Caffeine

Caffeine (sometimes called 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 paralyzes and kills many insects feeding upon them.

Caffeine is a central nervous system (CNS) stimulant, having the effect of warding off drowsiness and restoring alertness. Caffeine-containing beverages, such as coffee and tea, enjoy great popularity, making 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 bean 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. 

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. However, chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with 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. For example, 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 mg of caffeine:
 * One 200 mg caffeine pill (in some countries these are 100 mg, in the UK these are 50 mg)
 * Two 8-fluid ounce containers of regular coffee (16 fluid ounces (4.73 dl) total)
 * Five 1-fluid ounce shots of espresso from robusta beans (5 fluid ounces (1,47 dl) total)
 * Five 8-fluid ounce cups of black tea (40 fluid ounces (1.18 l) total)
 * Five 12-fluid ounce cans of soda (60 fluid ounces total (1.77 l), although these can vary widely in content)
 * Ten 8-fluid ounce cups of green tea (80 fluid ounces (2.36 l) total)
 * One and a half pounds (0,68kg total) of milk chocolate
 * Fifty 8-fluid ounce cups of decaffeinated coffee (400 fluid ounces (11.82 l) total)

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
Although tea has been consumed in China for thousands of years, the first documented use of caffeine in a beverage for its pharmacological effect was in the 15th century by the Sufis of Yemen, who used coffee to stay awake during prayers. In the 16th century there were coffee houses in Istanbul, Cairo and Mecca, and in the 17th century coffee houses opened for the first time in Europe.

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).

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. It is important to note, however, that caffeine cannot replace sleep, and should be used only occasionally as an alertness aid.

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.

Caffeine metabolism
Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. 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 symptoms.

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:
 * Paraxanthine (84%) – Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
 * Theobromine (12%) – Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate.
 * Theophylline (4%) – Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

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. 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 (adrenaline) and norepinephrine released via the hypothalamic-pituitary-adrenal axis. 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 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 caffeines 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. 

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.

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.

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 pills, equivalent of about 250 cups of coffee. A few other deaths by caffeine overdose have been known, almost always in the case of massive 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 for 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.

Caffeine toxicity

 * Johns Hopkins University Caffeine Dependence Study
 * eMedicine Caffeine-Related Psychiatric Disorders
 * The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
 * L Tondo and N Rudas, "The course of a seasonal bipolar disorder influenced by caffeine," Journal of Affective Disorders, 1991;22 (4):249-251 Abstract
 * DC Mackay and JW Rollins, "Caffeine and caffeinism," Journal of the Royal Naval Medical Service, 1989;75(2):65-7. Abstract
 * K Gilliland and D Andress, "Ad lib caffeine consumption, symptoms of caffeinism, and academic performance," American Journal of Psychiatry, 1981; 138:512-514 Abstract
 * American Psychiatric Association, 158th annual meeting. Abstract #NR45. "First Graders' Behavior Problems Linked to Caffeinated Cola." Fulltext
 * Whalen R, "Caffeine-Induced Anaphylaxis, A Progressive Toxic Dementia" Fulltext
 * JA Sours, "Case reports of anorexia nervosa and caffeinism," American Journal of Psychiatry, 1983; 140:235-236 Abstract

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