Caffeine
Caffeine
Caffeine
Caffeine
Caffeine
Identifiers
PubChem [2]
2519
ChemSpider [3]
2424
UNII [4]
3G6A5W338E
EC-number [5]
200-362-1
DrugBank [6]
DB00201
ChEBI [7]
27732
SMILES
InChI
InChI key
Properties
Molecular formula CH NO
8 10 4 2
Molar mass 194.19 g/mol
Hazards
MSDS [10]
ICSC 0405
EU Index 613-086-00-5
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
Product Serving size Caffeine per serving (mg) Caffeine per liter (mg)
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 —
Guayakí Yerba Mate (loose leaf) 6 g (0.2 U.S. oz) [38] 358 about
85
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
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.
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.
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
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
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
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
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.
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 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]
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
See also
• Coffee substitute
References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=58-08-2
[2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=2519
[3] http:/ / www. chemspider. com/ 2424
[4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=3G6A5W338E
[5] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=200-362-1
[6] http:/ / redpoll. pharmacy. ualberta. ca/ drugbank/ cgi-bin/ getCard. cgi?CARD=DB00201
[7] http:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:27732
[8] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=407
[9] This is the pKa for protonated caffeine, given as a range of values included in Harry G. Brittain, Richard J. Prankerd (2007). Profiles of Drug
Substances, Excipients and Related Methodology, volume 33: Critical Compilation of pKa Values for Pharmaceutical Substances (http:/ /
books. google. com/ ?id=D3vBu5Tx4XwC& pg=PT15& lpg=PT15). Academic Press. ISBN 012260833X. .
[10] http:/ / www. ilo. org/ legacy/ english/ protection/ safework/ cis/ products/ icsc/ dtasht/ _icsc04/ icsc0405. htm
[11] Peters, Josef M. (1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature" (http:/ / jcp. sagepub. com/ cgi/ reprint/ 7/ 3/
131). The Journal of Clinical Pharmacology and the Journal of New Drugs (7): 131–141. .
[12] http:/ / en. wikipedia. org/ wiki/ %3Acaffeine
[13] "caffeine or caffein" (http:/ / dictionary. reference. com/ browse/ caffein). Collins English Dictionary (10th ed.). HarperCollins Publishers.
2009. . Retrieved 2010-11-08.
[14] Pelletier first used the word "cafeine" in print in Dictionnaire de Médecine (http:/ / books. google. com/ books?id=rFw_AAAAcAAJ&
pg=PA35#v=onepage& q& f=false). 4. Paris: Béchet Jeune. April 1822. pp. 35-36. .
[15] Nathanson, J. (1984). "Caffeine and related methylxanthines: possible naturally occurring pesticides". Science 226 (4671): 184–7.
doi:10.1126/science.6207592. PMID 6207592.
[16] Lovett, Richard (24 September 2005). "Coffee: The demon drink?" (http:/ / www. newscientist. com/ article. ns?id=mg18725181. 700) (fee
required). New Scientist (2518). . Retrieved 2009-08-03.
[17] "21 CFR 182.1180" (http:/ / edocket. access. gpo. gov/ cfr_2003/ aprqtr/ 21cfr182. 1180. htm). U.S. Code of Federal Regulations. U.S.
Office of the Federal Register. 2003-04-01. p. 462. . Retrieved 2009-08-03.
[18] Maughan, R. J.; Griffin, J. (2003). "Caffeine ingestion and fluid balance: a review". Journal of Human Nutrition and Dietetics 16 (6):
411–20. doi:10.1046/j.1365-277X.2003.00477.x. PMID 19774754.
[19] O'connor, Anahad (2008-03-04). "Really? The Claim: Caffeine Causes Dehydration" (http:/ / www. nytimes. com/ 2008/ 03/ 04/ health/
nutrition/ 04real. html?_r=1). The New York Times. . Retrieved 2009-08-03.
