Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is the world's most widely consumed psychoactive drug. Unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. There are several known mechanisms of action to explain the effects of caffeine. The most prominent is that it reversibly blocks the action of adenosine on its receptor and consequently prevents the onset of drowsiness induced by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system.
Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guanine bases of 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 and confers on them several survival and reproductive benefits. The most well known source of caffeine is the coffee bean, a misnomer for the seed of Coffea plants. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to improve performance. To make these drinks, caffeine is extracted by steeping the plant product in water, a process called infusion. Caffeine-containing drinks, such as coffee, tea, and cola, are very popular; in 2005, 90% of North American adults consumed caffeine daily.
Caffeine can have both positive and negative health effects. It can be used to prevent and treat bronchopulmonary dysplasia of prematurity, and to treat apnea of prematurity: caffeine citrate was placed on the WHO Model List of Essential Medicines in 2007. It may confer a modest protective effect against some diseases, including Parkinson's disease 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. 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. Caffeine can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake. 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).
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 doses 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 available as a dietary supplement, can be lethal in tablespoon-sized amounts.
- 1 Uses
- 2 Side effects
- 3 Overdose
- 4 Interactions
- 5 Pharmacology
- 6 Chemistry
- 7 Natural occurrence
- 8 Products
- 9 History
- 10 Society and culture
- 11 Other organisms
- 12 Research
- 13 References
- 14 Bibliography
- 15 External links
Caffeine is used in:
- bronchopulmonary dysplasia in premature infants for both prevention and treatment. It may improve weight gain during therapy and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay. On the other hand, subtle long-term side effects are possible.
- apnea of prematurity as a primary treatment, but not prevention.
- orthostatic hypotension treatment.
Caffeine is a central nervous system stimulant and is used to reduce physical fatigue and to prevent or treat drowsiness. It produces increased wakefulness, increased focus, and better general body coordination. 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 approximately one hour after consumption, and a moderate dose usually subsides in about three or four hours. Caffeine can delay or prevent sleep, and improves task performance during sleep deprivation. Shift workers have fewer mistakes caused by drowsiness. At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, arousal, and concentration. A 2014 systematic review and meta-analysis found that concurrent caffeine and L-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching; these effects are most pronounced during the first hour post-dose.
Both caffeine and coffee are proven ergogenic aids in humans. Caffeine improves athletic performance in aerobic (especially endurance sports) and anaerobic conditions. Moderate doses of caffeine (around 5 mg/kg) can improve sprint performance, cycling and running time trial performance, endurance (i.e., it delays the onset of muscle fatigue and central fatigue), and cycling power output.
Adolescents and adults
Health Canada has not developed advice for adolescents because of insufficient data. Nonetheless, they suggest that daily caffeine intake for this age group be no more than 2.5 mg/kg body weight. This is because the maximum adult caffeine dose may not be appropriate for light weight adolescents or for younger adolescents who are still growing. The daily dose of 2.5 mg/kg body weight would not cause adverse health effects in the majority of adolescent caffeine consumers. This is a conservative suggestion since older and heavier weight adolescents may be able to consume adult doses of caffeine without suffering adverse effects. For the rest of the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.
In healthy children, caffeine intake produces effects that are "modest and typically innocuous". For children age 12 and under, Health Canada recommends a maximum daily caffeine intake of no more than 2.5 milligrams per kilogram of body weight. Based on average body weights of children, this translates to the following age-based intake limits:
|Age range||Maximum recommended daily caffeine intake|
|4–6||45 mg (slightly more than in 12 oz of a typical soft drink)|
|10–12||85 mg (about ½ cup of coffee)|
Caffeine can increase blood pressure and cause vasoconstriction. Long-term consumption at sufficiently high doses has been associated with chronic arterial stiffness. Coffee and caffeine can affect gastrointestinal motility and gastric acid secretion.
Doses of caffeine equivalent to the amount normally found in standard servings of tea, coffee and carbonated soft drinks appear to have no diuretic action. However, acute ingestion of caffeine in large doses (at least 250–300 mg, equivalent to the amount found in 2–3 cups of coffee or 5–8 cups of tea) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks. This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); it is mediated via proximal tubular adenosine receptor blockade. The acute increase in urinary output may increase the risk of dehydration. However, chronic users of caffeine develop a tolerance to this effect, and experience no increase in urinary output.
Caffeine in low doses may cause weak bronchodilation for up to four hours in asthmatics.
Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common, and include mild anxiety, jitteriness, insomnia, increased sleep latency, and reduced coordination. Caffeine can have negative effects on anxiety disorders. According to a 2011 literature review, caffeine use is positively associated with anxiety and panic disorders. At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety. For some people, discontinuing caffeine use can significantly reduce anxiety.
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. However, as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy. 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. 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. 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). There is also some evidence that caffeine intake by pregnant women is associated with a higher risk of giving birth to a low birth weight baby.
Caffeine's potential impact on female fertility, and its precise impact on pregnancy, is still being studied, but (as with many other substances in these circumstances) caution and moderation is warranted in any case until further information is known. For women of childbearing age, Health Canada recommends a maximum daily caffeine intake of no more than 300 mg, or a little over two 8 oz (237 mL) cups of coffee.
Whether or not caffeine can result in an addictive disorder depends on how addiction is defined. Some diagnostic models, such as the ICDM-9 and ICD-10, include a classification of caffeine addiction under a broader diagnostic model. Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.
"Caffeine addiction" was added to the ICDM-9 and ICD-10; however, its addition was contested with claims that this diagnostic model of caffeine addiction is not supported by evidence. The American Psychiatric Association's DSM-5 does not include the diagnosis of a caffeine addiction but proposes criteria for the disorder for more study.
Dependence and withdrawal
Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. Mild to increasingly severe physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day; some symptoms associated with psychological dependence may also occur during withdrawal. Caffeine dependence can involve withdrawal symptoms such as fatigue, headache, irritability, depressed mood, reduced contentedness, inability to concentrate, sleepiness or drowsiness, stomach pain, and joint pain. Withdrawal headaches are experienced by roughly half of those who stop consuming caffeine for two days following an average daily intake of 235 mg.
The ICD-10 includes a diagnostic model for caffeine dependence, but the DSM-5 does not. The APA, which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of this disorder is unclear. The DSM-5 instead lists "caffeine use disorder" in the emerging models section of the manual.
Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine (750 to 1200 mg/day spread throughout the day) have been shown to produce complete tolerance to some, but not all of the effects of caffeine. Doses as low as 100 mg/day, such as a 6 oz. cup of coffee or two to three 12 oz. servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption. Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.
Effect of genetics on withdrawal symptoms
Gene polymorphism could be associated with caffeine withdrawal symptoms and beta-1 and beta-2 play roles in caffeine withdrawal. For example, compared to people with homozygous Gly16 allele, people with the heterozygote ADR beta-2 Gly16 Arg gene polymorphism have a higher chance of feeling fatigue after 48 hours of caffeine withdrawal. It has been suspected that beta2- adrenoceptors are the main cause for this increase in mental fatigue symptoms. Beta 2- adrenoceptors are receptors that regulate glycogenolysis, secret insulin and intramuscularly transport glucose that is used for cerebral and muscle activity. Another example is given by the genes ADRbeta1 Gly16 Arg and CYP1A2-163A>C polymorphisms. They are associated with peoples' mood swings and increased depression level. Among subjects homozygous for the CYP1A2 allele, ADRbeta1 Gly389 allele carriers are reported to have a higher percentage of depression level increase when compared to Arg389 homozygotes subjects. Adrenergic receptors, again, play a key role in this symptom, as altered norepinephrine (an adrenoceptor agonist) neurotransmission contribute to the etiology of depression. This symptom is often seen in faster caffeine metabolizers, because caffeine effects diminish quicker in these people and provide them less opportunity to adapt to caffeine loss.
Risk of other diseases
Coffee consumption is associated with a lower overall risk of cancer. 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. 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. A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive. Moderate coffee consumption may decrease the risk of cardiovascular disease, and it may somewhat reduce the risk of type 2 diabetes. 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. Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals. It may protect people from liver cirrhosis. There is no evidence that coffee stunts a child's growth. Caffeine may increase the effectiveness of some medications including ones used to treat headaches. Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.
Consumption of 1 – 1.5 g per day is associated with a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.
Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90). 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. 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.
Massive overdose can result in death. 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). 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. The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease A death was reported in a man with liver cirrhosis who overdosed on caffeinated mints.
According to DSST, alcohol provides a reduction in performance and caffeine has a significant improvement in performance. When alcohol and caffeine are consumed jointly, the effects produced by caffeine are affected, but the alcohol effects remain the same. For example, when additional caffeine is added, the drug effect produced by alcohol is not reduced. However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed. Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.
