Caffeine

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Caffeine is a central nervous system stimulant found naturally in certain plants. It is most commonly consumed from coffee, tea, chocolate and some foods/drinks containing products derived from plants like kola nuts, yerba mate and guarana berries.

Caffeine is a bitter, white crystalline xanthine alkaloid that is a psychoactive stimulant drug. It was first isolated from coffee beans in 1819.

Common sources of caffeine include coffee beans, tea leaves, cocoa beans, and plants like kola nuts, yerba mate and guarana berries. It is widely consumed by humans in beverages like coffee, tea and soft drinks as well as some foods.

Caffeine 1

Caffeine
Caffeine

Identifiers

CAS number [1]


58-08-2  

PubChem [2]
2519  

ChemSpider [3]
2424  

UNII [4]
3G6A5W338E  

EC-number [5]
200-362-1

DrugBank [6]
DB00201

ChEBI [7]
27732

IUPHAR ligand [8]


407  

RTECS number EV6475000

SMILES

InChI

InChI key

Properties

Molecular formula CH NO
8 10 4 2
Molar mass 194.19 g/mol

Exact mass 194.080376 u

Appearance Odorless, white needles or powder

Density 1.23 g/cm3, solid


Caffeine 2

Melting point 227–228 °C (anhydrous); 234–235 °C (monohydrate)

Boiling point 178 °C subl.

Solubility in water 2.17 g/100 ml (25 °C)


18.0 g/100 ml (80 °C)
67.0 g/100 ml (100 °C)

Acidity (pKa) [9]


−0.13–1.22

Dipole moment 3.64 D (calculated)

Hazards

MSDS [10]
ICSC 0405

EU Index 613-086-00-5

EU classification not listed

R-phrases R22

S-phrases (S2)

NFPA 704

LD50 [11]
192 mg/kg (rat, oral)
[12]
 (what is this?)   (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

Infobox references

Caffeine (also spelled caffein)[13] is a bitter, white crystalline xanthine alkaloid that is a psychoactive stimulant
drug. Caffeine was discovered in 1820 by a German chemist, Friedlieb Ferdinand Runge, and in 1821 by French
chemists working independently; viz., by Robiquet and by Pelletier and Caventou. It was Pelletier who coined the
word "cafeine," whence "caffeine".[14]
Caffeine is found in varying quantities in the beans, leaves, and fruit of some plants, where it acts as a natural
pesticide that paralyzes and kills certain insects feeding on the plants.[15] It is most commonly consumed by humans
in infusions extracted from the bean of the coffee plant and the leaves of the tea bush, as well as from various foods
and drinks containing products derived from the kola nut. Other sources include yerba mate, guarana berries, and the
Yaupon Holly.
In humans, caffeine acts as a central nervous system (CNS) stimulant, temporarily warding off drowsiness and
restoring alertness. Caffeine is the world's most widely consumed psychoactive substance,[16] but, unlike many other
psychoactive substances, is legal and unregulated in nearly all jurisdictions. Beverages containing caffeine, such as
coffee, tea, soft drinks, and energy drinks, enjoy great popularity; in North America, 90% of adults consume caffeine
daily.[16] The U.S. Food and Drug Administration (FDA) lists caffeine as a "multiple purpose generally recognized
as safe food substance".[17]
Caffeine has diuretic properties when administered in sufficient doses to subjects that do not have a tolerance for
it.[18] Regular users, however, develop a strong tolerance to this effect,[18] and studies have generally failed to
support the common notion that ordinary consumption of caffeinated beverages contributes significantly to
dehydration.[19] [20] [21]
Caffeine 3

Occurrence
Caffeine is found in many plant species, where it acts as a natural
pesticide, with high caffeine levels being observed in seedlings that are
still developing foliage, but are lacking mechanical protection;[22]
Caffeine paralyzes and kills certain insects feeding upon the plant.[15]
High caffeine levels have also been found in the surrounding soil of
coffee bean seedlings. Therefore, it is understood that caffeine has a
natural function as both a natural pesticide and an inhibitor of seed
germination of other nearby coffee seedlings, thus giving it a better
chance of survival.[23]
Roasted coffee beans, a common source of
caffeine Common sources of caffeine are coffee, tea, and (to a lesser extent)
chocolate derived from cocoa beans.[24] Less commonly used sources
of caffeine include the yerba maté and guarana plants,[25] which are sometimes used in the preparation of teas and
energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these
plants.[26] [27] Some yerba mate enthusiasts assert that mateine is a stereoisomer of caffeine, which would make it a
different substance altogether.[25] This is not true because caffeine is an achiral molecule[28] , and therefore has no
enantiomers; nor does it have other stereoisomers[29] . The disparity in experience and effects between the various
natural caffeine sources could be because plant sources of caffeine also contain widely varying mixtures of other
xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as
polyphenols that can form insoluble complexes with caffeine.[30]

One of the world's primary sources of caffeine is the coffee "bean" (which is the seed of the coffee plant), from
which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the
method of preparation used;[31] even beans within a given bush can show variations in concentration. In general, one
serving of coffee ranges from 80-100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to
approximately 100-125 milligrams for a cup (120 milliliters) of drip coffee. In general, dark-roast coffee has less
caffeine than lighter roasts because the roasting process reduces the bean's caffeine content.[32] [33] Arabica coffee
normally contains less caffeine than the robusta variety.[31] Coffee also contains trace amounts of theophylline, but
no theobromine.
Tea is another common source of caffeine. Although tea contains more caffeine than coffee (by dry weight), a typical
serving contains much less, as tea is normally brewed much weaker. Besides strength of the brew, growing
conditions, processing techniques- and other variables also affect caffeine content. Certain types of tea may contain
somewhat more caffeine than other teas. Tea contains small amounts of theobromine and slightly higher levels of
theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very
poor indicator of caffeine content.[34] Teas like the pale Japanese green tea gyokuro, for example, contain far more
caffeine than much darker teas like lapsang souchong, which has very little.
Caffeine 4

[35] [36] [37]


Caffeine content of select common food and drugs.

