In the 1960s, the days of acid rock, songs such as “Lucy in the Sky with Diamonds” and “Spoonful” celebrated drugs such as LSD and cocaine. In the more timid culture of the 1990s, caffeine has become a drug noticed and venerated by the young. There have been several recent songs about the mind- and body-altering power of caffeine in coffee. We have also noticed an increase in the word “caffeine” figuring into phrases, such as “he needs a shot of caffeine,” that formerly referenced other drugs such as adrenaline.
An Internet thread in the alt.drugs.caffeine newsgroup began with a message to the effect that a handful of chocolate-covered coffee beans, which are “SO easy to just sit and munch,” release as much caffeine when eaten as you get from drinking a cup of coffee, so it is wise to be careful and not eat the whole bag. In response a member of a rock band called Cathead reminisced about some uses of whole beans backstage before concerts:
Before every show (back in the good old days) we would share a bag (i.e. You know the bags they offer in the bulk section of Safeway?) of espresso beans. I can only say that each show back then was really intense…every time.14
Is the coffee and tea party really nearly over? Some people, evidently disgusted with the caffeine craze sweeping the world at the turn of the millennium, have lined up to prophesy the end of the excitement. Several books have appeared in the last few years cautioning people about the supposed dangers of caffeine consumption. One of their number is Caffeine Blues: Wake up to the Hidden Dangers of America’s #1 Drug, by Stephen A.Cherniske (Warner Books, 1998). The publisher states that this book, which presents a daunting panoply of dire warnings about caffeine reminiscent of Simon Pauli, “exposes the harmful side effects of caffeine and gives readers a step-by-step program to reduce intake, boost energy, create a new vibrant life and recognize the dangers.” Another is Danger: Caffeine, by Patra M.Sevastiade (Rosen Publishing Group, 1998), a book intended for children five to nine that “explains how caffeine affects the body and the harm overuse of it can cause.” Still another is Addiction-Free—Naturally: Liberating Yourself from Tobacco, Caffeine, Sugar, Alcohol, Prescription Drugs, Cocaine, and Narcotics, by Brigette Mars (Inner Traditions International, 2000), which, as the title makes obvious, puts caffeine in some pretty nasty company. A more unusual contribution to cautionary caffeine literature is Brief Epidemiology of Crime: With Particular Reference to the Relationship between Caffeine and Alcohol Use and Crime, by Peter D.Hay (Peter D.Hay, 1999).
Cartoons by Robert Thierrien, Jr., a.k.a. BADBOB. These energetic images, among a series by the artist celebrating caffeine’s place in contemporary culture, have been widely reproduced on T-shirts and coffee mugs. (By permission of the artist)
Organizations have arisen to help people avoid what their members regard as the evils of caffeine. Among them are Caffeine Anonymous, a twelve-step program of caffeine addicts who gather weekly at a church to support each other’s efforts to quit. More radical are the efforts of Caffeine Prevention Plus, a nonprofit organization “dedicated to caffeine and coffee prevention.” A consultant for this redoubtable group recently wrote an article advocating that coffee be made an illegal substance because of the harm it poses for coffee drinkers and society. In his scientismic polemic to outlaw caffeine, he explains that the putative therapeutic benefits of caffeine are figments of the “coffee lobby” and that there are other compounds available to do anything caffeine can do and do it better. In addition, according to this group, caffeine is solely responsible for more than 25 percent of British bad business decisions, including the Barings bank disaster, and is believed to be involved in aggravating more than 50 percent of all marital disputes in the United States.