[20] Armstrong, Lawrence E.; Casa, Douglas J.; Maresh, Carl M.; Ganio, Matthew S. (2007). "Caffeine, Fluid-Electrolyte Balance, Temperature
Regulation, and Exercise-Heat Tolerance". Exercise and Sport Sciences Reviews: 135–140. doi:10.1097/jes.0b013e3180a02cc1.
[21] Armstrong, LE; Pumerantz, AC; Roti, MW; Judelson, DA; Watson, G; Dias, JC; Sokmen, B; Casa, DJ et al. (2005). "Fluid, electrolyte, and
renal indices of hydration during 11 days of controlled caffeine consumption.". International journal of sport nutrition and exercise
metabolism 15 (3): 252–65. PMID 16131696.
[22] Frischknecht, Peter M.; Ulmer-Dufek, Jindra; Baumann, Thomas W. (1986). "Purine alkaloid formation in buds and developing leaflets of
Coffea arabica: Expression of an optimal defence strategy?". Phytochemistry 25: 613–6. doi:10.1016/0031-9422(86)88009-8.
Caffeine 17
[23] Baumann, T. W. (1984). "Metabolism and excretion of caffeine during germination of Coffea arabica L" (http:/ / pcp. oxfordjournals. org/
content/ 25/ 8/ 1431. abstract). Plant and Cell Physiology 25 (8): 1431–6. .
[24] Matissek, R (1997). "Evaluation of xanthine derivatives in chocolate: nutritional and chemical aspects" (http:/ / cat. inist. fr/
?aModele=afficheN& cpsidt=2861730). European Food Research and Technology 205 (3): 175–84. .
[25] "Does Yerba Maté Contain Caffeine or Mateine?" (http:/ / www. erowid. org/ plants/ yerba_mate/ yerba_mate_chemistry1. shtml). The
Vaults of Erowid. December 2003. . Retrieved 2009-08-03.
[26] "PubChem: mateina" (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=pccompound& term=mateina). National Library of
Medicine. . Retrieved 2009-08-03.. Generally translated as mateine in articles written in English
[27] "PubChem: guaranine" (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=pccompound& term=guaranine). National Library of
Medicine. . Retrieved 2009-08-16.
[28] Thomas Vallombroso (2001). Organic Chemistry: Pearls of Wisdom. Boston Medical Publishing Corp. p. 48. ISBN 978-1584090168.
[29] Marshall Cavendish (2006). The Facts About Caffeine. Marshall Cavendish. p. 43. ISBN 9780761422426.
[30] Balentine D. A., Harbowy M. E. and Graham H. N. (1998). G Spiller. ed. Tea: the Plant and its Manufacture; Chemistry and Consumption
of the Beverage.
[31] "Caffeine" (http:/ / www. ico. org/ caffeine. asp). International Coffee Organization. . Retrieved 2009-08-01.
[32] "Coffee and Caffeine FAQ: Does dark roast coffee have less caffeine than light roast?" (http:/ / coffeefaq. com/ site/ node/ 15). . Retrieved
2009-08-02.
[33] "All About Coffee: Caffeine Level" (http:/ / www. jeremiahspick. com/ caffeine-e-13. html). Jeremiah’s Pick Coffee Co. . Retrieved
2009-08-03.
[34] "Caffeine in tea vs. steeping time" (http:/ / www. nobleharbor. com/ tea/ caffiene. html). September 1996. . Retrieved 2009-08-02.
[35] "Caffeine Content of Food and Drugs" (http:/ / web. archive. org/ web/ 20070614144016/ http:/ / www. cspinet. org/ nah/ caffeine/
caffeine_content. htm). Nutrition Action Health Newsletter. Center for Science in the Public Interest. December 1996. Archived from the
original (http:/ / www. cspinet. org/ nah/ caffeine/ caffeine_content. htm) on 2007-06-14. . Retrieved 2009-08-03.}
[36] "Caffeine Content of Beverages, Foods, & Medications" (http:/ / www. erowid. org/ chemicals/ caffeine/ caffeine_info1. shtml). The Vaults
of Erowid. July 7, 2006. . Retrieved 2009-08-03.}
[37] The Caffeine Database (http:/ / www. energyfiend. com/ the-caffeine-database/ )
[38] [1-lb. (http:/ / guayaki. com/ product/ 41/ Traditional-Yerba-Mate-).html "Traditional Yerba Mate in Biodegradable Bag"]. Guayaki Yerba
Mate. [1-lb.].html. Retrieved 2010-07-17.
