Caffeine

Caffeine 1

Caffeine

Caffeine

Identifiers

CAS number 58-08-2 [1] 

PubChem 2519 [2] 

ChemSpider 2424 [3] 

UNII 3G6A5W338E [4] 

EC-number 200-362-1 [5]

DrugBank DB00201 [6]

ChEBI 27732 [7]

IUPHAR ligand 407 [8] 

RTECS number EV6475000

SMILES

InChI

InChI key

Properties

Molecular formula C8H10N4O2

Molar mass 194.19 g/mol

Exact mass 194.080376 u

Appearance Odorless, white needles or powder

Density 1.23 g/cm3, solid

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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) −0.13–1.22[9]

Dipole moment 3.64 D (calculated)

Hazards

MSDS ICSC 0405 [10]

EU Index 613-086-00-5

EU classification not listed

R-phrases R22

S-phrases (S2)

NFPA 704

LD50 192 mg/kg (rat, oral)[11]

 (what is this?)   (verify) [12]

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 stimulantdrug. Caffeine was discovered in 1820 by a German chemist, Friedlieb Ferdinand Runge, and in 1821 by Frenchchemists working independently; viz., by Robiquet and by Pelletier and Caventou. It was Pelletier who coined theword "cafeine," whence "caffeine".[14]

Caffeine is found in varying quantities in the beans, leaves, and fruit of some plants, where it acts as a naturalpesticide that paralyzes and kills certain insects feeding on the plants.[15] It is most commonly consumed by humansin infusions extracted from the bean of the coffee plant and the leaves of the tea bush, as well as from various foodsand drinks containing products derived from the kola nut. Other sources include yerba mate, guarana berries, and theYaupon Holly.In humans, caffeine acts as a central nervous system (CNS) stimulant, temporarily warding off drowsiness andrestoring alertness. Caffeine is the world's most widely consumed psychoactive substance,[16] but, unlike many otherpsychoactive substances, is legal and unregulated in nearly all jurisdictions. Beverages containing caffeine, such ascoffee, tea, soft drinks, and energy drinks, enjoy great popularity; in North America, 90% of adults consume caffeinedaily.[16] The U.S. Food and Drug Administration (FDA) lists caffeine as a "multiple purpose generally recognizedas safe food substance".[17]

Caffeine has diuretic properties when administered in sufficient doses to subjects that do not have a tolerance forit.[18] Regular users, however, develop a strong tolerance to this effect,[18] and studies have generally failed tosupport the common notion that ordinary consumption of caffeinated beverages contributes significantly todehydration.[19] [20] [21]

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Occurrence

Roasted coffee beans, a common source ofcaffeine

Caffeine is found in many plant species, where it acts as a naturalpesticide, with high caffeine levels being observed in seedlings that arestill 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 ofcoffee bean seedlings. Therefore, it is understood that caffeine has anatural function as both a natural pesticide and an inhibitor of seedgermination of other nearby coffee seedlings, thus giving it a betterchance of survival.[23]

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 andenergy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of theseplants.[26] [27] Some yerba mate enthusiasts assert that mateine is a stereoisomer of caffeine, which would make it adifferent substance altogether.[25] This is not true because caffeine is an achiral molecule[28] , and therefore has noenantiomers; nor does it have other stereoisomers[29] . The disparity in experience and effects between the variousnatural caffeine sources could be because plant sources of caffeine also contain widely varying mixtures of otherxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such aspolyphenols 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), fromwhich coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and themethod of preparation used;[31] even beans within a given bush can show variations in concentration. In general, oneserving of coffee ranges from 80-100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, toapproximately 100-125 milligrams for a cup (120 milliliters) of drip coffee. In general, dark-roast coffee has lesscaffeine than lighter roasts because the roasting process reduces the bean's caffeine content.[32] [33] Arabica coffeenormally contains less caffeine than the robusta variety.[31] Coffee also contains trace amounts of theophylline, butno theobromine.Tea is another common source of caffeine. Although tea contains more caffeine than coffee (by dry weight), a typicalserving contains much less, as tea is normally brewed much weaker. Besides strength of the brew, growingconditions, processing techniques- and other variables also affect caffeine content. Certain types of tea may containsomewhat more caffeine than other teas. Tea contains small amounts of theobromine and slightly higher levels oftheophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a verypoor indicator of caffeine content.[34] Teas like the pale Japanese green tea gyokuro, for example, contain far morecaffeine than much darker teas like lapsang souchong, which has very little.

