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Caffeine
 

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Caffeine
General
Systematic name 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
Other names 1,3,7-trimethylxanthine
trimethylxanthine
theine
mateine
guaranine
methyltheobromine
Molecular formula C8H10N4O2
SMILES O=C1C2=C(N=CN2C)N(C(=O)N1C)C
Molar mass 194.19 g/mol
Appearance Odorless, white needles or powder
CAS number *
Properties
Density and phase 1.2 g/cm3, solid
Solubility in water Slightly soluble
Melting point 237 °C
Boiling point 178 °C (sublimes)
Acidity (pKa) 10.4
Hazards
MSDS External MSDS
Main hazards May be fatal if inhaled, swallowed
or absorbed through the skin.
NFPA 704
Flash point N/A
RTECS number EV6475000
Except where noted otherwise, data are given for
materials in their standard state (at 25 °C, 100 kPa)
Chemical infobox
Caffeine (sometimes called guaranine when found in guarana, mateine when found in mate, and theine when found in tea) is a xanthine alkaloid found in the leaves and beans of the coffee tree, in tea, yerba mate, guarana berries, and in small quantities in cocoa, the kola nut and the Yaupon holly. In plants, caffeine acts as a natural pesticide that paralyses and kills many insects feeding upon them. The name is derived apparently from Italian caffè ("coffee") plus the alkaloid suffix -ine.

Caffeine is a central nervous system (CNS) stimulant, having the effect of warding off drowsiness and restoring alertness. Beverages containing caffeine — such as coffee, tea, soda and energy drinks — enjoy popularity great enough to make caffeine the world's most popular psychoactive drug.

In nature, caffeine is found with widely varying concentrations of the other xanthine alkaloids theophylline and theobromine, which are cardiac stimulants. When caffeine appears to have different effects depending on the source, it is due primarily to varying concentrations of other stimulants and absorption rates of the mixture.

Sources of caffeine

Caffeine is a plant alkaloid, found in numerous plant varieties, the most commonly used of which are coffee, tea, and to some extent cocoa. Other, less commonly used, sources of caffeine include the plants yerba mate and guaraná, which are sometimes used in the preparation of teas and, more recently, energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these plants.

The world's primary source of caffeine is the coffee bean (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the variety of coffee bean and the method of preparation used, but in general one serving of coffee ranges from about 40 mg for a single shot (30mL) of arabica variety espresso to about 100 mg for strong drip coffee. Generally, dark roast coffee has less caffeine than lighter roasts since the roasting process reduces caffeine content of the bean. Arabica coffee normally contains less caffeine content than the Robusta variety. Coffee also contains trace amounts of theophylline, but no theobromine. http://www.nobleharbor.com/tea/caffiene.html

Tea is another common source of caffeine in many cultures. Tea generally contains somewhat less caffeine per serving than coffee, usually about half as much, depending on the strength of the brew, though certain types of tea, such as black and oolong, contain somewhat more caffeine than most other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee.

Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 mg to 50 mg of caffeine per serving. By contrast, energy drinks such as Red Bull contain as much as 80 mg of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana PMID 16533867, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.

Chocolate derived from cocoa is a weak stimulant, mostly due to its content of theobromine and theophylline, but it also contains a small amount of caffeine.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15549276 However, chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with coffee. A typical serving of a milk chocolate bar (28g) has about as much caffeine as a cup of decaffeinated coffee.

Finally, caffeine may also be purchased in most areas in the form of pills that contain from 50mg to 200mg. Caffeine pills are regulated differently by different nations.

The European Union requires that a warning be placed on the packaging of any food whose caffeine content exceeds 150 mg per litre. In many other countries, however, caffeine is classified as a flavouring and is unregulated.

Caffeine equivalents

In general, each of the following contains approximately 200 milligrams * of caffeine:

Note: Caffeine content is highly unpredictable in coffee and tea drinks, especially in tea. Preparation has a huge impact on tea, and colour is a very poor indicator of caffeine content. Teas like the green Japanese Gyokuro contain far more caffeine than much darker teas like Lapsang Souchong, which has very little. Even approximate caffeine contents assigned to teas are generally at best a very inaccurate guess.