[39] Haskell, C. F.; Kennedy, D. O.; Wesnes, K. A.; Milne, A. L.; Scholey, A. B. (2006). "A double-blind, placebo-controlled, multi-dose
evaluation of the acute behavioural effects of guarana in humans". Journal of Psychopharmacology 21 (1): 65–70.
doi:10.1177/0269881106063815. PMID 16533867.
[40] Smit, Hendrik J.; Gaffan, Elizabeth A.; Rogers, Peter J. (2004). "Methylxanthines are the psycho-pharmacologically active constituents of
chocolate". Psychopharmacology 176 (3-4): 412–9. doi:10.1007/s00213-004-1898-3. PMID 15549276.
[41] "Caffeine Accessories" (http:/ / www. thinkgeek. com/ caffeine/ accessories). ThinkGeek, Inc. . Retrieved 2009-08-01.
[42] Otberg, N.; Teichmann, A.; Rasuljev, U.; Sinkgraven, R.; Sterry, W.; Lademann, J. (2007). "Follicular Penetration of Topically Applied
Caffeine via a Shampoo Formulation". Skin Pharmacology and Physiology 20 (4): 195–8. doi:10.1159/000101389. PMID 17396054.
[43] Bolton, Sanford (1981). "Caffeine: Psychological Effects, Use and Abuse" (http:/ / intraspec. ca/ 1981-v10n03-p202. pdf). Orthomolecular
Psychiatry 10 (3): 202–211. .
[44] Bennett Alan Weinberg, Bonnie K. Bealer (2001). The world of caffeine (http:/ / books. google. com/ ?id=YdpL2YCGLVYC& pg=PA195).
Routledge. p. 195. ISBN 0415927226. .
[45] Funk, G. D. (2009). "Losing sleep over the caffeination of prematurity" (http:/ / www. pubmedcentral. nih. gov/ articlerender.
fcgi?tool=pmcentrez& artid=2793860). The Journal of Physiology 587 (Pt 22): 5299–300. doi:10.1113/jphysiol.2009.182303.
PMID 19915211. PMC 2793860.
[46] Escohotado, Antonio; Ken Symington (1999). A Brief History of Drugs: From the Stone Age to the Stoned Age. Park Street Press.
ISBN 0-89281-826-3.
[47] (in Czech) Všechny čaje Číny. Michal Synek (translator). Prague: DharmaGaia Praha. 1998. pp. 19–20. ISBN 80-85905-48-5. Translation of
Kit Chow, Ione Kramer (1990). All the Tea in China. San Francisco: China Books & Periodicals Inc. ISBN 0-8351-2194-1.
[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+
and+ coffee+ beans& q=siege of vienna and coffee beans). New York: The Tea and Coffee Trade Journal Company. p. 40. ISBN 0810340925.
.
[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.)
[58] Weinberg, BA; BK Bealer (2001). The World of Caffeine. Routledge. ISBN 0-415-92722-6.
[59] Oudry (March 1827) Nouvelle Bibliothèque médicale, vol. 1, page 477ff. See also: Oudry (1827) "Theïn, eine organische Salzbase im Thee"
(Theïn, an organic base in tea), Geiger's Magazin für Pharmacie, vol. 19, pages 49-50.
[60] Gerardus Johannes Mulder (1838) "Über Kaffein und Thein" (On caffeine and theine), Journal für practische Chemie, vol. 15, pages 280ff.