Product Serving size Caffeine per serving (mg) Caffeine per liter (mg)

Caffeine tablet (regular-strength) 1 tablet 100 —

Caffeine tablet (extra-strength) 1 tablet 200 —

Excedrin tablet 1 tablet 65 —

Hershey's Special Dark (45% cacao content) 1 bar (43 g; 1.5 oz) 31 —

Hershey's Milk Chocolate (11% cacao content) 1 bar (43 g; 1.5 oz) 10 —

Percolated coffee 207 mL (7 U.S. fl oz) 80–135 386–652

Drip coffee 207 mL (7 U.S. fl oz) 115–175 555–845

Coffee, decaffeinated 207 mL (7 U.S. fl oz) 5–15 24–72

Coffee, espresso 44–60 mL (1.5-2 U.S. fl oz) 100 1691–2254

Black tea 177 mL (6 U.S. fl oz) 50 282

Green tea 177 mL (6 U.S. fl oz) 30 170

Guayakí Yerba Mate (loose leaf) 6 g (0.2 U.S. oz) [38] 358 about
85

Coca-Cola Classic 355 mL (12 U.S. fl oz) 34 96

Barq's Root Beer 355 mL (12 U.S. fl oz) 22.5 63

Mountain Dew 355 mL (12 U.S. fl oz) 54 154

Vault 355 mL (12 U.S. fl oz) 69 194

Guaraná Antarctica 350 mL (11 U.S. fl oz) 30 100

Monster energy drink 500 mL (16.4 U.S. fl oz) 160 320

Jolt Cola 695 mL (23.5 U.S. fl oz) 280 403

Red Bull 250 mL (8.2 U.S. fl oz) 80 320

Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks
typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks such as Red Bull can
start at 80 milligrams 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, 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.[39]
Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate
may be due to a combination of theobromine and theophylline as well as caffeine.[40] A typical 28-gram serving of a
milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee, although some dark chocolate
currently in production contains as much as 160 mg per 100g.
In recent years, various manufacturers have begun putting caffeine into shower products such as shampoo and
soap.[41] Studies show that caffeine in shampoo applied for two minutes is absorbed through the skin, mostly through
hair follicles, and reaches the blood stream.[42]
Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improves
mental alertness. These effects have been borne out by research that shows that caffeine use (whether in tablet form
or not) results in decreased fatigue and increased attentiveness.[43] These tablets are commonly used by students
studying for their exams and by people who work or drive for long hours.[44]
Caffeine is also used pharmacologically to treat apnea in premature newborns and as such is one of the 10 drugs
most commonly given in neonatal intensive care,[45] though questions are now raised based on experimental animal
Caffeine 5

research whether it might have subtle harmful side-effects.[45]

History
Main articles: History of chocolate, History of coffee,
Origin and history of tea
Humans have consumed caffeine since the Stone Age.[46]
Early peoples found that chewing the seeds, bark, or leaves of
certain plants had the effects of easing fatigue, stimulating
awareness, and elevating one's mood. Only much later was it
found that the effect of caffeine was increased by steeping
such plants in hot water. Many cultures have legends that
attribute the discovery of such plants to people living many
thousands of years ago.

According to one popular Chinese legend, the Emperor of


China Shennong, reputed to have reigned in about 3000 BCE,
accidentally discovered that when some leaves fell into
boiling water, a fragrant and restorative drink resulted.[47] [48] Coffeehouse in Palestine, circa 1900.
[49]
Shennong is also mentioned in Lu Yu's Cha Jing, a
famous early work on the subject of tea.[50] The history of coffee has been recorded as far back as the ninth century.
During that time, coffee beans were available only in their native habitat, Ethiopia. A popular legend traces its
discovery to a goatherder named Kaldi, who apparently observed goats that became elated and sleepless at night
after grazing on coffee shrubs and, upon trying the berries that the goats had been eating, experienced the same
vitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th-century
Persian physician al-Razi. In 1587, Malaye Jaziri compiled a work tracing the history and legal controversies of
coffee, entitled ʕUmdat aṣ-Ṣafwa Fī Ḥill al-Qahwah. In this work, Jaziri recorded that one Sheikh, Jamal-al-Din
al-Dhabhani, mufti of Aden, was the first to adopt the use of coffee in 1454, and that in the 15th century the Sufis of
Yemen routinely used coffee to stay awake during prayers.

Towards the close of the 16th century, the use of coffee was recorded by a European resident in Egypt, and about
this time it came into general use in the Near East. The appreciation of coffee as a beverage in Europe, where it was
first known as "Arabian wine," dates from the 17th century. A legend states that, after the Ottoman Turks retreated
from the walls of Vienna after losing a battle for the city, many sacks of coffee beans were found among their
baggage. Europeans did not know what to do with all the coffee beans, being unfamiliar with them. So Franz George
Kolschitzky, a Pole who had actually worked for the Turks, offered to take them. He subsequently taught the
Viennese how to make coffee, and the first coffee house in the Western world was opened in Vienna, thus starting a
long tradition of coffee appreciation.[51] In Britain, the first coffee houses were opened in London in 1652, at St
Michael's Alley, Cornhill. They soon became popular throughout Western Europe, and played a significant role in
social relations in the 17th and 18th centuries.[52]
Use of the kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West
African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In 1911, kola became
the focus of one of the earliest documented health scares when the US government seized 40 barrels and 20 kegs of
Coca-Cola syrup in Chattanooga, Tennessee, alleging that the caffeine in its drink was "injurious to health".[53] On
March 13, 1911, the government initiated United States v. Forty Barrels and Twenty Kegs of Coca-Cola, hoping to
force Coca-Cola to remove caffeine from its formula by making claims that the product was adulterated and
misbranded. The allegation of adulteration was, in substance, that the product contained an added poisonous or
added deleterious ingredient; caffeine, which might render the product injurious to health. It was alleged to be
Caffeine 6