Smoking tobacco increases caffeine clearance by 56%.
Oral birth control
Consumption of caffeine while orally administering birth control can extend the half-life of caffeine; therefore, greater attention should be taken during caffeine consumption.
|Structure of a typical chemical synapse|
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.
Receptor and ion channel targets
Caffeine is a receptor antagonist at all adenosine receptor subtypes (A1, A2A, A2B, and A3 receptors). Antagonism at these receptors stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heartrate, and constricts blood vessels. Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects; adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the adenosine A1 receptor.
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 antagonist.
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). It is also a competitive antagonist of the ionotropic glycine receptor.
Effects on striatal dopamine
While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1–D1 receptor heterodimer (this is a receptor complex with 1 adenosine A1 receptor and 1 dopamine D1 receptor) and the A2A–D2 receptor heterotetramer (this is a receptor complex with 2 adenosine A2A receptors and 2 dopamine D2 receptors). The A2A–D2 receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.
Caffeine also causes the release of dopamine in the dorsal striatum and nucleus accumbens core (a substructure within the ventral striatum), but not the nucleus accumbens shell, by antagonizing A1 receptors in the axon terminal of dopamine neurons and A1–A2A heterodimers (a receptor complex composed of 1 adenosine A1 receptor and 1 adenosine A2A receptor) in the axon terminal of glutamate neurons. During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance.
Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. As a competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity. Caffeine also affects the cholinergic system where it inhibits the enzyme acetylcholinesterase.
Caffeine antagonizes adenosine A2A receptors in the ventrolateral preoptic area (VLPO), thereby reducing inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal. Disinhibition of the tuberomammillary nucleus is the chief mechanism by which caffeine produces wakefulness-promoting effects.
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues. Peak blood concentration is reached within 1–2 hours. It is eliminated by first-order kinetics. Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and chlorobutanol and caffeine (for the treatment of hyperemesis). However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e. 1/3.5) of the oral amounts.
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. Nicotine decreases the half-life by 30–50%, while oral contraceptives can double it and pregnancy can raise it to as much as 15 hours during the last trimester. 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. 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.
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines, each of which has its own effects on the body:
- Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in blood plasma.
- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean (chocolate).
- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.
1,3,7-Trimethyluric acid is a minor caffeine metabolite. 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.
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. This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation.
Pure anhydrous caffeine is a bitter-tasting white odorless powder with a melting point of 235–238 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL). It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it. Caffeine does not contain any stereogenic centers and hence is classified as an achiral molecule.
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.
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.
- 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.
- 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.
"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.
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.
Some analog substances have been created which mimic caffeine's properties with either function or structure or both. Of the latter group are the xanthines DMPX and 8-chlorotheophylline, which is an ingredient in dramamine. Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.[unreliable source?] Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.
Some other caffeine analogs:
Around sixty plant species are known to contain caffeine. Common sources are the "bean" (seed) of the coffee plant (the quantity varies, but 1.3% is a typical value); 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: high caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection. 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.
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.[clarification needed]
|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||124–418|
|Guayakí yerba mate (loose leaf)||6 g (0.21 oz)||85||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|
The world's primary source of caffeine is the coffee "bean" (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; 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. Arabica coffee typically contains half the caffeine of the robusta variety. 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.
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.
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.
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 0 to 55 milligrams of caffeine per 12 ounce 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.
- 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.
- 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.
- The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea, which is both brewed locally and sold commercially throughout the world.
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. 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.
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. These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.
Other oral products
One U.S. company is marketing oral dissolvable caffeine strips. Another intake route is SpazzStick, a caffeinated lip balm. 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.
Taking caffeine by inhalation was under scrutiny by some U.S. lawmakers in 2011.
Combinations with other drugs
- Some beverages combine alcohol with caffeine to create a caffeinated alcoholic drink. The stimulant effects of caffeine may mask the depressant effects of alcohol, potentially reducing the user's awareness of their level of intoxication. Such beverages have been the subject of bans due to safety concerns. In particular, United States Food and Drug Administration has classified caffeine added to malt liquor beverages as an "unsafe food additive".
- Ya ba contains a combination of methamphetamine and caffeine.
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. Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.
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. 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.
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.
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".
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". Archaeologists have found evidence of this use far into antiquity, possibly dating to Late Archaic times.
