Caffeine
6868
226057167
2008-07-16T17:11:40Z
193.128.243.6
/* History */ Corrected typo for year of discovery of theine
{{otheruses}}
{{Chembox new
| Name = Caffeine
| ImageFile = Caffeine.svg
| ImageSize = 175px
| ImageName = Caffeine
| ImageFile1 = Caffeine-3D-QuteMol.png
| ImageSize1 = 135px
| ImageName1 = Caffeine
| 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
| SMILES = C[n]1cnc2N(C)C(=O)N(C)C(=O)c12
| CASNo = 58-08-2
| RTECS = EV6475000
}}
| Section2 = {{Chembox Properties
| Formula = [[carbon|C]]<sub>8</sub>[[hydrogen|H]]<sub>10</sub>[[nitrogen|N]]<sub>4</sub>[[oxygen|O]]<sub>2</sub>
| MolarMass = 194.19 g·mol<sup>−1</sup>
| Appearance = Odorless, white needles or powder
| Density = 1.2 g·cm<sup>−3</sup>, solid
| Solubility = 22 mg·mL<sup>−1</sup> (25 °C)<br />180 mg·mL<sup>−1</sup> (80 °C)<br />670 mg·mL<sup>−1</sup> (100 °C)
| MeltingPt = 237 °C (non-equilibrium, superheated)
| BoilingPt = 178 °C ([[sublimation (chemistry)|sublimes]])
}}
| Section7 = {{Chembox Hazards
| ExternalMSDS = [http://www.sciencestuff.com/msds/C1410.html External MSDS]
| MainHazards = May be fatal if inhaled, swallowed<br/>or absorbed through the skin.
| NFPA-H = 2
| NFPA-F = 1
| NFPA-R =
| FlashPt = N/A
| LD50 = 192 mg/kg (rat, oral)<ref name=ld50/>}}
}}
'''Caffeine''' is a bitter white crystalline [[xanthine]] [[alkaloid]] that acts as a [[psychoactive]] [[stimulant]] [[drug]] and a mild [[diuretic]] (speeds up urine production)<ref>[http://www.coffeescience.org/media/athletic CoffeeScience.org<!-- Bot generated title -->]</ref> in humans and other animals. 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>[http://dictionary.reference.com/browse/caffeine caffeine - Definitions from Dictionary.com<!-- Bot generated title -->]</ref> Caffeine is also called '''guaranine''' when found in [[guarana]], '''mateine''' when found in [[mate (beverage)|mate]], and '''theine''' when found in [[tea]]; all of these names are synonyms for the same chemical compound.
Caffeine is found in varying quantities in the [[bean]]s, [[leaf|leaves]], and [[fruit]] of over 60 [[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|bean]]s 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]] or from [[cacao]]. 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 most others, 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=2007-11-19 | format=fee required | doi = 10.1096/fj.03-0496fje.; | doi_brokendate = 2008-06-25}}</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=2007-02-16 |date=2003-04-01 |work=U.S. [[Code of Federal Regulations]] |publisher=U.S. [[Office of the Federal Register]] |pages=462 }}</ref> One 2008 study suggested that women consuming 200 milligrams or more of caffeine per day had about twice the miscarriage risk as women who drank none, while another 2008 study found no link 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
| language = English
| date = 2008-01-20
| url = http://www.usatoday.com/news/health/2008-01-20-caffeine_N.htm
| accessdate = 2008-02-20}}</ref>
==Occurrence==
[[Image:Coffee beans.jpg|180px|left|thumb|Roasted coffee beans, the world's primary source of caffeine]]
Caffeine is a [[plant]] [[alkaloid]], 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.
| authorlink =
| coauthors = Urmer-Dufek J. and Baumann T.W.]]
| title = Purine alkaloid formation in buds and developing leaflets of Coffea arabica: expression of an optimal defence strategy?
| journal = Phytochemistry
| volume = 25
| issue = 3
| pages = 613–616
| date = 1986
| publisher = Journal of the Phytochemical Society of Europe and the Phytochemical Society of North America.
| url = http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TH7-431C7JN-PW-1&_cdi=5275&_user=121707&_orig=browse&_coverDate=12%2F31%2F1986&_sk=999749996&view=c&wchp=dGLzVlz-zSkWA&md5=c6a5ac763c68cd7daca8d0279bd66d24&ie=/sdarticle.pdf
| format = [[PDF]]
| id = ISSN: 0031-9422
| doi = 10.1016/0031-9422(86)88009-8 }}</ref> caffeine [[paralyze]]s 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=184–187
| date=[[12 October]] [[1984]]
| pmid=6207592
| url=http://www.sciencemag.org/cgi/content/abstract/226/4671/184 | doi = 10.1126/science.6207592 <!--Retrieved from url by DOI bot-->}}</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<ref>{{cite journal
| last = Baumann
| first = T. W.
| authorlink =
| 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 = 1431–1436
| date = 1984
| publisher = Oxford Journals
| url = http://pcp.oxfordjournals.org/cgi/reprint/25/8/1431
| format = [[PDF]]
| id = ISSN: 0032-0781 }}</ref> thus giving it a better chance of survival.
