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Koffein - Caffeine.svg
Caffeine molecule
Systematic (IUPAC) name
Clinical data
Pregnancy cat.
Legal status
No addiction liability[1]
Routesoral, insufflation, enema, rectal, intravenous
Pharmacokinetic data
Protein binding25–36%[2]
MetabolismPrimarily CYP1A2;[2]
Other enzymes: CYP2E1, CYP2C8, CYP2C9, CYP3A4[2]
Onset of actionUp to 45 minutes[3]
Half-lifeAdults: 3–7 hours[2]
Neonates: 65–130 hours[2]
Excretionurine (100%)
CAS number58-08-2 YesY
ATC codeN06BC01
PubChemCID 2519
IUPHAR ligand407
ChemSpider2424 YesY
KEGGD00528 YesY
Chemical data
Mol. mass194.19 g/mol
Physical data
Density1.23 g/cm³
Melt. point235–238 °C (455–460 °F) (anhydrous)[4][5]
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This article is about the stimulant drug. For other uses, see Caffeine (disambiguation).
Koffein - Caffeine.svg
Caffeine molecule
Systematic (IUPAC) name
Clinical data
Pregnancy cat.
Legal status
No addiction liability[1]
Routesoral, insufflation, enema, rectal, intravenous
Pharmacokinetic data
Protein binding25–36%[2]
MetabolismPrimarily CYP1A2;[2]
Other enzymes: CYP2E1, CYP2C8, CYP2C9, CYP3A4[2]
Onset of actionUp to 45 minutes[3]
Half-lifeAdults: 3–7 hours[2]
Neonates: 65–130 hours[2]
Excretionurine (100%)
CAS number58-08-2 YesY
ATC codeN06BC01
PubChemCID 2519
IUPHAR ligand407
ChemSpider2424 YesY
KEGGD00528 YesY
Chemical data
Mol. mass194.19 g/mol
Physical data
Density1.23 g/cm³
Melt. point235–238 °C (455–460 °F) (anhydrous)[4][5]

Caffeine (/kæˈfn, ˈkæfn, ˈkæfɪn/) is a bitter, white crystalline xanthine alkaloid found in the parts of certain plants. The caffeine ingested by insects when they feed on these parts functions as a natural pesticide that can paralyze and kill them. It can also enhance the reward memory of pollinators such as honey bees.

Caffeine is found in the seeds of the coffee plant; the leaves of the tea bush; and in kola nuts, the usual source of caffeine as an additive for various foods and drinks, and for tablets. Other sources include yaupon holly leaves, the South American holly yerba mate leaves, guarana berries, and guayusa. Caffeine is extracted from the plant part containing it by steeping it in water, a process called infusion. Beverages containing caffeine enjoy great popularity: in North America, 90% of adults consume caffeine daily.[6]

There are several known mechanisms of action to explain the effects of caffeine. One is its ability to block the interaction between adenosine and its receptor. In the absence of caffeine and when a person is awake and alert, little adenosine is present in central nervous system (CNS) neurons. With a continued wakeful state, over time it accumulates and reversibly binds with adenosine receptors found on certain CNS neurons, resulting in a cellular response causing gradually increasing drowsiness and ultimately sleep, a state necessary for metabolic removal of many substances toxic to neurons. When caffeine is consumed, it reversibly binds with adenosine receptors without activating them, and thus blocks (antagonizes) the interaction of adenosine with its receptor. This temporarily prevents or relieves drowsiness, and thus maintains or restores alertness. Other effects of caffeine are: it increases epinephrine, and it acts as a phosphodiesterase inhibitor and as a acetylcholinesterase inhibitor. In addition, some of its metabolites have actions, such as theobromine, which is a vasodilator and diuretic.

Caffeine is classified as a CNS stimulant. It is the world's most widely consumed psychoactive drug, but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. Part of the reason caffeine is classified by the Food and Drug Administration as "generally recognized as safe" (GRAS) is that toxic doses, over 10 grams per day for an adult, are much higher than the typically used doses of under 500 milligrams per day: an over twentyfold difference. A cup (7 ounces) of coffee contains 80–175 mg. of caffeine, depending on which bean is used and how it is prepared: by drip, percolation, or espresso.[7]