misbranded in that the name 'Coca Cola' was a representation of the presence of the substances coca and cola; that
the product 'contained no coca and little if any cola' and thus was an 'imitation' of these substances and was offered
for sale under their 'distinctive name.'[54] Although the judge ruled in favor of Coca-Cola, two bills were introduced
to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of
"habit-forming" and "deleterious" substances, which must be listed on a product's label.
The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. In the
New World, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile
pepper, and achiote. Xocolatl was believed to fight fatigue, a belief that is probably attributable to the theobromine
and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa
beans were often used as currency.
Xocolatl was introduced to Europe by the Spaniards and became a popular beverage by 1700. They also introduced
the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as
Black Bean.
The leaves and stems of the Yaupon Holly (Ilex vomitoria) were used by Native Americans to brew a tea called Asi
or the "black drink".[55] Archaeologists have found evidence of this use stretch back far into antiquity, possibly
dating to Late Archaic times.

Synthesis and properties


In 1819, the German chemist Friedrich Ferdinand
Runge isolated relatively pure caffeine for the first
time.[56] [57] According to Runge, he did this at the
behest of Johann Wolfgang von Goethe.[58] In 1827,
Oudry isolated "theine" from tea,[59] but it was later
proved by Mulder[60] and by Jobst[61] that theine was
the same as caffeine.[58] The structure of caffeine was
elucidated near the end of the 19th century by Hermann
Emil Fischer, who was also the first to achieve its total
synthesis.[62] This was part of the work for which
Fischer was awarded the Nobel Prize in 1902. The Anhydrous (dry) USP-grade caffeine
nitrogen atoms are all essentially planar (in sp2 orbital
hybridization), resulting in the caffeine molecule's having aromatic character. Being readily available as a byproduct
of decaffeination, caffeine is not usually synthesized.[63] If desired, it may be synthesized from dimethylurea and
malonic acid.[64]

Pharmacology
Global consumption of caffeine has been estimated at 120,000 tonnes per year,[65] making it the world's most
popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.
Caffeine is a central nervous system and metabolic stimulant,[66] and is used both recreationally and medically to
reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine and
other methylxanthine derivatives are also used on newborns to treat apnea and correct irregular heartbeats. Caffeine
stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness,
faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord
level at higher doses.[43] Once inside the body, it has a complex chemistry, and acts through several mechanisms as
described below.
Caffeine 7

Metabolism and half-life


Caffeine from coffee or other
beverages is absorbed by the stomach
and small intestine within 45 minutes
of ingestion and then distributed
throughout all tissues of the body.[67] It
is eliminated by first-order kinetics.[68]
Caffeine can also be ingested rectally,
evidenced by the formulation of
suppositories of ergotamine tartrate
and caffeine (for the relief of
migraine)[69] and chlorobutanol and
caffeine (for the treatment of
hyperemesis).[70]

The biological half-life of caffeine —


the time required for the body to
eliminate one-half of the total amount
of caffeine — varies widely among
Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%),
individuals according to such factors as theobromine (12%), and theophylline (4%)
age, liver function, pregnancy, some
concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults,
caffeine's half-life is approximately 4.9 hours.[71] In women taking oral contraceptives, this is increased to 5–10
hours,[72] and in pregnant women the half-life is roughly 9–11 hours.[73]

Caffeine can accumulate in individuals with severe liver disease, increasing its half-life up to 96 hours.[74] In infants
and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30
hours. Other factors such as smoking can shorten caffeine's half-life.[75] Fluvoxamine (Luvox) reduced the clearance
of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold; from 4.9 hours to 56 hours.[71]
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (to be specific, the 1A2
isozyme) into three metabolic dimethylxanthines,[76] each of which has its 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 the cocoa bean, 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 metabolized and then excreted in the urine.
Caffeine 8

Mechanism of action
Caffeine readily crosses the
blood–brain barrier that separates the
bloodstream from the interior of the
brain. Once in the brain, the principal
mode of action is as a nonselective
antagonist of adenosine receptors.[77]
[78]
The caffeine molecule is
structurally similar to adenosine, and
binds to adenosine receptors on the
surface of cells without activating them
(an "antagonist" mechanism of action).
Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain. Therefore, caffeine acts as a
competitive inhibitor.

Adenosine is found in every part of the body, because it plays a role in the fundamental ATP-related energy
metabolism and is necessary for RNA synthesis, but it has special functions in the brain. There is a great deal of
evidence that concentrations of brain adenosine are increased by various types of metabolic stress including anoxia
and ischemia. The evidence also indicates that brain adenosine acts to protect the brain by suppressing neural activity
and also by increasing blood flow through A2A and A2B receptors located on vascular smooth muscle.[79] By
counteracting adenosine, caffeine reduces resting cerebral blood flow between 22% and 30%.[80] Caffeine also has a
generally disinhibitory effect on neural activity. It has not been shown, however, how these effects cause increases in
arousal and alertness.