The most commonly used caffeine-containing plants are [[coffee]], [[tea]], and to a lesser extent<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 = 175–184 | year = 1997}}</ref> [[cocoa]]. Other, less commonly used, sources of caffeine include the [[yerba mate]]<ref name=mateine>{{cite web
| title = Does Yerba Maté Contain Caffeine or Mateine?#
| publisher = [[Erowid|The Vaults of Erowid]]
| date = December 2003
| url = http://www.erowid.org/plants/yerba_mate/yerba_mate_chemistry1.shtml|accessdate = 2006-08-16 }}</ref> and [[guarana]] plants, which are sometimes used in the preparation of teas and energy drinks. Two of caffeine's alternative names, ''mateine''<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 = 2006-08-16 }}. Generally translated as ''mateine'' in articles written in English</ref> and ''guaranine'',<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 = 2006-08-16 }}</ref> are derived from the names of these plants. 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. Many natural 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>{{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>
The world's primary source of caffeine is the coffee bean (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=2006-08-21}}</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=2007-01-02}}</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=2007-06-14}}</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. Tea usually contains about half as much caffeine per serving as coffee, depending on the strength of the brew. Certain types of tea, such as [[black tea|black]] and [[oolong]], contain somewhat more caffeine than most other teas. Tea contains small amounts of [[theobromine]] and slightly higher levels of [[theophylline]] than coffee. Preparation has 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
| date=September 1996
| url=http://www.nobleharbor.com/tea/caffiene.html
| accessdate=2006-08-12}}</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 milligrams of caffeine per serving. By contrast, [[energy drink]]s such as [[Red Bull]] contain as much as 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of [[decaffeination]] or from chemical synthesis. [[Guarana]], a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of [[theobromine]] and [[theophylline]] in a naturally occurring [[slow-release]] [[excipient]].<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
| date = January 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
| date = 2004 Nov
|pmid=15549276 | doi = 10.1007/s00213-004-1898-3 <!--Retrieved from PMID by DOI bot-->
}}</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 = 2007-12-31 }}</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 = 2008-01-13 }}</ref>
In recent years various manufacturers have begun putting caffeine into tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness and is used by students that are studying for their exams. It is also used by people who work or drive for long hours. <ref>{{cite web
| title = Altasterol Caffeine Pro+ and mental alertness
| publisher = Articles base & Alta Care Laboratoires
| url = http://www.articlesbase.com/supplements-and-vitamins-articles/altasterol-caffeine-pro-and-mental-alertness-435631.html }}</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 early history in Asia|Origin and early 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 | date = May 1999 | id = 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 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 |date=October 1995 | url = http://www.amazon.com/dp/0880014164/ | id = 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 browsing 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 | date = 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 | date = 1991 January | 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."<ref>{{cite web | last = Jarvis | first = Gail | title = The Rise and Fall of Cocaine Cola | date = [[May 21]] [[2002]] | url = http://www.lewrockwell.com/jarvis/jarvis17.html|accessdate = 2006-08-19 }}</ref> 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 Maya]]n 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.
Chocolate was introduced to [[Europe]] by the [[Spanish people|Spaniard]]s 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.
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 | date = January 2001 | id = 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>[http://nobelprize.org/nobel_prizes/chemistry/laureates/1902/press.html Nobel Prize Presentation Speech by Professor Hj. Théel, President of the Swedish Royal Academy of Sciences on December 10, 1902.]</ref> This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
Today, global consumption of caffeine has been estimated at 120,000 tonnes per annum,<ref name="abc.net">{{cite web | title = What's your poison: caffeine | publisher = Australian Broadcasting Corporation | date = 1997 | url = http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm | accessdate = 2006-08-20 }}</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. In North America, 90% of adults consume some amount of caffeine daily.<ref name="demon drink"/>
==Pharmacology==
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 May-Aug | 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 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">{{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 | date = 1981 | url = http://www.garynull.com/Documents/CaffeineEffects.htm | accessdate = 2006-08-12 | doi = 10.1152/physrev.00004.2004<br | doi_brokendate = 2008-06-25 }}</ref> Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.
