Open Access Articles- Top Results for Caffeine


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

File:Koffein - Caffeine.svg
Caffeine molecule
Systematic (IUPAC) name
Clinical data
AHFS/ monograph
  • AU: A
  • US: C (Risk not ruled out)
  • AU: Unscheduled
  • CA: Unscheduled
  • NZ: Unscheduled
  • UK: Unscheduled
  • US: Unscheduled
  • UN: Unscheduled
  • EU: Unscheduled
Physical: low–moderate[1][2]
Psychological: trivial
oral, insufflation, enema, rectal, intravenous
Pharmacokinetic data
Bioavailability 99%
Protein binding 25–36%[3]
Metabolism Primary: CYP1A2[3]
Minor: CYP2E1,[3] CYP3A4,[3] CYP2C8,[3] CYP2C9[3]
Onset of action Up to 45 minutes[4]
Half-life Adults: 3–7 hours[3]
Neonates: 65–130 hours[3]
Excretion urine (100%)
58-08-2 7pxY
PubChem CID 2519
IUPHAR ligand 407
DrugBank DB00201 7pxY
ChemSpider 2424 7pxY
UNII 3G6A5W338E 7pxY
KEGG D00528 7pxY
ChEBI CHEBI:27732 7pxY
Synonyms Guaranine
Chemical data
Formula C8H10N4O2
194.19 g/mol
Physical data
Density 1.23 g/cm3
Melting point Script error: No such module "convert". (anhydrous)[5][6]

Caffeine (/kæˈfn, ˈkæfn, ˈkæfɪn/) is a central nervous system (CNS) stimulant of the methylxanthine class of psychoactive drugs.[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. It is a bitter, white crystalline purine, a methylxanthine alkaloid, and thus closely related chemically to the adenine and guanine contained in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, nuts, or leaves of a number of plants native to South America and East Asia. The most well known source of caffeine is the seed (commonly incorrectly referred to as the "bean") of Coffea plants. 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.[8]

Caffeine is classified by the Food and Drug Administration as "generally recognized as safe" (GRAS). Toxic doses, over 10 grams per day for an adult, are much higher than typical dose of under 500 milligrams per day. A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used and how it is prepared (e.g. drip, percolation, or espresso). Thus it requires roughly 50-100 ordinary cups of coffee to reach a lethal dose. However pure powdered caffeine, which is widely available as a dietary supplement, can be lethal in tablespoon-sized amounts. 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.[9] It may confer a modest protective effect against some diseases,[10] including Parkinson's disease[11] 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 non-decaffeinated coffee per day but more likely with over 5 cups per day.[12] 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.[13][14] Mild physical dependence can occur with chronic caffeine use and is associated with withdrawal symptoms such as headaches and irritability.[1][15] Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent 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, which can inhibit the growth of and kill competing seedlings (and potentially 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.



Caffeine is used in

Enhancing performance

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.[26] 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.[26]

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.[27] In shift workers it leads to fewer mistakes caused by drowsiness.[28]

In athletes, moderate doses of caffeine can improve sprint,[29] endurance,[30] and team sports performance,[31] but the improvements are usually not substantial. Some evidence suggests that coffee does not produce the performance enhancing effects observed in other caffeine sources.[32]

Side effects

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.[33] The caffeine-induced disorders recognized in the "The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition American Psychiatric Association (2013).[34] (DSM-5) are: caffeine-induced anxiety disorder, caffeine-induced sleep disorder, caffeine intoxication, caffeine withdrawal and caffeine-related disorder not otherwise specified. Caffeine in low doses may cause weak bronchodilation for up to four hours in asthmatics: it should therefore be avoided prior to having any lung function test performed.[35]


Caffeine can have negative effects on anxiety disorders.[36] A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder.[37][38] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety[39] or, rarely, trigger mania or psychosis. In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk.[40] Caffeine does not improve memory or learning,[41] but can improve cognitive functions in people who are fatigued, possibly due to its effect on alertness.[42] For some people, discontinuing caffeine use can significantly reduce anxiety.[43]


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.[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 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.[46][47]

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.[48] However, as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy.[49][50] 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.[51] 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.[14] 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).[52]

Risk of disease

Coffee consumption is associated with a lower overall risk of cancer.[53] 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.[54] 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.[54] A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.[55][56][57] Moderate coffee consumption may decrease the risk of cardiovascular disease,[12] and it may somewhat reduce the risk of type 2 diabetes.[58] 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.[59] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.[60] It may protect people from liver cirrhosis.[61] There is no evidence that coffee stunts a child's growth.[62] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.[63] Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.[64]