Adenosine is released in the brain through a complex mechanism.[79] There is evidence that adenosine functions as a
synaptically released neurotransmitter in some cases, but stress-related adenosine increases appear to be produced
mainly by extracellular metabolism of ATP. It is not likely that adenosine is the primary neurotransmitter for any
group of neurons, but rather that it is released together with other transmitters by a number of neuron types. Unlike
most neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in a
voltage-controlled manner, but the possibility of such a mechanism has not been completely ruled out.
Several classes of adenosine receptors have been described, with different anatomical distributions. A1 receptors are
widely distributed, and act to inhibit calcium uptake. A2A receptors are heavily concentrated in the basal ganglia, an
area that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lower
densities. There is evidence that A 2A receptors interact with the dopamine system, which is involved in reward and
arousal. (A2A receptors can also be found on arterial walls and blood cell membranes.)
Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be more specifically
involved in control of the sleep-wake cycle. Robert McCarley and his colleagues have argued that accumulation of
adenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that the
effects may be mediated both by inhibition of wake-promoting neurons via A1 receptors, and activation of
sleep-promoting neurons via indirect effects on A2A receptors.[81] More recent studies have provided additional
evidence for the importance of A2A, but not A1, receptors.[82]
Some of the secondary effects of caffeine are probably caused by actions unrelated to adenosine. Like other
methylated xanthines, caffeine is both a
1. competitive nonselective phosphodiesterase inhibitor [83] which raises intracellular cAMP, activates PKA,
inhibits TNF-alpha [84] [85] and leukotriene [86] synthesis, and reduces inflammation and innate immunity.[86]
Caffeine is also added to agar, which partially inhibits the growth of Saccharomyces cerevisiae by inhibiting
cyclic AMP phosphodiesterase.[87]
Caffeine 9

2. nonselective adenosine receptor antagonist [78] (see above).


Phosphodiesterase inhibitors inhibit cAMP-phosphodiesterase (cAMP-PDE) enzymes, which convert cyclic AMP
(cAMP) in cells to its noncyclic form, thus allowing cAMP to build up in cells. Cyclic AMP participates in
activation of protein kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By
blocking its removal, caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as
amphetamine, methamphetamine, and methylphenidate. Increased concentrations of cAMP in parietal cells causes an
increased activation of protein kinase A (PKA), which in turn increases activation of H+/K+ ATPase, resulting
finally in increased gastric acid secretion by the cell. Cyclic AMP also increases the activity of the funny current,
which directly increases heart rate. Caffeine is also a structural analogue of strychnine and, like it (though much less
potent), a competitive antagonist at ionotropic glycine receptors.[88]
Metabolites of caffeine also contribute to caffeine's effects. 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.
Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles.
Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope
that increases heart rate and efficiency.[89]

Caffeine has a significant effect on spiders,


which is reflected here in the erratic
construction of their webs.
Caffeine 10

Effects when taken in moderation


The precise amount of caffeine necessary to
produce effects varies from person to person
depending on body size and degree of tolerance
to caffeine. It takes less than an hour for caffeine
to begin affecting the body and a mild dose
wears off in three to four hours.[43] Consumption
of caffeine does not eliminate the need for sleep,
it only temporarily reduces the sensation of
being tired. In general, 25 to 50 milligrams of
caffeine is sufficient for most people to report
increased alertness and arousal as well as
subjectively lower levels of fatigue.[91]

With these effects, caffeine is an ergogenic,


increasing a person's capability 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 that consumed
caffeine compared to control subjects.[92] Other
studies attained much more dramatic results; one
particular study of trained runners showed a 44% Overview of the more common side effects of caffeine, sometimes appearing
[90]
increase in "race-pace" endurance, as well as a at levels below overdose.

51% increase in cycling endurance, after a


dosage of 9 milligrams of caffeine per kilogram of body weight.[93] 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.[94]

Caffeine citrate has proven to be of short- and long-term benefit in treating the breathing disorders of apnea of
prematurity and bronchopulmonary dysplasia in premature infants.[90] The only short-term risk associated with
caffeine citrate treatment is a temporary reduction in weight gain during the therapy,[95] and longer term studies (18
to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.[96]
Caffeine relaxes the internal anal sphincter muscles and thus should be avoided by those with fecal incontinence.[97]
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 also a pronounced effect on
mollusks and various insects as well as spiders.[98]
Caffeine also increases the effectiveness of some drugs. Many over-the-counter headache drugs include caffeine in
their formula. It is also used with ergotamine in the treatment of migraine and cluster headaches as well as to
overcome the drowsiness caused by antihistamines.
Caffeine may also have hepatoprotective properties. Studies have shown that increased caffeine consumption is
associated with less severe liver injury among those at high risk for liver disease, such as those with alcoholism,
obesity, or hemochromatosis. The mechanism by which this occurs is not known.[99] [100]
Caffeine 11

Tolerance and withdrawal


Because caffeine is primarily an antagonist of the central nervous
system's receptors for the neurotransmitter adenosine, the bodies of
individuals that regularly consume caffeine adapt to the continuous
presence of the drug by substantially increasing the number of
adenosine receptors in the central nervous system. First, the
stimulatory effects of caffeine are substantially reduced, a phenomenon
known as a tolerance adaptation. Second, because these adaptive
responses to caffeine make individuals much more sensitive to
adenosine, a reduction in caffeine intake will effectively increase the
normal physiological effects of adenosine, resulting in unwelcome
withdrawal symptoms in tolerant users.[101]

Other research questions the idea that up-regulation of adenosine


receptors is responsible for tolerance to the locomotor stimulant effects
of caffeine, noting, among other things, that this tolerance is
insurmountable by higher doses of caffeine (it should be surmountable
if tolerance were due to an increase in receptors), and that the increase
in adenosine receptor number is modest and does not explain the large
tolerance that develops to caffeine.[102]

