stamp Act was repealed in 1766, it was replaced by the Trade and Revenue Act of 1767, which did the same thing. These measures made the colonists unhappy over paying taxes they had not helped formulate (taxation without representation), and in 1767 this resulted in a general boycott on the consumption of English tea. Coffee use increased, but the primary increase was in the smuggling of tea. In 1773, Parliament gave the East India Company the right to sell tea in the American colonies without paying the tea taxes. The company was also allowed to sell the tea through its own agents, thus eliminating the profits of the merchants in the colonies.

Several boatloads of this tea, which would be sold cheaper than any before, sailed toward various ports in the colonies. The American merchants, who would not have made any profit on this tea, were the primary ones who rebelled at the cheap tea. Some ships were turned away from port, but the beginning of the end came with the 342 chests of tea that turned the Boston harbor into a teapot on the night of December 16, 1773.

The revolution in America and the colonists’ rejection of tea helped tea sales in Great Britain—to be a tea drinker was to be loyal to the Crown. Although their use of coffee increases yearly and that of tea declines, the English are still tea drinkers. The annual per-capita consumption of tea in the United Kingdom is about 4.5 pounds, led only by Turkey and Ireland. In comparison, Americans consume about one-half pound of tea per person per year.

Tea starts its life on a four- to five-foot bush high in the mountains of China, Sri Lanka, India, or Indonesia. Unpruned, the bush would grow into a 15- to 30-foot tree, which would be difficult to pluck, as picking tea leaves is called. The pluckers select only the bud-leaf and the first two leaves at each new growth.

In one day a plucker will pluck enough leaves to make 10 pounds of tea as sold in the grocery store. Plucking is done every 6 to 10 days in warm weather as new growth develops on the many branches. The leaves are dried, rolled to crush the cells in the leaf, and placed in a cool, damp place for fermentation (oxidation) to occur. This oxidation turns the green leaves to a bright copper color. Nonoxidized leaves are packaged and sold as green tea, sales of which have seen large increases in recent years. Oxidized tea is called black tea and accounts for about 84 percent of the tea Americans consume. Oolong tea is greenish-brown, consisting of partially oxidized leaves.

Until 1904, the only choices available were sugar, cream, and lemon with your hot tea. At the Louisiana Purchase Exposition in St. Louis in 1904, iced tea was sold for the first time. It now accounts for 85 percent of all tea consumed in America. Tea lovers found 1904 to be a very good year. Fifteen hundred miles east of the fair, a New York City tea merchant decided to send out his samples in handsewn silk bags rather than tin containers. Back came the orders—send us tea, and send it in the same little bags you used to send the samples. From that inauspicious beginning evolved the modern tea bag machinery, which cuts the filter paper, weighs the tea, and attaches the tag—all this at a rate of 150 to 180 tea bags per minute.

Pound for pound, loose black tea contains a higher concentration of caffeine than coffee beans. However, because about 200 cups of tea can be made from each pound of dry tea leaves, compared with 50 or 60 cups of coffee per pound, a typical cup of tea has less caffeine than a typical cup of coffee. The caffeine content of teas varies widely, depending on brand and the strength of the brew. Most teas have 40 to 60 mg of caffeine per cup.

The market has been flooded with a variety of tea products. Most tea is sold in tea bags these days, but instant teas, some containing flavorings and sweeteners, are popular for convenience. Flavored teas—which contain mint, spices, or other substances along with tea—offer other options. The biggest boom in recent years has been in so-called herbal teas, which mostly contain no real “tea.” These teas are made up of mixtures of other plant leaves and flowers for both flavor and color and have become quite popular among people who avoid caffeine.

Although tea contains another chemical that derived its name from the tea plant, theophylline (“divine leaf”) is present only in very small, nonpharmacological amounts in the beverage. Theophylline is very effective at relaxing the bronchial passages and is prescribed for use by asthmatics.

Chocolate

Now we come to the third legend, concerning the origin of the third xanthine-containing plant. Long before Columbus landed on San Salvador, Quetzalcoatl, Aztec god of the air, gave humans a gift from paradise: the chocolate tree. Linnaeus was to remember this legend when he named the cocoa tree Theobroma, “food of the gods.” The Aztecs treated it as such, and the cacao bean was an important part of their economy, with the cacao bush being cultivated widely. Montezuma, emperor of Mexico in the early 16th century, is said to have consumed nothing other than 50 goblets of chocolatl every day. The chocolatl—from the Mayan words choco (“warm”) and latl (“beverage”)—was flavored with vanilla but was far from the chocolate of today. It was a thick liquid, like honey, that was sometimes frothy and had to be eaten with a spoon.