===Metabolism===
[[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 is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and 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 | date = 1981 | pmid = 7333346 | doi = 10.1007/BF00609587 }}</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 consumed at a given time—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 3–4 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 | date = 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 | date = 1985 | pmid = 4084271 }}</ref> Caffeine can accumulate in individuals with severe [[liver disease]] when its half-life can increase 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 = 202–211 | date = 1981 | url = http://www.garynull.com/Documents/CaffeineEffects.htm | accessdate = 2006-08-14 | doi = 10.1152/physrev.00004.2004<br | doi_brokendate = 2008-06-25 }}</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]] | id = ISBN 1-58255-396-3 }}</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 = 2006-08-14 }}</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. They are presented here side by side for comparison.]]
Caffeine acts through multiple mechanisms involving both action on receptors and channels on the cell membrane, as well as intracellular action on calcium and [[Cyclic adenosine monophosphate|cAMP]] pathways. By virtue of its [[purine]] structure it can act on some of the same targets as adenosine related nucleosides and nucleotides, like the cell surface P1 [[GPCR]]s for adenosine, as well as the intracellular [[Ryanodine receptor]] (RyR) which is the physiological target of cADPR ([[cyclic ADP-ribose]]), and [[phosphodiesterase|cAMP-phosphodiesterase]] (cAMP-PDE). Although the action is [[agonist]]ic in some cases, it is [[Receptor antagonist|antagonist]]ic in others. Physiologically, however, caffeine action is unlikely due to increased RyR opening, as it requires plasma concentration above lethal dosage. The action is most likely through adenosine receptors.{{Fact|date=March 2008}}
Like [[alcohol]], [[nicotine]], and [[antidepressant]]s, caffeine readily crosses the [[blood brain barrier]]. Once in the brain, the principal mode of action of caffeine is as an [[Receptor antagonist|antagonist]] of [[adenosine receptor]]s found in the brain.<ref>{{cite journal | last = Fisone G | 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 |date=April 2004| pmid = 15095008 | url = http://www.springerlink.com/content/605nwu366ay2c6xt/ | doi = 10.1007/s00018-003-3269-3 <!--Retrieved from url by DOI bot--> }}</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]].
Caffeine being a competitive inhibitor of adenosine, an understanding of adenosine’s role in the central nervous system is crucial. One of the roles of adenosine is as a signal that one neuron can use to tell another to stop releasing neurotransmitter because it can’t handle the stimulation. In doing this it is acting as a retrograde neurotransmitter (a neurotransmitter that is released by the post-synaptic cell and received by the pre-synaptic cell in the direction opposite to most neurotransmitters).<ref name = "evxxec">Fredholm, B.B., 1995. Adenosine, adenosine receptors and the actions of caffeine. Pharmac. Toxic. 76, pp. 93-101</ref> Adenosine is the final breakdown product of [[ATP|adenosine triphosphate]] (ATP), which is the cellular currency of energy. When cells have used the energy of adenosine triphosphate it breaks into [[adenosine diphosphate]], which is then used for energy and broken down into [[adenosine monophosphate]]. Finally, the last phosphate bond is broken for energy in the cell’s last attempt to squeeze molecular power from this molecule: adenosine monophosphate is broken down into simple [[adenosine]]. At this point, the neuron has very little energy left for the successful firing of an [[action potential]]. Adenosine from this process is then released from the postsynaptic cell and binds to receptors on the presynaptic cell. If the release of adenosine is great enough, this release has an inhibitory effect on the release of neurotransmitter from the presynaptic neuron’s axon terminal. This triggers a mechanism that inhibits the further secretion of excitatory neurotransmitters into the [[Chemical synapse|synapse]]. It is as if the postsynaptic neuron is telling the presynaptic neuron that its resources are scarce and it needs time to recover before further stimulation by neurotransmitters. Thus, adenosine works to inhibit activity of the central nervous system.