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Caffeine content of select common food and drugs.[35] [36] [37]

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) 85[38] 358 about

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 drinkstypically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks such as Red Bull canstart at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients usedor is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredientof energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in anaturally occurring slow-release excipient.[39]

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolatemay be due to a combination of theobromine and theophylline as well as caffeine.[40] A typical 28-gram serving of amilk chocolate bar has about as much caffeine as a cup of decaffeinated coffee, although some dark chocolatecurrently 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 andsoap.[41] Studies show that caffeine in shampoo applied for two minutes is absorbed through the skin, mostly throughhair follicles, and reaches the blood stream.[42]

Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improvesmental alertness. These effects have been borne out by research that shows that caffeine use (whether in tablet formor not) results in decreased fatigue and increased attentiveness.[43] These tablets are commonly used by studentsstudying 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

Coffeehouse in Palestine, circa 1900.

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 ofcertain plants had the effects of easing fatigue, stimulatingawareness, and elevating one's mood. Only much later was itfound that the effect of caffeine was increased by steepingsuch plants in hot water. Many cultures have legends thatattribute the discovery of such plants to people living manythousands of years ago.

According to one popular Chinese legend, the Emperor ofChina Shennong, reputed to have reigned in about 3000 BCE,accidentally discovered that when some leaves fell intoboiling water, a fragrant and restorative drink resulted.[47] [48]

[49] Shennong is also mentioned in Lu Yu's Cha Jing, afamous 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 itsdiscovery to a goatherder named Kaldi, who apparently observed goats that became elated and sleepless at nightafter grazing on coffee shrubs and, upon trying the berries that the goats had been eating, experienced the samevitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th-centuryPersian physician al-Razi. In 1587, Malaye Jaziri compiled a work tracing the history and legal controversies ofcoffee, entitled ʕUmdat aṣ-Ṣafwa Fī Ḥill al-Qahwah. In this work, Jaziri recorded that one Sheikh, Jamal-al-Dinal-Dhabhani, mufti of Aden, was the first to adopt the use of coffee in 1454, and that in the 15th century the Sufis ofYemen 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 aboutthis time it came into general use in the Near East. The appreciation of coffee as a beverage in Europe, where it wasfirst known as "Arabian wine," dates from the 17th century. A legend states that, after the Ottoman Turks retreatedfrom the walls of Vienna after losing a battle for the city, many sacks of coffee beans were found among theirbaggage. Europeans did not know what to do with all the coffee beans, being unfamiliar with them. So Franz GeorgeKolschitzky, a Pole who had actually worked for the Turks, offered to take them. He subsequently taught theViennese how to make coffee, and the first coffee house in the Western world was opened in Vienna, thus starting along tradition of coffee appreciation.[51] In Britain, the first coffee houses were opened in London in 1652, at StMichael's Alley, Cornhill. They soon became popular throughout Western Europe, and played a significant role insocial 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

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misbranded in that the name 'Coca Cola' was a representation of the presence of the substances coca and cola; thatthe product 'contained no coca and little if any cola' and thus was an 'imitation' of these substances and was offeredfor sale under their 'distinctive name.'[54] Although the judge ruled in favor of Coca-Cola, two bills were introducedto 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 theNew World, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chilepepper, and achiote. Xocolatl was believed to fight fatigue, a belief that is probably attributable to the theobromineand caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoabeans were often used as currency.Xocolatl was introduced to Europe by the Spaniards and became a popular beverage by 1700. They also introducedthe cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known asBlack Bean.The leaves and stems of the Yaupon Holly (Ilex vomitoria) were used by Native Americans to brew a tea called Asior the "black drink".[55] Archaeologists have found evidence of this use stretch back far into antiquity, possiblydating to Late Archaic times.