Cortez introduced sugarcane plantations to Mexico in the early 1520s and supported the continued cultivation of the Theobroma cacao bush. When he returned to Spain in 1528, Cortez carried with him cakes of processed cocoa. The cakes were eaten, as well as being ground up and mixed with water for a drink. Although chocolate was introduced to Europe almost a century before coffee and tea, its use spread very slowly. Primarily this was because the Spanish kept the method of preparing chocolate from the cacao bean a secret until the early 17th century. When knowledge of the technique spread, so did the use of chocolate.

During the 17th century, chocolate drinking reached all parts of Europe, primarily among the wealthy. Maria Theresa, wife of France’s Louis XIV, had a “thing” about chocolate, and this furthered its use among the wealthy and fashionable. Gradually it became more of a social drink, and by the 1650s chocolate houses were open in England, although usually chocolate was sold alongside coffee and tea in the established coffeehouses.

In the early 18th century, health warnings were issued in England against the use of chocolate, but use expanded. Its use and importance are well reflected in a 1783 proposal in the U.S. Congress that the United States raise revenue by taxing chocolate as well as coffee, tea, liquor, sugar, molasses, and pepper.

Although the cultivation of chocolate never became a matter to fight over, it, too, has spread around the world. The New World plantations were almost destroyed by disease at the beginning of the 18th century, but cultivation had already begun in Asia, and today a large part of the crop comes from Africa.

Until 1828, all chocolate sold was a relatively indigestible substance obtained by grinding the cacao kernels after processing. The preparation had become more refined over the years, but it still followed the Aztec procedure of letting the pods dry in the sun, then roasting them before removing the husks to get to the kernel of the plant. The result of grinding the kernels is a thick liquid called chocolate liquor. This is baking chocolate. In 1828, a Dutch patent was issued for the manufacture of “chocolate powder” by removing about two-thirds of the fat from the chocolate liquor.

The fat that was removed, cocoa butter, became important when someone found that, if it was mixed with sugar and some of the chocolate powder, it could easily be formed into slabs or bars. In 1847, the first chocolate bars appeared, but it was not until 1876 that the Swiss made their contribution to the chocolate industry by inventing milk chocolate, which was first sold under the Nestlé label. By FDA standards, milk chocolate today must contain at least 12 percent milk solids, although better grades contain almost twice that amount.

The unique xanthine in chocolate is theobromine. Its physiological actions closely parallel those of caffeine, but it is much less potent in its effects on the central nervous system. The average cup of cocoa contains about 200 mg of theobromine but only 4 mg of caffeine. Table 11.1 compares the caffeine contents of various forms of coffee, tea, and chocolate.

Other Sources of Caffeine

Soft Drinks

The early history of cola drinks is not shrouded in the mists that veil the origins of the other xanthine drinks, so there is no problem in selecting the correct legend. And that’s what the story of Coca-Cola is: a true legend in our time. From a green nerve tonic in 1886 in Atlanta, Georgia, that did not sell well at all, Coca-Cola has grown into “the real thing,” providing “the pause that refreshes,” selling almost 3 billion cases a year and operating in more than 200 countries.

Dr. J. C. Pemberton’s green nerve tonic in the late 1800s contained caramel, fruit flavoring, phosphoric acid, caffeine, and a secret mixture called Merchandise No. 5. The unique character of Coca-Cola and its later imitators comes from a blend of fruit flavors that makes it impossible to identify any of its parts. An early ad for Coca-Cola suggested its varied uses:

The “INTELLECTUAL BEVERAGE” and TEMPERANCE DRINK contains the valuable TONIC and NERVE STIMULANT properties of the Coca plant and Cola (or Kola) nuts, and makes not only a delicious, exhilarating, refreshing and invigorating Beverage (dispensed from the soda water fountain or in other carbonated beverages), but a valuable Brain Tonic, and a cure for all nervous affections—SICK HEADACHE, NEURALGIA, HYSTERIA, MELANCHOLY, &c.4

Coca-Cola was touted as “the new and popular fountain drink, containing the tonic properties of the wonderful coca plant and the famous cola nut.” In 1903, the company admitted its beverage contained small amounts of cocaine, but soon after that it quietly removed all the cocaine; a government analysis of Coca-Cola in 1906 did not find any.