History of caffeine use

Coffee beans are indigenous to the land of Ethiopia, and by the fourth century CE, it was introduced to Arabia and the rest of the East.http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm

Tea has been consumed in China for thousands of years, where traditional stories tell that monks drank tea to stay awake during meditation practice. One legend has it that Bodhidharma cut his eyelids off to be able to stay awake longer, and the first tea plants grew from the spot where he flung them upon the ground.

In the 15th century the Sufis of Yemen used coffee to stay awake during prayers. In the 16th century there were coffee houses in Istanbul, Cairo and Mecca, and in 1573 coffee was introduced to the Europeans. Tea was introduced later in 1657 and became very popular. Even later milk chocolate was introduced into Switzerland in 1876, near the end of the 19th century cola products started to appear around the world. http://web1.caryacademy.org/chemistry/rushin/StudentProjects/CompoundWebSites/1998/Caffeine/history_of_caffeine.htm

In 1819, relatively pure caffeine was isolated for the first time by the German chemist Friedrich Ferdinand Runge. According to the legend, he did this at the instigation of Johann Wolfgang von Goethe (Weinberg & Bealer 2001).

As of today, global consumption of caffeine has been estimated to be 120,000 tonnes per annum.http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm This number equates to one serving of one caffeine oriented beverage per person on the planet per day.

Production of caffeine

Caffeine can be consumed in several forms, though the highest percent of the drug comes in the form of coffee. Coffee comes in at 54% of total caffeine consumed and tea at 43% with the remainder coming mostly from chocolate products.

Caffeine’s production itself comes in several different forms. The oldest form of caffeine’s use comes from its homeland in Ethiopia where Ethiopians were known to mix crushed dried coffee beans with fat which they rolled into balls and used as food on journeys. During its spread into the Islamic sector, caffeine was usually used as a beverage made from infusing ground roasted beans. This was the same method and production that was later used in Europe.

Because caffeine comes from a certain plant it needs a certain environment and temperature in which it grows the best. The main requirement for a good coffee plant is to have ample sunshine and rain; these types of conditions are only common in tropical or sub-tropical regions. As of today, the most dominant producer of coffee is Brazil, rich in tropical forests and having the large amounts of area on which the plant can be grown. Brazil is responsible for 28% of the total global production of coffee plants, Colombia is in second place at 16% and Indonesia finishes the top three at less than 7%. Total global production comes from over 70 different nations.http://www.alkenmrs.com/coffee/coffee-beans-producers.html

Caffeine's quantitative publication in food products

As of today, the soft drink corporations acknowledge caffeine’s similar effect on children and adults. It is also noted that there is a broad variation in the types of responses that people get. The soft drink corporations' main solution to the issue is to provide soda that is caffeine-free. The majority of soda producers and all of the major brands, provide sodas with either very low quantities or no caffeine at all as part of the ingredients.http://www.mercola.com/2001/mar/10/soda_pop_dangers.htm

This raises the question of how consumers can determine the caffeine content of a product. Right now, caffeine has to be listed under the ingredients of various foods if it is a part of the product. However, there is no regulation for the amount of caffeine that can be present in food; therefore, there is almost never any numerical information provided to answer that. It is also difficult to tell how much caffeine is in a product just by knowing that some caffeine is present.http://www.mercola.com/2001/mar/10/soda_pop_dangers.htm

There has been extensive research on caffeine and the drug’s effect on human bodies in regards to health. The Food and Drug Administration (FDA) concluded in 1958 that caffeine is recognized as safe for consumption. A recent review claims to have found no signs or evidence that caffeine’s use in carbonated beverages would produce unhealthy effects on the consumer.

The American Medical Association (AMA) also views caffeine as being safe for consumption. They state that moderate coffee and tea drinkers probably don’t need to have concern for their health in regards to caffeine consumption.http://www.ific.org/publications/brochures/caffeinebroch.cfm

Pepsi products now print the caffine content of their soft drink on the label.