Synthesis and properties

Anhydrous (dry) USP-grade caffeine

In 1819, the German chemist Friedrich FerdinandRunge isolated relatively pure caffeine for the firsttime.[56] [57] According to Runge, he did this at thebehest of Johann Wolfgang von Goethe.[58] In 1827,Oudry isolated "theine" from tea,[59] but it was laterproved by Mulder[60] and by Jobst[61] that theine wasthe same as caffeine.[58] The structure of caffeine waselucidated near the end of the 19th century by HermannEmil Fischer, who was also the first to achieve its totalsynthesis.[62] This was part of the work for whichFischer was awarded the Nobel Prize in 1902. Thenitrogen atoms are all essentially planar (in sp2 orbitalhybridization), resulting in the caffeine molecule's having aromatic character. Being readily available as a byproductof decaffeination, caffeine is not usually synthesized.[63] If desired, it may be synthesized from dimethylurea andmalonic acid.[64]

PharmacologyGlobal consumption of caffeine has been estimated at 120,000 tonnes per year,[65] making it the world's mostpopular 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 toreduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine andother methylxanthine derivatives are also used on newborns to treat apnea and correct irregular heartbeats. Caffeinestimulates 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 cordlevel at higher doses.[43] Once inside the body, it has a complex chemistry, and acts through several mechanisms asdescribed below.

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Metabolism and half-life

Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%),theobromine (12%), and theophylline (4%)

Caffeine from coffee or otherbeverages is absorbed by the stomachand small intestine within 45 minutesof ingestion and then distributedthroughout all tissues of the body.[67] Itis eliminated by first-order kinetics.[68]

Caffeine can also be ingested rectally,evidenced by the formulation ofsuppositories of ergotamine tartrateand caffeine (for the relief ofmigraine)[69] and chlorobutanol andcaffeine (for the treatment ofhyperemesis).[70]

The biological half-life of caffeine —the time required for the body toeliminate one-half of the total amountof caffeine — varies widely amongindividuals according to such factors asage, liver function, pregnancy, someconcurrent 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 5–10hours,[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 infantsand young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30hours. Other factors such as smoking can shorten caffeine's half-life.[75] Fluvoxamine (Luvox) reduced the clearanceof 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 1A2isozyme) 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.

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Mechanism of action

Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain.

Caffeine readily crosses theblood–brain barrier that separates thebloodstream from the interior of thebrain. Once in the brain, the principalmode of action is as a nonselectiveantagonist of adenosine receptors.[77]

[78] The caffeine molecule isstructurally similar to adenosine, andbinds to adenosine receptors on thesurface of cells without activating them(an "antagonist" mechanism of action).Therefore, caffeine acts as acompetitive inhibitor.

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

Adenosine is released in the brain through a complex mechanism.[79] There is evidence that adenosine functions as asynaptically released neurotransmitter in some cases, but stress-related adenosine increases appear to be producedmainly by extracellular metabolism of ATP. It is not likely that adenosine is the primary neurotransmitter for anygroup of neurons, but rather that it is released together with other transmitters by a number of neuron types. Unlikemost neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in avoltage-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 arewidely distributed, and act to inhibit calcium uptake. A2A receptors are heavily concentrated in the basal ganglia, anarea that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lowerdensities. There is evidence that A 2A receptors interact with the dopamine system, which is involved in reward andarousal. (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 specificallyinvolved in control of the sleep-wake cycle. Robert McCarley and his colleagues have argued that accumulation ofadenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that theeffects may be mediated both by inhibition of wake-promoting neurons via A1 receptors, and activation ofsleep-promoting neurons via indirect effects on A2A receptors.[81] More recent studies have provided additionalevidence 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 othermethylated xanthines, caffeine is both a1. 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 inhibitingcyclic AMP phosphodiesterase.[87]

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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 inactivation of protein kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. Byblocking its removal, caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such asamphetamine, methamphetamine, and methylphenidate. Increased concentrations of cAMP in parietal cells causes anincreased activation of protein kinase A (PKA), which in turn increases activation of H+/K+ ATPase, resultingfinally 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 lesspotent), a competitive antagonist at ionotropic glycine receptors.[88]

Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an increase in thelipolysis 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 inotropethat increases heart rate and efficiency.[89]

Caffeine has a significant effect on spiders,which is reflected here in the erratic

construction of their webs.