PART 4
the natural history of caffeine
13
caffeine in the laboratory
After the fall of Rome, the sciences originated by the Greeks lay quiescent for more than a millennium, eventually falling under the spell of such alchemical adepts as Albertus Magnus (1193–1280) and Philippus Aureolus Paracelsus (1490–1541). These sciences were quickened in Restoration England by the members of one of the oldest and most important coffee klatches in history, the Royal Society. Still one of the leading scientific societies in the world, the Royal Society began in 1655 as the Oxford Coffee Club, an informal confraternity of scientists and students who, as we said earlier, convened in the house of Arthur Tillyard after prevailing upon him to prepare and serve the novel and exotic drink. To appreciate the audaciousness of the club members, we must remember that coffee was then regarded as a strange and powerful drug from a remote land, unlike anything that had ever been seen in England. It was not, at first, enjoyed for its taste, as it was brewed in a way that most found bitter, murky, and unpleasant, but was consumed exclusively for its stimulating and medicinal properties. The members of the Oxford Coffee Club took their coffee tippling to London sometime before 1662, the year they were granted a charter by Charles II as the Royal Society of London for the Improvement of Natural Knowledge.
Historical reflection on changing fashions in drug use might justify the saying, “By their drugs you shall know them.” Members of the Sons of Hermes, the leading alchemical society of the Middle Ages, experimented with plants and herbs, almost certainly including the Solanaceæ family, commonly known as nightshades, which comprises thorn apple, belladonna, madragrora, and henbane.1 These plants contain the hallucinogenics atropine, scopolamine, and hyoscyamine, which were used historically as intoxicants and poisons and more recently as “truth serums.” These drugs often produce visions, characteristically inducing three-dimensional psychotic delusions, often populated with vividly real people, fabulous animals, or otherworldly beings. Because of atropine’s ability to bring about a transporting delirium, witches rubbed an atropine-laced ointment into their skin to induce visions of flying. Obviously, the Solanaceæ drugs are as well-suited to the fabulous, symbolic, magical, transformational doctrines of alchemy as caffeine is to the rational, verifiable, sensibly grounded, and literal endeavors of modern science.
It may therefore not be entirely adventitious that the thousand-year lapse of European science in the Middle Ages, during which naturalism commingled promiscuously with magic, ended at the same time that the first coffeehouses opened in England and that coffee, fresh from the Near East, became suddenly popular with the intellectual and social avant-garde in Oxford and London. The aristocratic Anglo-Irish Robert Boyle (1627–91), the father of modern chemistry, regarded in his time as the leading scientist in England, was a founding member of the original Oxford Coffee Club. Credited with drawing the first clear line between alchemy and chemistry, Boyle formulated the precursor to the modern theory of the elements, achieving the first significant advance in chemical theory in more than two thousand years.2 Within a few years after the English craze for caffeine began, the modern revolutions, not only in chemistry, but in physics and mathematics as well, were well under way. Twentieth-century scientific studies suggest that caffeine can increase vigilance, improve performance, especially of repetitive or boring tasks such as laboratory research, and increase stamina for both mental and physical work. In consequence of its avid use by the most creative scientists of the second half of the seventeenth century, caffeine may well have expedited the inauguration of both modern chemistry and physics and, in this sense, have been the only drug in history with some responsibility for stimulating the formulation of the theoretical foundations of its own discovery.
Caffeine and Chemistry
Caffeine is a chemical compound built of four of the most common elements on earth: carbon, hydrogen, nitrogen, and oxygen. The pure chemical compound is collected as a residue of coffee decaffeination, recovered from waste tea leaves, produced by methylating the organic compounds theophylline or theobromine, or synthesized from dimethylurea and malonic acid. At room temperature, caffeine, odorless and slightly bitter, consists of a white, fleecy powder resembling cornstarch or of long, flexible, silky, prismatic crystals. It is moderat
ely soluble in water at body temperature and freely soluble in hot water. Caffeine will not melt; like dry ice, it sublimes, passing directly from a solid to a gaseous state, at a temperature of 458 degrees Fahrenheit.3
A computer-generated model of the caffeine molecule.