The name Coca-Cola was originally conceived to indicate the nature of its two ingredients with tonic properties: coca leaves and cola (kola) nuts. In 1909, the FDA seized a supply of Coca-Cola syrup and made two charges against the company. One was that the syrup was misbranded because it contained “no coca and little if any cola” and, second, that it contained an “added poisonous ingredient,” caffeine.

Before a 1911 trial in Chattanooga, Tennessee, the company paid for research into the physiological effects of caffeine and, when all the information was in, the company won. The government appealed the decision. In 1916, the U.S. Supreme Court upheld the lower court by rejecting the charge of misbranding, stating that the company had repeatedly said that “certain extracts from the leaves of the coca shrub and the nut kernels of the cola tree were used for the purpose of obtaining a flavor” and that “the ingredients containing these extracts,” with the cocaine eliminated, was called Merchandise No. 5. Today, coca leaves are imported by a pharmaceutical company in New Jersey. The cocaine is extracted for medical use and the decocainized leaves are shipped to the Coca-Cola plant in Atlanta, where Merchandise No. 5 is produced. A 1931 report indicated that Merchandise No. 5 contained an extract of three parts coca leaves and one part cola nuts, but to this day it remains a secret formula.

In 1981, the FDA changed its rules, so that a cola no longer has to contain caffeine. If it does contain caffeine, it may not be more than 0.02 percent, which is 0.2 mg/ml, or a little less than 6 mg per ounce. Some consumer and scientist groups believe that all cola manufacturers should indicate on the label the amount of caffeine the beverage contains. This has not happened, even though soft drinks, as with other food products, must now list nutrition information, such as calories, fat, sodium, and protein content.

Table 11.2 lists the caffeine content in a 12-ounce serving of popular soft drinks. Diet soft drinks, most now sweetened with aspartame, and caffeine-free colas are commanding a larger share of the market, but regular colas are still the single most popular type of soft drink. As with beers and some other products, the modern marketing strategy seems to be for each company to try to offer products of every type, in order to cover the market. Also as with beers, the large companies are buying up their competitors: In 2012, the Coca-Cola and PepsiCo companies represented more than 65 percent of total shipments. Coca-Cola Classic remains the most popular single brand, with almost 20 percent of the total market. Although more soft drinks are consumed in the United States than in any other country, per-capita consumption of soft drinks has declined a bit from its maximum of 50 gallons per- capita to about 45, due to competition from energy drinks and bottled water.

Energy Drinks

Some consumers have always preferred to obtain their caffeine from soft drinks instead of from coffee. This led to the development and promotion of Jolt cola, which had the maximum allowable caffeine content per ounce, or almost 72 mg in a 12-ounce can. This might be a lot for a soft drink, but it isn’t a great deal when compared to 235 mg in a 12-ounce cup of Starbucks coffee. Mountain Dew’s hugely successful television marketing campaign links its product with heavy-metal music and extreme skiing, snowboarding, and similar high-energy activities. The parent company, PepsiCo, said on the Mountain Dew website that “Doing the ‘Dew’ is like no other soft drink experience because of its daring, high-energy, high-intensity, active, extreme citrus taste,” but most of its users know its caffeine content is higher than the major brands of colas (but still not high compared with brewed coffee). Then along came the Austrian sensation in a small can, Red Bull. Touted as an “energy drink,” the main active ingredient in this expensive drink is caffeine, at 80 mg per 8.3-ounce can (still less than a cup of coffee). The original marketers seemed to be aiming the product at people who exercise and want to “build” their bodies by including some ingredients found in dietary supplements sold to athletes, such as the amino acid taurine. Although rumors abound about Red Bull, the product does not appear to have any unique properties, and there is no evidence that the ingredients besides caffeine and sugar have any particular effect, either psychologically or in helping one to gain strength. Studies on combining energy drinks with alcohol indicate that any important interaction between the two is based on combining caffeine and alcohol.5

Much of the explosion in soft drink varieties has been aimed at this “high-energy” market. (The hype has been pretty high energy, even if the products are nothing special, urging consumers to “feed the rush,” or “blow your mind” using the drink.) The list of Mountain Dew competitors includes Kick and Surge, while Red Bull imitators have names like Stallion, Whoopass, Adrenaline Rush, Monster, and Rockstar.