[61] Carl Jobst (1838) "Thein identisch mit Kaffein" (Theine is identical to caffeine), Liebig's Annalen der Chemie und Pharmacie, vol. 25,
pages 63-66.
[62] "Nobel Prize Presentation Speech by Professor Hj. Théel, President of the Swedish Royal Academy of Sciences" (http:/ / nobelprize. org/
nobel_prizes/ chemistry/ laureates/ 1902/ press. html). December 10, 1902. . Retrieved 2009-08-03.
[63] Simon Tilling. "Crystalline Caffeine" (http:/ / www. chm. bris. ac. uk/ webprojects2001/ tilling/ synthesis. htm). Bristol University. .
Retrieved 2009-08-03.
[64] Ted Wilson, Norman J. Temple (2004). Beverages in Nutrition and Health. Humana Press. p. 172. ISBN 1588291731.
[65] "What's your poison: caffeine" (http:/ / www. abc. net. au/ quantum/ poison/ caffeine/ caffeine. htm). Australian Broadcasting Corporation.
1997. . Retrieved 2009-08-03.
[66] Nehlig, A; Daval, JL; Debry, G (1992). "Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and
psychostimulant effects". Brain Research Reviews 17 (2): 139–70. doi:10.1016/0165-0173(92)90012-B. PMID 1356551.
Caffeine 19
[67] Liguori, A (1997). "Absorption and Subjective Effects of Caffeine from Coffee, Cola and Capsules". Pharmacology Biochemistry and
Behavior 58: 721–6. doi:10.1016/S0091-3057(97)00003-8.
[68] Newton, R.; Broughton, L. J.; Lind, M. J.; Morrison, P. J.; Rogers, H. J.; Bradbrook, I. D. (1981). "Plasma and salivary pharmacokinetics of
caffeine in man". European Journal of Clinical Pharmacology 21 (1): 45–52. doi:10.1007/BF00609587. PMID 7333346.
[69] Graham, John R. (1954). "Rectal Use of Ergotamine Tartrate and Caffeine Alkaloid for the Relief of Migraine". New England Journal of
Medicine 250 (22): 936–8. doi:10.1056/NEJM195406032502203. PMID 13165929.
[70] Brødbaek HB, Damkier P (2007). "[The treatment of hyperemesis gravidarum with chlorobutanol-caffeine rectal suppositories in Denmark:
practice and evidence]" (in Danish). Ugeskr. Laeg. 169 (22): 2122–3. PMID 17553397.
[71] Drug Interaction: Caffeine Oral and Fluvoxamine Oral (http:/ / www. medscape. com/ druginfo/ druginteractions?drug_408=Caffeine Oral&
drug_1049=Fluvoxamine Oral& ) Medscape Multi-Drug Interaction Checker
[72] Meyer, FP; Canzler, E; Giers, H; Walther, H (1991). "Time course of inhibition of caffeine elimination in response to the oral depot
contraceptive agent Deposiston. Hormonal contraceptives and caffeine elimination". Zentralbl Gynakol 113 (6): 297–302. PMID 2058339.
[73] Ortweiler, W; Simon, HU; Splinter, FK; Peiker, G; Siegert, C; Traeger, A (1985). "Determination of caffeine and metamizole elimination in
pregnancy and after delivery as an in vivo method for characterization of various cytochrome p-450 dependent biotransformation reactions".
Biomed Biochim Acta. 44 (7–8): 1189–99. PMID 4084271.
[74] Bolton, Ph.D., Sanford (1981). "Caffeine: Psychological Effects, Use and Abuse". Orthomolecular Psychiatry 10 (3): 202–11.
[75] Springhouse (January 1, 2005). Physician's Drug Handbook; 11th edition. Lippincott Williams & Wilkins. ISBN 1-58255-396-3.
[76] "Caffeine" (http:/ / www. pharmgkb. org/ do/ serve?objId=PA448710& objCls=Drug& tabType=Properties#biotransformation). The
Pharmacogenetics and Pharmacogenomics Knowledge Base. . Retrieved 2010-10-25.
