View source for Caffeine

{{chembox
| Name = Caffeine
| ImageFile = Caffeine.svg
|   ImageSize = 150px
|   ImageName = Hybrid skeletal structure of the caffeine molecule
| IUPACName = 1,3,7-trimethyl- 1''H''-purine- 2,6(3''H'',7''H'')-dione
|   OtherNames = 1,3,7-trimethylxanthine, trimethylxanthine,<br />theine, methyltheobromine
| Section1 = {{Chembox Identifiers
|   InChI = 1/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
|   CASNo = 58-08-2
|    CASNo_Ref = {{cascite}}
|   EC-number = 200-362-1
|   ChemSpiderID = 2424
|   SMILES = C[n]1cnc2N(C)C(=O)N(C)C(=O)c12
|   RTECS = EV6475000
|   DrugBank = DB00201
  }}
| Section2 = {{Chembox Properties
|   Formula = C<sub>8</sub>H<sub>10</sub>N<sub>4</sub>O<sub>2</sub>
|   MolarMass = 194.19 g/mol
|   Appearance = Odorless, white needles or powder
|   Density = 1.23 g/cm<sup>3</sup>, solid
|   Solubility = 2.17 g/100 ml (25 °C)<br />18.0 g/100 ml (80 °C)<br />67.0 g/100 ml (100 °C)
|   MeltingPt = 227–228 °C (anhydrous); 234–235 °C (monohydrate)
|   BoilingPt = 178 °C ''[[sublimation (chemistry)|subl.]]''
|   pKa = −0.13–1.22<ref>This is the pKa for protonated caffeine, given as a range of values included in {{cite book |title=Profiles of Drug Substances, Excipients and Related Methodology, volume 33: Critical Compilation of Pka Values for Pharmaceutical Substances |author=Harry G. Brittain, Richard J. Prankerd |publisher=Academic Press |year=2007 |isbn=012260833X|url=http://books.google.co.jp/books?id=D3vBu5Tx4XwC&pg=PT15&lpg=PT15}}</ref>
|   Dipole = 3.64 [[Debye|D]] (calculated)
  }}
| Section7 = {{Chembox Hazards
|   ExternalMSDS = [http://www.ilo.org/public/english/protection/safework/cis/products/icsc/dtasht/_icsc04/icsc0405.htm ICSC 0405]
|   EUIndex = 613-086-00-5
|   EUClass = Harmful ('''Xn''')
|   RPhrases = {{R22}}
|   SPhrases = {{S2}}
|   NFPA-H = 2
|   NFPA-F = 0
|   NFPA-R = 0
|   LD50 = 192 mg/kg (rat, oral)<ref name="ld50"/>
  }}
}}

'''Caffeine''' is a bitter, white crystalline [[xanthine]] [[alkaloid]] that is a [[psychoactive]] [[stimulant]] [[drug]]. Caffeine was discovered by a German chemist, [[Friedrich Ferdinand Runge]], in 1819. He coined the term ''kaffein'', a chemical compound in [[coffee]], which in English became ''caffeine''.<ref>{{cite web|url=http://dictionary.reference.com/browse/caffeine |title=caffeine - Definitions from Dictionary.com|accessdate=2009-08-03}}</ref> Caffeine is also part of the chemical mixtures and insoluble complexes '''guaranine''' found in [[guarana]], '''mateine''' found in [[mate (beverage)|mate]], and '''theine''' found in [[tea]]; all of which contain additional [[alkaloid]]s such as the [[cardiac]] stimulants [[theophylline]] and [[theobromine]], and often other chemicals such as [[polyphenols]] which can form insoluble complexes with caffeine.<ref name="Ref-1">{{cite book|author = Balentine D. A., Harbowy M. E. and Graham H. N.|title = Tea: the Plant and its Manufacture; Chemistry and Consumption of the Beverage|journal = Caffeine|year = 1998|editor = G Spiller}}</ref>

Caffeine is found in varying quantities in the [[bean]]s, [[leaf|leaves]], and [[fruit]] of some plants, where it acts as a natural [[pesticide]] that [[paralyze]]s and kills certain [[insect]]s feeding on the plants. It is most commonly consumed by humans in infusions extracted from the [[coffee bean|cherries]] of the [[Coffea arabica|coffee plant]] and the leaves of the [[Camellia sinensis|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 is a [[central nervous system]] (CNS) [[stimulant]], having the effect of temporarily warding off [[drowsiness]] and restoring alertness. Beverages containing caffeine, such as [[coffee]], [[tea]], [[soft drink]]s, and [[energy drink]]s enjoy great popularity. Caffeine is the world's most widely consumed [[psychoactive substance]], but unlike many other psychoactive substances it is legal and unregulated in nearly all jurisdictions. In North America, 90% of adults consume caffeine daily.<ref name="demon drink">{{cite journal|last = Lovett|first = Richard|title = Coffee: The demon drink?|journal = New Scientist|issue = 2518|date = 24 September 2005|url=http://www.newscientist.com/article.ns?id=mg18725181.700|accessdate=2009-08-03|format=fee required}}</ref> The U.S. [[Food and Drug Administration]] lists caffeine as a "multiple purpose [[generally recognized as safe]] food substance".<ref name="GRAS">{{cite web |url=http://edocket.access.gpo.gov/cfr_2003/aprqtr/21cfr182.1180.htm |title=21 CFR 182.1180 |accessdate=2009-08-03|date=2003-04-01 |work=U.S. [[Code of Federal Regulations]] |publisher=U.S. [[Office of the Federal Register]] |page=462}}</ref>

Caffeine has [[diuretic]] properties, at least when administered in sufficient doses to subjects who do not have a [[drug tolerance|tolerance]] for it.<ref name="diuretic">{{cite journal|last=Griffin |first = R. J. |title=Caffeine ingestion and fluid balance: a review|journal=Journal of human nutrition and dietetics|issue=6|volume=16|year=2003|doi=10.1046/j.1365-277X.2003.00477.x|page=411}}</ref> Regular users, however, develop a strong tolerance to this effect,<ref name="diuretic"/> and studies have generally failed to support the common notion that ordinary consumption of caffeinated beverages contributes significantly to dehydration.<ref name="really">{{cite news|url=http://www.nytimes.com/2008/03/04/health/nutrition/04real.html?_r=1 |title=Really? The Claim: Caffeine Causes Dehydration|publisher= The New York Times|accessdate=2009-08-03}}</ref><ref name="armstrong2007">{{cite journal
| author = Armstrong LE, Casa DJ, Maresh CM, Ganio MS
| year = 2007
| title = Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance
| journal = Exerc. Sport Sci. Rev.
| volume = 35
| issue = 3
| pages = 135–140
| pmid = 17620932
| doi = 10.1097/jes.0b013e3180a02cc1}} (Review article)</ref><ref name="armstrong2005">{{cite journal
| author = Armstrong LE, Pumerantz AC, Roti MW, Judelson DA, Watson G, Dias JC, Sokmen B, Casa DJ, Maresh CM, Lieberman H, Kellogg M.
| year = 2005
| title = Fluid, electrolyte, and renal indices of hydration during 11 days of controlled caffeine consumption
| journal = Int. J. Sport Nutr. Exerc. Metab.
| volume = 15
| issue = 3
| pages = 252–265
| pmid = 16131696}} (Placebo controlled randomized clinical trial)</ref>

==Occurrence==
[[Image:Roasted coffee beans.jpg|180px|left|thumb|Roasted coffee beans, the world's primary source of caffeine]]
Caffeine is found in many [[plant]] species, where it acts as a natural [[pesticide]], with high caffeine levels being reported in seedlings that are still developing foliages, but are lacking mechanical protection;<ref>{{cite journal|last = Frischknecht|first = P. M.|coauthors = Urmer-Dufek J. and Baumann T.W.|title = Purine formation in buds and developing leaflets of Coffea arabica: expression of an optimal defence strategy?|journal = [[Phytochemistry (journal)|Phytochemistry]]|volume = 25|issue = 3|pages = 613–6|year = 1986|publisher = Journal of the Phytochemical Society of Europe and the Phytochemical Society of North America.|doi = 10.1016/0031-9422(86)88009-8}}</ref> caffeine [[Paralysis|paralyzes]] and kills certain [[insect]]s feeding upon the plant.<ref>{{cite journal|last=Nathanson|first=J. A.|title=Caffeine and related methylxanthines: possible naturally occurring pesticides|journal=Science|volume=226|issue=4671|pages=184–7|year=1984|pmid=6207592|doi = 10.1126/science.6207592}}</ref> High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. It is therefore understood that caffeine has a natural function as both a natural pesticide and as an inhibitor of seed germination of other nearby coffee seedlings thus giving it a better chance of survival.<ref>{{cite journal|last = Baumann|first = T. W.|coauthors = Gabriel H.|title = Metabolism and excretion of caffeine during germination of Coffea arabica L|journal = Plant and Cell Physiology|volume = 25|issue = 8|pages = 1431–6|year = 1984}}</ref>