Effects of caffeine

Caffeine is a central nervous system stimulant, and is used both recreationally and medically to restore mental alertness when unusual weakness or drowsiness occurs. Doses of 100-200 mg result in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination. It also results in restlessness, a loss of fine motor control, headaches, and dizziness.http://mass-spec.chem.cmu.edu/VMSL/Caffeine/Caffeine_effects.htm It is important to note, however, that consumption of caffeine does not eliminate a need for sleep--it only temporarily minimizes the sensation of being tired.

Caffeine is sometimes administered in combination with medicines to increase their effectiveness, such as with ergotamine in the treatment of migraine and cluster headaches, or with certain pain relievers such as aspirin or acetaminophen. Caffeine may also be used to overcome the drowsiness caused by antihistamines. Breathing problems (apnea) in premature infants are sometimes treated with citrated caffeine, which is available only by prescription in many countries.

While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on spiders, for example, than most other drugs do. Noever, R., J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity. NASA Tech Briefs 19(4):82. Published in New Scientist magazine, 27 April 1995.

Caffeine metabolism

Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion, caffeine has a physiological half-life of three and a half to six hours.http://www.garynull.com/Documents/CaffeineEffects.htm It is widely distributed in total body water and is eliminated by apparent first-order kinetics that can be described by a one-compartment open-model system. Continued consumption of caffeine can lead to tolerance. Upon withdrawal, the body becomes oversensitive to adenosine, causing the blood pressure to drop dramatically, which causes headaches and other related symptoms.

The principle mode of action of caffeine http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_442.html is as an antagonist of adenosine receptors in the brain. The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effect of caffeine. Caffeine can also increase levels of epinephrine http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=8081318&query_hl=21&itool=pubmed_DocSum, possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood. It is notable that these stimulatory effects are substantially reduced in those accustomed to caffeine consumption. This caffeine tolerance adaptation is largely due to the substantial increase in adenosine receptors in the brain that results from chronic use of caffeine.

Because of the adaptive responses to chronic caffeine usage, lack of caffeine can result in unwelcome symptoms in chronic users http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_861.html. The headaches that some caffeine users experience when the caffeine levels in their systems are low are due to the vasodilatory and blood pressure reducing effects of greater adenosine activity in the brain, and the fatigue that they experience is due to consequential reduced catecholamine activity. A reduction in serotonin levels when caffeine use is stopped can cause mild depression. The quite long time it takes for an individual to become more susceptible to stimulation by caffeine again if they refrain from using caffeine for an extended period is largely explained by the long time it takes for the number of adenosine receptors in the brain to revert to "normal" levels (uninfluenced by caffeine consumption).

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system into three metabolic dimethylxanthines, which each have their own effects on the body:

Each of these metabolites is further metabolised and then excreted in the urine.

Mechanism of action

The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (a "false transmitter" method of antagonism). This may be relevant in its diuretic properties, since adenosine is known to constrict preferentially the afferent arterioles of the glomerular apparatus; inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). In the brain, adenosine binding also causes blood vessels to dilate (presumably to let more oxygen in during sleep).http://home.howstuffworks.com/caffeine.htm This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine or adrenaline and norepinephrine released via the hypothalamic-pituitary-adrenal axishttp://pharmrev.aspetjournals.org/cgi/content/full/51/1/83 Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs and a release of glucose by the liver.

Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in the messaging cascade produced by cells in response to stimulation by epinephrine, so by blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate.

The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles (Dews et al. 1984).

With these effects, caffeine is considered an ergogenic: increasing the capacity for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who consumed caffeine compared to control tests (Ivy et al. 1979). Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight (Graham & Spriet 1991). The extensive boost shown in the runners is not an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits (Trice & Hayes 1995).