[77] Fisone, G.; Borgkvist, A.; Usiello, A. (2004). "Caffeine as a psychomotor stimulant: mechanism of action". Cellular and Molecular Life
Sciences (CMLS) 61: 857–72. doi:10.1007/s00018-003-3269-3.
[78] Daly, JW; Jacobson, KA; Ukena, D (1987). "Adenosine receptors: development of selective agonists and antagonists.". Progress in clinical
and biological research 230: 41–63. PMID 3588607.
[79] Latini, Serena; Pedata, Felicita (2008). "Adenosine in the central nervous system: release mechanisms and extracellular concentrations".
Journal of Neurochemistry 79 (3): 463–84. doi:10.1046/j.1471-4159.2001.00607.x. PMID 11701750.
[80] Addicott, Merideth A.; Yang, Lucie L.; Peiffer, Ann M.; Burnett, Luke R.; Burdette, Jonathan H.; Chen, Michael Y.; Hayasaka, Satoru;
Kraft, Robert A. et al. (2009). "The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?" (http:/ / www.
pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez& artid=2748160). Human Brain Mapping 30 (10): 3102–14.
doi:10.1002/hbm.20732. PMID 19219847. PMC 2748160.
[81] Basheer, R; Strecker, R; Thakkar, M; McCarley, R (2004). "Adenosine and sleep?wake regulation". Progress in Neurobiology 73 (6):
379–96. doi:10.1016/j.pneurobio.2004.06.004. PMID 15313333.
[82] Huang, Zhi-Li; Qu, Wei-Min; Eguchi, Naomi; Chen, Jiang-Fan; Schwarzschild, Michael A; Fredholm, Bertil B; Urade, Yoshihiro; Hayaishi,
Osamu (2005). "Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine". Nature Neuroscience: 858–9.
doi:10.1038/nn1491.
[83] Essayan, David M. (2001). "Cyclic nucleotide phosphodiesterases". Journal of Allergy and Clinical Immunology 108 (5): 671–80.
doi:10.1067/mai.2001.119555. PMID 11692087.
[84] Deree, Jessica; Martins, Joilson O.; Melbostad, Heidi; Loomis, William H.; Coimbra, Raul (2008). "Insights into the regulation of TNF-a
production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition" (http:/ / www. pubmedcentral. nih. gov/
articlerender. fcgi?tool=pmcentrez& artid=2664230). Clinics 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMID 18568240.
PMC 2664230.
[85] Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar
macrophages" (http:/ / ajrccm. atsjournals. org/ cgi/ pmidlookup?view=long& pmid=9927365). Am. J. Respir. Crit. Care Med. 159 (2):
508–11. PMID 9927365. .
[86] Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. (2005). "Leukotrienes: underappreciated mediators of innate immune responses."
(http:/ / www. jimmunol. org/ cgi/ content/ full/ 174/ 2/ 589). J Immunol. 174 (2): 589–94. PMID 15634873. .
[87] Caesar, R.; Warringer, J.; Blomberg, A. (2006). "Physiological Importance and Identification of Novel Targets for the N-Terminal
Acetyltransferase NatB" (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez& artid=1405896). Eukaryotic Cell 5 (2):
368–78. doi:10.1128/EC.5.2.368-378.2006. PMID 16467477. PMC 1405896.
[88] Duan, L.; Yang, J.; Slaughter, M. M. (2009). "Caffeine inhibition of ionotropic glycine receptors" (http:/ / www. pubmedcentral. nih. gov/
articlerender. fcgi?tool=pmcentrez& artid=2756438). The Journal of Physiology 587 (Pt 16): 4063–75. doi:10.1113/jphysiol.2009.174797.
PMID 19564396. PMC 2756438.
[89] Dews, P.B. (1984). Caffeine: Perspectives from Recent Research. Berlin: Springer-Valerag. ISBN 978-0387135328.
