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Caffeine

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This article is about the stimulant. For other uses, see Caffeine (disambiguation).

Caffeine
Caffeine molecule
Clinical data
Other namesMethyltheobromine
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: A
Dependence
liability		Low–moderate[1]
Addiction
liability		None[1]
Routes of
administration		oral, insufflation, enema, rectal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability99%
Protein binding25–36%[2]
MetabolismPrimary: CYP1A2[2]
Minor: CYP2E1, CYP3A4, CYP2C8, CYP2C9[2]
Onset of actionUp to 45 minutes[3]
Elimination half-lifeAdults: 3–7 hours[2]
Neonates: 65–130 hours[2]
Excretionurine (100%)
Identifiers
  • 1,3,7-Trimethylpurine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.000.329 Edit this at Wikidata
Chemical and physical data
FormulaC8H10N4O2
Molar mass194.19 g/mol g·mol−1
3D model (JSmol)
Density1.23 g/cm3
Melting point235 to 238 °C (455 to 460 °F) (anhydrous)[4][5]
  • Canonical
    CN1C=NC2=C1C(=O)N(C(=O)N2C)C
  • InChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
  • Key:RYYVLZVUVIJVGH-UHFFFAOYSA-N checkY
Data page
Caffeine (data page)

Caffeine (/kæˈfiːn, ˈkæfiːn, ˈkæfiːɪn/) is a bitter, white crystalline purine, a methylxanthine alkaloid, and thus closely related chemically to the adenine and guanine contained in deoxyribonucleic acid (DNA). It is found in the seeds, nuts, or leaves of a small number of plants native to South America. The most well known source of caffeine is the seed (commonly incorrectly referred to as the "bean") of the Coffea arabica coffee plant. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to increase one's energy level. Caffeine is extracted from the plant part containing it for making beverages by steeping it in water, a process called infusion. These beverages are very popular: in North America, 90% of adults consume caffeine daily.[6]

Caffeine is a psychological stimulant.[7] 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 what "bean" (seed) is used and how it is prepared: by drip, percolation, or espresso. There are several known mechanisms of action to explain the effects of caffeine. The most prominent is to reversibly block the action of adenosine on its receptor, which blocks the onset of drowsiness induced by adenosine. Caffeine also stimulates selected portions of the autonomic nervous system.

Caffeine can have both positive and negative health effects. It can be used to treat bronchopulmonary dysplasia of prematurity, and to prevent apnea of prematurity: caffeine citrate was placed on the WHO Model List of Essential Medicines in 2007.[8] It may confer a modest protective effect against some diseases,[9] including Parkinson's disease[10] and certain types of cancer. One meta-analysis 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.[11] 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.[12][13] Mild psychological dependence can occur with chronic caffeine use.[1] Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use.[citation needed]

Caffeine confers a survival advantage on the plant containing it in three ways. First, if it is ingested by an insect feeding on and potentially damaging or killing the plant, caffeine functions as a natural pesticide which can paralyze and kill the insect. Second, droppings from the plant infuse the surrounding soil with caffeine, inhibiting the growth of and potentially killing competing seedlings, including its own progeny and itself. Third, caffeine can enhance the reward memory of pollinators such as honey bees, thus increasing the numbers of its progeny.

Effects

Main article: Health effects of caffeine
Health effects of caffeine

Desired

Caffeine is a central nervous system and metabolic stimulant,[7] and is used to reduce physical fatigue and to prevent or treat drowsiness. 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 these effects varies from person to person, depending on body size and degree of tolerance. Desired effects begin less than an hour after consumption, and a moderate dose usually subsides in about five hours.[14]

Caffeine has the desired effect of delaying/preventing sleep, but does not affect all people in the same way. It also improves performance during sleep deprivation.[15] In shift workers it leads to fewer mistakes caused by drowsiness.[16]

In athletes, moderate doses of caffeine can improve sprint,[17] endurance,[18] and team sports performance,[19] but the improvements are usually not substantial. Some evidence suggests that coffee does not produce the performance enhancing effects observed in other caffeine sources.[20]

Undesired

Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common, and include mild anxiety, jitteriness, insomnia, and interference with co-ordination in athletes.[21] The caffeine-induced disorders recognized n the "The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition American Psychiatric Association (2013).[22] (DSM-5) are: caffeine-induced anxiety disorder, caffeine-induced sleep disorder, caffeine intoxication, caffeine withdrawal and caffeine-related disorder not otherwise specified.