Caffeine tolerance develops very quickly, especially among heavy "Monster" Energy Drink - Containing 160 mg of
caffeine. One of many brands and compositions
coffee and energy drink consumers. Complete tolerance to the sleep
marketed to consumers. The image above is
disruption effects of caffeine develops after consuming 400 mg of proposed for deletion. See files for deletion to
caffeine 3 times a day for 7 days. Complete tolerance to subjective help reach a consensus on what to do.
effects of caffeine was observed to develop after consuming 300 mg 3
times per day for 18 days, and possibly even earlier.[103] In another experiment, complete tolerance of caffeine was
observed when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has been
observed in those that consume more average doses of caffeine.[104]

Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of
adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in
the head and causing a headache and nausea. This means caffeine has vasoconstriction properties.[105] Reduced
catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine
use is stopped can cause anxiety, irritability, inability to concentrate, and diminished motivation to initiate or to
complete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be known
as a "crash".[106]

Withdrawal symptoms — possibly including headache, irritability, an inability to concentrate, drowsiness, insomnia
and pain in the stomach, upper body, and joints[107] — may appear within 12 to 24 hours after discontinuation of
caffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required for
the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption.
Analgesics, such as aspirin, may relieve the pain symptoms, as may a small dose of caffeine.
Caffeine 12

Overuse
In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as
caffeinism.[108] [109] Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and
mental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia),
insomnia, headaches, respiratory alkalosis, and heart palpitations.[110] [111] Furthermore, because caffeine increases
the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and
gastroesophageal reflux disease.[112] Caffeine may also increase the toxicity of certain other drugs, such as
paracetamol.[113]
There are four caffeine-induced psychiatric disorders recognized by the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder,
and caffeine-related disorder not otherwise specified (NOS).

Caffeine intoxication

An acute overdose of caffeine usually in excess of


about 300 milligrams, dependent on body weight and
level of caffeine tolerance, can result in a state of
central nervous system over-stimulation called
caffeine intoxication (DSM-IV 305.90),[114] or
colloquially the "caffeine jitters". The symptoms of
caffeine intoxication are not unlike overdoses of
other stimulants. It may include restlessness,
fidgetiness, nervousness, excitement, euphoria,
insomnia, flushing of the face, increased urination,
gastrointestinal disturbance, muscle twitching, a
rambling flow of thought and speech, irritability,
irregular or rapid heart beat, and psychomotor
agitation.[111] In cases of much larger overdoses,
mania, depression, lapses in judgment, disorientation,
disinhibition, delusions, hallucinations, and
psychosis may occur, and rhabdomyolysis
(breakdown of skeletal muscle tissue) can be [90]
Main symptoms of caffeine intoxication.
provoked.[115] [116]

Extreme overdose can result in death.[117] The median lethal dose (LD50) given orally, is 192 milligrams per
kilogram in rats.[11] The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimated
to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult
taken within a limited time frame that is dependent on half-life. Though achieving lethal dose with caffeine would be
exceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with
serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine. An exception
to this would be taking a drug such as fluvoxamine, which blocks the liver enzyme responsible for the metabolism of
caffeine, thus increasing the central effects and blood concentrations of caffeine dramatically at 5-fold. It is not
contraindicated, but highly advisable to minimize the intake of caffeinated beverages, as drinking one cup of coffee
will have the same effect as drinking five under normal conditions.[118] [119] [120] [121] Death typically occurs due to
ventricular fibrillation brought about by effects of caffeine on the cardiovascular system.

Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms,
but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may
Caffeine 13

be required.

Detection in biological fluids


Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of
poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of
2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims
of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for
which a level in excess of 15 mg/L is usually considered to represent abuse.[122]

Anxiety and sleep disorders


Two infrequently diagnosed caffeine-induced disorders that are recognized by the American Psychological
Association (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder, which can result from
long-term excessive caffeine intake.
In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to
induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.[114]
In some individuals, large amounts of caffeine can induce anxiety severe enough to necessitate clinical attention.
This caffeine-induced anxiety disorder can take many forms, from generalized anxiety to panic attacks,
obsessive-compulsive symptoms, or even phobic symptoms.[114] Because this condition can mimic organic mental
disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, akathisia, or even schizophrenia, a
number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily
medicated when the treatment for caffeine-induced psychosis would simply be to stop further caffeine intake.[123] A
study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as
many as one person in ten of the population.[109]

Effects on memory and learning


An array of studies found that caffeine could have nootropic effects,
inducing certain changes in memory and learning.
Researchers have found that long-term consumption of low dose
caffeine slowed hippocampus-dependent learning and impaired
long-term memory in mice. Caffeine consumption for 4 weeks also
significantly reduced hippocampal neurogenesis compared to controls
during the experiment. The conclusion was that long-term consumption
of caffeine could inhibit hippocampus-dependent learning and memory
partially through inhibition of hippocampal neurogenesis.[124]

In another study, caffeine was added to rat neurons in vitro. The


dendritic spines (a part of the brain cell used in forming connections
between neurons) taken from the hippocampus (a part of the brain
associated with memory) grew by 33% and new spines formed. After
an hour or two, however, these cells returned to their original
shape.[125]
Anhydrous caffeine (SP)
Another study showed that human subjects — after receiving 100
milligrams of caffeine — had increased activity in brain regions located in the frontal lobe, where a part of the
working memory network is located, and the anterior cingulate cortex, a part of the brain that controls attention. The
caffeinated subjects also performed better on the memory tasks.[126]
Caffeine 14

However, a different study showed that caffeine could impair short-term memory and increase the likelihood of the
tip of the tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-term
memory when the information to be recalled is related to the current train of thought, but also to hypothesize that
caffeine hinders short-term memory when the train of thought is unrelated.[127] In essence, caffeine consumption
increases mental performance related to focused thought while it may decrease broad-range thinking abilities.