[90] "Caffeine (Systemic)" (http:/ / web. archive. org/ web/ 20070223063601/ http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ uspdi/ 202105.
html). MedlinePlus. 2000-05-25. Archived from the original (http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ uspdi/ 202105. html) on
2007-02-23. . Retrieved 2009-08-03.
[91] Rasmussen, JL; Gallino, M (1997). "Effects of caffeine on subjective reports of fatigue and arousal during mentally demanding activities".
European Journal of Clinical Pharmacology 37 (1): 61–90. PMID 7794434.
[92] Ivy, JL; Costill, DL; Fink, WJ; Lower, RW (1979). "Influence of caffeine and carbohydrate feedings on endurance performance". Med Sci
Sports 11 (1): 6–11. PMID 481158.
Caffeine 20
[93] Graham, TE; Spriet, LL (1991). "Performance and metabolic responses to a high caffeine dose during prolonged exercise". J Appl Physiol
71 (6): 2292–8. PMID 1778925.
[94] Verkhratsky, A. (2005). "Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons". Physiological
Reviews 85: 37–44. doi:10.1152/physrev.00004.2004.
[95] Schmidt, Barbara; Roberts, Robin S.; Davis, Peter; Doyle, Lex W.; Barrington, Keith J.; Ohlsson, Arne; Solimano, Alfonso; Tin, Win et al.
(2006). "Caffeine Therapy for Apnea of Prematurity". New England Journal of Medicine 354 (20): 2112–21. doi:10.1056/NEJMoa054065.
PMID 16707748.
[96] Schmidt, Barbara (2005). "Methylxanthine Therapy for Apnea of Prematurity: Evaluation of Treatment Benefits and Risks at Age 5 Years in
the International Caffeine for Apnea of Prematurity (CAP) Trial". Biology of the Neonate 88 (3): 208–213. doi:10.1159/000087584.
PMID 16210843.
[97] "Fecal incontinence" (http:/ / digestive. niddk. nih. gov/ ddiseases/ pubs/ fecalincontinence/ ). NIH. . Retrieved 2009-08-03.
[98] 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, 29 April 1995 (http:/ / www. newscientist. com/ article/ mg14619750. 500-spiders-on-speed-get-weaving. html)
[99] http:/ / www. washingtonpost. com/ wp-dyn/ content/ article/ 2005/ 12/ 04/ AR2005120400950. html. Washington Post. 2005-12-05.
Retrieved 2010-11-03
[100] http:/ / www. sciencedaily. com/ releases/ 2010/ 01/ 100105100023. htm. Science Daily. 2010-01-06. Retrieved 2010-11-03.
[101] Green, R M; Stiles, G L (1986). "Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral
cortex." (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez& artid=423330). Journal of Clinical Investigation 77 (1):
222–7. doi:10.1172/JCI112280. PMID 3003150. PMC 423330.
[102] Holtzman SG, Mante S, Minneman KP (1991). "Role of adenosine receptors in caffeine tolerance". J. Pharmacol. Exp. Ther. 256 (1):
62–8. PMID 1846425.
[103] "Caffeine — A Drug of Abuse?" (http:/ / www. acnp. org/ G4/ GN401000165/ CH161. html). . Retrieved 2009-08-03.
[104] "Information About Caffeine Dependence" (http:/ / www. caffeinedependence. org/ caffeine_dependence. html). . Retrieved 2009-08-03.
[105] "Vasoconstriction" (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 002338. htm). .
[106] "Health risks of Stimulants, healthandgoodness.com" (http:/ / www. healthandgoodness. com/ health/ stimulants_risks. html). . Retrieved
2009-08-03.
[107] Juliano, Laura M.; Griffiths, Roland R. (2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs,
incidence, severity, and associated features". Psychopharmacology 176 (1): 1–29. doi:10.1007/s00213-004-2000-x. PMID 15448977.