Side effects of caffeine

The minimum lethal dose of caffeine ever reported is 3,200 mg, administered intravenously. The LD50 of caffeine is estimated between 13 and 19 grams for oral administration for an average adult. The LD50 of caffeine is dependent on weight and individual sensitivity and estimated to be about 150 to 200 mg per kg of body mass, roughly 140 to 180 cups of coffee for an average adult taken within a limited timeframe that is dependent on half-life. The half-life, or time it takes for the amount of caffeine in the blood to decrease by 50%, ranges from 3.5 to 10 hours. In adults the half-life is generally around 5 hours. However, contraceptive pills increase this to around 12 hours, and, for women over 3 months pregnant, it varies from 10 to 18 hours. In infants and young children, the half-life may be longer than in adults. With common coffee and a very rare half-life of 100 hours, it would require 3 cups of coffee every hour for 100 hours just to reach LD50. Though achieving lethal dose with coffee would be exceptionally difficult, there have been many reported deaths from intentional overdosing on caffeine pills.

Too much caffeine, especially over an extended period of time, can lead to a number of physical and mental conditions. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) states: "The 4 caffeine-induced psychiatric disorders include caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS)."

An overdose of caffeine can result in a state termed caffeine intoxication or caffeine poisoning. Its symptoms are both physiological and psychological. Symptoms of caffeine intoxication include: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, muscle twitching, rambling flow of thought and speech, paranoia, cardiac arrhythmia or tachycardia, and psychomotor agitation, gastrointestinal complaints, increased blood pressure, rapid pulse, vasoconstriction (tightening or constricting of superficial blood vessels) sometimes resulting in cold hands or fingers, increased amounts of fatty acids in the blood, and an increased production of gastric acid. In extreme cases mania, depression, lapses in judgment, disorientation, loss of social inhibition, delusions, hallucinations and psychosis may occur.http://www.nlm.nih.gov/medlineplus/ency/article/002579.htm

It is commonly assumed that only a small proportion of people exposed to caffeine develop symptoms of caffeine intoxication. However, because it mimics organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia, a growing number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated. Shannon et al (1998) point out that:

"Caffeine-induced psychosis, whether it be delirium, manic depression, schizophrenia, or merely an anxiety syndrome, in most cases will be hard to differentiate from other organic or non-organic psychoses....The treatment for caffeine-induced psychosis is to withhold further caffeine." A study in the British Journal of Addiction declared that "although infrequently diagnosed, caffeinism is thought to afflict as many as one person in ten of the population" (JE James and KP Stirling, 1983).

Because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease. Furthermore, it can also lead to nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, heart palpitations and hyperreflexia.http://www.coffeefaq.com/caffaq.html#CaffeineAndHealth

It is suggested that "slow metabolizers" who carry a variant of polymorphic cytochrome P450 1A2 (CYP1A2) enzyme have an increased risk of nonfatal myocardial infarction (see references).

Withdrawal

Individuals who consume caffeine regularly develop a reduction in sensitivity to caffeine; when such individuals reduce their caffeine intake, their body becomes oversensitive to adenosine, with the result that blood pressure drops dramatically, leading to an excess of blood in the head (though not necessarily on the brain), causing a headache. Other symptoms may include nausea, fatigue, drowsiness, anxiety and irritability; in extreme cases symptoms may include depression, inability to concentrate and diminished motivation to initiate or to complete daily tasks at home or at work.

Withdrawal symptoms may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually lasts from one to five days. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.

Currently caffeine withdrawal is recognized as meriting further study by the DSM-IV, although recent research demonstrating its clinical significance means that it will likely be included as an Axis-1 disorder in the DSM-V http://www.cbsnews.com/stories/2004/09/30/health/webmd/main646620.shtml

Effects on fetuses and newborn children

There is some evidence that caffeine may be dangerous for fetuses and newborn children. In animal studies, caffeine intake during pregnancy has been demonstrated to have teratogenic effects and increase the risk of learning problems and hyperactivity in rats and mice, respectively. The applicability of these results to human infants is disputed since the concentrations involved were high and rodents are more susceptible to most mutagens. In a 1985 study conducted by scientists of Carleton University, Canada, children born by mothers who had consumed more than 300 mg/d caffeine (about 3 cups of coffee or 6 cups of tea) were found to have, on the average, lower birth weight and head circumference than the children of mothers who had consumed little or no caffeine. In addition, use of large amounts of caffeine by the mother during pregnancy may cause problems with the heart rhythm of the fetus. For these reasons, some doctors recommend that women largely discontinue caffeine consumption during pregnancy and possibly also after birth until the newborn child is weaned.