Caffeine being a competitive inhibitor of adenosine, it binds to the adenosine receptor, but does not trigger the chemical cascade that inhibits neurotransmitter release and blocks the site so adenosine cannot bind and get its message across the synapse. By inhibiting adenosine, caffeine excites the central nervous system and allows for continued stimulation of neurons that otherwise would not fire or would not release neurotransmitter into the synapse.<ref name = "evxxec"/><ref>Rathbone, MP et al, 1999. Trophic effects of purines in neurons and glial cells. Progress in Neurobiology. 59, pp. 663–690</ref><ref>Mitchell, J.B., Lupica, C.R. and Dunwiddie, T.V., 1993. Activity-dependent release of endogenous adenosine modulates synaptic responses in the rat hippocampus. Neuroscience 13, pp. 3439–3447.</ref><ref>Caulia O., Morellia M., 2005. Caffeine and the dopaminergic system. Behavioural Pharmacology. 16, pp. 63–77.</ref>
The reduction in adenosine activity results in increased activity of the [[neurotransmitter]] [[dopamine]], largely accounting for its stimulatory effects. This inhibition of adenosine is the only known biochemical effect that caffeine has in humans at the concentrations achieved during normal human consumption of the drug.<ref name = "evxxec"/> Further, coffee & tea drinkers on the whole do not consume enough caffeine to release dopamine in the [[nucleus accumbens]] shell, the key structure associated with motivation, reward & addiction. However, in high doses, caffeine induces dopamine release in nucleus accumbens, not unlike other psychostimulants, such as [[cocaine]].<ref>Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. Marcello Solinas, Sergi Ferré, Zhi-Bing You, Marzena Karcz-Kubicha, Patrizia Popoli, Steven R. Goldberg. The Journal of Neuroscience, August 1, 2002, 22(15):6321-6324.</ref> In low and moderate doses, caffeine appears to increase [[dopamine]] and [[acetylcholine]] release in the [[prefrontal cortex]] (PFC) (providing a mechanism for reinforcment) and stimulates the [[caudate nucleus]], increasing wakefulness & locomotor activity. Sustained caffeine usage causes tolerance to the (prefrontal cortical) dopamine-mediated effects and hence the locomotor stimulation, but not to its [[cholinergic]] effects in the PFC, which could account for its capability for sustained arousal even in the caffeine-tolerant.<ref>{{cite journal | author = Nehlig A, | title = Are we dependent upon coffee and caffeine?
A review on human and animal data | journal = Neurosci Biobehav Rev | volume = 23 | issue = 4 | pages = 563–76 | date = March 1999 | url = http://nootropics.com/caffeine.html | doi = 10.1016/S0149-7634(98)00050-5}}</ref><ref>{{cite journal | author = Stephen G. Holtzman, | title = Complete, reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine | journal = Life Sciences | volume = 33 | issue = 8 | pages = 779–787 | date = 1983-08-22 | doi = 10.1016/0024-3205(83)90784-1}}</ref><ref>{{cite journal | author = Stephen G. Holtzman, | title = Complete, reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine | journal = Pharmacology Biochemistry and Behavior | volume = 30 | issue = 4 | pages = 809–815 | date = August 1988 | doi = 10.1016/0091-3057(88)90104-9}}</ref> Caffeine also increases levels of [[epinephrine|epinephrine/adrenaline]],<ref>{{cite journal | author = Graham T, Rush J, van Soeren M | title = Caffeine and exercise: metabolism and performance. | journal = Can J Appl Physiol | volume = 19 | issue = 2 | pages = 111–38 | year = 1994|pmid = 8081318}}</ref> possibly via a different mechanism. Acute usage of caffeine also increases levels of [[serotonin]], causing positive changes in mood.<ref name=fredholm>{{cite journal | author = Fredholm B, Bättig K, Holmén J, Nehlig A, Zvartau E | title = Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. | journal = Pharmacol Rev | volume = 51 | issue = 1 | pages = 83–133 | year = 1999|pmid = 10049999 | doi = 10.1152/physrev.00004.2004}}''[http://pharmrev.aspetjournals.org/cgi/content/full/51/1/83 Full text]''</ref>
<!-- Very technical: rewrite this section. Also, cited source is excellent, but doesn't have anything to do with diuresis.
The inhibition of adenosine may be relevant in its [[diuretic]] properties. Because adenosine is known to constrict preferentially the afferent arterioles of the [[glomerulus]], limiting blood flow and therefore [[urine]] production; its inhibition may cause vasodilation, with an increase in renal blood flow ([[Renal blood flow|RBF]]) and glomerular filtration rate ([[Glomerular filtration rate|GFR]]). This effect, called [[competitive inhibition]], interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of [[epinephrine]] and [[norepinephrine|norepinephrine/noradrenaline]] released via the [[hypothalamic-pituitary-adrenal axis]].<ref name=fredholm/> Epinephrine, the natural [[endocrine system|endocrine]] response to a perceived threat, stimulates the [[sympathetic nervous system]], leading to an increased heart rate, [[blood pressure]] and [[blood]] flow to [[muscle]]s, a decreased blood flow to the [[skin]] and inner [[Organ (anatomy)|organ]]s. Biochemically, it stimulates [[glycogenolysis]], inhibits [[glycolysis]], and stimulates [[gluconeogenesis]] to produce more [[glucose]] in the muscles and release of [[glucose]] into the blood stream from the liver.