The most commonly used sources of caffeine are [[coffee]], [[tea]], and to a lesser extent [[cacao]].<ref>{{cite journal|last = Matissek|first = R|title = Evaluation of xanthine derivatives in chocolate: nutritional and chemical aspects|url=http://cat.inist.fr/?aModele=afficheN&cpsidt=2861730|journal = European Food Research and Technology|volume = 205|issue = 3|pages = 175–84|year = 1997}}</ref> Less commonly used sources of caffeine include the [[yerba maté]] and [[guarana]] plants,<ref name="mateine">{{cite web|title = Does Yerba Maté Contain Caffeine or Mateine?|publisher = [[Erowid|The Vaults of Erowid]]|month = December|year = 2003|url = http://www.erowid.org/plants/yerba_mate/yerba_mate_chemistry1.shtml|accessdate = 2009-08-03}}</ref> 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.<ref>{{cite web|title = PubChem: mateina|publisher = National Library of Medicine|url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pccompound&term=mateina|accessdate = 2009-08-03}}. Generally translated as ''mateine'' in articles written in English</ref><ref>{{cite web|title = PubChem: guaranine|publisher = National Library of Medicine|url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pccompound&term=guaranine|accessdate = 2009-08-16}}</ref> Some yerba mate enthusiasts assert that mateine is a [[stereoisomer]] of caffeine, which would make it a different substance altogether.<ref name="mateine"/> This is not true because caffeine is an [[Chirality (chemistry)|achiral]] molecule, and therefore has no [[enantiomer]]s; nor does it have other stereoisomers. The disparity in experience and effects between the various natural caffeine sources could be due to the fact that plant sources of caffeine also contain widely varying mixtures of other [[xanthine]] [[alkaloid]]s, including the [[cardiac]] stimulants [[theophylline]] and [[theobromine]] and other substances such as [[polyphenols]] which can form insoluble complexes with caffeine.<ref name="Ref-1"/>

The world's primary source of caffeine is the coffee "bean" (which is actually the seed of the [[Coffea|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;<ref name="ICO">{{cite web|title=Caffeine|publisher=International Coffee Organization|url=http://www.ico.org/caffeine.asp|accessdate=2009-08-01}}</ref> even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 40 milligrams, for a single shot (30 milliliters) of ''arabica''-variety [[espresso]], to about 100 milligrams for a cup (120 milliliters) of drip coffee. Generally, dark-roast coffee has less caffeine than lighter roasts because the roasting process reduces the bean's caffeine content.<ref name="caffaq_roast">{{cite web|title=Coffee and Caffeine FAQ: Does dark roast coffee have less caffeine than light roast?|url=http://coffeefaq.com/site/node/15|accessdate=2009-08-02}}</ref><ref name="jeremiahspick">{{cite web|title=All About Coffee: Caffeine Level|publisher=Jeremiah’s Pick Coffee Co|url=http://www.jeremiahspick.com/caffeine-e-13.html|accessdate=2009-08-03}}</ref> [[Coffea arabica|''Arabica'']] coffee normally contains less caffeine than the [[Coffea canephora|''robusta'']] variety.<ref name="ICO"/> Coffee also contains trace amounts of [[theophylline]], but no [[theobromine]].

[[Tea]] is another common source of caffeine. Although tea contains more caffeine than coffee, 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.<ref>{{cite web|title=Caffeine in tea vs. steeping time|month=September|year=1996|url=http://www.nobleharbor.com/tea/caffiene.html|accessdate=2009-08-02}}</ref> 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 is also a common ingredient of [[soft drink]]s such as [[cola]], originally prepared from [[kola nut]]s. Soft drinks typically contain about 10 to 50&nbsp;milligrams of caffeine per serving. By contrast, [[energy drink]]s such as [[Red Bull]] can start at 80&nbsp;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]].<ref>{{cite journal|last = Haskell|first = C. F.|coauthors = Kennedy D., Wesnes K. A., Milne A. L., Scholey A. B.|title = A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans|journal = J Psychopharmacol|volume = 21|issue = 1|pages = 65–70|year = 2007|pmid = 16533867|doi = 10.1177/0269881106063815}}</ref>

[[Chocolate]] derived from [[cocoa]] 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.<ref>{{cite journal|last = Smit|first = H. J.|coauthors = Gaffan E. A., Rogers P. J.|title = Methylxanthines are the psycho-pharmacologically active constituents of chocolate|journal = Psychopharmacology|volume = 176|issue = 3–4|pages = 412–9|year = 2004|pmid=15549276|doi = 10.1007/s00213-004-1898-3}}</ref> Chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with [[coffee]]. A typical 28-gram serving of a milk [[chocolate bar]] has about as much caffeine as a cup of ''decaffeinated'' coffee.

In recent years various manufacturers have begun putting caffeine into shower products such as [[shampoo]] and [[soap]], claiming that caffeine can be absorbed through the skin.<ref>{{cite web|title = Caffeine Accessories|publisher = ThinkGeek, Inc|url = http://www.thinkgeek.com/caffeine/accessories|accessdate = 2009-08-01}}</ref> However, the effectiveness of such products has not been proven, and they are likely to have little stimulatory effect on the central nervous system because caffeine is not readily absorbed through the skin.<ref>{{cite web|title = Does caffeinated soap really work?|publisher = Erowid|url = http://www.erowid.org/ask/ask.php?ID=3010|accessdate = 2009-08-03}}</ref>

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.<ref name="effects">{{cite journal|last = Bolton, Ph.D.|first = Sanford|coauthors = Gary Null, M.S.|title = Caffeine: Psychological Effects, Use and Abuse|journal = Orthomolecular Psychiatry|volume = 10|issue = 3|pages = 202–211|year = 1981}}</ref> These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.<ref>{{cite book|url=http://books.google.co.jp/books?id=YdpL2YCGLVYC&pg=PA195|page=195|title=The world of caffeine|author=Bennett Alan Weinberg, Bonnie K. Bealer|publisher=Routledge|year=2001|isbn=0415927226}}</ref>

==History==

[[Image:CoffeePalestineStereo.jpg|thumb|right|220px|A coffeehouse in Palestine, circa 1900]]
:''Main articles: [[Cocoa#History|History of cocoa]], [[History of coffee]], [[Tea#Origin and history|Origin and history of tea]]''
Humans have consumed caffeine since the [[Stone Age]].<ref>{{cite book|last = Escohotado|first = Antonio|coauthors = Ken Symington|title = A Brief History of Drugs: From the Stone Age to the Stoned Age|publisher = Park Street Press|year = 1999|isbn=0-89281-826-3}}</ref> Early peoples found that chewing the seeds, bark, or leaves of certain plants had the effects of easing fatigue, stimulating awareness, and elevating one's mood. Only much later was it found that the effect of caffeine was increased by steeping such plants in hot water. Many cultures have legends that attribute the discovery of such plants to people living many thousands of years ago.

According to one popular Chinese legend, the [[Emperor of China]] [[Shennong]], reputed to have reigned in about 3000 BC, accidentally discovered that when some leaves fell into boiling water, a fragrant and restorative [[caffeinated drink|drink]] resulted.<ref>Chow p. 19–20 (Czech edition); also Arcimovicova p. 9, Evans p. 2 and others</ref> Shennong is also mentioned in Lu Yu's ''[[Cha Jing]]'', a famous early work on the subject of tea.<ref>{{cite book|last = Yu|first = Lu|title = The Classic of Tea: Origins & Rituals|publisher = Ecco Pr; Reissue edition |month=October|year=1995|isbn=0-88001-416-4}}</ref>
The history of coffee has been recorded as far back as the ninth century. During that time, coffee beans were available only in their native habitat, [[Ethiopia]]. A popular legend traces its discovery to a [[goatherder]] named [[Kaldi]], who apparently observed goats that became elated and sleepless at night after grazing on coffee shrubs and, upon trying the berries that the goats had been eating, experienced the same vitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th century [[Persian people|Persian]] physician [[al-Razi]]. In 1587, [[Malaye Jaziri]] compiled a work tracing the history and legal controversies of coffee, entitled "Undat al safwa fi hill al-qahwa". In this work, Jaziri recorded that one [[Sheikh]], Jamal-al-Din al-Dhabhani, [[mufti]] of [[Aden]], was the first to adopt the use of coffee in 1454, and that in the 15th century the [[sufism|Sufis]] of [[Yemen]] routinely used coffee to stay awake during prayers.