Over-the-Counter Drugs

Few people realize that many nonprescription drugs also include caffeine, some in quite large amounts. Table 11.3 lists the caffeine content of some of these drugs. Presumably many people who buy “alertness tablets,” such as NoDoz, are aware that they are buying caffeine. But many buyers of such things as Excedrin might not realize how much caffeine they are getting. Imagine the condition of someone who took a nonprescription water-loss pill and a headache tablet containing caffeine, who then drank a couple of cups of coffee.

Considering all the various sources of caffeine, it is estimated that 80 percent of Americans regularly use caffeine in some form, and that the average intake is 200 mg per day.6 As with other psychoactive substances, this “average” takes in a wide range, with some users regularly consuming 1,000 mg or more each day.

Caffeine Pharmacology

Xanthines are the oldest stimulants known. Xanthine is a Greek word meaning “yellow,” the color of the residue that remains after xanthines are heated with nitric acid until dry. The three xanthines of primary importance are caffeine, theophylline, and theobromine. These three chemicals are methylated xanthines and are closely related alkaloids. Most alkaloids are insoluble in water, but these are unique, because they are slightly water soluble.

These three xanthines have similar effects on the body. Caffeine has the greatest effect. Theobromine has almost no stimulant effect on the central nervous system and the skeletal muscles. Theophylline is the most potent, and caffeine the least potent, agent on the cardiovascular system. Caffeine, so named because it was isolated from coffee in 1820, has been the most extensively studied and, unless otherwise indicated, is the drug under discussion here.

Time Course

In humans, the absorption of caffeine is rapid after oral intake; peak blood levels are reached 30 minutes after ingestion. Although maximal CNS effects are not reached for about 2 hours, the onset of effects can begin within half an hour after intake. The half-life of caffeine in humans is about 3 hours, and no more than 10 percent is excreted unchanged.

Cross-tolerance exists among the methylated xanthines; loss of tolerance can take more than 2 months of abstinence. The tolerance, however, is low grade, and by increasing the dose two to four times an effect can be obtained even in the tolerant individual. There is less tolerance to the CNS stimulation effect of caffeine than to most of its other effects. The direct action on the kidneys, to increase urine output, and the increase of salivary flow do show tolerance.

Dependence on caffeine is real (see the Taking Sides box). People who are not coffee drinkers or who have been drinking only decaffeinated coffee often report unpleasant effects (nervousness, anxiety) after being given caffeinated coffee, but those who regularly consume caffeine report mostly pleasant mood states after drinking coffee. Various experiments have reported on the reinforcing properties of caffeine in regular coffee drinkers; one of the most clear-cut studies allowed patients on a research ward to choose between two coded instant coffees, identical except that one contained caffeine. Participants had to choose at the beginning of each day which coffee they would drink for the rest of that day. People who had been drinking caffeine-containing coffee before this experiment almost always chose the caffeine-containing coffee.7 Thus, the reinforcing effect of caffeine probably contributes to psychological dependence.

There has long been clear evidence of physical dependence on caffeine as well. The most reliable withdrawal sign is a headache, which occurs an average of 18 to 19 hours after the most recent caffeine intake. Other symptoms include increased fatigue and decreased sense of vigor. These withdrawal symptoms are strongest during the first 2 days of withdrawal, then decline over the next 5 or 6 days.8

Mechanism of Action

For years no one really knew the mechanism whereby the methylxanthines had their effects on the CNS. In the early 1980s, evidence was presented that caffeine and the other xanthines block the brain’s receptors for a substance known as adenosine, which is a neurotransmitter or neuromodulator. Adenosine normally acts in several areas of the brain to produce behavioral sedation by inhibiting the release of other neurotransmitters. Caffeine’s stimulant action results from blocking the receptors for this inhibitory effect. One possible therapeutic use of caffeine or other adenosine blockers could be in slowing neural degeneration in diseases such as Parkinson’s.10

Physiological Effects

The pharmacological effects on the CNS and the skeletal muscles are probably the basis for the wide use of caffeine-containing beverages. With two cups of coffee taken close together (about 200 mg of caffeine), the cortex is activated, the EEG shows an arousal pattern, and drowsiness and fatigue decrease. This CNS stimulation is also the basis for “coffee nerves,” which can occur at low doses in sensitive individuals and in others when they have consumed large amounts of caffeine. In the absence of tolerance, even 200 mg will increase the time it takes to fall asleep and will cause sleep disturbances. There is a strong relationship between the mood-elevating effect of caffeine and the extent to which it will keep the individual awake.