Caffeine can have both positive and negative health effects. It may confer a modest protective effect against some diseases,[8] including Parkinson's disease[9] and certain types of cancer. A metanalysis concluded that cardiovascular disease such as coronary artery disease and stroke is less likely with 3-5 cups of coffee per day but more likely with over 5 cups per day.[10] Caffeine can be used to treat asthma, bronchopulmonary dysplasia of prematurity, and to prevent apnea of prematurity. Some people experience insomnia or sleep disruption if they consume caffeine, especially during the evening hours, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit consumption to the equivalent of two cups of coffee per day or less.[11][12] Drug dependence, an adaptive state associated with withdrawal symptoms after stopping long term intake, can occur with chronic caffeine use.[1] Tolerance to increased blood pressure, heart rate and urine production develops with chronic use.[citation needed]


Caffeine is a central nervous system and metabolic stimulant,[13] and is used both recreationally and medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It produces increased wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination.[14] The amount of caffeine needed to produce effects varies from person to person, depending on body size and degree of tolerance. Effects begin less than an hour after consumption, and a moderate dose usually wears off in about five hours.[14]

Caffeine has a number of effects on sleep, but does not affect all people in the same way. It improves performance during sleep deprivation but may lead to subsequent insomnia.[15] In shift workers it leads to fewer mistakes caused by tiredness.[16] In athletics, moderate doses of caffeine can improve sprint,[17] endurance,[18] and team sports performance,[19] but the improvements are usually not very large. Some evidence suggests that coffee does not produce the ergogenic effects observed in other caffeine sources.[20] High doses of caffeine, however, can impair athletic performance by interfering with coordination.[21] There is also evidence that caffeine may be helpful at high altitude.[22]

Risk of disease

Coffee consumption is associated with a lower overall risk of cancer.[23] This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer.[24] There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer.[24] Moderate coffee consumption may decrease the risk of cardiovascular disease,[10] and it may somewhat reduce the risk of type 2 diabetes.[25] Drinking four or more cups of coffee per day does not affect the risk of hypertension compared to drinking little or no coffee. However those who drink 1–3 cups per day may be at a slightly increased risk.[26] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.[27] It may protect people from liver cirrhosis.[28] There is no evidence that coffee stunts a child's growth.[29] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.[30] Similarly, intravenous caffeine is often used in hospitals to provide temporary pain relief for headaches caused by low cerebrospinal fluid pressure.

During pregnancy

Caffeine consumption during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts.[31] However as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy.[32][33] For example the UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee.[34] The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women.[12] Although the evidence that caffeine may be harmful during pregnancy is equivocal, there is some evidence that the hormonal changes during pregnancy slow the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting effects (as long as 15 hours in the third trimester).[35]


Caffeine given to asthma patients in low doses (5 mg/kg of body weight) causes weak bronchodilation and thus a small improvement in lung function.[36] Caffeine can also be effective in preventing bronchopulmonary dysplasia in premature infants.[37] It may cause weight gain during therapy;[38] and while some authors have raised the possibility of subtle long-term side effects,[39] treatment has benefits[40] including reducing the incidence of cerebral palsy, and language and cognitive delay.[41][42] Caffeine is also the primary treatment of apnea of prematurity[43]

Increased urine production

When doses of caffeine equivalent to 2–3 cups of coffee are administered to people who have not consumed caffeine during prior days, it results in a mild increase in urinary output.[44] This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); and is mediated via proximal tubular adenosine receptor blockade.[45] Because of this effect, some authorities have recommended that athletes or airline passengers avoid caffeine to reduce the risk of dehydration,i.e. hypertonicity, or extracellular fluid volume depletion. However, chronic users of caffeine have been shown to develop a strong tolerance to these effects,and thus have no chronic increase in urine production.[46][47]

Central nervous system function

Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA): caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety disorder and caffeine-related disorder not otherwise specified (NOS).[48] The DSM-IV defines a person with caffeine-induced sleep disorder as an individual who regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.[48] As of 2010 the effect of caffeine on people with ADHD is not known.[49] Some studies have however found modest protective effect against Alzheimer disease, but the evidence is inconclusive.[50][51][52]

Caffeine can have negative effects on anxiety disorders.[53] A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder.[54][55] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety[56] or, rarely, trigger mania or psychosis. In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk.[49] In moderate doses, caffeine typically does not affect learning or memory,[57] and can improve cognitive functions, especially in people who are fatigued, possibly due to its effect on alertness.[58] For some people, anxiety can be very much reduced by discontinuing caffeine use.[59]

Dependence, addiction, tolerance, and withdrawal

Main article: Caffeine dependence

With repetitive use, physical dependence may occur.[1] Caffeine has no addiction liability.[1] Tolerance to some effects, particularly to caffeine's autonomic effects, develops quickly especially among heavy coffee and energy drink consumers.[60] Some coffee drinkers develop tolerance to its sleep-disrupting effects, but others apparently do not.[35]

Withdrawal symptoms – including headaches, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints – may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days.[61] Withdrawal headaches are experienced by 52% of people who stopped consuming caffeine for two days after an average of 235 mg caffeine per day prior to that.[62] In prolonged caffeine users, symptoms such as increased depression and anxiety, nausea, vomiting, physical pains and intense desire for caffeine are also reported. Peer knowledge, support and interaction may aid withdrawal.