Effects on the heart


Caffeine binds to receptors on the surface of heart muscle cells, which leads to an increase in the level of cAMP
inside the cells (by blocking the enzyme that degrades cAMP), mimicking the effects of epinephrine (which binds to
receptors on the cell that activate cAMP production). cAMP acts as a "second messenger," and activates a large
number of protein kinase A (PKA; cAMP-dependent protein kinase). This has the overall effect of increasing the rate
of glycolysis and increases the amount of ATP available for muscle contraction and relaxation. According to one
study, caffeine in the form of coffee, significantly reduces the risk of heart disease in epidemiological studies.
However, the protective effect was found only in participants who were not severely hypertensive (i.e., patients that
are not suffering from a very high blood pressure). Furthermore, no significant protective effect was found in
participants aged less than 65 years or in cerebrovascular disease mortality for those aged equal or more than 65
years.[128] Research also suggests that drinking caffeinated coffee can cause a temporary increase in the stiffening of
arterial walls.[129]

Effects on children
It is a common myth that excessive intake of caffeine results in stunted growth within children, particularly younger
children and teenagers—recently, scientific studies have disproved the notion.[130] Children are found to experience
the same effects from caffeine as adults.
However, subsidiary beverages that contain caffeine, such as energy drinks, most of which contain high amounts of
caffeine, have been banned in many schools throughout the world, due to other adverse effects having been observed
in prolonged consumption of caffeine.[131] In one study, caffeinated cola has been linked to hyperactivity in
children.[132]

Caffeine intake during pregnancy


A 2008 study suggested that pregnant women who consume 200 milligrams or more of caffeine per day have about
twice the miscarriage risk as women who consume none. However, another 2008 study found no correlation between
miscarriage and caffeine consumption.[133] The UK Food Standards Agency has recommended that pregnant women
should limit their caffeine intake to less than 200 mg of caffeine a day—the equivalent of two cups of instant coffee,
or one half to two cups of fresh coffee.[134] [135] The FSA noted that the design of the studies made it impossible to
be certain that the differences were due to caffeine per se, instead of other lifestyle differences possibly associated
with high levels of caffeine consumption, but judged the advice to be prudent.
Dr De-Kun Li of Kaiser Permanente Division of Research, writing in the American Journal of Obstetrics and
Gynecology, concluded that an intake of 200 milligrams or more per day, representing two or more cups,
"significantly increases the risk of miscarriage".[136] However, Dr. David A. Savitz, a professor in community and
preventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on the
subject published in the January issue of Epidemiology, found no link between miscarriage and caffeine
consumption.[133]
Caffeine 15

Effects on exercise recovery


A 2008 study at RMIT University in Bundoora, Australia and published in the Journal of Applied Physiology found
a correlation between caffeine ingestion and the rate at which the body replenishes its muscle glycogen stores. The
ingestion of caffeine along with carbohydrates after an exhaustive workout resulted in a 60% increase in the body's
storage of muscle glycogen when compared to participants who did not ingest the caffeine.[137] The dosage used was
8mg per kilogram of body weight.

Genetics and caffeine metabolism


A 2006 study by Dr. Ahmed El-Sohemy at the University of Toronto discovered a link between a gene affecting
caffeine metabolism and the effects of coffee on health.[138] Some people metabolize caffeine more slowly than the
general population due to variations in a specific cytochrome P450 gene,[139] and there is evidence people with this
gene may be at a higher risk of myocardial infarction when consuming large amounts of coffee. For rapid
metabolizers, however, coffee seemed to have a preventative effect. Slow and fast metabolizers are comparably
common in the general population, and this has been blamed for the wide variation in studies of the health effects of
caffeine.

Intraocular pressure and caffeine


Recent data has suggested that caffeine consumption can raise intraocular pressure.[140] This may be a significant
consideration for those with open angle glaucoma.[141]

Decaffeination
Extraction of caffeine from coffee, to
produce decaffeinated coffee and caffeine, 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
flavor, they have been superseded by the
following main methods:

Water extraction Fibrous crystals of purified caffeine. Dark field light microscope image, the image
covers an area of approximately 11 by 7 mm.
Coffee beans are soaked in water. The
water, which contains many other
compounds in addition to caffeine and contributes to the flavor 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 its original flavor.[142] Coffee manufacturers recover the caffeine and resell it for use in
soft drinks and over-the-counter caffeine tablets.
Caffeine 16

Supercritical carbon dioxide extraction


Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that
are otherwise used. 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 in a "supercritical" state: It has gaslike
properties that allow it to penetrate deep into the beans but also liquid-like properties that 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.[142]

Extraction by organic solvents


Certain organic solvents such as ethyl acetate present much less health and environmental hazard than previously
used chlorinated and aromatic organic solvents. Another method is to use triglyceride oils obtained from spent coffee
grounds.