-->
Caffeine is also a known competitive inhibitor of the enzyme [[phosphodiesterase|cAMP-phosphodiesterase]] (cAMP-PDE), which converts [[Cyclic adenosine monophosphate|cyclic AMP]] (cAMP) in cells to its noncyclic form, 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.
Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the [[endoplasmic reticulum]](ER). This release is only partially blocked by Ryanodine receptor blockade with [[ryanodine]], [[dantrolene]], [[ruthenium red]], and [[procaine]] (thus may involve [[ryanodine receptor]] and probably some additional calcium channels), but completely abolished after calcium depletion of ER by [[SERCA]] inhibitors like [[Thapsigargin]] (TG) or [[cyclopiazonic acid]] (CPA).<ref>{{cite journal | author = Verkhratsky A. | title = Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons | journal = Physiol. Rev. | volume = 85 | issue = 1 | pages = 201–279 | year = 2005|doi = 10.1152/physrev.00004.2004 | pmid = 15618481}}</ref> The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate. This mode of action of caffeine is probably due to mimicking the action of the physiologic metabolite of NAD called cADPR ([[cyclic ADP ribose]]) which has a similar potentiating action on [[Ryanodine receptor]]s.
Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons.
The metabolites of caffeine contribute to caffeine's effects. Theobromine is a [[vasodilation|vasodilator]] that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth [[muscle relaxant]] that chiefly affects [[bronchiole]]s and acts as a [[chronotropic|chronotrope]] and [[inotrope]] that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the [[lipolysis]] process, which releases [[glycerol]] and [[fatty acids]] into the blood to be used as a source of fuel by the muscles.<ref>{{cite book | last = Dews | first = P.B. | title = Caffeine: Perspectives from Recent Research | publisher = Berlin: Springer-Valerag | date = 1984 | id = ISBN 978-0387135328 }}</ref>
[[Image:Caffeinated spiderwebs.jpg|170px|left|thumb|Caffeine has a significant effect on [[spider]]s, which is reflected in their [[spider web|web]] construction]]
===Effects when taken in moderation===
The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours.<ref name= "effects" /> Consumption of caffeine does not eliminate the need for sleep: it only temporarily reduces the sensation of being tired.
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 tests.<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 Spring | 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 | date = 1991 December | pmid = 1778925 }}</ref> The extensive boost shown in the runners is not an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.<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 | date = March 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 displasia in [[premature birth|premature]] infants. [[Caffeine citrate|Citrated caffeine]],<ref>{{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 = 2006-08-12 }}</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 = [[May 18]] [[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 = [[November 8]] [[2007]] |url=http://content.nejm.org/cgi/content/short/357/19/1893 | doi = 10.1056/NEJMoa073679 <!--Retrieved from URL by DOI bot--> | 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 |url=http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=87584&Ausgabe=230969&ProduktNr=224215 | doi = 10.1159/000087584 <!--Retrieved from url by DOI bot--> }}</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, [[27 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>[http://digestive.niddk.nih.gov/ddiseases/pubs/fecalincontinence/ Fecal incontinence], NIH</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="Caffeine Content of Food and Drugs">{{cite web |title=Caffeine Content of Food and Drugs |work=Nutrition Action Health Newsletter |publisher=[[Center for Science in the Public Interest]] |date=December 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 = 2006-08-22 }}</ref><ref name="Erowid Caffeine Content">{{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=2006-08-22}}</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
| —
|-
| [[Chocolate]], Dark ([[Hershey's]] Special Dark)
| {{nowrap|1 bar (43 [[gram|g]]; 1.5 [[ounce|oz]])}}
| 31
| —
|-
| Chocolate, Milk (Hershey Bar)
| {{nowrap|1 bar (43 g; 1.5 oz)}}
| 10
| —
|-
| [[Coffee]], brewed
| {{nowrap|207 [[Milliliter#SI prefixes applied to the litre|mL]] (7 U.S. [[fluid ounce|fl oz]])}}
| 80–135
| 386–652
|-
| [[Coffee]], drip
| {{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
| 24
|-
| 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
|
|-
| Tea, leaf or bag
| {{nowrap|177 mL (6 U.S. fl oz)}}
| 50
| 281
|-
| Tea, green
| {{nowrap|177 mL (6 U.S. fl oz)}}
| 30
| 169
|-
| Soft drink, [[Coca-Cola]] Classic
| {{nowrap|355 mL (12 U.S. fl oz)}}
| 34
| 96
|-
| Soft drink, [[Mountain Dew]]
| {{nowrap|355 mL (12 U.S. fl oz)}}
| 54.5
| 154
|-
| Soft drink, [[Jolt Cola]]
| {{nowrap|694 mL (23.5 U.S. fl oz)}}
| 150
| 216
|-
| [[Red Bull]]
| {{nowrap|250 mL (8.2 U.S. fl oz)}}
| 80
| 320
|-