Chemical identification, isolation, and synthesis
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). According to Runge, he did this at the behest of Johann Wolfgang von Goethe. 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. However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating: "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). 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 ...
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. This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
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. Charles II of England tried to ban it in 1676, Frederick II of Prussia banned it in 1777, 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". 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.[unreliable source?]
Society and culture
The Food and Drug Administration (FDA) in the United States currently allows only beverages containing less than 0.02% caffeine; but caffeine powder, which is sold as a dietary supplement, is unregulated. It is a regulatory requirement that the label of most prepackaged foods must declare a list of ingredients, including food additives such as caffeine, in descending order of proportion. However, there is no regulatory provision for mandatory quantitative labeling of caffeine, (e.g., milligrams caffeine per stated serving size). There are a number of food ingredients that naturally contain caffeine. These ingredients must appear in food ingredient lists. However, as is the case for "food additive caffeine", there is no requirement to identify the quantitative amount of caffeine in composite foods containing ingredients that are natural sources of caffeine. While coffee or chocolate are broadly recognized as caffeine sources, some ingredients (e.g. guarana, yerba maté) are likely less recognized as caffeine sources. For these natural sources of caffeine, there is no regulatory provision requiring that a food label identify the presence of caffeine nor state the amount of caffeine present in the food.
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.
Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine. 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: " . . . the Church revelation spelling out health practices (Doctrine and Covenants 89) does not mention the use of caffeine. The Church's health guidelines prohibit alcoholic drinks, smoking or chewing of tobacco, and 'hot drinks' – taught by Church leaders to refer specifically to tea and coffee."
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.
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.
Caffeine is toxic to birds and to dogs and cats, and has a pronounced adverse effect on mollusks, various insects, and spiders. This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight. Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the pollen producing plants.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 375. ISBN 9780071481274.
Long-term caffeine use can lead to mild physical dependence. A withdrawal syndrome characterized by drowsiness, irritability, and headache typically lasts no longer than a day. True compulsive use of caffeine has not been documented.
- Karch SB (2009). Karch's pathology of drug abuse (4th ed.). Boca Raton: CRC Press. pp. 229–230. ISBN 9780849378812.
The suggestion has also been made that a caffeine dependence syndrome exists ... In one controlled study, dependence was diagnosed in 16 of 99 individuals who were evaluated. The median daily caffeine consumption of this group was only 357 mg per day (Strain et al., 1994).
Since this observation was first published, caffeine addiction has been added as an official diagnosis in ICDM 9. This decision is disputed by many and is not supported by any convincing body of experimental evidence. ... All of these observations strongly suggest that caffeine does not act on the dopaminergic structures related to addiction, nor does it improve performance by alleviating any symptoms of withdrawal
- American Psychiatric Association (2013). "Substance-Related and Addictive Disorders" (PDF). American Psychiatric Publishing. pp. 1–2. Retrieved 10 July 2015.
Substance use disorder in DSM-5 combines the DSM-IV categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe. ... Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with “addiction” when in fact dependence can be a normal body response to a substance. ... DSM-5 will not include caffeine use disorder, although research shows that as little as two to three cups of coffee can trigger a withdrawal effect marked by tiredness or sleepiness. There is sufficient evidence to support this as a condition, however it is not yet clear to what extent it is a clinically significant disorder.
- Introduction to Pharmacology Third Edition. Abingdon: CRC Press. 2007. pp. 222–223. ISBN 9781420047424.
- Juliano LM, Griffiths RR (2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features" (PDF). Psychopharmacology (Berl.). 176 (1): 1–29. doi:10.1007/s00213-004-2000-x. PMID 15448977. Archived (PDF) from the original on 29 January 2012.
Results: Of 49 symptom categories identified, the following 10 fulfilled validity criteria: headache, fatigue, decreased energy/ activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy/not clearheaded. In addition, flu-like symptoms, nausea/vomiting, and muscle pain/stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%. Typically, onset of symptoms occurred 12–24 h after abstinence, with peak intensity at 20–51 h, and for a duration of 2–9 days.
- Poleszak, Ewa; Szopa, Aleksandra; Wyska, Elżbieta; Kukuła-Koch, Wirginia; Serefko, Anna; Wośko, Sylwia; Bogatko, Karolina; Wróbel, Andrzej; Wlaź, Piotr (July 2015). "Caffeine augments the antidepressant-like activity of mianserin and agomelatine in forced swim and tail suspension tests in mice". Pharmacological Reports. 68: 56–61. doi:10.1016/j.pharep.2015.06.138. Retrieved 12 September 2015.