Anxiety

Caffeine can have negative effects on anxiety disorders.[23] A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder.[24][25] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety[26] or, rarely, trigger mania or psychosis. In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk.[27] but does not improve memory or learning.[28] but can improve cognitive functions in people who are fatigued, possibly due to its effect on alertness.[29] For some people, anxiety can be very much reduced by discontinuing caffeine use.[30]

Lung

Caffeine can also be effective in preventing bronchopulmonary dysplasia in premature infants.[31] It may cause weight gain during therapy;[32] and while some authors have raised the possibility of subtle long-term side effects,[33] treatment has benefits[34] including reducing the incidence of cerebral palsy, and language and cognitive delay.[35][36] Caffeine is also the primary treatment of apnea of prematurity[37] Caffeine in people with asthma at low doses may cause weak bronchodilation and thus a small improvement in lung function for up to four hours and so should be avoided prior to taking any lung function test.[38]

Kidney

Caffeine increases urine output acutely, but not chronically. 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.[39] 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.[40] Because of this effect, some authorities have recommended that athletes and airline passengers avoid caffeine to reduce the risk of dehydration, i.e. hypernatremia, and the risk of extracellular fluid volume depletion. However, chronic users of caffeine develop a tolerance to these effects, and have no chronic increase in urinary output.[41][42]

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.[43] However as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy.[44][45] 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.[46] 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.[13] 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).[47]

Risk of disease

Coffee consumption is associated with a lower overall risk of cancer.[48] 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.[49] 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.[49] A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.[50][51][52] Moderate coffee consumption may decrease the risk of cardiovascular disease,[11] and it may somewhat reduce the risk of type 2 diabetes.[53] 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.[54] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.[55] It may protect people from liver cirrhosis.[56] There is no evidence that coffee stunts a child's growth.[57] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.[58] Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.[59]

Psychopharmacological effects

Psychopharmacological terms[60][61]
• addiction – a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences
• drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
• drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake
• physical dependence – dependence that involves physical–somatic withdrawal symptoms (e.g., fatigue)
• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)

Dependence and withdrawal

Dependence, an adaptive state associated with undesirable withdrawal symptoms after stopping long term intake, may occur.[1] 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.[62] 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.[63] 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.

Addiction

Chronic caffeine use likely does not result in drug addiction.[1] Caffeine addiction was however added to the ICDM 9; however, its addition is disputed.[64] Caffeine does not for example appear to affect dopamine release.[64]

Tolerance

Tolerance to the desired effect of alertness does not occur. Tolerance to some undesired effects, particularly to caffeine's autonomic effects, develops quickly, especially among heavy coffee and energy drink consumers.[65] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.[47]

Overdose

Torso of a young man with overlaid text of main side-effects of caffeine overdose.
Primary symptoms of caffeine intoxication[66]

Consumption of 1000–1500 mg per day is associated with a condition known as caffeinism.[67] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and heart palpitations after caffeine use.[68]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90).[69] 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.[66] 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.[70][71]

Extreme overdose can result in death.[72][73] 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.[74] 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[75] There has been a reported death of a man who had liver cirrhosis overdosing on caffeinated mints.[76][77][78]

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.[66]

Quantity of 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.[79]

Sources

Plants

See also: Caffeinated drink

Around sixty plant species are known to contain caffeine.[80] Common sources are the "bean" (seed) of the coffee plant; in the leaves of the tea bush; and in kola nuts. Other sources include yaupon holly leaves, South American holly yerba mate leaves, seeds from Amazonian maple guarana berries, and Amazonian holly guayusa leaves. Temperate climates around the world have produced unrelated caffeine containing plants.