[108] Mackay, DC; Rollins, JW (1989). "Caffeine and caffeinism". Journal of the Royal Naval Medical Service 75 (2): 65–7. PMID 2607498.
[109] James, Jack E.; Stirling, Keryn P. (1983). "Caffeine: A Survey of Some of the Known and Suspected Deleterious Effects of Habitual Use".
Addiction 78: 251–8. doi:10.1111/j.1360-0443.1983.tb02509.x.
[110] Leson, CL; McGuigan, MA; Bryson, SM (1988). "Caffeine overdose in an adolescent male.". Journal of toxicology. Clinical toxicology 26
(5-6): 407–15. PMID 3193494.
[111] "Caffeine-related disorders" (http:/ / www. minddisorders. com/ Br-Del/ Caffeine-related-disorders. html). Encyclopedia of Mental
Disorders. . Retrieved 2009-08-03.
[112] "Gastroesophageal Reflux Disease (GERD)" (http:/ / web. archive. org/ web/ 20080423214804/ http:/ / www. csmc. edu/ pf_5543. html).
Cedars-Sinai. Archived from the original (http:/ / www. csmc. edu/ pf_5543. html) on April 23, 2008. . Retrieved 2009-08-03.
[113] http:/ / www. hepatitis-central. com/ mt/ archives/ 2009/ 02/ acetaminophen_c. html 2009-02-02. Retrieved 2010-11-03.
[114] American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). American Psychiatric
Association. ISBN 0-89042-062-9.
[115] "Caffeine overdose" (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 002579. htm). MedlinePlus. 2006-04-04. . Retrieved
2009-08-03.
[116] Verkhratsky, A. (2005). "Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons". Physiological
Reviews 85: 381–3. doi:10.1152/physrev.00004.2004.
[117] "Man Dies From Caffeine Overdose" (http:/ / www. torontosun. com/ news/ world/ 2010/ 10/ 30/ 15889811. html). Toronto Sun. Quebecor
Media Inc. October 30, 2010. .
[118] Kerrigan, S; Lindsey, T (2005). "Fatal caffeine overdose: Two case reports". Forensic Science International 153 (1): 67–69.
doi:10.1016/j.forsciint.2005.04.016. PMID 15935584.
[119] Holmgren, P; Nordén-Pettersson, L; Ahlner, J (2004). "Caffeine fatalities—four case reports". Forensic Science International 139 (1):
71–3. doi:10.1016/j.forsciint.2003.09.019. PMID 14687776.
[120] Verkhratsky, A. (2005). "Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons". Physiological
Reviews 85: 244–9. doi:10.1152/physrev.00004.2004.
[121] Verkhratsky, A. (2005). "Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons". Physiological
Reviews 85: 571–2. doi:10.1152/physrev.00004.2004.
[122] Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 214–7.
ISBN 093189008X.
[123] Shannon, MW; Haddad LM, Winchester JF (1998). Clinical Management of Poisoning and Drug Overdose (3rd ed.). Philadelphia:
Saunders. ISBN 0-7216-6409-1.
Caffeine 21
[124] Han, M; Park, K; Baek, S; Kim, B; Kim, J; Kim, H; Oh, S (2007). "Inhibitory effects of caffeine on hippocampal neurogenesis and
function". Biochemical and Biophysical Research Communications 356 (4): 976–80. doi:10.1016/j.bbrc.2007.03.086. PMID 17400186.
[125] "Caffeine clue to better memory" (http:/ / news. bbc. co. uk/ 2/ hi/ science/ nature/ 472473. stm). BBC News. 1999-10-12. . Retrieved
2009-08-03.
[126] "Caffeine Boosts Short-Time Memory" (http:/ / news. softpedia. com/ news/ Caffeine-Boosts-Short-Time-Memory-13828. shtml). .
Retrieved 2009-08-03.
[127] Lesk, Valerie E.; Womble, Stephen P. (2004). "Caffeine, Priming, and Tip of the Tongue: Evidence for Plasticity in the Phonological
System.". Behavioral Neuroscience 118: 453–6. doi:10.1037/0735-7044.118.3.453.