| [[Wired Energy Drink|Wired X344]]
| {{nowrap|473 mL (16 U.S. fl oz)}}
| 344
| 727
|-
| [[Foosh Energy Mints]]
| 1 mint
| 100
| —
|-
| [[Buzz Bites]]
| 1 chew
| 100
| —
|-
| [[Buckfast Tonic Wine]]
| {{nowrap|750 mL (25.4 U.S. fl oz)}}
| 281
| 375
|}
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 | date = January 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 |doi=|url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&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 mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300 mg 3 times per day for 18 days, and possibly even earlier.<ref>[http://www.acnp.org/G4/GN401000165/CH161.html Caffeine - A Drug of Abuse?]</ref> In another experiment, complete tolerance of caffeine was observed when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine.<ref>[http://www.caffeinedependence.org/caffeine_dependence.html 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>[http://www.healthandgoodness.com/health/stimulants_risks.html Health risks of Stimulants, healthandgoodness.com]</ref>
[[Withdrawal]] symptoms—possibly including headache, irritability, an inability to concentrate, and stomach aches<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 = 2004-09-21 | 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 | date = January 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 | date = June 2004 | url = http://www.webmd.com/content/article/46/1826_50681.htm | accessdate = 2006-08-14 }}</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 Summer | 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 |date=September 1983 | pmid = 6354232 | doi = 10.1111/j.1360-0443.1983.tb02509.x }}</ref> Caffeinism usually combines caffeine [[chemical dependency|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]]<ref name="COAM">{{cite web | title = Caffeine overdose in an adolescent male | publisher = J Toxicol Clin Toxicol | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3193494&query_hl=34&itool=pubmed_docsum|accessdate = 2006-08-14 }}</ref> and [[heart palpitation]]s.<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 = 2006-08-14 }}</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 = 2006-08-14 }}</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====
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'',<ref name="DSM-IV">{{cite book | authorlink = http://www.psych.org/ | title = Diagnostic and Statistical Manual of Mental Disorders, fourth Edition.|publisher = [[American Psychiatric Association]] | date = 1994 | id = ISBN 0-89042-062-9 }}</ref> colloquially "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]], loss of social inhibition, [[delusions]], [[hallucinations]], [[psychosis]], [[rhabdomyolysis]], and [[death]] may occur.<ref>{{cite web | title = Caffeine overdose | publisher = MedlinePlus | date = 2006-04-04 | url = http://www.nlm.nih.gov/medlineplus/ency/article/002579.htm | accessdate = 2006-08-14 }}</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 | date = 1999 December | 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 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 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.<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 = [[October 4]], [[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 = [[January 6]], [[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 | date = December 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 | date = December 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 Psychiatric 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. | date = 1998 | id = ISBN 0-7216-6409-1 }}</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"/>
===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>[http://www.researchmatters.harvard.edu/story.php?article_id=198 Effects of caffeine on Parkinson's disease, Harvard research]</ref> The mechanism by which caffeine affects 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]]}}</ref>
===Effects on memory and learning===
An array of studies found that caffeine could have [[nootropic]] effects, inducing certain changes in memory and learning. However, it is still not definitely clear whether the effect is negative or positive.
Researchers have found that long-term consumption of low dose caffeine slowed [[hippocampus]]-dependent learning and impaired long-term memory. 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>
{{Citation
| last1 = Han | first1 = ME
| author1-link = Han ME
| last2 = Park | first2 = KH
| author2-link = Park KH
| last3 = Baek | first3 = SY
| a-uthor3-link = Baek SY
| last4 = Kim | first4 = BS
| author4 = Kim BS
| last5 = Han | first5 = JB
| author5-link = Han ME
| last6 = Kim
| author6-link = Kim JB
| last7 = Oh | first6 = SO
| author7-link = Oh SO
| title = Inhibitory effects of caffeine on hippocampal neurogenesis and function.
| journal = Biochem Biophys Res Commun.
| volume = 18
| issue = 4
| pages = 976–80
| publisher = Epub
| location = Korea
| date = [[2007-03-26]]
| year = 2007
| url = http://www.ncbi.nlm.nih.gov/pubmed/17400186?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
| issn = 0343-6993 }}.