Towards the close of the 16th century, the use of coffee was recorded by a [[Europe]]an 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. During this time "[[coffee house]]s" were established, the first being opened in [[Constantinople]] and [[Venice]]. In Britain, the first coffee houses were opened in [[London]] in 1652, at St Michael's Alley, [[Cornhill, London|Cornhill]]. They soon became popular throughout [[Western Europe]], and played a significant role in [[social relation]]s in the 17th and 18th centuries.<ref>{{cite encyclopedia|title = Coffee|encyclopedia = Encyclopædia Britannica|year = 1911}}</ref>

The [[kola nut]], like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many [[West Africa]]n 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|Chattanooga]], [[Tennessee]], alleging that the caffeine in its drink was "injurious to health".<ref>{{cite journal|last = Benjamin|first = LT Jr|coauthors = Rogers AM, Rosenbaum A|title = Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911|journal = J Hist Behav Sci|volume = 27|issue = 1|pages = 42–55|year = 1991|pmid = 2010614| doi = 10.1002/1520-6696(199101)27:1<42::AID-JHBS2300270105>3.0.CO;2-1}}</ref> On March 13, 1911, the government initiated ''The [[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, such as that the excessive use of Coca-Cola at one girls' school led to "wild nocturnal freaks, violations of college rules and female proprieties, and even immoralities." Although the judge ruled in favor of Coca-Cola, two bills were introduced to the [[United States House of Representatives|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]] use comes from residue found in an [[Maya civilization|ancient Mayan]] pot dated to 600 BC. In the New World, chocolate was consumed in a bitter and spicy drink called ''xocoatl'', often seasoned with [[vanilla]], [[chile pepper]], and [[achiote]]. Xocoatl 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.

Xocoatl was introduced to [[Europe]] by the [[Spanish people|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 [[alchemy|alchemical]] processes, where it was known as Black Bean.

The leaves and stems of the [[Ilex vomitoria|Yaupon Holly (Ilex vomitoria)]] were used by [[Indigenous peoples of the Americas|Native Americans]] to brew a [[tea]] called [[black drink|Asi]] or the [[Black Drink]] the use of which among Native American groups archaeologists have demonstrated to stretch back far into antiquity, possibly dating to [[Archaic period in the Americas|Late Archaic times]].

==Synthesis and properties==
[[Image:Caffeine USP.jpg|thumb|250px|right|[[Anhydrous]] (dry) [[United States Pharmacopoeia|USP]]-grade caffeine]]
In 1819, the [[Germany|German]] chemist [[Friedrich Ferdinand Runge]] isolated relatively pure caffeine for the first time. According to Runge, he did this at the behest of [[Johann Wolfgang von Goethe]].<ref name="weinberg">{{cite book|last = Weinberg|first = BA|coauthors = BK Bealer|title = The World of Caffeine|publisher = Routledge|year = 2001|isbn=0-415-92722-6}}</ref> In 1827, Oudry isolated "theine" from tea, but it was later proved by [[Gerardus Johannes Mulder|Mulder]] and Jobat that theine was the same as caffeine.<ref name="weinberg"/> The structure of caffeine was elucidated near the end of the 19th century by [[Hermann Emil Fischer]], who was also the first to achieve its [[total synthesis]].<ref>{{cite web|accessdate=2009-08-03|url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1902/press.html |title=Nobel Prize Presentation Speech by Professor Hj. Théel, President of the Swedish Royal Academy of Sciences|date=December 10, 1902}}</ref> This was part of the work for which Fischer was awarded the Nobel Prize in 1902. 
The nitrogen atoms are all essentially planar (in sp<sup>2</sup> [[orbital hybridisation]]), resulting in the caffeine molecule having [[aromaticity|aromatic]] character.
Being readily available as a byproduct of decaffeination, caffeine is not usually [[Chemical synthesis|synthesized]].<ref>{{cite web|author = Simon Tilling|publisher = [[Bristol University]]|url = http://www.chm.bris.ac.uk/webprojects2001/tilling/synthesis.htm|title = Crystalline Caffeine|accessdate=2009-08-03}}</ref> If desired, it may be synthesized from [[dimethylurea]] and [[malonic acid]].<ref>{{cite book|title = Beverages in Nutrition and Health|author = Ted Wilson, Norman J. Temple|page = 172|isbn = 1588291731|publisher = Humana Press|year = 2004}}</ref>

==Pharmacology==
Global consumption of caffeine has been estimated at 120,000&nbsp;tonnes per annum,<ref name="abc.net">{{cite web|title = What's your poison: caffeine|publisher = Australian Broadcasting Corporation|year = 1997|url = http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm|accessdate=2009-08-03}}</ref> making it the world's most popular psychoactive substance. This number equates to one serving of a caffeine beverage for every person, per day. Caffeine is a [[central nervous system]] and metabolic stimulant,<ref>{{cite journal|last = Nehlig|first = A|coauthors = Daval JL, Debry G|title = Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic, and psychostimulant effects|journal = Brain Res Rev|volume = 17|issue = 2|pages = 139–70|date = 1992|pmid = 1356551|doi = 10.1016/0165-0173(92)90012-B}}</ref> 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.<ref name="effects"/> Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.

===Metabolism and half-life ===
[[Image:Caffeine metabolites.svg|thumb|right|350px|Caffeine is metabolized in the liver into three primary metabolites:
[[paraxanthine]] (84%), [[theobromine]] (12%), and [[theophylline]] (4%)]]
Caffeine from coffee or other beverages is absorbed by the stomach and small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body.<ref>{{cite journal |title=Absorption and subjective effects of caffeine from coffee, cola and capsules |author=Liguori A, Hughes JR, Grass JA |journal=Pharmacol Biochem Behav |volume=58 |pages=721–6 |year=1997 |pmid=9329065 |doi=10.1016/S0091-3057(97)00003-8}}</ref> It is eliminated by [[Rate equation|first-order kinetics]].<ref>{{cite journal|last = Newton|first = R|coauthors = Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID|title = Plasma and salivary pharmacokinetics of caffeine in man|journal = European Journal of Clinical Pharmacology|volume = 21|issue = 1|pages = 45–52|year = 1981|pmid = 7333346|doi = 10.1007/BF00609587}}</ref> Caffeine can also be ingested rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine)<ref>{{cite journal |author=Graham JR |title=Rectal use of ergotamine tartrate and caffeine for the relief of migraine; though in some migraine sufferers, caffeine itself is a trigger for attacks |journal=N. Engl. J. Med. |volume=250 |issue=22 |pages=936–8 |year=1954 |pmid=13165929}}</ref> and chlorobutanol and caffeine (for the treatment of [[hyperemesis]]).<ref>{{cite journal |author=Brødbaek HB, Damkier P |title=[The treatment of hyperemesis gravidarum with chlorobutanol-caffeine rectal suppositories in Denmark: practice and evidence] <!--that's not a formatting mistake; title really does have square-brackets around it --> |language=Danish |journal=Ugeskr. Laeg. |volume=169 |issue=22 |pages=2122–3 |year=2007 |pmid=17553397}}</ref>