The differing perceptions in the effects of ingesting beverages made from various plants containing caffeine could be explained by the fact that these beverages also contain varying mixtures of other methylxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.[81][clarification needed]

Products

Caffeine Content in Select Food and Drugs[82][83][84][85][86]
Product Serving size Caffeine per serving (mg) Caffeine (mg/L)
Caffeine tablet (regular-strength) 1 tablet 100 —
Caffeine tablet (extra-strength) 1 tablet 200 —
Excedrin tablet 1 tablet 65 —
Hershey's Special Dark (45% cacao content) 1 bar (43 g or 1.5 oz) 31 —
Hershey's Milk Chocolate (11% cacao content) 1 bar (43 g or 1.5 oz) 10 —
Percolated coffee 207 mL (7.0 US fl oz) 80–135 386–652
Drip coffee 207 mL (7.0 US fl oz) 115–175 555–845
Coffee, decaffeinated 207 mL (7.0 US fl oz) 5–15 24–72
Coffee, espresso 44–60 mL (1.5–2.0 US fl oz) 100 1,691–2,254
Tea – black, green, and other types, – steeped for 3 min. 177 millilitres (6.0 US fl oz) 22–74[85][86]
Guayakí yerba mate (loose leaf) 6 g (0.21 oz) 85[87] approx. 358
Coca-Cola Classic 355 mL (12.0 US fl oz) 34 96
Mountain Dew 355 mL (12.0 US fl oz) 54 154
Pepsi Max 355 mL (12.0 US fl oz) 69 194
Guaraná Antarctica 350 mL (12 US fl oz) 30 100
Jolt Cola 695 mL (23.5 US fl oz) 280 403
Red Bull 250 mL (8.5 US fl oz) 80 320

Products containing caffeine are coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,[88] caffeine tablets, other oral products, and inhalation.

Coffee

The world's primary source 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;[89] 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.[90][91] Arabica coffee typically contains half the caffeine of the robusta variety.[89] In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount.[90][91]

Tea

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed more weakly than coffee. 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.[92]

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.[92]

No-Doz 100 mg caffeine tablets

Soft drinks and energy drinks

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain 10 to 69 milligrams of caffeine per 12 ounce serving.[reference needed] 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.[93]

Other beverages

  • Mate is a drink popular in many parts of South America. Its preparation consists of filling a gourd with the leaves of the South American holly yerba mate, pouring hot but not boiling water over the leaves, and drinking with a straw, the bombilla, which acts as a filter so as to draw only the liquid and not the yerba leaves.[citation needed]
  • Guaraná seeds ("beans") are used in making the commercially sold beverage Guaraná Antarctica, which originated in Brazil and is currently the fifteenth most popular soft drink in the world.[citation needed]
  • The leaves of Ilex guayusa, the Equadorian holly tree, are placed in boiling water to make a guayusa tea, which is both brewed locally and sold commercially throughout the world.[citation needed]

Chocolate

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.[94] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount caffeine as coffee: 80–160 mg per 100 g.[83]

Tablets

Tablets offer the advantages over coffee and tea of convenience, known dosage, and avoiding concomitant fluid intake. Manufacturers of caffeine tablets claim that using caffeine of pharmaceutical quality improves mental alertness.[citation needed] These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.[95]

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.[96] Another unusual intake route is SpazzStick, a caffeinated lip balm.[97] Alert Energy Caffeine Gum was introduced in the United States in 2013, but was voluntarily withdrawn after an announcement of an investigation by the FDA of the health effects of added caffeine in foods.[98]

Inhalation

Taking caffeine by inhalation was under scrutiny by some U.S. lawmakers in 2011.[99]

Combinations with other drugs

Some alcoholic beverages also contain caffeine. These beverages are considered unsafe and not approved to be marketed by the FDA.[100]

Ya ba tablets contain methamphetamine and caffeine.

Coffee decaffeination

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:

  • Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.[101]
  • Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.[101]
  • Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.[101]

"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.[102]

Biosynthesis

Caffeine biosynthesis[103]
Caffeine laboratory synthesis[104][105]

Caffeine may be synthesized from dimethylurea and malonic acid,[104][105][106] but is rarely obtained from synthesis since it is readily available as a byproduct of decaffeination.[107]

Chemical properties

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).[108] It is also moderately soluble in ethanol (1.5 g/100 mL).[108] It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.[109] Caffeine does not contain any stereogenic centers[110] and hence is classified as an achiral molecule.[111]

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 the location from which 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.[112]

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

Structure of a typical chemical synapse

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.[113] 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.[114] 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][115]

Other receptors

Caffeine is also a receptor 1[disambiguation needed] antagonist and an antagonist of the ryanodine receptors (RYR1, RYR2, and RYR3).[116] It is also a competitive antagonist of the ionotropic glycine receptor.[117]

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.