- "Caffeine". DrugBank. University of Alberta. 16 September 2013. Retrieved 8 August 2014.
- "Caffeine". Pubchem Compound. NCBI. Retrieved 16 October 2014.
178 deg C (sublimes)
238 DEG C (ANHYD)
- "Caffeine". ChemSpider. Royal Society of Chemistry. Retrieved 16 October 2014.
Experimental Melting Point:
234–236 °C Alfa Aesar
237 °C Oxford University Chemical Safety Data
238 °C LKT Labs [C0221]
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
Experimental Boiling Point:
178 °C (Sublimes) Alfa Aesar
178 °C (Sublimes) Alfa Aesar 39214
- Nehlig A, Daval JL, Debry G (1992). "Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects". Brain Res. Brain Res. Rev. 17 (2): 139–70. doi:10.1016/0165-0173(92)90012-B. PMID 1356551.
- Lovett R (24 September 2005). "Coffee: The demon drink?". New Scientist (2518). (subscription required (. ))
- WHO Model List of Essential Medicines (PDF) (18th ed.). World Health Organization. October 2013 [April 2013]. p. 34 [p. 38 of pdf]. Retrieved 23 December 2014.
- Cano-Marquina A, Tarín JJ, Cano A (May 2013). "The impact of coffee on health". Maturitas. 75 (1): 7–21. doi:10.1016/j.maturitas.2013.02.002. PMID 23465359. Retrieved 15 January 2014.
- Qi H, Li S (23 July 2003). "Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease". Geriatr Gerontol Int. 14: 430–439. doi:10.1111/ggi.12123. PMID 23879665.
- Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB (11 February 2014). "Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.". Circulation. 129 (6): 643–59. doi:10.1161/circulationaha.113.005925. PMID 24201300.
- Mayo Clinic staff. "Pregnancy Nutrition: Foods to avoid during pregnancy". Mayo Clinic. Retrieved 15 April 2012.
- American College of Obstetricians and Gynecologists (August 2010). "ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstet Gynecol. 116 (2 Pt 1): 467–8. doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.
- Robertson D, Wade D, Workman R, Woosley RL, Oateshttp JA (1981). "Tolerance to the humoral and hemodynamic effects of caffeine in man". The Journal of Clinical Investigation. 67 (4): 1111–1117. doi:10.1172/JCI110124. PMC .
- Kugelman A, Durand M (2011). "A comprehensive approach to the prevention of bronchopulmonary dysplasia". Pediatr Pulmonol. 46 (12): 1153–65. doi:10.1002/ppul.21508. PMID 21815280.
- Schmidt B (2005). "Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial". Biol. Neonate. 88 (3): 208–13. doi:10.1159/000087584. PMID 16210843.
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W (2006). "Caffeine therapy for apnea of prematurity". N. Engl. J. Med. 354 (20): 2112–21. doi:10.1056/NEJMoa054065. PMID 16707748.
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W (November 2007). "Long-term effects of caffeine therapy for apnea of prematurity". N. Engl. J. Med. 357 (19): 1893–902. doi:10.1056/NEJMoa073679. PMID 17989382.
- Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS (January 2012). "Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity". JAMA. 307 (3): 275–82. doi:10.1001/jama.2011.2024. PMID 22253394.
- Funk GD (2009). "Losing sleep over the caffeination of prematurity". J. Physiol. (Lond.). 587 (Pt 22): 5299–300. doi:10.1113/jphysiol.2009.182303. PMC . PMID 19915211.
- Mathew OP (2011). "Apnea of prematurity: pathogenesis and management strategies". J Perinatol. 31 (5): 302–10. doi:10.1038/jp.2010.126. PMID 21127467.
- Henderson-Smart, DJ; De Paoli, AG (8 December 2010). "Prophylactic methylxanthine for prevention of apnoea in preterm infants.". The Cochrane database of systematic reviews (12): CD000432. doi:10.1002/14651858.CD000432.pub2. PMID 21154344.
- "Caffeine: Summary of Clinical Use". IUPHAR Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 13 February 2015.
- Gupta, V; Lipsitz, LA (October 2007). "Orthostatic hypotension in the elderly: diagnosis and treatment.". The American Journal of Medicine. 120 (10): 841–7. doi:10.1016/j.amjmed.2007.02.023. PMID 17904451.