The [[Biological half-life|half-life]] of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of [[enzymes]] in the [[liver]] needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 4.9 hours. In women taking oral contraceptives this is increased to 5–10 hours,<ref>{{cite journal|last = Meyer|first = FP|coauthors = Canzler E, Giers H, Walther H.|title = Time course of inhibition of caffeine elimination in response to the oral depot contraceptive agent Deposiston. Hormonal contraceptives and caffeine elimination|journal = Zentralbl Gynakol|volume = 113|issue = 6|pages = 297–302|year = 1991|pmid = 2058339}}</ref> and in pregnant women the half-life is roughly 9–11 hours.<ref>{{cite journal|last = Ortweiler|first = W|coauthors = Simon HU, Splinter FK, Peiker G, Siegert C, Traeger A.|title = 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|journal = Biomed Biochim Acta.|volume = 44|issue = 7–8|pages = 1189–99|year = 1985|pmid = 4084271}}</ref> Caffeine can accumulate in individuals with severe [[liver disease]], increasing its half-life up to 96 hours.<ref>{{cite journal|last = Bolton, Ph.D.|first = Sanford|coauthors = Gary Null, M.S.|title = Caffeine: Psychological Effects, Use and Abuse|journal = Orthomolecular Psychiatry|volume = 10|issue = 3|pages = 202–11|year = 1981}}</ref> 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.<ref>{{cite book|last = Springhouse|title = Physician's Drug Handbook; 11th edition|publisher = Lippincott Williams & Wilkins|date = January 1, 2005|isbn=1-58255-396-3}}</ref> [[Fluvoxamine]] reduced the apparent oral clearance of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold (from 4.9 hours to 56 hours).<ref>[http://www.medscape.com/druginfo/druginteractions?drug_408=Caffeine%20Oral&drug_1049=Fluvoxamine%20Oral& Drug Interaction: Caffeine Oral and Fluvoxamine Oral] Medscape Multi-Drug Interaction Checker</ref>

Caffeine is metabolized in the [[liver]] by the [[cytochrome P450 oxidase]] enzyme system (specifically, the [[CYP1A2|1A2]] isozyme) into three [[metabolism|metabolic]] [[xanthine|dimethylxanthines]],<ref>
{{cite web|title = Caffeine|publisher = The Pharmacogenetics and Pharmacogenomics Knowledge Base|url = http://www.pharmgkb.org/do/serve?objId=464&objCls=DrugProperties#biotransformationData|accessdate=2009-08-03}}</ref> which each have their own effects on the body:
* [[Paraxanthine]] (84%): Has the effect of increasing [[lipolysis]], leading to elevated [[glycerol]] and free [[fatty acid]] levels in the [[blood plasma]].
* [[Theobromine]] (12%): Dilates [[blood vessel]]s and increases [[urine]] volume. Theobromine is also the principal alkaloid in [[cocoa]], and therefore [[chocolate]].
* [[Theophylline]] (4%): Relaxes [[smooth muscle]]s of the [[bronchus|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.

===Mechanism of action===
[[Image:Caffeine and adenosine.svg|thumb|left|350px|Caffeine's principal mode of action is as an [[receptor antagonist|antagonist]] of [[adenosine]] receptors in the brain.]]

Like [[alcohol]] and [[nicotine]], 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 an [[Receptor antagonist|antagonist]] of [[adenosine receptor]]s.<ref>{{cite journal|last = Fisone|first = G|coauthors = Borgkvist A, Usiello A|title = Caffeine as a psychomotor stimulant: mechanism of action|journal = Cell Mol Life Sci|volume = 61|issue = 7–8|pages = 857–72|year=2004| pmid = 15095008|doi = 10.1007/s00018-003-3269-3}}</ref> 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). Therefore, caffeine acts as a [[competitive inhibitor]].

Adenosine is found in every part of the body, because it plays a role in the fundamental [[Adenosine triphosphate|ATP]]-related energy metabolism, 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 by increasing blood flow.<ref name="Latini" /> Thus, caffeine, by counteracting adenosine, has a generally disinhibitory effect on brain 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.<ref name="Latini">{{cite journal |last= Latini |first=S |coauthors=Pedata F |title=Adenosine in the central nervous system: release mechanisms and extracellular concentrations. |journal=J Neurochem |volume=79 |pages=463–84 |year=2001 |pmid=11701750|doi= 10.1046/j.1471-4159.2001.00607.x}}</ref> 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. A<sub>1</sub> receptors are widely distributed, and act to inhibit calcium uptake. A<sub>2A</sub> 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 <sub>2A</sub> receptors interact with the [[dopamine]] system, which is involved in reward and arousal. (A<sub>2A</sub> 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 A<sub>1</sub> receptors, and activation of sleep-promoting neurons via indirect effects on A<sub>2A</sub> receptors.<ref>{{cite journal |last=Basheer |first=R |coauthors=Strecker RE, Thakkar MM, McCarley RW |title=Adenosine and sleep-wake regulation. |journal=Prog Neurobiol |year=2004 |volume=73 |pages=379–96 |pmid=15313333 |doi=10.1016/j.pneurobio.2004.06.004}}</ref> More recent studies have provided additional evidence for the importance of A<sub>2A</sub>, but not A<sub>1</sub>, receptors.<ref>{{cite journal |last=Huang |first=ZL |coauthors=Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB, Urade Y, Hayaishi O |title=Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. |journal=Nature Neurosci |volume=8 |pages=858–9 |year=2005 |pmid=15965471 |url=http://people.bu.edu/gaowx/(47)Huang-caffeine-sleep-NatNeurosci-05.pdf |accessdate=2008-09-21|format=PDF}}</ref>

Some of the secondary effects of caffeine are probably caused by actions unrelated to adenosine. Caffeine is known to be a competitive inhibitor of the enzyme [[phosphodiesterase|cAMP-phosphodiesterase]] (cAMP-PDE), which converts [[Cyclic adenosine monophosphate|cyclic AMP]] (cAMP) in cells to its noncyclic form, thus allowing cAMP to build up in cells. Cyclic AMP participates in activation of [[protein kinase A]] (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal caffeine intensifies and prolongs the effects of [[epinephrine]] and epinephrine-like drugs such as [[amphetamine]], [[methamphetamine]], or [[methylphenidate]]. Increased concentrations of cAMP in [[parietal cell]]s causes an increased activation of [[CAMP-dependent protein kinase|protein kinase A]] (PKA) which in turn increases activation of [[Hydrogen potassium ATPase|H+/K+ ATPase]], resulting finally in increased [[gastric acid]] secretion by the cell. Cyclic AMP also increases the activity of the [[funny current]], which directly increases heart rate.

Metabolites of caffeine also contribute to caffeine's effects. [[Paraxanthine]] is responsible for an increase in the [[lipolysis]] process, which releases [[glycerol]] and [[fatty acids]] into the blood to be used as a source of fuel by the muscles. Theobromine is a [[vasodilation|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 [[bronchiole]]s and acts as a [[chronotropic|chronotrope]] and [[inotrope]] that increases heart rate and efficiency.<ref>{{cite book|last = Dews|first = P.B.|title = Caffeine: Perspectives from Recent Research|publisher = Berlin: Springer-Valerag|year = 1984|isbn=978-0387135328}}</ref>

[[Image:Caffeinated spiderwebs.jpg|170px|left|thumb|Caffeine has a significant effect on [[spider]]s, which is reflected in the construction of their [[spider web|webs]].]]

===Effects when taken in moderation===
[[File:Main side effects of Caffeine.png|thumb|280px|right|Overview of the more common side effects of caffeine, possibly appearing even at levels below overdose.<ref name=Medline/>]]
The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours.<ref name="effects" /> Consumption of caffeine does not eliminate the need for sleep, it only temporarily reduces the sensation of being tired throughout the day. In general, 25 to 50 milligrams of caffeine is sufficient for most people to report increased alertness and arousal as well as subjectively lower levels of fatigue. <ref>{{cite journal|last = Rasmussen|first = JL|coauthors = Werning SA, McGowan CA, Gola JM|title = Effects of caffeine on subjective reports of fatigue and arousal during mentally demanding activities|journal = European Journal of Clinical Pharmacology|volume = 37|issue = 1|pages = 61–90|year = 1997|pmid = 7794434}}</ref>

With these effects, caffeine is an [[ergogenic aid|ergogenic]], increasing the capacity for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who consumed caffeine compared to control subjects.<ref>{{cite journal|last = Ivy|first = JL|coauthors = Costill DL, Fink WJ, Lower RW|title = Influence of caffeine and carbohydrate feedings on endurance performance|journal = Med Sci Sports|volume = 11|issue = 1|pages = 6–11|date = 1979|pmid = 481158}}</ref> Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight.<ref>{{cite journal|last = Graham|first = TE|coauthors = Spriet, LL|title = Performance and metabolic responses to a high caffeine dose during prolonged exercise|journal = J Appl Physiol|volume = 71|issue = 6|pages = 2292–8|year = 1991|pmid = 1778925}}</ref> Additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.<ref>{{cite journal|last = Trice|first = I|coauthors = Haymes, EM|title = Effects of caffeine ingestion on exercise-induced changes during high-intensity, intermittent exercise|journal = Int J Sport Nutr|volume = 5|issue = 1|pages = 37–44|year = 1995|pmid = 7749424|doi = 10.1152/physrev.00004.2004}}</ref>