Reinforcement disorders

Dependence and withdrawal

Physical dependence (i.e., a state with undesirable physical withdrawal symptoms after stopping long-term caffeine use) may occur.[1] The associated withdrawal symptoms include drowsiness, headaches, irritability, inability to concentrate, and pain in the stomach, upper body, and joints.[1][15] Withdrawal headaches are experienced by roughly half of those who stop consuming caffeine for two days following an average daily intake of 235 mg.[65]


Caffeine use does not result in addiction.[1][2] By definition, a "caffeine addiction" would involve compulsive caffeine use despite significant adverse consequences.[66][67] The compulsive state associated with an addiction arises through pathological positive reinforcement.[66][67] Long term high-dose caffeine intake has not been shown to cause drug addiction in experimental models, nor has compulsive consumption of caffeine or caffeinated beverages been observed in humans.[1][2] Caffeine addiction was added to the ICDM-9; however, its addition is contested since this diagnostic model of caffeine addiction is not supported by evidence.[1][2] Evidence from research models suggests that caffeine does not act upon the dopaminergic neural mechanisms that give rise to an addiction.[2]


Tolerance (i.e., the diminishing effect of a drug resulting from repeated administration at a given dose) to the desired effect of alertness does not occur following repeated use. Tolerance to some undesired effects, particularly to caffeine's autonomic effects, develops quickly, especially among heavy coffee and energy drink consumers.[68] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.[52]


File:Main symptoms of Caffeine overdose.svg
Primary symptoms of caffeine intoxication[69]

Consumption of 1000–1500 mg per day is associated with a condition known as caffeinism.[70] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.[71]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90).[72] 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.[69] 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.[73][74]

Massive overdose can result in death.[75][76] The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be 150 to 200 milligrams per kilogram of body mass (75-100 cups of coffee for a 70 kilogram adult).[77] A number of fatalities have been caused by overdoses of readily available powdered caffeine supplements, for which the estimated lethal amount is less than a tablespoon.[78] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease[79] A death was reported in a man with liver cirrhosis who overdosed on caffeinated mints.[80][81][82]

Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration.[69]



Structure of a typical chemical synapse
File:Caffeine and adenosine.svg
Caffeine's primary mechanism of action is as an antagonist of adenosine receptors in the brain

In the absence of caffeine and when a person is awake and alert, little adenosine is present in (CNS) neurons. With a continued wakeful state, over time it accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes adenosine receptors; in other words, caffeine prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.[3]

Receptor and ion channel targets

Caffeine is a receptor antagonist at all adenosine receptor subtypes (A1, A2A, A2B, and A3 receptors).[3] Antagonism at these receptors stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heartrate, and constricts blood vessels.[3] Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;[3][83] adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Increased heart rate is caused by blockade of the adenosine A1 receptor.[3]

Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). 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.[84]

In addition to its activity at adenosine receptors, caffeine is an inositol triphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3).[85] It is also a competitive antagonist of the ionotropic glycine receptor.[86]

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.[87] As a competitive nonselective phosphodiesterase inhibitor,[88] caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha[89][90] and leukotriene[91] synthesis, and reduces inflammation and innate immunity.[91] Caffeine is also significantly implicated in cholinergic system where it e.g. inhibits enzyme acetylcholinesterase.[92]

Performance enhancing mechanism

A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine.[93] 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.[94]

Metabolite pharmacodynamics

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.[95]


File:Caffeine metabolites.svg
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 distributed throughout all bodily tissues.[4] Peak blood concentration is reached within 1–2 hours.[citation needed] It is eliminated by first-order kinetics.[96] Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine)[97] and chlorobutanol and caffeine (for the treatment of hyperemesis).[98]

Caffeine's biological half-life – the time required for the body to eliminate one-half of a dose – varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for caffeine metabolism) and age. In healthy adults, caffeine's half-life is between 3–7 hours.[3] Nicotine decreases the half-life by 30–50%,[52] while oral contraceptives can double it[52] and pregnancy can raise it to as much as 15 hours during the last trimester.[52] In newborns the half-life can be 80 hours or more, dropping very rapidly with age, possibly to less than the adult value by age 6 months.[52] The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and increases its elimination half-life more than tenfold; from 4.9 hours to 56 hours.[99]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,[100] each of which has its own effects on the body:

1,3,7-Trimethyluric acid is a minor caffeine metabolite.[3] 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.[101]

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 others.[102] 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.