Caffeine withdrawal is categorized as a mental disorder in the DSM-5 (the 5th edition of the Diagnostic and Statistical Manual published by the American Psychiatric Association).[63] Previous versions of the manual included "caffeine intoxication" but not caffeine withdrawal.


Torso of a young man with overlaid text of main side-effects of caffeine overdose.
Primary symptoms of caffeine intoxication[64]

Consumption of 1000–1500 mg per day is associated with a condition known as caffeinism.[65] Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and mental conditions including nervousness, irritability, restlessness, insomnia, headaches, and heart palpitations after caffeine use.[66]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90).[48] This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g., more than 400–500 mg at a time). The symptoms of caffeine intoxication are comparable to the symptoms of overdoses of other stimulants: they may include restlessness, fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation.[64] In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.[67][68]

Extreme overdose can result in death.[69][70] The median lethal dose (LD50) given orally is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or roughly 80 to 100 cups of coffee for an average adult.[71] Though achieving lethal dose of caffeine is difficult with coffee, it is easily achieved with seventy 200 milligram caffeine pills. The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease[72] There has been a reported death of a man who had liver cirrhosis overdosing on caffeinated mints.[73][74][75] Drugs such as fluvoxamine or levofloxacin can have a similar effect by blocking the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine five-fold.[68][69][76][77] The exact cause of death in such cases is uncertain, but may result from cardiac arrhythmia leading to cardiac arrest.

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.[64]

Global consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.[78]

Function in plants

Caffeine is found in many plant species, where it acts as a natural pesticide: it can paralyze and kill certain insects feeding on the plant.[79] High caffeine levels are found in coffee seedlings when they are developing foliage and lacking mechanical protection.[80] High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine functions as both a natural pesticide and an inhibitor of seed germination of other nearby coffee seedlings, thus giving it a better chance of survival.[81] Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the plant.[82]


Caffeine Content in Select Food and Drugs[83][84][85][86][87]
ProductServing sizeCaffeine per serving (mg)Caffeine (mg/L)
Caffeine tablet (regular-strength)1 tablet100
Caffeine tablet (extra-strength)1 tablet200
Excedrin tablet1 tablet65
Hershey's Special Dark (45% cacao content)1 bar (43 g or 1.5 oz)31
Hershey's Milk Chocolate (11% cacao content)1 bar (43 g or 1.5 oz)10
Percolated coffee207 mL (7.0 US fl oz)80–135386–652
Drip coffee207 mL (7.0 US fl oz)115–175555–845
Coffee, decaffeinated207 mL (7.0 US fl oz)5–1524–72
Coffee, espresso44–60 mL (1.5–2.0 US fl oz)1001,691–2,254
Tea – black, green, and other types, – steeped for 3 min.177 millilitres (6.0 US fl oz)22–74[86][87]124–416
Guayakí yerba mate (loose leaf)6 g (0.21 oz)85[88]approx. 358
Coca-Cola Classic355 mL (12.0 US fl oz)3496
Mountain Dew355 mL (12.0 US fl oz)54154
Pepsi Max355 mL (12.0 US fl oz)69194
Guaraná Antarctica350 mL (12 US fl oz)30100
Jolt Cola695 mL (23.5 US fl oz)280403
Red Bull250 mL (8.5 US fl oz)80320

Common sources of caffeine are coffee, tea, soft drinks and energy drinks, caffeine supplements, and (to a lesser extent) chocolate derived from cocoa beans.[89] Less commonly used sources of caffeine include the yerba mate, guarana and ilex guayusa plants,[90] 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.[91]

The disparity in experience and effects between the various natural caffeine sources could be because plant sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as polyphenols that can form insoluble complexes with caffeine.[92][clarification needed]


One of the world's primary sources of caffeine is the coffee "bean" (which is the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used;[93] even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee.[94][95] Arabica coffee typically contains half the caffeine of the robusta variety.[93]

In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces a small amount of the bean's caffeine content.[94][95]


Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed much weaker. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, certain types of tea may contain somewhat more caffeine than other teas.[96]

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. 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.[96]

No-Doz 100 mg caffeine tablets

Soft drinks

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.[97]


Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.[98] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee, although dark chocolate has about the same caffeine as coffee by weight. Some dark chocolate currently in production contains as much as 160 mg per 100 g[84] – which is double the caffeine content of the highest caffeinated drip coffee by weight.