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Effects when taken in moderation

Overview of the more common side effects of caffeine, sometimes appearingat levels below overdose.[90]

The precise amount of caffeine necessary toproduce effects varies from person to persondepending on body size and degree of toleranceto caffeine. It takes less than an hour for caffeineto begin affecting the body and a mild dosewears off in three to four hours.[43] Consumptionof caffeine does not eliminate the need for sleep,it only temporarily reduces the sensation ofbeing tired. In general, 25 to 50 milligrams ofcaffeine is sufficient for most people to reportincreased alertness and arousal as well assubjectively lower levels of fatigue.[91]

With these effects, caffeine is an ergogenic,increasing a person's capability for mental orphysical labor. A study conducted in 1979showed a 7% increase in distance cycled over aperiod of two hours in subjects that consumedcaffeine compared to control subjects.[92] Otherstudies attained much more dramatic results; oneparticular study of trained runners showed a 44%increase in "race-pace" endurance, as well as a51% increase in cycling endurance, after adosage 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% longerduring high-intensity circuits.[94]

Caffeine citrate has proven to be of short- and long-term benefit in treating the breathing disorders of apnea ofprematurity and bronchopulmonary dysplasia in premature infants.[90] The only short-term risk associated withcaffeine citrate treatment is a temporary reduction in weight gain during the therapy,[95] and longer term studies (18to 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 onmollusks and various insects as well as spiders.[98]

Caffeine also increases the effectiveness of some drugs. Many over-the-counter headache drugs include caffeine intheir formula. It is also used with ergotamine in the treatment of migraine and cluster headaches as well as toovercome the drowsiness caused by antihistamines.Caffeine may also have hepatoprotective properties. Studies have shown that increased caffeine consumption isassociated 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]

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Tolerance and withdrawal

"Monster" Energy Drink - Containing 160 mg ofcaffeine. One of many brands and compositions

marketed to consumers. The image above isproposed for deletion. See files for deletion to

help reach a consensus on what to do.

Because caffeine is primarily an antagonist of the central nervoussystem's receptors for the neurotransmitter adenosine, the bodies ofindividuals that regularly consume caffeine adapt to the continuouspresence of the drug by substantially increasing the number ofadenosine receptors in the central nervous system. First, thestimulatory effects of caffeine are substantially reduced, a phenomenonknown as a tolerance adaptation. Second, because these adaptiveresponses to caffeine make individuals much more sensitive toadenosine, a reduction in caffeine intake will effectively increase thenormal physiological effects of adenosine, resulting in unwelcomewithdrawal symptoms in tolerant users.[101]

Other research questions the idea that up-regulation of adenosinereceptors is responsible for tolerance to the locomotor stimulant effectsof caffeine, noting, among other things, that this tolerance isinsurmountable by higher doses of caffeine (it should be surmountableif tolerance were due to an increase in receptors), and that the increasein adenosine receptor number is modest and does not explain the largetolerance that develops to caffeine.[102]

Caffeine tolerance develops very quickly, especially among heavycoffee and energy drink consumers. Complete tolerance to the sleepdisruption effects of caffeine develops after consuming 400 mg ofcaffeine 3 times a day for 7 days. Complete tolerance to subjectiveeffects of caffeine was observed to develop after consuming 300 mg 3times per day for 18 days, and possibly even earlier.[103] In another experiment, complete tolerance of caffeine wasobserved when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has beenobserved 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 ofadenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood inthe head and causing a headache and nausea. This means caffeine has vasoconstriction properties.[105] Reducedcatecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeineuse is stopped can cause anxiety, irritability, inability to concentrate, and diminished motivation to initiate or tocomplete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be knownas a "crash".[106]

Withdrawal symptoms — possibly including headache, irritability, an inability to concentrate, drowsiness, insomniaand pain in the stomach, upper body, and joints[107] — may appear within 12 to 24 hours after discontinuation ofcaffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required forthe 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.