Physical and chemical properties

Pure anhydrous caffeine is a white odorless powder with a melting point of 235–238 °C.[5][6] Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL).[103] It is also moderately soluble in ethanol (1.5 g/100 mL).[103] It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.[104] Caffeine does not contain any stereogenic centers[105] and hence is classified as an achiral molecule.[106]

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.[107]


Caffeine may be synthesized from dimethylurea and malonic acid,[108][109][110] but is rarely obtained from synthesis since it is readily available as a byproduct of decaffeination.[111]

Detection in body 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.[113]


Some analog substances have been created which mimic caffeine's properties with either function or structure or both, one of the latter is the drug DMPX.[114]

Natural occurrence

Around sixty plant species are known to contain caffeine.[115] Common sources are the "bean" (seed) of the coffee plant (the quantity varies, but 1.3% is a typical value[116]); 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.

Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant:[117] high caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.[118] 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.[119]

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.[120][clarification needed]


Caffeine Content in Select Food and Drugs[121][122][123][124][125]
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 (Script error: No such module "convert".) 31
Hershey's Milk Chocolate (11% cacao content) 1 bar (Script error: No such module "convert".) 10
Percolated coffee Script error: No such module "convert". 80–135 386–652
Drip coffee Script error: No such module "convert". 115–175 555–845
Coffee, decaffeinated Script error: No such module "convert". 5–15 24–72
Coffee, espresso Script error: No such module "convert". 100 1,691–2,254
Tea – black, green, and other types, – steeped for 3 min. Script error: No such module "convert". 22–74[124][125] 124–418
Guayakí yerba mate (loose leaf) Script error: No such module "convert". 85[126] approx. 358
Coca-Cola Classic Script error: No such module "convert". 34 96
Mountain Dew Script error: No such module "convert". 54 154
Pepsi Max Script error: No such module "convert". 69 194
Guaraná Antarctica Script error: No such module "convert". 30 100
Jolt Cola Script error: No such module "convert". 280 403
Red Bull Script error: No such module "convert". 80 320

Products containing caffeine are coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,[127] caffeine tablets, other oral products, and inhalation.



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;[128] 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.[129][130] Arabica coffee typically contains half the caffeine of the robusta variety.[128] 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.[129][130]


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.[131]

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.[131]

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.[citation 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.[132]

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 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.[133] 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.[122]


No-Doz 100 mg caffeine 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.[134]

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.[135] Another unusual intake route is SpazzStick, a caffeinated lip balm.[136] 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.[137]


Taking caffeine by inhalation was under scrutiny by some U.S. lawmakers in 2011.[138]

Combinations with other drugs


Main article: Decaffeination
File:CaffeineCrystals Fibrous 10xDarkField.jpg
Fibrous crystals of purified caffeine. Dark field light microscope image, the image covers an area of approx. 7 x 11mm.

Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, 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.[140]
  • 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.[140]
  • 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.[140]

"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.[141]


Discovery and spread of use

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.[142] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[143]

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.[144] 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.[145]

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".[146] Archaeologists have found evidence of this use far into antiquity,[147] possibly dating to Late Archaic times.[146]

Chemical identification, isolation, and synthesis

File:Pierre Joseph Pelletier.jpg
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).[148] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[149][150] 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.[151] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:[152] "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).[153] 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,[154] whereas Pelletier was the first to perform an elemental analysis.[155]

In 1827, M. Oudry isolated "théine" from tea,[156] but it was later proved by Mulder[157] and by Carl Jobst[158] that theine was actually caffeine.[150]

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.[159] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.[160]

Society and culture


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.[161]


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.[162][163][164] Charles II of England tried to ban it in 1676,[165][166] Frederick II of Prussia banned it in 1777,[167][168] and coffee was banned in Sweden at various times between 1756 and 1823.

In 1911, caffeine 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".[169] 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.[170][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]


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."[171]

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.[172][173]

Other organisms

File:Caffeinated spiderwebs modified.jpg
Caffeine has a significant effect on spiders, which is illustrated here in the erratic construction of their webs.

Pseudomonas putida CBB5 can live on pure caffeine, and can cleave caffeine into carbon dioxide and ammonia.[174]

Caffeine is toxic to birds[175] and to dogs and cats,[176] and has a pronounced adverse effect on mollusks, various insects, and spiders.[177] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.[178] Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the pollen producing plants.[179]



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    Melting Point
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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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  • Bersten, Ian (1999). Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria. Sydney: Helian Books. ISBN 0-9577581-0-3. 
  • Pendergrast, Mark (2001) [1999]. Uncommon Grounds: The History of Coffee and How It Transformed Our World. London: Texere. ISBN 1-58799-088-1. 

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