[128] Greenberg, J.A.; Dunbar, CC; Schnoll, R; Kokolis, R; Kokolis, S; Kassotis, J (2007). "Caffeinated beverage intake and the risk of heart
disease mortality in the elderly: a prospective analysis". Am J Clin Nutr 85 (2): 392–8. PMID 17284734.
[129] (http:/ / hyper. ahajournals. org/ cgi/ content/ full/ 38/ 2/ 227)
[130] "Fact or fiction: Common diet myths dispelled" (http:/ / www. msnbc. msn. com/ id/ 16280050). MSNBC. December 2006. . Retrieved
2009-08-03.
[131] "Caffeine and Your Child" (http:/ / www. kidshealth. org/ parent/ food/ general/ caffeine. html). KidsHealth. January 2005. . Retrieved
2009-08-03.
[132] "Caffeinated Cola Makes Kids Hyperactive" (http:/ / children. webmd. com/ news/ 20050523/ caffeinated-cola-make-kids-hyperactive).
WebMD. May 2005. . Retrieved 2010-02-05.
[133] Rubin, Rita (2008-01-20). "New studies, different outcomes on caffeine, pregnancy" (http:/ / www. usatoday. com/ news/ health/
2008-01-20-caffeine_N. htm). USA TODAY. . Retrieved 2009-08-03.
[134] "Food Standards Agency publishes new caffeine advice for pregnant women" (http:/ / www. food. gov. uk/ news/ pressreleases/ 2008/ nov/
caffeineadvice). . Retrieved 2009-08-03.
[135] Danielle Dellorto (January 21, 2008). "Study: Caffeine may boost miscarriage risk" (http:/ / www. cnn. com/ 2008/ HEALTH/ conditions/
01/ 21/ hfh. caffeine. miscarriage/ index. html?iref=mpstoryview). CNN. . Retrieved 2009-08-03.
[136] "Kaiser Permanente Study Shows Newer, Stronger Evidence that Caffeine During Pregnancy Increases Miscarriage Risk" (http:/ / ckp. kp.
org/ newsroom/ national/ archive/ nat_080121_caffeine. html). . Retrieved 2009-08-03.
[137] "Post-Workout Caffeine Consumption (and Other Recovery Tips)" (http:/ / www. usatriathlon. org/ resources/ multisport-zone/
fuel-station/ post-workout-caffeine-consumption-and-other-recovery-tips). . Retrieved 2010-10-05.
[138] Michael O'Riordan (March 7, 2006). "Heavy coffee drinkers with slow caffeine metabolism at increased risk of nonfatal MI" (http:/ / www.
theheart. org/ article/ 659871. do). theheart.org by WebMD. . Retrieved 2009-08-03.
[139] Cornelis, M. C. (2006). "Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction". JAMA: the Journal of the American Medical
Association 295: 1135–41. doi:10.1001/jama.295.10.1135.
[140] Higginbotham EJ, Kilimanjaro HA, Wilensky JT, Batenhorst RL, Hermann D (May 1989). "The effect of caffeine on intraocular pressure
in glaucoma patients". Ophthalmology 96 (5): 624–6. PMID 2636858.
[141] Avisar, Rahamim; Avisar, Erez; Weinberger, Dov (2002). "Effect of Coffee Consumption on Intraocular Pressure". The Annals of
Pharmacotherapy 36 (6): 992–5. doi:10.1345/aph.1A279. PMID 12022898.
[142] Senese, Fred (2005-09-20). "How is coffee decaffeinated?" (http:/ / antoine. frostburg. edu/ chem/ senese/ 101/ consumer/ faq/
decaffeinating-coffee. shtml). General Chemistry Online. . Retrieved 2009-08-03.
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
Image:Roasted coffee beans.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Roasted_coffee_beans.jpg License: Public Domain Contributors: User:MarkSweep
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