[[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 birth|premature]] infants.<ref name=Medline> {{cite web|title = Caffeine (Systemic)|publisher = MedlinePlus|date = 2000-05-25|url = http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202105.html |archiveurl=http://web.archive.org/web/20070223063601/http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202105.html |archivedate=2007-02-23|accessdate=2009-08-03}}</ref> The only short term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy,<ref>{{cite journal|last = Schmidt|first = B|coauthors = Roberts, RS, Davis, P, Doyle, LW, et al.|title = Caffeine therapy for apnea of prematurity|journal = N Engl J Med|volume = 354|issue = 20|pages = 2112–21|date = 2006|doi = 10.1056/NEJMoa054065|pmid = 16707748}}</ref> and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.<ref>{{cite journal|last = Schmidt|first = B|coauthors = Robin S. Roberts, M.Sc., Peter Davis, M.D., Lex W. Doyle, M.D., Keith J. Barrington, M.D., Arne Ohlsson, M.D., Alfonso Solimano, M.D., Win Tin, M.D.|title = Long-Term Effects of Caffeine Therapy for Apnea of Prematurity|journal = N Engl J Med|volume = 357|issue = 19|pages = 1893–1902 |date = 2007|doi = 10.1056/NEJMoa073679|pmid = 17989382}}</ref><ref>{{cite journal|last = Schmidt|first = B|title = 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|journal = Neonatology|volume = 88|issue = 3|pages = 208–213 |year =2005|doi = 10.1159/000087584}}</ref>

While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses, and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on [[spider]]s, for example, than most other drugs do.<ref>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.</ref>

Caffeine relaxes the [[Sphincter ani internus muscle|internal anal sphincter muscles]] and thus should be avoided by those with [[fecal incontinence]].<ref>{{cite web|url=http://digestive.niddk.nih.gov/ddiseases/pubs/fecalincontinence/ |title=Fecal incontinence|publisher=NIH|accessdate=2009-08-03}}</ref>

===Tolerance and withdrawal===
{| class="sortable wikitable" style="width:35%; float:right; clear:right; margin:0 0 0.5em 1em; font-size:85%;"
|+ Caffeine content of select common food and drugs.<ref name="Content">{{cite web |title=Caffeine Content of Food and Drugs |work=Nutrition Action Health Newsletter |publisher=[[Center for Science in the Public Interest]] |month=December|year=1996 |url=http://www.cspinet.org/nah/caffeine/caffeine_content.htm |archiveurl=http://web.archive.org/web/20070614144016/http://www.cspinet.org/nah/caffeine/caffeine_content.htm |archivedate=2007-06-14|accessdate=2009-08-03}}}</ref><ref name="Erowid">{{cite web |title=Caffeine Content of Beverages, Foods, & Medications |publisher=[[Erowid|The Vaults of Erowid]] |date=July 7, 2006 |url=http://www.erowid.org/chemicals/caffeine/caffeine_info1.shtml |accessdate=2009-08-03}}}</ref>
<br /><!-- note moved to header to keep table sortable. -->
|-
! Product
!width="26%"| Serving size
!width="12%"| Caffeine per serving ([[Kilogram#SI multiples|mg]])
!width="12%"| Caffeine per [[litre]] ([[Kilogram#SI multiples|mg]])
|-
| Caffeine tablet (regular strength)
| 1 tablet
| 100
| —
|-
| Caffeine tablet (extra strength)
| 1 tablet
| 200
| —
|-
| [[Excedrin]] tablet
| 1 tablet
| 65
| —
|-
| [[Hershey's]] Special Dark
| {{nowrap|1 bar (43 [[gram|g]]; 1.5 [[ounce|oz]])}}
| 31
| —
|-
| Hershey's milk chocolate
| {{nowrap|1 bar (43 g; 1.5 oz)}}
| 10
| —
|-
| Percolated [[coffee]]
| {{nowrap|207 [[Milliliter#SI prefixes applied to the litre|mL]] (7 U.S. [[fluid ounce|fl oz]])}}
| 80–135
| 386–652
|-
| Drip coffee
| {{nowrap|207 [[Milliliter#SI prefixes applied to the litre|mL]] (7 U.S. [[fluid ounce|fl oz]])}}
| 115–175
| 555–845
|-
| Coffee, [[decaffeinated]]
| {{nowrap|207 mL (7 U.S. fl oz)}}
| 5-15
| 24-72
|-
| Coffee, [[espresso]]
| {{nowrap|44–60 mL (1.5-2 U.S. fl oz)}}
| 100
| 1691–2254
|-
| Coffee, [[Starbucks]]
| {{nowrap|(Tall 12 U.S. fl oz)}}
| 240
| 650-700
|-
| [[Black tea]]
| {{nowrap|177 mL (6 U.S. fl oz)}}
| 50
| 282
|-
| [[Green tea]]
| {{nowrap|177 mL (6 U.S. fl oz)}}
| 30
| 169
|-
| [[Coca-Cola]] Classic
| {{nowrap|355 mL (12 U.S. fl oz)}}
| 34
| 96
|-
| [[Mountain Dew]]
| {{nowrap|355 mL (12 U.S. fl oz)}}
| 54.5
| 154
|-
| [[Jolt Cola]]
| {{nowrap|695 mL (23.5 U.S. fl oz)}}
| 280
| 402
|-
| [[Red Bull]]
| {{nowrap|250 mL (8.2 U.S. fl oz)}}
| 80
| 320
|-
| [[XS Energy Drink]]
| {{nowrap|250ml (8.2 U.S. fl oz)}}
| 83
| 332
|-
| [[Monster Energy]]
| {{nowrap|473 mL (16 U.S. fl oz)}}
| 160
| 338
|-
| [[Mother (energy drink)|Mother Energy Drink]]
| {{nowrap|500 mL (16.4 U.S. fl oz)}}
| 160
| 320
|-
| [[V (drink)|V Energy Drink]]
| {{nowrap|250 mL (8.5 U.S. fl oz)}}
| 77.5
| 310
|-
| [[Wired Energy Drink|Wired X505]]
| {{nowrap|709 mL (24 U.S. fl oz)}}
| 505
| 1067
|-
| [[Buckfast Tonic Wine]]
| {{nowrap|750 mL (25.4 U.S. fl oz)}}
| 281
| 375
|-
| [[NOS (drink)|NOS]]
| {{nowrap|650 mL (22 U.S. fl oz)}}
| 343
| 528
|-
| [[Brawndo]]
| {{nowrap|240 mL (8 U.S. fl oz)}}
| 100
| 417
|-
| [[Relentless (drink)|Relentless]]
| {{nowrap|500 mL (17 U.S. fl oz)}}
| 160
| 320
|}

Because caffeine is primarily an [[Receptor antagonist|antagonist]] of the central nervous system's receptors for the [[neurotransmitter]] [[adenosine]], the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of [[adenosine receptor]]s in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences.<ref name="PMID 3003150">{{cite journal|last = Green|first = RM|coauthors = Stiles GL|title = Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex|journal = J Clin Invest|volume = 77|issue = 1|pages = 222–227|year = 1986|pmid = 3003150|doi = 10.1172/JCI112280}}</ref> First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a [[Drug tolerance|tolerance adaptation]]. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.<ref name="PMID 3003150"/>

Other research questions the idea that up-regulation of adenosine receptors is responsible for tolerance to the locomotor stimulant effects of caffeine, noting, among other things, that this tolerance is insurmountable by higher doses of caffeine (it should be surmountable if tolerance was due to an increase in receptors), and that the increase in adenosine receptor number is modest and does not explain the large tolerance which develops to caffeine.<ref name="pmid1846425">{{cite journal |author=Holtzman SG, Mante S, Minneman KP |title=Role of adenosine receptors in caffeine tolerance |journal=J. Pharmacol. Exp. Ther. |volume=256 |issue=1 |pages=62–8 |year=1991 |pmid=1846425}}</ref>