</ref>
In one study, caffeine was added to rat neurons ''[[in vitro]]''. The [[dendritic spines]] (a part of the brain cell used in forming connections between neurons) taken from the [[hippocampus]] (a part of the brain associated with memory) grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.<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]]}}</ref>
Another study showed that 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 cingulum]], 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 }}</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, focused thought coupled with caffeine consumption increases mental performance.
===Effects on the heart===
Caffeine increases the levels of cAMP in the heart cells, mimicking the effects of [[epinephrine]]. cAMP diffuses through the cell and acts as a "secondary messenger," activating protein kinase A (PKA; [[cAMP-dependent protein kinase]]). 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 | month = Feb | 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 = 392–398 | pmid = 17284734 }}</ref>
===Effects on children===
Scientific studies contradict the common belief that caffeine consumption causes stunted growth in children.<ref>{{cite web | title = Fact or fiction: Common diet myths dispelled | publisher = MSNBC | date = December 2006 | url = http://www.msnbc.msn.com/id/16280050 | accessdate = 2007-05-10 }}</ref> However, as with adults, nausea, urinary urgency, nervousness, or other effects from an elevated caffeine intake via chocolate milk, sodas, cold medicines, iced tea, coffee and other products that are widely used, may be reasons to limit the amount of caffeine that is consumed each day.<ref>{{cite web | title = Caffeine and Your Child | publisher = KidsHealth | date = January 2005 | url = http://www.kidshealth.org/parent/food/general/caffeine.html | accessdate = 2007-05-10 }}</ref>
===Caffeine intake during pregnancy===
The [[Food Standards Agency]] has recommended that pregnant women should limit their caffeine intake to less than 300 mg of caffeine a day – the equivalent of four cups of coffee a day. A higher intake may be associated with miscarriage.<ref>[http://www.food.gov.uk/news/newsarchive/2001/oct/caffeinepregnancy Agency issues caffeine advice to pregnant women]</ref><ref>[http://www.cnn.com/2008/HEALTH/conditions/01/21/hfh.caffeine.miscarriage/index.html?iref=mpstoryview Study: Caffeine may boost miscarriage risk]</ref>
Dr De-Kun Li of Kaiser Permanente Division of Research, which appears in the American Journal of Obstetrics and Gynecology, concludes that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage".<ref>[http://ckp.kp.org/newsroom/national/archive/nat_080121_caffeine.html Kaiser Permanente Study Shows Newer, Stronger Evidence that Caffeine During Pregnancy Increases Miscarriage Risk<!-- Bot generated title -->]</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" />
==Production==
[[Image:Caffeine USP.jpg|thumb|250px|right|[[Anhydrous]] (dry) [[United States Pharmacopoeia|USP]]-grade caffeine]]
Caffeine extracted from coffee and tea during the decaffeination process is sold or used as an additive. Being readily available as a byproduct of decaffeination, caffeine is not usually [[synthesized]].<ref>{{cite web | author = Simon Tilling | publisher = [[Bristol University]] | url = http://www.chm.bris.ac.uk/webprojects2001/tilling/synthesis.htm | title = Crystalline Caffeine}}</ref> If desired, it may be synthesized from [[dimethyl urea]] and [[malonic acid]].<ref>{{cite book | title = Beverages in Nutrition and Health | author = Ted Wilson, Norman J. Temple | pages = 172 | isbn = 1588291731 | publisher = Humana Press | year = 2004}}</ref>
==Decaffeination==
{{main|Decaffeination}}
Pure caffeine is a white powder, and can be extracted from a variety of natural sources. Caffeine extraction is an important industrial process and can be performed using a number of different solvents. [[Benzene]], [[chloroform]], [[trichloroethylene]] and [[dichloromethane]] have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods:
===Water extraction===
Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute 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=2006-08-21}}</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 (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO<sub>2</sub> is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 [[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 nonhazardous organic solvents===
Organic solvents such as [[ethyl acetate]] present much less health and environmental hazard than previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are [[ethanol]] and [[acetic acid]], both nonhazardous in small quantities. Another method is to use triglyceride oils obtained from spent coffee grounds.