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OveruseIn large amounts, and especially over extended periods of time, caffeine can lead to a condition known ascaffeinism.[108] [109] Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical andmental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia),insomnia, headaches, respiratory alkalosis, and heart palpitations.[110] [111] Furthermore, because caffeine increasesthe production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, andgastroesophageal reflux disease.[112] Caffeine may also increase the toxicity of certain other drugs, such asparacetamol.[113]

There are four caffeine-induced psychiatric disorders recognized by the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder,and caffeine-related disorder not otherwise specified (NOS).

Caffeine intoxication

Main symptoms of caffeine intoxication.[90]

An acute overdose of caffeine usually in excess ofabout 300 milligrams, dependent on body weight andlevel of caffeine tolerance, can result in a state ofcentral nervous system over-stimulation calledcaffeine intoxication (DSM-IV 305.90),[114] orcolloquially the "caffeine jitters". The symptoms ofcaffeine intoxication are not unlike overdoses ofother stimulants. It may include restlessness,fidgetiness, nervousness, excitement, euphoria,insomnia, flushing of the face, increased urination,gastrointestinal disturbance, muscle twitching, arambling flow of thought and speech, irritability,irregular or rapid heart beat, and psychomotoragitation.[111] In cases of much larger overdoses,mania, depression, lapses in judgment, disorientation,disinhibition, delusions, hallucinations, andpsychosis may occur, and rhabdomyolysis(breakdown of skeletal muscle tissue) can beprovoked.[115] [116]

Extreme overdose can result in death.[117] The median lethal dose (LD50) given orally, is 192 milligrams perkilogram in rats.[11] The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimatedto be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adulttaken within a limited time frame that is dependent on half-life. Though achieving lethal dose with caffeine would beexceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, withserious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine. An exceptionto this would be taking a drug such as fluvoxamine, which blocks the liver enzyme responsible for the metabolism ofcaffeine, thus increasing the central effects and blood concentrations of caffeine dramatically at 5-fold. It is notcontraindicated, but highly advisable to minimize the intake of caffeinated beverages, as drinking one cup of coffeewill have the same effect as drinking five under normal conditions.[118] [119] [120] [121] Death typically occurs due toventricular 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 ofpoisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victimsof acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, forwhich 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 PsychologicalAssociation (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder, which can result fromlong-term excessive caffeine intake.In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient toinduce 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 mentaldisorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, akathisia, or even schizophrenia, anumber of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarilymedicated when the treatment for caffeine-induced psychosis would simply be to stop further caffeine intake.[123] Astudy in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict asmany as one person in ten of the population.[109]

Effects on memory and learning

Anhydrous caffeine (SP)

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 dosecaffeine slowed hippocampus-dependent learning and impairedlong-term memory in mice. Caffeine consumption for 4 weeks alsosignificantly reduced hippocampal neurogenesis compared to controlsduring the experiment. The conclusion was that long-term consumptionof caffeine could inhibit hippocampus-dependent learning and memorypartially through inhibition of hippocampal neurogenesis.[124]

In another study, caffeine was added to rat neurons in vitro. Thedendritic spines (a part of the brain cell used in forming connectionsbetween neurons) taken from the hippocampus (a part of the brainassociated with memory) grew by 33% and new spines formed. Afteran hour or two, however, these cells returned to their originalshape.[125]

Another study showed that human subjects — after receiving 100milligrams of caffeine — had increased activity in brain regions located in the frontal lobe, where a part of theworking memory network is located, and the anterior cingulate cortex, a part of the brain that controls attention. Thecaffeinated 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 thetip of the tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-termmemory when the information to be recalled is related to the current train of thought, but also to hypothesize thatcaffeine hinders short-term memory when the train of thought is unrelated.[127] In essence, caffeine consumptionincreases mental performance related to focused thought while it may decrease broad-range thinking abilities.