Phosphodiesterase inhibition

Caffeine (as is adenosine) is a competitive nonselective phosphodiesterase inhibitor.[118][119] and raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha[120][121] and leukotriene[122] synthesis, and reduces inflammation and innate immunity.[122]

Acetylcholinesterase inhibition

Caffeine is also significantly implicated in cholinergic system where it e.g. inhibits enzyme acetylcholinesterase.[123]

Increased circulating epinephrine

Caffeine increases epinephrine, which both mobilizes free fatty acids from fat and/or intramuscular triglycerides, making them more available as an energy source; and decreases glycogen breakdown, making it less available. This increased availability of free fatty acids increases fat oxidation and spares muscle glycogen, which may enhance athletic endurance/performance.[124]

Decreased neuronal activation threshold

In the nervous system, caffeine may reduce the perception of effort by lowering the neuron activation threshold, making it easier to recruit muscles for exercise.[125]

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 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.[126]

Pharmacokinetics

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.[127] It is eliminated by first-order kinetics.[128] Caffeine can also be absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine)[129] and chlorobutanol and caffeine (for the treatment of hyperemesis).[130]

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 factors of pregnancy, some concurrent drugs, liver function level of enzymes in the liver needed for caffeine metabolism, and even age. In healthy adults, caffeine's half-life is roughly 6 hours.[2] Nicotine decreases the half-life by 30–50% -making it 3–4 hours;[47] oral contraceptives can double it;[47] and pregnancy can raise it even more -to as much as 15 hours during the last trimester.[47] 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.[47] 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.[131]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,[132] 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.[133]

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.[134] 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.[135]

History

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
Main articles: History of chocolate, History of coffee, History of tea, and History of yerba mate

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.[136] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[137]

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.[138] 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.[139]

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".[140] Archaeologists have found evidence of this use far into antiquity,[141] possibly dating to Late Archaic times.[140]

Chemical identification, isolation, and synthesis

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).[142] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[143][144] 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.[145] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:[146] "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).[147] 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,[148] whereas Pelletier was the first to perform an elemental analysis.[149]

In 1827, M. Oudry isolated "théine" from tea,[150] but it was later proved by Mulder[151] and by Carl Jobst[152] that theine was actually caffeine.[144]

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.[153] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.[154]

Society and culture

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.[155][156][157] Charles II of England tried to ban it in 1676,[158][159] Frederick II of Prussia banned it in 1777,[160][161] 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".[162] 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.[163][unreliable source?] The Food and Drug Administration (FDA) in the United States currently allows only beverages containing less than 0.02% caffeine;[161] but caffeine powder, which is sold as a dietary supplement, is unregulated.[162]

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."[164]

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.[165][166]

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.
See also: Effect of psychoactive drugs on animals

Plants

Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant:[167] high caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.[168] In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival.[169] Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the plant.[170]

Bacteria

Pseudomonas putida CBB5 can live on pure caffeine, and can cleave caffeine into carbon dioxide and ammonia.[171]

Other animals

Caffeine is toxic to birds[172] and to dogs and cats,[173] and has a pronounced adverse effect on mollusks, various insects, and spiders.[174] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.[175]

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    Melting Point
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  143. ^ In 1819, Runge was invited to show Goethe how belladonna caused dilation of the pupil, which Runge did, using a cat as an experimental subject. Goethe was so impressed with the demonstration that: "Nachdem Goethe mir seine größte Zufriedenheit sowol über die Erzählung des durch scheinbaren schwarzen Staar Geretteten, wie auch über das andere ausgesprochen, übergab er mir noch eine Schachtel mit Kaffeebohnen, die ein Grieche ihm als etwas Vorzügliches gesandt. "Auch diese können Sie zu Ihren Untersuchungen brauchen," sagte Goethe. Er hatte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein." (After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. "You can also use these in your investigations," said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.)
    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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Bibliography

  • Bersten, Ian (1999). Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria. Sydney: Helian Books. ISBN 0-9577581-0-3.{{cite book}}: CS1 maint: ref duplicates default (link)
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