The negative effects of caffeine on the developing fetus can be attributed to the ability of caffeine to inhibit two DNA damage response proteins known as Ataxia-Telangiectasia Mutated (ATM) or ATM-Rad50 Related (ATR). These proteins control much of the cells' ability to stop cell cycle in the presence of DNA damage, such as DNA single/double strand breaks and nucleotide dimerization. DNA damage can occur relatively frequently in actively dividing cells, such as those in the developing fetus. Caffeine is used in laboratory setting as an inhibitor to these proteins and it has been shown in a study by Lawson et al. in 2004, that women who use caffeine during pregnancy have a higher likelihood of miscarriage than those who do not. Since the dosage rate of self-administration is difficult to control and the effects of caffeine on the fetus are related to random occurrence (DNA damage), a minimal toxic dose to the fetus has yet to be established.

Caffeine pills

Caffeine pills are often used by college students and shift workers as a convenient way to fight sleep, and are often considered harmless. However, like any medication, caffeine can be harmful or deadly in sufficient quantities. Due to the amount of caffeine present in standard pills, it is possible to consume a dangerous amount of caffeine in this form.

Periodically, caffeine pills come under media fire in connection with the death of a college student due to a large overdose of caffeine. One example is the death of a North Carolina student, Jason Allen, who swallowed most of a bottle of 90 such pillshttp://www.collegepublisher.com/media/paper87/DFPArchive/science/1103981.html, equivalent to about 250 cups of coffee. A few other deaths by caffeine overdose have been known, almost always in the case of excessive pill consumption.

Extraction of pure caffeine

It is very difficult to know the exact amount of caffeine in a particular drink that is not automatically prepared. The amount of caffeine in a single serving of coffee varies considerably due to many variables. Concentration can vary from bean to bean within a given bush; preparation of the raw bean will affect concentration, as well as multiple variables involved in brewing.

Caffeine extraction is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavour, they have been superseded by two main methods:

Water extraction of caffeine

Coffee beans are soaked in water. The water—which contains not only caffeine but also many other compounds which contribute to the flavour of coffee—is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and medicines.

Supercritical carbon dioxide extraction of caffeine

Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds) but is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1°C and pressures above 73 atm. Under these conditions, CO2 is said to be in a "supercritical" state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97-99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.

References

  • Weinberg BA, Bealer BK. The world of caffeine. New York & London: Routledge, 2001. ISBN 0-415-92722-6.
  • JE James and KP Stirling, "Caffeine: A Summary of Some of the Known and Suspected Deleterious Habits of Habitual Use," British Journal of Addiction, 1983;78:251-58.
  • Hughes JR, McHugh P, Holtzman S. "Caffeine and schizophrenia." Psychiatr Serv 1998;49:1415-7. Fulltext. PMID 9826240.
  • Shannon MW, Haddad LM, Winchester JF. Clinical Management of Poisoning and Drug Overdose, 3rd ed.. 1998. ISBN 0721664091.
  • Diagnostic and Statistical Manual of Mental Disorders ISBN 0890420610
  • Trice, I., and Haymes, E. (1995). "Effects of caffeine ingestion on exercise-induced changes during high intensity, intermittent exercise". International Journal of Sports Nutrition. 37-44.
  • Tarnopolsky, M. A. (1994). "Caffeine and endurance performances". Sports Medicine (Vol. 18 Ed. 2): 109 – 125.
  • Ivy, J., Costill, D., Fink, W. et al. (1979). "Influence of caffeine and carbohydrate feedings on endurance performance". Medical Science Sports Journal (Vol. 11). 6-11.
  • Dews, P.B. (1984). "Caffeine: Perspectives from Recent Research". Berlin: Springer-Valerag.
  • Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction JAMA. 2006 Mar 8;295(10):1135-41 PMID 16522833

External links

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