Effects on the heartCaffeine binds to receptors on the surface of heart muscle cells, which leads to an increase in the level of cAMPinside the cells (by blocking the enzyme that degrades cAMP), mimicking the effects of epinephrine (which binds toreceptors on the cell that activate cAMP production). cAMP acts as a "second messenger," and activates a largenumber of protein kinase A (PKA; cAMP-dependent protein kinase). This has the overall effect of increasing the rateof glycolysis and increases the amount of ATP available for muscle contraction and relaxation. According to onestudy, 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 thatare not suffering from a very high blood pressure). Furthermore, no significant protective effect was found inparticipants aged less than 65 years or in cerebrovascular disease mortality for those aged equal or more than 65years.[128] Research also suggests that drinking caffeinated coffee can cause a temporary increase in the stiffening ofarterial walls.[129]

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

Caffeine intake during pregnancyA 2008 study suggested that pregnant women who consume 200 milligrams or more of caffeine per day have abouttwice the miscarriage risk as women who consume none. However, another 2008 study found no correlation betweenmiscarriage and caffeine consumption.[133] The UK Food Standards Agency has recommended that pregnant womenshould 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 tobe certain that the differences were due to caffeine per se, instead of other lifestyle differences possibly associatedwith 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 andGynecology, 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 andpreventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on thesubject published in the January issue of Epidemiology, found no link between miscarriage and caffeineconsumption.[133]

Caffeine 15

Effects on exercise recoveryA 2008 study at RMIT University in Bundoora, Australia and published in the Journal of Applied Physiology founda correlation between caffeine ingestion and the rate at which the body replenishes its muscle glycogen stores. Theingestion of caffeine along with carbohydrates after an exhaustive workout resulted in a 60% increase in the body'sstorage of muscle glycogen when compared to participants who did not ingest the caffeine.[137] The dosage used was8mg per kilogram of body weight.

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

Intraocular pressure and caffeineRecent data has suggested that caffeine consumption can raise intraocular pressure.[140] This may be a significantconsideration for those with open angle glaucoma.[141]

Decaffeination

Fibrous crystals of purified caffeine. Dark field light microscope image, the imagecovers an area of approximately 11 by 7 mm.

Extraction of caffeine from coffee, toproduce decaffeinated coffee and caffeine, isan important industrial process and can beperformed using a number of differentsolvents. Benzene, chloroform,trichloroethylene and dichloromethane haveall been used over the years but for reasonsof safety, environmental impact, cost andflavor, they have been superseded by thefollowing main methods:

Water extraction

Coffee beans are soaked in water. Thewater, which contains many othercompounds 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, leavingdecaffeinated coffee with its original flavor.[142] Coffee manufacturers recover the caffeine and resell it for use insoft drinks and over-the-counter caffeine tablets.

Caffeine 16

Supercritical carbon dioxide extractionSupercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents thatare otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperaturesabove 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: It has gaslikeproperties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of thecaffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine canthen be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.[142]

Extraction by organic solventsCertain organic solvents such as ethyl acetate present much less health and environmental hazard than previouslyused chlorinated and aromatic organic solvents. Another method is to use triglyceride oils obtained from spent coffeegrounds.

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 exercisemetabolism 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 ofCoffea 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). TheVaults 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 ofMedicine. . 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 ofMedicine. . 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 theoriginal (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 Vaultsof 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 ofchocolate". 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 ofKit 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 andJoseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal, Jahres-Bericht über die Fortschritte derphysischen 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'swork 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 incoffee, which simultaneously, in 1821, was discovered by Robiquet and by Pelletier and Caventou, by whom however nothing was madeknown 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 etCaventou 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. Sapublication 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 searchingfor quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to thesame family as the cinchona [quinine] tree -- on their part, Mssrs. Pelletier and Caventou obtained caffeine; but because their research had adifferent 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 caffeinebetter 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) inDictionnaire 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 quelquespropriéte's caractéristiques des bases salifiables organiques" (Researchs into the elemental composition and some characteristic properties oforganic 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 physischenWissenschaften 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 seinenphytochemischen Entdeckungen 1820, p.146-7.) dieselben Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eherbeschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zussamenkunft der Societé dePharmacie in Paris die erste mündliche Mittheilung darüber gab." (However, at this point, it should not remain unmentioned that Runge (in hisPhytochemical Discoveries, 1820, pages 146-147) specified the same method and described caffeine by the name Caffeebase a year earlierthan Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting ofthe 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 andBehavior 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 ofcaffeine 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 ofMedicine 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 depotcontraceptive 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 inpregnancy 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-aproduction 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 alveolarmacrophages" (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-TerminalAcetyltransferase 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) on2007-02-23. . 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 SciSports 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 Physiol71 (6): 2292–8. PMID 1778925.