Caffeine tolerance develops very quickly, especially among heavy coffee and energy drink consumers. Complete tolerance to sleep disruption effects of caffeine develops after consuming 400&nbsp;mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300&nbsp;mg 3 times per day for 18 days, and possibly even earlier.<ref>{{cite web|url=http://www.acnp.org/G4/GN401000165/CH161.html|accessdate=2009-08-03|title= Caffeine - A Drug of Abuse?}}</ref> In another experiment, complete tolerance of caffeine was observed when the subject consumed 750–1200&nbsp;mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine.<ref>{{cite web|url=http://www.caffeinedependence.org/caffeine_dependence.html|accessdate=2009-08-03|title= Information About Caffeine Dependence}}</ref> 

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]]. Reduced [[catecholamine]] activity may cause feelings of [[fatigue (physical)|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 (mood)|depression]]. Together, these effects have come to be known as a "crash".<ref>{{cite web|url=http://www.healthandgoodness.com/health/stimulants_risks.html|accessdate=2009-08-03|title= Health risks of Stimulants, healthandgoodness.com}}</ref>

[[Withdrawal]] symptoms—possibly including headache, irritability, an inability to concentrate, drowsiness, insomnia and pain in the stomach, upper body, and joints<ref>{{cite journal|last = Juliano|first = L M|title = A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features|journal = Psychopharmacology|volume = 176|issue = 1|pages = 1–29|date = 2004|doi=10.1007/s00213-004-2000-x}}</ref>—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. [[Analgesic]]s, such as [[aspirin]], can relieve the pain symptoms, as can a small dose of caffeine.<ref>{{cite journal|last = Sawynok|first = J|title = Pharmacological rationale for the clinical use of caffeine|journal = Drugs|volume = 49|issue = 1|pages = 37–50|year = 1995|pmid = 7705215|doi = 10.1152/physrev.00004.2004}}</ref> Most effective is a combination of both an analgesic and a small amount of caffeine.

This is not the only case where caffeine increases the effectiveness of a drug. Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief.<ref>{{cite web|title = Headache Triggers: Caffeine|publisher = WebMD|month = June|year = 2004|url = http://www.webmd.com/content/article/46/1826_50681.htm|accessdate=2009-08-03}}</ref> For this reason, 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 [[antihistamine]]s.

===Overuse===<!-- This section is linked from [[Controlled Substances Act]] -->
In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as ''caffeinism.''<ref>{{cite journal|last = Mackay|first = DC|coauthors = Rollins JW.|title = Caffeine and caffeinism|journal = Journal of the Royal Naval Medical Service|volume = 75|issue = 2|pages = 65–7 |date=1989|pmid = 2607498}}</ref><ref name="BJoA">{{cite journal|last = James|first = JE|coauthors = KP Stirling|title = Caffeine: A summary of some of the known and suspected deleterious effects of habitual use|journal = British Journal of Addiction|volume = 78|issue = 3|pages = 251–8 |year=1983|pmid = 6354232|doi = 10.1111/j.1360-0443.1983.tb02509.x}}</ref> Caffeinism usually combines caffeine [[Substance dependence|dependency]] with a wide range of unpleasant physical and mental conditions including [[anxiety|nervousness]], [[irritability]], [[anxiety]], [[Tremor|tremulousness]], [[muscle twitching]] ([[hyperreflexia]]), [[insomnia]], [[headaches]], [[respiratory alkalosis]], and [[heart palpitation]]s.<ref name="COAM">{{cite journal |author=Leson CL, McGuigan MA, Bryson SM |title=Caffeine overdose in an adolescent male |journal=J. Toxicol. Clin. Toxicol. |volume=26 |issue=5-6 |pages=407–15 |year=1988 |pmid=3193494}}</ref><ref name="EofMD">{{cite web|title = Caffeine-related disorders|publisher = Encyclopedia of Mental Disorders|url = http://www.minddisorders.com/Br-Del/Caffeine-related-disorders.html|accessdate=2009-08-03}}</ref> Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to [[peptic ulcer]]s, erosive [[esophagitis]], and [[gastroesophageal reflux disease]].<ref>{{cite web|title = Gastroesophageal Reflux Disease (GERD)|publisher = Cedars-Sinai|url = http://www.csmc.edu/pf_5543.html|accessdate=2009-08-03}}</ref>

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====
[[File:Main symptoms of Caffeine overdose.png|thumb|right|260px|Main symptoms of caffeine intoxication.<ref name="Medline"/>]]

An acute overdose of caffeine, usually in excess of about 300 milligrams, dependent on body weight and level of caffeine tolerance, can result in a state of central nervous system over-stimulation called ''caffeine intoxication'' ([[DSM-IV]] 305.90),<ref name="DSM-IV">{{cite book|title = Diagnostic and Statistical Manual of Mental Disorders |edition=4<sup>th</sup> |publisher = [[American Psychiatric Association]]|year = 1994|isbn=0-89042-062-9|author = American Psychiatric Association.}}</ref> or colloquially the "caffeine jitters". The symptoms of caffeine intoxication are not unlike overdoses of other [[stimulants]]. It may include restlessness, [[nervousness]], excitement, insomnia, flushing of the face, [[diuresis|increased urination]], [[Gastrointestinal tract|gastrointestinal]] disturbance, [[fasciculation|muscle twitching]], a rambling flow of thought and speech, irritability, [[cardiac arrhythmia|irregular]] or [[tachycardia|rapid heart beat]], and [[psychomotor agitation]].<ref name="EofMD"/> In cases of much larger overdoses, [[mania]], [[depression (mood)|depression]], lapses in judgment, [[disorientation]], [[disinhibition]], [[delusions]], [[hallucinations]], and [[psychosis]] may occur, and [[rhabdomyolysis]] (breakdown of skeletal muscle tissue) can be provoked.<ref>{{cite web|title = Caffeine overdose|publisher = MedlinePlus|date = 2006-04-04|url = http://www.nlm.nih.gov/medlineplus/ency/article/002579.htm|accessdate=2009-08-03}}</ref><ref>{{cite journal|last = Kamijo|first = Y|coauthors = Soma K, Asari Y, Ohwada T|title = Severe rhabdomyolysis following massive ingestion of oolong tea: caffeine intoxication with coexisting hyponatremia|journal = Veterinary and Human Toxicology|volume = 41|issue = 6|pages = 381–3|year = 1999|pmid = 10592946|doi = 10.1152/physrev.00004.2004}}</ref>

In cases of extreme overdose, death can result. The median lethal dose ([[LD50|LD<sub>50</sub>]]) given orally, is 192&nbsp;milligrams per kilogram in rats.<ref name="ld50">{{cite journal|title = Factors Affecting Caffeine Toxicity: A Review of the Literature|last=Peters| first=Josef M.|journal = The Journal of Clinical Pharmacology and the Journal of New Drugs|year= 1967|issue=7|pages=131–141 |url = http://jcp.sagepub.com/cgi/reprint/7/3/131}}</ref> The LD<sub>50</sub> of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200&nbsp;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 [[Biological halflife|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.<ref>{{cite journal|last = Kerrigan|first = S|coauthors = Lindsey T|title = Fatal caffeine overdose: two case reports|journal = Forensic Sci Int|volume = 153|issue = 1|pages = 67–69|date = 2005|url = http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=6700 |format=reprint |pmid=15935584|doi = 10.1016/j.forsciint.2005.04.016}}</ref><ref>{{cite journal|last = Holmgren|first = P|coauthors = Nordén-Pettersson L, Ahlner J|title = Caffeine fatalities — four case reports|journal = Forensic Sci Int|volume = 139|issue = 1|pages = 71–73|date = 2004|url = http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=6702 |format=reprint |pmid=14687776|doi = 10.1016/j.forsciint.2003.09.019}}</ref><ref>{{cite journal|last = Walsh|first = I|coauthors = Wasserman GS, Mestad P, Lanman RC|title = Near-fatal caffeine intoxication treated with peritoneal dialysis|journal = Pediatr Emerg Care|volume = 3|issue = 4|pages = 244–9|year = 1987|pmid = 3324064|doi = 10.1152/physrev.00004.2004}}</ref><ref>{{cite journal|last = Mrvos|first = RM|coauthors = Reilly PE, Dean BS, Krenzelok EP|title = Massive caffeine ingestion resulting in death|journal = Vet Hum Toxicol|volume = 31|issue = 6|pages = 571–2|year = 1989|pmid = 2617841|doi = 10.1152/physrev.00004.2004}}</ref> 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 be required.