==Stereochemistry==
The nitrogen atoms are all essentially planar (in sp<sup>2</sup> [[orbital hybridisation]]). Even though some are often drawn with three single bonds, the lone pairs on these atoms are involved in resonance with adjacent double-bonded carbon atoms, resulting in the caffeine molecule having [[aromaticity|aromatic]] character.
==Religion==
Some [[Mormons]] 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= 2008-05-13 }}</ref> do not consume caffeine. Followers of both religions believe that God wishes them to be free of all addictions.
[[The Church of Jesus Christ of Latter-day Saints]] has no official position on this matter, but advises against any harmful, habit forming drinks. ''See [[Word of Wisdom#Cola and other caffeinated beverages|Word of Wisdom]].''
[[Gaudiya Vaishnavism|Gaudiya Vaishnava Hindus]] generally also abstain from caffeine, as it clouds the mind and over-stimulates 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.
==References==
{{reflist|2}}
==External links==
{{Wiktionary}}
=== 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://magma.nationalgeographic.com/ngm/0501/feature1/index.html National Geographic January 2005: Caffeine]
* [http://www.caffeinezone.com Caffeine Zone: Social and Medical info on caffeine and its effects.]
* [http://www.caffeinated.jp/ #caffeine! The Caffeine Information Archive]
* [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]
===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://www.mycaffeineaddiction.com The Effects Of Caffeine Addiction]
* [http://www.garynull.com/Documents/CaffeineEffects.htm Caffeine: Psychological Effects, Use & Abuse]
* [http://news.bbc.co.uk/2/hi/health/7326839.stm Protects brain from Alzheimer's?]
==Appendix==
===Relative content: comparison of different sources===
{| class="toccolours" border="1" style="margin: 0 2em 1em 0; border-collapse: collapse; font-size: 90%"
!Caffeine equivalents<ref name="Caffeine Content of Food and Drugs" /><ref name="Erowid Caffeine Content" />
|-
|In general, each of the following contains approximately 200 [[kilogram#SI multiples|milligrams]] of caffeine:
<div class="toccolors" style="-moz-column-count:2; column-count:2;">
* '''One''' 200 milligram caffeine pill
* '''One''' 12 [[fluid ounce]] cup of regular [[Starbucks]] coffee (355 [[Milliliter#SI prefixes applied to the litre|millilitres]])
* '''One and one quarter''' 16 fluid ounce cans of [[Monster Energy]] (590 millilitres)
* '''One and a half''' [[Pound (mass)|pound]]s of [[milk chocolate]]<sup>[a]</sup> (680 [[gram]]s)
* '''Two''' 8 fluid ounce containers of regular [[coffee]] (470 millilitres)
* '''1/2 tube of '''[[Spazzstick]] Caffeinated Lip Balm'''
* '''Two''' [[Foosh Energy Mints]]
* '''Two''' [[Buzz Bites]] Chocolate Energy Chews
* '''Two and a half''' 10 fluid ounce bottles of [[Bawls]] caffeinated drink (740 millilitres)
* '''Three''' 6 fluid ounce cups of [[black tea]] (0.54 litres) (70 mg per 6 oz cup<ref name="Caffeine Content of Food and Drugs" />)
* '''Three''' standard [[Excedrin]] pills
* '''Three''' 8 fluid ounce cups of [[Red Bull]] energy drink (710 millilitres)
* '''Four''' 8 fluid ounce cups of [[Vault (soft drink)|Vault]] energy drink (1.0 [[litre]])
* '''Five''' 1 fluid ounce shots of [[espresso]] from [[Coffea canephora|robusta]] beans (150 millilitres)
* '''Five''' 8 fluid ounce cups of [[Mountain Dew]] (1.2 litres)
* '''Five''' 12 fluid ounce cans of typical [[soda pop]] (1.8 litres) (variable)
* '''Eight and a half''' 8 fluid ounce cups of [[Coca-Cola Classic]] (68 fl oz is approximately 2.0 litres)
* '''Ten''' 8 fluid ounce cups of [[green tea]] (2.4 litres)
* '''Fifty''' 8 fluid ounce cups of [[decaf]]feinated coffee (12 litres)
</div>
Notes:
a. Chocolate and other products of [[cacao]] contain substantial quantities of other caffeine-like chemicals (especially [[theobromine]]) as well as actual caffeine. The properties of these substances are in at least some respects very similar to caffeine.
|}
{{Coffee|nocat=1}}
{{Stimulants}}
{{Psychostimulants, agents used for ADHD and nootropics}}
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