[94] Verkhratsky, A. (2005). "Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons". PhysiologicalReviews 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 inthe 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 andfunction". 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. . Retrieved2009-08-03.

[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 PhonologicalSystem.". 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 heartdisease 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. Retrieved2010-11-08.

• "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 ContributorsCaffeine  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, ArnonChaffin, 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, 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DarkAudit, DarkCow, DarkFalls, Dasani, Dave6, Davewho2, Dawn Bard, Dawson, Dbollard99, Dchitsaz, DeadEyeArrow, Deelkar, Delink, Delldot, Delta G, Denelson83, Deor, DerHexer, Derek.cashman, Deskana, Devon Fyson, Devvyn, Dez82, Diderot, Dino, Discospinster, Disordered, Dlohcierekim, Dlohcierekim's sock,DoSiDo, DocWatson42, Dogman15, Dolphin29, Dorgan, Download, Dpoduval, Dr U, Dr. Rubinsaw, Dr.Franich, Dr.saptarshi, DrBob, DragonflySixtyseven, Dragonjohann, Dreslough, Drilnoth,Drknexus, Drphilharmonic, Druellen, Drw25, Dsg123456789, Dubrovski, Duckman17, Dudeterd, Duomillia, Durge16, Dustingoetz, Dvortygirl, Dwo, Dysepsion, Dysprosia, ERcheck, ESkog,EVula, Ecopetition, Edcolins, Edgar181, Editor182, Edsanville, Eequor, EggplantWizard, Egonw, Ekem, El3ctr0nika, Elb2000, Elchocolato, Eleland, Eliah, ElisaEXPLOSiON, Ellomate, Eloil,Elroch, Elusive Pete, Elwikipedista, Emokidbrandon, Emopwnlol, Enviroboy, Epastore, Epbr123, Equazcion, Eras-mus, Euku, Everyguy, Everyking, Evlekis, Excirial, 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Image Sources, Licenses and ContributorsFile:Caffeine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine.svg  License: Public Domain  Contributors: Icey, ClockworkSoulFile:Caffeine_3d_structure.png  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine_3d_structure.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:User:Giorgiogp2Image:Caffeine-3D-vdW.png  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine-3D-vdW.png  License: Public Domain  Contributors: Benjah-bmm27File:Yes check.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Yes_check.svg  License: Public Domain  Contributors: User:Gmaxwell, User:WarX

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Image:Roasted coffee beans.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Roasted_coffee_beans.jpg  License: Public Domain  Contributors: User:MarkSweepFile:Kahvihuone.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Kahvihuone.jpg  License: Public Domain  Contributors: User:InfrogmationImage:Caffeine USP.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine_USP.jpg  License: Attribution  Contributors: Original uploader was Rafti Institute at en.wikipediaImage:Caffeine metabolites.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine_metabolites.svg  License: Public Domain  Contributors: IceyImage:Caffeine and adenosine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine_and_adenosine.svg  License: Public Domain  Contributors: Delhovlyn, Icey, 1 anonymouseditsImage:Caffeinated spiderwebs.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeinated_spiderwebs.jpg  License: Public Domain  Contributors: Gracefool, JenVan, TheDJ, 5anonymous editsFile:Main side effects of Caffeine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Main_side_effects_of_Caffeine.png  License: Public Domain  Contributors: Mikael HäggströmImage:M-Energy Drink.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:M-Energy_Drink.jpg  License: Public Domain  Contributors: User:Editor182File:Main symptoms of Caffeine overdose.png  Source: http://en.wikipedia.org/w/index.php?title=File:Main_symptoms_of_Caffeine_overdose.png  License: Public Domain  Contributors:Mikael HäggströmFile:Caffeine.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Caffeine.JPG  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:DorganFile:CaffeineCrystals Fibrous 10xDarkField.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:CaffeineCrystals_Fibrous_10xDarkField.jpg  License: Creative CommonsAttribution-Sharealike 3.0  Contributors: User:Zephyris

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