Higher dose levels (about 500 mg) are needed to affect the autonomic centers of the brain, and heart rate and respiration can increase at this dose. The direct effect on the cardiovascular system is in opposition to the effects mediated by the autonomic centers. Caffeine acts directly on the vascular muscles to cause dilation, whereas stimulation of the autonomic centers results in constriction of blood vessels. Usually dilation occurs, but in the brain the blood vessels are constricted, and this constriction might be the basis for caffeine’s ability to reduce migraine headaches.

The opposing effects of caffeine, directly on the heart and indirectly through effects on the medulla, make it very difficult to predict the results of normal (i.e., less than 500 mg) caffeine intake. At higher levels, the heart rate increases, and continued use of large amounts of caffeine can produce an irregular heartbeat in some individuals.

The basal metabolic rate might be increased slightly (10 percent) in chronic caffeine users, because 500 mg has frequently been shown to have this effect. This action probably combines with the stimulant effects on skeletal muscles to increase physical work output and decrease fatigue after the use of caffeine.

Behavioral Effects

Stimulation

A hundred years ago, French essayist Balzac spoke with feeling when describing the effects of coffee:

It causes an admirable fever. It enters the brain like a bacchante. Upon its attack, imagination runs wild, bares itself, twists like a pythoness and in this paroxysm a poet enjoys the supreme possession of his faculties; but this is a drunkenness of thought as wine brings about a drunkenness of the body.11

The research data are not so uniformly positive—the effects of caffeine depend on the difficulty of the task, the time of day, and to a great extent how much caffeine the subject typically consumes. When regular users of high amounts of caffeine (more than 300 mg/day, the equivalent of three cups of brewed coffee) were tested on a variety of study-related mental tasks without caffeine, they performed more poorly than did users of low amounts, perhaps because of withdrawal effects. Although their performance was improved after being given caffeine, they still performed more poorly on several of the tasks than did users of low amounts. It seems as though the beneficial short-term effects can be offset by the effects of tolerance and dependence in regular users.12 High consumption of either coffee or energy drinks among college students has been associated with lower academic performance.13 It is not clear from these studies if students who are struggling use more caffeine to compensate, or if more caffeine use actually interferes with overall performance.

There is considerable evidence that 200 to 300 mg of caffeine will partially offset fatigue-induced decrement in the performance of motor tasks. Like the amphetamines, but to a much smaller degree, caffeine prolongs the amount of time an individual can perform physically exhausting work.

Headache

Caffeine’s vasoconstrictive effects are considered to be responsible for the drug’s ability to relieve headaches. Studies indicate that caffeine-containing analgesics are beneficial in reducing headache pain in either migraine or tension headaches.15 As for migraine headaches, in 1998, the FDA allowed the relabeling of extra-strength Excedrine, which contains 65 mg caffeine, for over-the-counter use as “Excedrine Migraine.”

ADHD

Many studies have looked at the effect of caffeine on the behavior of children diagnosed with attention-deficit/hyperactivity disorder, and the results have been inconsistent. Caffeine is not currently considered an approved treatment for ADHD, but animal models continue to suggest this as a possibility16 (see Chapter 6).

Sobering Up

It has long been thought that coffee can help a drinker to “sober up,” but little evidence supports the value of this. Caffeine will not lower blood alcohol concentration, but it might arouse the drinker. As they say—put coffee in a sleepy drunk and you get a more awake drunk. However, that awake drunk will still be uncoordinated, have slowed reaction times, and should not be driving a car or engaging in any other dangerous activity.

Causes for Concern

Because caffeine is probably the most widely used psychoactive drug in the world (it’s acceptable to those in most Judeo-Christian as well as Islamic traditions), it is understandable that it would elicit both good and bad reports. Although there is not yet clear evidence that moderate caffeine consumption is dangerous, the scientific literature has investigated the possible effects of caffeine in cancer, benign breast disease, reproduction, and heart disease. Part of the problem in knowing for certain about some of these things is that epidemiological research on caffeine consumption is difficult to do well, because of the many sources of caffeine and the variability of caffeine content in coffee. Coffee drinkers also tend to smoke more, for example, so the statistics have to correct for smoking behavior.