See also
• Coffee substitute

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[47] (in Czech) Všechny čaje Číny. Michal Synek (translator). Prague: DharmaGaia Praha. 1998. pp. 19–20. ISBN 80-85905-48-5. Translation of
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[48] Jana Arcimovičová, Pavel Valíček (1998) (in Czech). Vůně čaje [Smell of Tea]. Benešov: Start. p. 9. ISBN 80-902005-9-1.
[49] John C. Evans (1992). Tea in China: The History of China's National Drink. Greenwood Press. p. 2. ISBN 0-313-28049-5.
[50] Yu, Lu (October 1995). The Classic of Tea: Origins & Rituals. Ecco Pr; Reissue edition. ISBN 0-88001-416-4.
[51] Ukers, W.H. (1922). All About Coffee (http:/ / books. google. com/ ?id=Y5tXt7aoLNoC& pg=PA50& lpg=PA50& dq=siege+ of+ vienna+
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[52] "Coffee". Encyclopædia Britannica. 1911.
[53] Benjamin, Ludy T.; Rogers, Anne M.; Rosenbaum, Angela (1991). "Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and
the Chattanooga trial of 1911". Journal of the History of the Behavioral Sciences 27 (1): 42–55.
doi:10.1002/1520-6696(199101)27:1<42::AID-JHBS2300270105>3.0.CO;2-1. PMID 2010614.
[54] FindLaw | Cases and Codes - U.S. Supreme Court - U.S. v. FORTY BARRELS AND TWENTY KEGS OF COCA COLA (http:/ / caselaw.
lp. findlaw. com/ scripts/ getcase. pl?court=us& vol=241& invol=265)
Caffeine 18

[55] Hudson, Charles M. (1979). Black Drink. University of Georgia Press. p. 89.
[56] Friedlieb Ferdinand Runge, Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie [Latest
phytochemical discoveries for the founding of a scientific phytochemistry] (Berlin, Germany: G. Reimer, 1820). In Chapter 6 ( pages 144-159
(http:/ / books. google. com/ books?id=KLg5AAAAcAAJ& pg=P146& lpg=P146#v=onepage& q& f=false)), Runge details his (partial)
isolation of caffeine, which he calls "Kaffebase" (i.e., a base (alkaline substance) that exists in coffee).
[57] In 1821, caffeine was isolated both by French chemist Pierre Jean Robiquet and by a pair of French chemists, Pierre-Joseph Pelletier and
Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal, Jahres-Bericht über die Fortschritte der
physischen Wissenschaften von Jacob Berzelius [Annual report on the progress of the physical sciences by Jacob Berzelius] (Dr. F. Wöhler,
trans.), vol. 4, page 180 (http:/ / books. google. com/ books?id=XJI8AAAAIAAJ& pg=RA1-PA180& lpg=RA1-PA180#v=onepage& q&
f=false), 1825. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's
work or of each other's work. Berzelius states on page 180: "Cafein is eine Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und
[von] Pelletier und Caventou entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt machte." (Caffeine is a substance in
coffee, which simultaneously, in 1821, was discovered by Robiquet and by Pelletier and Caventou, by whom however nothing was made
known about it in print.)
In Pelletier's article on caffeine -- "Cafeine", pages 35-36 (http:/ / books. google. com/ books?id=rFw_AAAAcAAJ& pg=PA35#v=onepage&
q& f=false) in Dictionnaire de Médecine (Paris, France: Béchet Jeune, April 1822), vol. 4 -- Pelletier himself corroborates Berzelius's account:
"Cafeine, s. f. Principe cristallisable décovert dans le café en 1821 par M. Robiquet. A la mème époque, cherchant la quinine dans le café,
parce que le café, considéré par plusieurs médecins come fébrifuge, est d'ailleurs de la mème famille que le quinquina, MM. Pelletier et
Caventou obtenaient de leur côté la cafeine; mais leur recherches n'ayant qu'un but indirect, et n'ayant pas été terminées, laissent à M.
Robiquet la priorité sur cet objet. Nous ignorons pourquoi M. Robiquet n'a pas publié l'analyse du café qu'il a lue à la société de pharmacie. Sa
publication nous aurait permis de mieux faire connaître la cafeine, et de donner des idées exactes sur la composition du café...." (Caffeine,
noun (feminine). Crystalizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period -- while they were searching
for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the
same family as the cinchona [quinine] tree -- on their part, Mssrs. Pelletier and Caventou obtained caffeine; but because their research had a
different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We will ignore why Mr.
Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would allow us to make caffeine
better known and give us accurate ideas of coffee's composition .... )
In Robiquet's article on coffee -- "Cafe," pages 50-61 (http:/ / cnum. cnam. fr/ CGI/ gpage. cgi?p1=50& p3=8KY1. 4/ 100/ 464/ 0/ 0) in
Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers, ... (Paris, France: Thomine et Fortic, 1823), vol. 4 --
Robiquet gives an account of his research on coffee on pages 54-56, detailing the extraction of caffeine and its properties on pages 55-56.
Pelletier's elemental analysis of caffeine appears on pages 182-183 (http:/ / books. google. com/ books?id=-BIAAAAAMAAJ& pg=PA182&
lpg=PA182#v=onepage& q& f=false) of the article: Dumas and Pelletier (1823) "Recherches sur la composition élémentaire et sur quelques
propriéte's caractéristiques des bases salifiables organiques" (Researchs into the elemental composition and some characteristic properties of
organic bases), Annales de Chimie et de Physique, vol. 24, pages 163-191.
Berzelius later acknowledged Runge's priority in the extraction of caffeine: Jahres-Bericht über die Fortschritte der physischen
Wissenschaften von Jacob Berzelius, vol 7, page 270 (http:/ / books. google. com/ books?id=iGs1AAAAcAAJ& pg=P270&
lpg=P270#v=onepage& q& f=false), 1828. Berzelius stated: "Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen
phytochemischen Entdeckungen 1820, p.146-7.) dieselben Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher
beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zussamenkunft der Societé de
Pharmacie in Paris die erste mündliche Mittheilung darüber gab." (However, at this point, it should not remain unmentioned that Runge (in his
Phytochemical Discoveries, 1820, pages 146-147) specified the same method and described caffeine by the name Caffeebase a year earlier
than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of
the Pharmacy Society in Paris.)
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External links
• Erowid Caffeine Vaults (http://www.erowid.org/chemicals/caffeine/caffeine.shtml)
• The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 (http://www.druglibrary.org/schaffer/
Library/studies/cu/CU21.html) Part 2 (http://www.druglibrary.org/schaffer/Library/studies/cu/CU22.
html)
• Aubrey, Allison (September 28, 2006). "Coffee: A Little Really Does Go a Long Way" (http://www.npr.org/
templates/story/story.php?storyId=6155178). NPR. Retrieved 2010-11-08.
• Triggs, John (April 17, 2007). "Does coffee really give you a buzz?" (http://www.express.co.uk/posts/view/
4664/Does-coffee-really-give-you-a-buzz-). Daily Express. Retrieved 2010-11-08.
• Caffeine: ChemSub Online (http://chemsub.online.fr/name/Caffeine.html)
• Mayo Clinic staff (October 3, 2009). "Caffeine content for coffee, tea, soda and more" (http://www.mayoclinic.
com/health/caffeine/AN01211). Mayo Clinic. Retrieved 2010-11-08.
• How to determine caffeine in decaffeinated coffee by NIR spectroscopy (http://www.camo.com/downloads/
resources/application_notes/decaffeinated_coffee_NIR_spectroscopy.pdf)
• Caffeine Content of Drinks (http://www.energyfiend.com/the-caffeine-database)
Caffeine 22