The formula for caffeine is C8H10N4O2, which means that each caffeine molecule comprises eight atoms of carbon, ten atoms of hydrogen, four atoms of nitrogen, and two atoms of oxygen. However, to understand the structure and properties of caffeine, or of any chemical compound, it is necessary not only to identify its atomic constituents but also to describe the way in which these constituents fit together. A compound’s chemical name articulates this chemical structure and serves to designate how its parts are arranged and connected. Caffeine has several chemical names, or alternative ways of representing its structure, the most common of which is 1,3,7-trimethylxanthine. The name revealing its structure most fully is 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl. Other chemical designations for caffeine include:
1,3,7-Trimethyl-2, 6-dioxopurine
7-Methyltheophylline
Methyltheobromine
To understand the way in which these names represent caffeine’s structure, it is helpful to consider them in the context of the structural descriptions of caffeine’s parent compound, purine, and of caffeine’s isomers, or close relations.
Caffeine is one of a group of purine alkaloids, sometimes called methylated xanthines, or simply, xanthines. Other methylated xanthines include theophylline, theobromine, and paraxanthine. All three are congeners, or chemical variations, of caffeine, and all three are primary products of caffeine metabolism in human beings. Purine itself is an organic molecule composed entirely of hydrogen and nitrogen. All purine bases, including caffeine, are nitrogenous compounds with two rings in the molecules, five- and six-membered, each including two nitrogen atoms. The purine alkaloid xanthine is created when two oxygen atoms are added to purine.
The other purine alkaloids, in turn, are built out of xanthine by adding methyl groups, that is, groups of one carbon and three hydrogen atoms, in varying numbers and positions. For example, caffeine, a trimethylxanthine, the most common methylxanthine in nature, is xanthine with three added methyl groups, in the first, third, and seventh positions. Similarly, theophylline (1,3-dimethylxanthine) consists of xanthine with methyl groups in the first and third positions, theobromine (3,7-dimethylxan-thine), consists of xanthine with methyl groups in the third and seventh positions, and paraxanthine (1,7-dimethylxanthine) consists of xanthine with methyl groups in the first and seventh positions. Because the body transforms caffeine into each of these isomers, they may well play a part in caffeine’s health effects.
Although purine itself does not occur in the human body, chemicals in the purine family are widely present there as throughout nature. In fact, in addition to being the parent compound of caffeine and other methylxanthines, purine is the parent compound of adenine and guanine, two of the four basic constituents of the nucleotides that form RNA and DNA, the molecular chains within the cells of every living organism that determine its genetic identity. Some scientists have speculated that, because of this similarity to genetic material, caffeine and its metabolites may introduce errors into cell reproduction, causing cancer, tumors, and birth defects. As of this writing, there is no credible evidence to substantiate such fears.
The molecular structure of caffeine and related compounds.
The Metabolism of Caffeine: From Cup to Bowl, or A Remembrance of Things Passed
Because caffeine is fat soluble and passes easily through all cell membranes, it is quickly and completely absorbed from the stomach and intestines into the blood-stream, which carries it to all the organs. This means that, soon after you finish your cup of coffee or tea, caffeine will be present in virtually every cell of your body. Caffeine’s permeability results in an evenness of distribution that is exceptional as compared with most other pharmacological agents; because the human body presents no significant physiological barrier to hinder its passage through tissue, the concentrations attained by caffeine are virtually the same in blood, saliva, and even breast milk and semen.
Caffeine’s stimulating effects largely depend on its power to infiltrate the central nervous system. This infiltration can only be accomplished by crossing the blood-brain barrier, a defensive mechanism that protects the central nervous system from biological or chemical exposure by preventing large molecules, such as viruses, from entering the brain or its surrounding fluid. Even following intravenous injection, many drugs fail to penetrate this barrier to reach the central nervous system, while others enter it much less rapidly than they enter other tissues. One of the secrets of caffeine’s power is that caffeine passes through this blood-brain barrier as if it did not exist.
Photomicrographs of caffeine crystals at a magnification of 28x. (Photograph taken by Paul Barrow at BioMedical Communications, University of Pennsylvania Medical Center, © 1999 Bennett Alan Weinberg and Bonnie K.Bealer.)