Cancer

In the early 1980s, an increased risk of pancreatic cancers was reported among coffee drinkers. However, studies since then have criticized procedural flaws in that report and have found no evidence of such a link. The 1984 American Cancer Society nutritional guidelines indicated there is no reason to consider caffeine a risk factor in human cancer.

Reproductive Effects

Although studies in pregnant mice have indicated that very large doses of caffeine can produce skeletal abnormalities in the pups, studies on humans have not found a relationship between caffeine and birth defects.17 Although there continues to be concern about reduced fertility with heavy caffeine consumption, the quality of the evidence is somewhat weak. However, the best advice for a woman who wants to become pregnant, stay pregnant, and produce a strong, healthy baby is to avoid caffeine, alcohol, tobacco, and any other drug that is not absolutely necessary for her health.

Heart Disease

There are many reasons for believing that caffeine might increase the risk of heart attacks, including the fact that it increases heart rate and blood pressure. Until recently, about as many studies found no relationship between caffeine use and heart attacks as did studies that found such a relationship. One interesting report used an unusual approach. Rather than ask people who had just had heart attacks about their prior caffeine consumption and compare them with people who were hospitalized for another ailment (the typical retrospective study), this study began in 1948 to track male medical students enrolled in the Johns Hopkins Medical School.18 More than 1,000 of these students were followed for 20 years or more after graduation and were periodically asked about various habits, including drinking, smoking, and coffee consumption. Thus, this was a prospective study, to see which of these habits might predict future health problems. Those who drank five or more cups per day were about 2.5 times as likely as nondrinkers to suffer from coronary heart disease. However, there is also some evidence that consuming small amounts of coffee can actually reduce the risk of heart attack. Therefore, as with alcohol, the relationship between coffee drinking and this important health risk is complex. A recent review indicated that moderate caffeine intake (two to three cups per day) may reduce the risk of type 2 diabetes and obesity, which increase cardiovascular risk. Overall, such moderate use seems to have neutral or even slightly beneficial effects on overall cardiac health.19

The latest research, then, says that two or three cups of coffee per day is OK, but four or five (or more!) increases the risk of heart attack. This is of special concern to those with other risk factors (e.g., smoking, family history of heart disease, obesity, high blood pressure, and high cholesterol levels).

Caffeinism

Caffeine is not terribly toxic, and overdose deaths are extremely rare. An estimated 10 g (equivalent to 100 cups of coffee) would be required to cause death from caffeine taken by mouth. Death is produced by convulsions, which lead to respiratory arrest.

However, caffeinism (excessive use of caffeine) can cause a variety of unpleasant symptoms, and because of caffeine’s domesticated social status it might be overlooked as the cause. For example, nervousness, irritability, tremulousness, muscle twitching, insomnia, flushed appearance, and elevated temperature can all result from excessive caffeine use. There can also be palpitations, heart arrhythmias, and gastrointestinal disturbances. In several cases in which serious disease has been suspected, the symptoms have miraculously improved when coffee was restricted.

Summary

· The ancient plants coffee, tea, and cacao contain caffeine and two related xanthines.

· Caffeine is also contained in soft drinks and nonprescription medicines.

· Caffeine has a longer-lasting effect than many people realize.

· Caffeine exerts a stimulating action in several brain regions by blocking inhibitory receptors for adenosine.

· In regular caffeine users, headache, fatigue, or depression can develop if caffeine use is stopped.

· Caffeine is capable of reversing the effects of fatigue on both mental and physical tasks, but it might not be able to improve the performance of a well-rested individual, particularly on complex tasks.

· Heavy caffeine use during pregnancy is not advisable.

· Daily use of large amounts of caffeine increases the risk of heart attack.

· Excessive caffeine consumption, referred to as caffeinism, can produce a panic reaction.

Review Questions

1. What role did the American Revolution and alcohol prohibition play in influencing American coffee consumption?

2. What are the differences among black tea, green tea, and oolong?

3. What are the two xanthines contained in tea and chocolate, besides caffeine?

4. Rank the caffeine content of a cup of brewed coffee, a cup of tea, a chocolate bar, and a 12-ounce serving of Coca-Cola.