News
• Alcohol and Drugs History Society: Caffeine news page (http://historyofalcoholanddrugs.typepad.com/
alcohol_and_drugs_history/caffeine/index.html)
• "Caffeine linked to psychiatric disorders" (http://www.canada.com/nationalpost/news/story.
html?id=30d6d514-1c68-441a-bbec-5b80ae23627f&k=45911). Postmedia News. December 2, 2006. Retrieved
2010-11-08.
• "Caffeine Withdrawal Recognized as a Disorder" (http://www.hopkinsmedicine.org/Press_releases/2004/
09_29_04.html). Johns Hopkins Hospital. September 29, 2004. Retrieved 2010-11-08.

Health
• Is Caffeine a Health Hazard? (http://www.benbest.com/health/caffeine.html)
• eMedicine Caffeine-Related Psychiatric Disorders (http://www.emedicine.com/med/topic3115.htm)
• "Daily caffeine 'protects brain'" (http://news.bbc.co.uk/2/hi/health/7326839.stm). BBC Online. April 2,
2008. Retrieved 2010-11-08.
Article Sources and Contributors 23

Article Sources and Contributors


Caffeine  Source: http://en.wikipedia.org/w/index.php?oldid=398342355  Contributors: -Freebird-, ...adam..., 129.186.219.xxx, 151.24.190.xxx, 168..., 194.200.130.xxx, 209.20.225.xxx, 21655,
2D, 2mcm, 5ii, 77Linda S., AK7, ALoopingIcon, AMuseo, AThing, Aadal, Aanidaani, Aarchiba, Aaron Schulz, Abune, Accounting4Taste, Acdx, Adamsjayhawk, Adashiel, Addthem,
AdjustShift, Aesahettr, Af40, Afluent Rider, Agha Nader, Agiligson, Ahoerstemeier, Airmason, Aitias, Ajlaird, Aksi great, Alabaster codify, Alansohn, Alcandre, Alex LaPointe, AlexDenney,
AlexPBenes, AlexiusHoratius, AliaGemma, Almafeta, Alrua, Altenmann, Alveolate, Ambix, Anaraug, Anchoress, Andre Engels, AndreNatas, Andrejj, Andrevan, Andryanade, Andy M. Wang,
Andycjp, Anespa, AngelHerraez, Angela26, Angelastic, Angr, Animum, Anonywiki, Antandrus, Anthiety, Antilived, Antön, Apothecia, Aragorn2, Arcadian, Ardkorjunglist, Ariesgurl, Arnon
Chaffin, Artichoker, Asaadi, Asbestos, Ashik, Ashmn1002, Askewchan, Astolfo Petrazzi, Astralblue, Atropos235, AxelBoldt, Axl, Az1568, Azer Red, B rob5111, B0at, BL,
Babablacksheephaveyouanywool, Badhotra, Bakabaka, Bammon, Barneyboo, Basketball110, Beetstra, Ben.c.roberts, BenFrantzDale, Benbest, Benjah-bmm27, Beno1000, BerserkerBen, Bfesser,
Bgeelhoed, Bhadani, Bibliomaniac15, Bigflavor, Bignoter, Billgordon1099, Bisco, Bkell, Black Kite, Blacklunarsun, Blahm, Blanchardb, Blood sliver, Bloodleech, Blue bear sd, Bobblewik,
Bobcoyote, Bobo192, Bogey97, Boku wa kage, Bongwarrior, Boobershmoober, Boysneaky, Bradalexdan, Brighterorange, Brion VIBBER, BryanHolland, Bubba hotep, Bumm13, Bws2cool,
C.Löser, C6541, CWii, Cacycle, Caesura, Caffeine is delicious, CaffeineLady, Caffeinestix, Cajunfusion, Caleb09, CalebNoble, CambridgeBayWeather, Can't sleep, clown will eat me,
Canberranone, Canderson7, Canthusus, Capi crimm, Captainpoopants, CardinalDan, Carewolf, Casforty, Casper2k3, Cataphract, Caturdayz, Cazort, Ccrrccrr, Cedders, Cgi1837, Chainsaw69,
Chamal N, Champlax, Charles Gaudette, Cheaposgrungy, Chem-awb, ChemNerd, Chemicalethos, Chensiyuan, Cherrycola, Chien tat, Chihowa, Chodorkovskiy, Chris Capoccia, Chrislk02,
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