The maximum concentrations of caffeine in the body, including in the blood circulating in the brain that is responsible for caffeine’s major stimulating effects, is typically attained within an hour after consumption of a cup of coffee or tea. Absorption is somewhat slower for caffeine imbibed in soft drinks. It is important to remember that the concentration of caffeine in any person’s body is a function not only of the amount of caffeine consumed but of the person’s body weight. After drinking a cup of coffee with a typical 100 mg of caffeine, a 200-pound man would attain a concentration of about 1 mg per kilogram of body weight. A 100-pound woman would attain about 2 mg per kilogram and would therefore (all other metabolic factors being considered equal) experience double the effects experienced by the man.
What becomes of all this ambient caffeine permeating your cells?
Factors Affecting Rate of Caffeine Metabolism in Humans
Slows Metabolism Speeds Metabolism
alcohol cigarettes
Asian Caucasian*
man woman
newborn child
oral contraceptives
liver damage
pregnancy
Note: A Japanese non-smoking man who was drinking alcohol with his coffee would probably feel the effects of caffeine about five times longer than would an Englishwoman who smoked cigarettes but did not drink or use oral contraceptives. If the man had liver damage, the difference could be even more dramatic. Remember this variability the next time you hear apparently contradictory reports from your friends about what caffeine does to them.
*Richard M.Gilbert, Caffeine: The Most Popular Stimulant, p. 62.
Caffeine and most other chemical compounds you ingest ultimately make their way to the liver, the body’s central blood purification factory. The bloodstream carries caffeine from the stomach and intestines, throughout the body, and, by means of the hepatic portal vein, through the liver. There it is metabolized, or converted into secondary products, called “metabolites,” which are finally excreted in the urine. More than 98 percent of the caffeine you consume is converted by the body in this way, leaving the remainder to pass through your system unchanged.
Caffeine’s biotransformation is complex, producing more than a dozen different metabolites. The study of these transformations in human beings has been impeded by the fact that the metabolic routes for caffeine demonstrate a remarkable variety among different species. This means that experiments with rats, mice, monkeys, and rabbits, for example, are of limited value in advancing our knowledge of what happens to caffeine in human beings. However, over the past two decades, sophisticated techniques for identifying the components of the caffeine molecule, distinguishing them from very similar compounds, and tracing the fate of caffeine in the body have revealed the human metabolic tree in considerable detail.
These extensive studies disclose that the liver accomplishes the biotransformation of caffeine in two primary ways:
Caffeine, a trimethylxanthine, may be �
�demethylated” into dimethylxanthines and monomethylxanthines by being stripped of either one or two of its three methyl groups.
Caffeine may be oxidized and converted to uric acids. This means that an oxygen atom is added to the caffeine molecule.
The first of these mechanisms predominates, with the result that the principal metabol ites of caffeine found in the bloodstream are the dimethylxanthines: paraxanthine, into which more than 70 percent of the caffeine is converted, theophylline, and theobromine. Paraxanthine is thus a sort of second incarnation of caffeine.
Although there are multiple alternative paths by which caffeine is metabolized in human beings, all of these pathways end in one or another uric acid derivative, which is then excreted in the urine. Complicating this picture is the fact that the profile of urinary metabolites, that is, the relative mix of the final metabolic products, exhibits marked variation among individuals, with differences observed as between children and adults, smokers and non-smokers, women who are taking oral contraceptives and those who are not.
An additional complicating factor is the fact that chemical metabolism can present cybernetic dynamics, which in this case means that the very process of metabolizing a methylxanthine can alter the speed at which additional amounts of methylxanthines will be metabolized. For example, it has been shown that the methylxanthine theobromine, a constituent of cacao and one of the primary metabolites of caffeine, is a metabolic inhibitor of theobromine itself, of theophylline, and possibly of caffeine as well. Studies reveal that daily intake of theobromine decreases the capacity to eliminate methylxanthines. This could mean, for example, that if you regularly eat chocolate, coffee or tea may keep you awake longer. Conversely, subjects on a methylxanthine-free diet for two weeks increased their capacity to eliminate theobromine. The fact that asthma patients being treated with theophylline need careful monitoring and frequent dosage adjustments is probably a result of these cybernetically governed variations in methylxanthine metabolism.
The World of Caffeine Page 32