5. How does caffeine interact with adenosine receptors?

6. What are some of the behavioral and physiological effects of excessive caffeine consumption?

7. Describe the effects of caffeine on migraine headaches, caffeine-withdrawal headaches, and other headaches.

8. What are the typical symptoms associated with caffeine withdrawal?

9. What are three possible ways in which caffeine use by a woman might interfere with reproduction?

10. What is the relationship between caffeine and panic attacks?

References

1. Meyer, H. Old English Coffee Houses. Emmaus, PA: Rodale Press, 1954.

2. Hosking, A.-M.,M. Juhasz, and N. Atanaskova Mesinkovska. “Complementary and Alternative Treatments for Alopecia: A Comprehensive Review.” Skin Appendage Disorders 5 (2) (2019), pp. 72–89.

3. First Research Industry Profile 2019: Coffee Shops. Available at www.firstresearch.com/Industry-Research/Coffee-Shops.html

4. Huisking, C. L. Herbs to Hormones. Essex, CT: Pequot Press, 1968.

5. Ferré, S., and M. C. O’Brien. “Alcohol and Caffeine: The Perfect Storm.” Journal of Caffeine Research 1 (2011), pp. 153–62.

6. Benson, S. M., K. M. Unice, and M. E. Glynn. “Hourly and Daily Intake Patterns among U.S. Caffeinated Beverage Consumers Based on the National Health and Nutrition Examination Survey (NHANES, 2013-2016).” Food and Chemical Toxicology 125 (2019), pp. 271–78.

7. Griffiths, R. R., and others. “Human Coffee Drinking: Reinforcing and Physical Dependence Producing Effects of Caffeine.” Journal of Pharmacology and Experimental Therapeutics 239 (1986), pp. 416–25.

8. Juliano, L. M., and others. “Development of the Caffeine Withdrawal Symptom Questionnaire: Caffeine Withdrawal Symptoms Cluster into Seven Factors.” Drug and Alcohol Dependence 124 (2012), pp. 229–34.

9. Juliano, L. M., and R. R. Griffiths. “A Critical Review of Caffeine Withdrawal: Empirical Validation of Symptoms and Signs, Incidence, Severity, and Associated Features.” Psychopharmacology 176 (2004), pp. 1–29.

10. Hong, C. T., L. Chan, and C. H. Bai. “The Effect of Caffeine on the Risk and Progression of Parkinson’s Disease: A Meta-Analysis.” Nutrients 12 (6) (2020), p. E1860.

11. Mickel, E. J. The Artificial Paradises in French Literature. Chapel Hill, NC: University of North Carolina Press, 1969.

12. Mitchell, P. J., and J. R. Redman. “Effects of Caffeine, Time of Day, and User History on Study-Related Performance.” Psychopharmacology (Berl) 109 (1992), p. 121.

13. Champlin, S. E., K. E. Pasch, and C. L. Perry. “Is the Consumption of Energy Drinks Associated with Academic Achievement among College Students?” Journal of Primary Prevention 37 (2016), pp. 345–59.

14. Nardi, A. E., and others. “Panic Disorder and Social Anxiety Disorder Subtypes in a Caffeine Challenge Test.” Psychiatry Research 169 (2008), pp. 149–53.

15. Lipton, R. B., H. C. Diener, M. S. Robbins, S. Y. Garas, and K. Patel. “Caffeine in the Management of Patients with Headache.” The Journal of Headache and Pain 18 (1) (2017), p. 107.

16. Ioannidis, K., S. R. Chamberlain, and U. Müller. “Ostracising Caffeine from the Pharmacological Arsenal for Attention-Deficit Hyperactivity Disorder—Was This a Correct Decision? A Literature Review.” Journal of Psychopharmacology 28 (9) (2014), pp. 830–36.

17. Bu, F. L., X. Feng, X. Y. Yang, J. Ren, and H. J. Cao. “Relationship between Caffeine Intake and Infertility: A Systematic Review of Controlled Clinical Studies.” BMC Womens Health 20 (1) (2020), p. 125.

18. LaCroix, A. Z., and others. “Coffee Consumption and the Incidence of Coronary Heart Disease.” New England Journal of Medicine 315 (1986), pp. 977–82.

19. O’Keefe, J. H., and others. “Effects of Habitual Coffee Consumption on Cardiometabolic Disease, Cardiovascular Health, and All-Cause Mortality. Journal of American College of Cardiology 62 (2013), pp. 1043–51.

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