====Anxiety and sleep disorders====
Two infrequently diagnosed caffeine-induced disorders that are recognized by the [[American Psychological Association]] (APA) are ''caffeine-induced sleep disorder'' and ''caffeine-induced anxiety disorder'', which can result from long-term excessive caffeine intake.

In the case of [[caffeine-induced sleep disorder]], an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.<ref name="DSM-IV" />

In some individuals, the large amounts of caffeine can induce [[anxiety]] severe enough to necessitate clinical attention. This caffeine-induced [[anxiety disorder]] can take many forms, from [[general anxiety disorder|generalized anxiety]] to [[panic attack]]s, [[obsessive-compulsive]] symptoms, or even [[Phobia|phobic symptoms]].<ref name="DSM-IV"/> Because this condition can mimic organic mental disorders, such as [[panic disorder]], [[generalized anxiety disorder]], [[bipolar disorder]], or even [[schizophrenia]], a number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced psychosis would simply be to stop further caffeine intake.<ref>{{cite book|last = Shannon|first = MW|coauthors = Haddad LM, Winchester JF|title = Clinical Management of Poisoning and Drug Overdose, 3rd ed.|year = 1998|isbn=0-7216-6409-1|publisher = Saunders|location = Philadelphia}}</ref> A study in the ''British Journal of Addiction'' concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population.<ref name="BJoA"/> Co administration of [[theanine]] was shown to greatly reduce this caffeine-induced anxiety.<ref name="pmid18006208">{{cite journal |author=Haskell CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB |title=The effects of l-theanine, caffeine and their combination on cognition and mood |journal=Biol Psychol |volume=77 |issue=2 |pages=113–22 |year=2008 |pmid=18006208 |doi=10.1016/j.biopsycho.2007.09.008}}</ref>

===Parkinson's disease===
Several large studies have shown that caffeine intake is associated with a reduced risk of developing [[Parkinson's disease]] (PD) in men, but studies in women have been inconclusive.<ref>{{cite web|url=http://www.sciam.com/article.cfm?id=caffeine-may-protect-agai |accessdate=2009-08-03|title=Cafeine may protect against parkinsons disease|publisher= Scientific American}}</ref> The mechanism by which caffeine is inversely correlated with PD remains a mystery. In animal models, researchers have shown that caffeine can prevent the loss of dopamine-producing nerve cells seen in Parkinson's Disease, but researchers still do not know how this occurs.<ref>{{cite news|url=http://www.ninds.nih.gov/news_and_events/news_articles/news_article_parkinson_caffeine_hrt.htm|title=New Findings About Parkinson's Disease: Coffee and Hormones Don't Mix|publisher=[[NIH|National Institute of Neurological Disorders and Stroke]]|accessdate=2009-08-03}}</ref>

===Effects on memory and learning===
[[File:Caffeine.JPG|thumb|right|Anhydrous caffeine]]
An array of studies found that caffeine could have [[nootropic]] effects, inducing certain changes in memory and learning. However, the tests performed contradict one another and the results have proven inconsistent and inconclusive.

Researchers have found that long-term consumption of low dose caffeine slowed [[hippocampus]]-dependent learning and impaired long-term memory in mice. Caffeine consumption for 4 weeks also significantly reduced hippocampal [[neurogenesis]] compared to controls during the experiment. The conclusion was that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.<ref>
{{cite journal |author=Han ME, Park KH, Baek SY, ''et al.'' |title=Inhibitory effects of caffeine on hippocampal neurogenesis and function |journal=Biochem. Biophys. Res. Commun. |volume=356 |issue=4 |pages=976–80 |year=2007|pmid=17400186 |doi=10.1016/j.bbrc.2007.03.086 |url=}}
</ref>.

In another study, caffeine was added to rat neurons ''[[in vitro]]''. The [[dendritic spine]]s (a part of the brain cell used in forming connections between neurons) taken from the [[hippocampus]] (a part of the brain associated with memory) grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.<ref>{{cite news|url=http://news.bbc.co.uk/2/hi/science/nature/472473.stm|title=Caffeine clue to better memory |date=1999-10-12|publisher=BBC News|accessdate=2009-08-03}}</ref>

Another study showed that human subjects—after receiving 100 milligrams of caffeine—had increased activity in brain regions located in the frontal lobe, where a part of the working memory network is located, and the [[anterior cingulate cortex]], a part of the brain that controls attention. The caffeinated subjects also performed better on the memory tasks.<ref>{{cite web|url=http://news.softpedia.com/news/Caffeine-Boosts-Short-Time-Memory-13828.shtml|title=Caffeine Boosts Short-Time Memory|accessdate=2009-08-03}}</ref>

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.<ref name="TOT-Lesk_Womble">{{cite journal|author=Lesk VE, Womble SP.|title=Caffeine, priming, and tip of the tongue: evidence for plasticity in the phonological system|journal=Behavioral Neuroscience.|year=2004|pages=453–61|volume=118|issue=2|pmid=15174922|doi=10.1037/0735-7044.118.3.453}}</ref> In essence, caffeine consumption increases mental performance related to focused thought while it may decrease broad-range thinking abilities.

===Effects on the heart===
Caffeine binds to receptors on the surface of heart muscle cells which leads to an increase in the level of [[Cyclic adenosine monophosphate|cAMP]] inside the cells (by blocking the enzyme that degrades cAMP), mimicking the effects of [[epinephrine]] (which binds to receptors on the cell that activate cAMP production). cAMP acts as a "second messenger," and activates a large number of protein kinase A (PKA; [[cAMP-dependent protein kinase]]). This has the overall effect of increasing the rate of [[glycolysis]] and increases the amount of [[Adenosine triphosphate|ATP]] available for muscle contraction and relaxation. According to one study, caffeine in the form of coffee, significantly reduces the risk of [[heart disease]] in epidemiological studies. However, the protective effect was found only in participants who were not severely [[hypertensive]] (i.e. patients that are not suffering from a very high blood pressure). Furthermore, no significant protective effect was found in participants aged less than 65 years or in [[cerebrovascular disease]] mortality for those aged equal or more than 65 years.<ref>{{cite journal|last = Greenberg|first = J.A.|coauthors = Dunbar, C.C.; Schnoll, R.; Kokolis, R.; Kokolis, S.; Kassotis, J.|year = 2007|title = Caffeinated beverage intake and the risk of heart disease mortality in the elderly: a prospective analysis|journal = Am J Clin Nutr|volume = 85|issue = 2|pages = 392–8|pmid = 17284734}}</ref>

===Effects on children===
It is a common myth that caffeine causes stunted growth in children.<ref>{{cite web|title = Fact or fiction: Common diet myths dispelled|publisher = MSNBC|month = December|year = 2006|url = http://www.msnbc.msn.com/id/16280050|accessdate=2009-08-03}}</ref>. However, scientific studies have contradicted that belief.  Children also can experience the same effects from caffeine as adults. Most energy drinks (containing extremely high amounts of caffeine) have been banned in many schools throughout the world.<ref>{{cite web|title = Caffeine and Your Child|publisher = KidsHealth|month = January|year = 2005|url = http://www.kidshealth.org/parent/food/general/caffeine.html|accessdate=2009-08-03}}</ref>

===Caffeine intake during pregnancy===
Despite its widespread use and the conventional view that it is a safe substance, a 2008 study suggested that pregnant women who consume 200 milligrams or more of caffeine per day have about twice the miscarriage risk as women who consume none. However, another 2008 study found no correlation between miscarriage and caffeine consumption.<ref name="PregDiffOutcomes">{{cite web|last = Rubin|first = Rita|title = New studies, different outcomes on caffeine, pregnancy|work = USA TODAY|date = 2008-01-20|url = http://www.usatoday.com/news/health/2008-01-20-caffeine_N.htm|accessdate=2009-08-03}}</ref> The UK [[Food Standards Agency]] has recommended that pregnant women should limit their caffeine intake to less than 200&nbsp;mg of caffeine a day – the equivalent of two cups of instant coffee or a half to two cups of fresh coffee.<ref>{{cite web|url=http://www.food.gov.uk/news/pressreleases/2008/nov/caffeineadvice|accessdate=2009-08-03|title= Food Standards Agency publishes new caffeine advice for pregnant women}}</ref><ref>{{cite news|url=http://www.cnn.com/2008/HEALTH/conditions/01/21/hfh.caffeine.miscarriage/index.html?iref=mpstoryview |accessdate=2009-08-03|title=Study: Caffeine may boost miscarriage risk|author=Danielle Dellorto|date=January 21, 2008|publisher=CNN|accessdate=2009-08-03}}</ref> The FSA noted that the design of the studies made it impossible to be certain that the differences were due to caffeine per se, instead of other lifestyle differences possibly associated with high levels of caffeine consumption, but judged the advice to be prudent.