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 caffeine use (whether in tablet form or not) results in decreased fatigue and increased attentiveness.[14]

These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.[99] One U.S. company is also marketing dissolving caffeine strips as an alternative to energy drinks.[100] Another unusual intake route is SpazzStick, a caffeinated lip balm.[101] As of 2013, a number of innovative caffeinated products such as Alert Energy Caffeine Gum, a Wrigley product, had been introduced in the United States, but were under scrutiny; after announcement of an investigation by the FDA of the health effects of added caffeine in foods, Alert Energy Caffeine Gum was voluntarily withdrawn from sale.[102]


Taking caffeine by inhalation was under scrutiny by some U.S. lawmakers in 2011.[103]

Chemical properties and biosynthesis

Pure anhydrous caffeine is a white odorless powder with a melting point of 235–238 °C.[4][5] Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL).[107] It is also moderately soluble in ethanol (1.5 g/100 mL).[107] It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.[108]

Caffeine does not contain any stereogenic centers[109] and hence is classified as an achiral molecule.[110]

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance form where the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2 hybridized and planar. Therefore the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.[111]

Caffeine is synthesized in plants from the purine nucleotides AMP, GMP, and IMP. These in turn are transformed into xanthosine and then theobromine, the latter being the penultimate precursor of caffeine.[112] Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized chemically.[113] If desired, it may be synthesized from dimethylurea and malonic acid.[105][106][114]

Mechanisms of action

Two skeletal formulas: left – caffeine, right – adenosine.
Caffeine's primary mechanism of action is as an antagonist of adenosine receptors in the brain
Adenosine receptor antagonism

Adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system by its ligand action on the adenosine receptor.[115] Caffeine is a receptor antagonist at all adenosine receptor subtypes (A1, A2A, A2B, and A3 receptors).[2] The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.[116] Antagonism of these adenosine receptors stimulates the vagal nucleus, reducing heart rate; the vasomotor center, constricting blood vessels; and the respiratory center, increasing respiratory rate.[2] It also promotes release of the neurotransmitters monoamines and acetylcholine, which endows caffeine with its stimulant effects.[2][117]

Other receptors

Caffeine is also a receptor 1 antagonist and an antagonist of the ryanodine receptors (RYR1, RYR2, and RYR3).[118] It is also a competitive antagonist of the ionotropic glycine receptor.[119]

Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that prevents some bloodstream substances from access to neurons. In addition to its activity at adenosine receptors, caffeine is an inositol triphosphate.

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.[120] As a competitive nonselective phosphodiesterase inhibitor,[121] caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha[122][123] and leukotriene[124] synthesis, and reduces inflammation and innate immunity.[124] Caffeine is also significantly implicated in cholinergic system where it e.g. inhibits enzyme acetylcholinesterase.[125]

Performance enhancement

A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine.[126] In the classic, or metabolic theory, caffeine may increase fat utilization and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or intramuscular triglycerides by increasing circulating epinephrine levels. The increased availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby enhancing endurance performance. In the nervous system, caffeine may reduce the perception of effort by lowering the neuron activation threshold, making it easier to recruit the muscles for exercise.[127]

Contribution of metabolites

Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and force of contraction.[128]


A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.
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 small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body.[3] Peak blood concentration is reached within 1–2 hours.[129] It is eliminated by first-order kinetics.[130] Caffeine can also be absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine)[131] and chlorobutanol and caffeine (for the treatment of hyperemesis).[132]

The biological half-life of caffeine – the time required for the body to eliminate one-half of the total amount of caffeine – varies widely among 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. It can also be significantly altered by drugs or hormonal states. In healthy adults, caffeine's half-life is roughly 3–7 hours.[2] Heavy cigarette smokers show a decrease in half-life of 30–50%,[35] oral contraceptives can double it,[35] and pregnancy can raise it even more, to as much as 15 hours during the last trimester.[35] In newborn infants the half-life can be 80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by the age of 6 months.[35] The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and prolongs its elimination half-life more than tenfold; from 4.9 hours to 56 hours.[133]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,[134] each of which has its own effects on the body:

1,3,7-Trimethyluric acid is a minor caffeine metabolite.[2] Each of these metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.[135]

A 2011 review found that increased caffeine intake was associated with a variation in two genes that increase the rate of caffeine catabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more caffeine per day than people who did not have this mutation.[136] This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene "forces" people to drink coffee.