Dr De-Kun Li of Kaiser Permanente Division of Research, writing in the American Journal of Obstetrics and Gynecology, concluded that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage".<ref>{{cite web|url=http://ckp.kp.org/newsroom/national/archive/nat_080121_caffeine.html|accessdate=2009-08-03|title= Kaiser Permanente Study Shows Newer, Stronger Evidence that Caffeine During Pregnancy Increases Miscarriage Risk}}</ref> However, Dr. David Savitz, a professor in community and preventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on the subject published in the January issue of Epidemiology, found no link between miscarriage and caffeine consumption.<ref name="PregDiffOutcomes" />

===Genetics and caffeine metabolism===
A 2006 study by Dr. Ahmed El-Sohemy at the University of Toronto discovered a link between a gene affecting caffeine metabolism and the effects of coffee on health.<ref>{{cite web|url=http://www.theheart.org/article/659871.do |accessdate=2009-08-03|title=Heavy coffee drinkers with slow caffeine metabolism at increased risk of nonfatal MI|date= March 7, 2006|author= Michael O'Riordan|publisher=theheart.org by WebMD}}</ref>
Some people metabolize caffeine more slowly than the general population due to variations in a specific [[cytochrome P450]] gene<ref name="pmid16522833">{{cite journal |author=Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H |title=Coffee, CYP1A2 genotype, and risk of myocardial infarction |journal=JAMA |volume=295 |issue=10 |pages=1135–41 |year=2006 |month=March |pmid=16522833 |doi=10.1001/jama.295.10.1135 |url=}}</ref>, and there is evidence people with this gene may be at a higher risk of myocardial infarction when consuming large amounts of coffee. For rapid metabolizers, however, coffee seemed to have a preventative effect. Slow and fast metabolizers are comparably common in the general population, and this has been blamed for the wide variation in studies of the health effects of caffeine.

==Decaffeination==
{{main|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===
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 carbon|activated charcoal]], which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor.<ref name="Decaffeination">{{cite web |last=Senese|first=Fred|title=How is coffee decaffeinated?|publisher=General Chemistry Online|date=2005-09-20|url=http://antoine.frostburg.edu/chem/senese/101/consumer/faq/decaffeinating-coffee.shtml|accessdate=2009-08-03}}</ref> Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter [[caffeine tablets]].

===Supercritical carbon dioxide extraction===
[[Supercritical carbon dioxide]] is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO<sub>2</sub> is forced through the green coffee beans at temperatures above 31.1&nbsp;°C and pressures above 73&nbsp;[[Atmosphere (unit)|atm]]. Under these conditions, CO<sub>2</sub> is in a "[[Supercritical fluid|supercritical]]" [[Phase (matter)|state]]: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97–99% of the caffeine. The caffeine-laden CO<sub>2</sub> is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by [[Activated carbon|charcoal]] [[adsorption]] (as above) or by [[distillation]], [[recrystallization]], or [[reverse osmosis]].<ref name="Decaffeination" />

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

==Religion==
Some [[Latter-day Saints]] ([[Mormons]]), [[Seventh-day Adventist Church|Seventh-day Adventists]], [[Church of God (Restoration)]] adherents, and [[Christian Scientists]]<ref>{{cite web |url= http://www.redding.com/news/2008/Apr/12/voices-faith-april-12-2008/ |title= Voices of Faith: April 12, 2008 |accessdate=2009-08-03}}</ref> do not consume caffeine. A few followers from these religions believe that God is opposed to the use of all non-medical psychoactive substances. 

[[The Church of Jesus Christ of Latter-day Saints]] has said the following with regard to caffeinated beverages: “With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided.” (Priesthood Bulletin, Feb. 1972, p. 4.)'' See also [[Word of Wisdom#Cola and other caffeinated beverages|Word of Wisdom]].''

[[Gaudiya Vaishnavism|Gaudiya Vaishnava Hindus]] generally also abstain from caffeine, as it is alleged to cloud the mind and over-stimulate the senses. To be initiated under a guru, one must have had no caffeine (along with alcohol, nicotine and other drugs) for at least a year.

In Islam the main rule on caffeine is that it is permissible, however it is worth noting that it should not be over used and cause severe harm to one's body. With regard to the caffeine in coffee, [[Imam Shihab al-Din]] said: 'it is ''[[halal]]'' (lawful) to drink, because all things are ''[[halal]]'' (lawful) except that which God has made ''[[haraam]]'' (unlawful)'. <ref>{{cite web||accessdate=2009-08-03|url=http://islamweb.net/ver2/Fatwa/ShowFatwa.php?lang=E&Id=84417&Option=FatwaId|title=Drinking drinks with caffeine}}</ref>

==References==
{{reflist|2}}

==External links==
{{portal|Pharmacy and Pharmacology|Tabletten.JPG}}
{{Wiktionary}}
{{wikinews|Alzheimer's disease reversed in mice using caffeine}}
=== General information ===
* [http://home.howstuffworks.com/caffeine.htm How Stuff Works: "How Caffeine Works"]
* [http://www.erowid.org/chemicals/caffeine/caffeine.shtml Erowid Caffeine Vaults]
* [http://sxph.org/caffeine/ Highly Caffeinated: The Caffeine Information Archive"]
* [http://ngm.nationalgeographic.com/ngm/0501/feature1/ National Geographic January 2005: Caffeine]
* [http://www.caffeinezone.com Caffeine Zone: Social and Medical info on caffeine and its effects.]
* [http://www.thenakedscientists.com/html/columnists/dalyacolumn2.htm Naked Scientists Online: Why do plants make caffeine?]
* [http://www.physsportsmed.com/issues/1997/11nov/caffeine.htm ''The Physician and Sportsmedicine'': Caffeine: A User's Guide]
* [http://www.druglibrary.org/schaffer/Library/studies/cu/CU21.html The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1] [http://www.druglibrary.org/schaffer/Library/studies/cu/CU22.html Part 2]
* [http://www.npr.org/templates/story/story.php?storyId=6155178 Coffee: A Little Really Does Go a Long Way, NPR, [[September 28]], 2006]
* [http://www.express.co.uk/posts/view/4664/Does-coffee-really-give-you-a-buzz- Does coffee really give you a buzz? by John Triggs in the Daily Express April 17 2007]
* [http://chemsub.online.fr/chemsearch/cas_number_58-08-2.html Caffeine: ChemSub Online]
* [http://www.mayoclinic.com/health/caffeine/AN01211 How much caffeine is in your daily habit? (Caffeine content in common foods and drinks) by Mayo Clinic Staff October 2007]
*[http://www.camo.com/downloads/resources/application_notes/decaffeinated_coffee_NIR_spectroscopy.pdf How to determine caffeine in decaffeinated coffee by NIR spectroscopy]

===News===
* [http://historyofalcoholanddrugs.typepad.com/alcohol_and_drugs_history/caffeine/index.html Alcohol and Drugs History Society: Caffeine news page]
*[http://www.canada.com/nationalpost/news/story.html?id=30d6d514-1c68-441a-bbec-5b80ae23627f&k=45911 National Post: Caffeine linked to psychiatric disorders]
* [http://www.hopkinsmedicine.org/Press_releases/2004/09_29_04.html Caffeine Withdrawal Recognized as a Disorder]

===Health===
* [http://www.benbest.com/health/caffeine.html Is Caffeine a Health Hazard?]
* [http://www.emedicine.com/med/topic3115.htm eMedicine Caffeine-Related Psychiatric Disorders]
* [http://news.bbc.co.uk/2/hi/health/7326839.stm Protects brain from Alzheimer's?]

{{Stimulants}}
{{Psychostimulants, agents used for ADHD and nootropics}}
{{Adenosinergics}}

[[Category:Xanthines]]
[[Category:IARC Group 3 carcinogens]]

{{Imported from Wikipedia|name=Caffeine|id=310918717}}