Detection in biological fluids

Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.[137]


Main article: Decaffeination
Fibrous crystals of purified caffeine. Dark field light microscope image, the image covers an area of approx. 11 by 7 mm.

Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an important[quantify] industrial process and can be performed using a number of 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:

"Decaffeinated" coffees do in fact contain caffeine in many cases — some commercially available decaffeinated coffee products contain considerable levels. One study found that decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of caffeine per cup for regular coffee.[139]


Discovery and spread of use

An old photo of a dozen old and middle-aged men sitting on the ground around a mat. A man in front sits next to a mortar and holds a bat, ready for grinding. A man opposite to him holds a long spoon.
Coffeehouse in Palestine, circa 1900

According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted.[140] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[141]

The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern Arabia.[142] From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.[143]

Kola nut use appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs.

The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. Also, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief 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.[citation needed]

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as "black bean".[citation needed]

The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink".[144] Archaeologists have found evidence of this use far into antiquity,[145] possibly dating to Late Archaic times.[144]

Chemical identification and isolation

Pierre Joseph Pelletier

In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the first time; he called it "Kaffebase" (i.e. a base that exists in coffee).[146] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[147][148] In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work.[149] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:[150] "However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris."

Pelletier's article on caffeine was the first to use the term in print (in the French form Caféine from the French word for coffee: café).[151] It corroborates Berzelius's account:

Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Messrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ...

Robiquet was one of the first to isolate and describe the properties of pure caffeine,[152] whereas Pelletier was the first to perform an elemental analysis.[153]

In 1827, M. Oudry isolated "théine" from tea,[154] but it was later proved by Mulder[155] and by Carl Jobst[156] that theine was actually caffeine.[148]

In 1895, German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from its chemical components (i.e. a "total synthesis"), and two years later, he also derived the structural formula of the compound.[157] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.[158]

Views of governments

Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca and in the Ottoman Empire made coffee illegal for some classes.[159][160][161] Charles II of England tried to ban it in 1676,[162][163] Frederick II of Prussia banned it in 1777,[164][165] and coffee was banned in Sweden at various times between 1756 and 1823.

In 1911, kola became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".[166] Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.[167][unreliable source?] The Food and Drug Administration (FDA) in the United States currently only allows beverages containing less than 0.02% caffeine;[161] but caffeine powder, which is sold as a dietary supplement, is unregulated.[162]

Views of religions

Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine.[citation needed] Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. 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 habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided."[168]

Gaudiya Vaishnavas generally also abstain from caffeine, because they believe it clouds the mind and over-stimulates the senses. To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.[citation needed]

Caffeinated beverages are widely consumed by Muslims today. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.[169][170]

Effects on other organisms

Left: picture of a regular spider web with a caption "drug-naive", right: heavily distorted spider web with a caption "caffeinated".
Caffeine has a significant effect on spiders, which is illustrated here in the erratic construction of their webs.

Caffeine is toxic to birds[171][172] dogs, and certain other animals. This is at least partly due to a poorer ability to metabolize the compound.[173] Caffeine also has a pronounced effect on mollusks, various insects, and spiders.[174]

Pseudomonas putida CBB5 can live on pure caffeine, and can cleave caffeine into carbon dioxide and ammonia.[175]


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    Boiling Point
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    Melting Point
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    234–236 °C Alfa Aesar
    237 °C Oxford University Chemical Safety Data
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    237 °C Jean-Claude Bradley Open Melting Point Dataset 14937
    238 °C Jean-Claude Bradley Open Melting Point Dataset 17008, 17229, 22105, 27892, 27893, 27894, 27895
    235.25 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
    236 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
    235 °C Jean-Claude Bradley Open Melting Point Dataset 6603
    234–236 °C Alfa Aesar A10431, 39214
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    This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was reprinted in: Johann Wolfgang von Goethe with F.W. von Biedermann, ed., Goethes Gespräche, vol. 10: Nachträge, 1755–1832 (Leipzig, (Germany): F.W. v. Biedermann, 1896), pages 89–96; see especially page 95.
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