- Bolton S (1981). "Caffeine: Psychological Effects, Use and Abuse" (PDF). Orthomolecular Psychiatry. 10 (3): 202–211.
- Snel J, Lorist MM (2011). "Effects of caffeine on sleep and cognition". Prog. Brain Res. Progress in Brain Research. 190: 105–17. doi:10.1016/B978-0-444-53817-8.00006-2. ISBN 978-0-444-53817-8. PMID 21531247.
- Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I (2010). Ker K, ed. "Caffeine for the prevention of injuries and errors in shift workers". Cochrane Database Syst Rev (5): CD008508. doi:10.1002/14651858.CD008508. PMC . PMID 20464765.
- Nehlig A (2010). "Is caffeine a cognitive enhancer?". J. Alzheimers Dis. 20 Suppl 1: S85–94. doi:10.3233/JAD-2010-091315. PMID 20182035.
Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on this, and caffeine appears to improve memory performance under suboptimal alertness. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. ... Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties.
- Camfield DA, Stough C, Farrimond J, Scholey AB (2014). "Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis". Nutr. Rev. 72 (8): 507–22. doi:10.1111/nure.12120. PMID 24946991.
- Pesta DH, Angadi SS, Burtscher M, Roberts CK (2013). "The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance". Nutr Metab (Lond). 10 (1): 71. doi:10.1186/1743-7075-10-71. PMC . PMID 24330705.
Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see [26,30,31]). Trained athletes seem to benefit from a moderate dose of 5 mg/kg , however, even lower doses of caffeine (1.0–2.0 mg/kg) may improve performance . Some groups found significantly improved time trial performance  or maximal cycling power , most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively. Theophylline, a metabolite of caffeine, seems to be even more effective in doing so . The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities . ... For both caffeine-naïve as well as caffeine-habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise . ... In summary, caffeine, even at physiological doses (3–6 mg/kg), as well as coffee are proven ergogenic aids and as such – in most exercise situations, especially in endurance-type events – clearly work-enhancing . It most likely has a peripheral effect targeting skeletal muscle metabolism as well as a central effect targeting the brain to enhance performance, especially during endurance events (see Table 1). Also for anaerobic tasks, the effect of caffeine on the CNS might be most relevant. ... Muendel et al.  found a 17% improvement in time to exhaustion after nicotine patch application compared to a placebo without affecting cardiovascular and respiratory parameters or substrate metabolism. In this sense, nicotine seems to exert similar effects as caffeine by delaying the development of central fatigue as impaired central drive is an important factor contributing to fatigue during exercise. ... The physiological effects of the above mentioned substances are well established. However, the ergogenic effect of some of the discussed drugs may be questioned and one has to consider the cohort tested for every specific substance. However, only caffeine has enough strength of evidence to be considered an ergogenic aid.
- Bishop D (2010). "Dietary supplements and team-sport performance". Sports Med. 40 (12): 995–1017. doi:10.2165/11536870-000000000-00000. PMID 21058748.
- Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (2011). "Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance?". Int J Sport Nutr Exerc Metab. 21 (1): 71–84. PMID 21411838.
- Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Prim. Care. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655.
Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task
- "It's Your Health – Caffeine". Health Canada. March 2010. Retrieved 8 November 2010.
- Castellanos, F. X.; Rapoport, J. L. (2002). "Effects of caffeine on development and behavior in infancy and childhood: A review of the published literature". Food and Chemical Toxicology. 40 (9): 1235–1242. doi:10.1016/S0278-6915(02)00097-2.
- Daniels JW, Molé PA, Shaffrath JD, Stebbins CL (1998). "Effects of caffeine on blood pressure, heart rate, and forearm blood flow during dynamic leg exercise". Journal of applied physiology. 85 (1): 154–9. PMID 9655769.
- D. Bracco, Ferrarra JM, Arnaud MJ, Jéquier E, Schutz Y (1995). "Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women". American Journal of Physiology. 269 (4): E671–8. PMID 7485480.
- Mahmud A, Feely J (2001). "Acute effect of caffeine on arterial stiffness and aortic pressure waveform". Hypertension. 38 (2): 227–31. doi:10.1161/01.HYP.38.2.227. PMID 11509481.
- Boekema PJ, Samsom M, Van Berge Henegouwen GP, Smout AJ (1999). "Coffee and gastrointestinal function: Facts and fiction. A review". Scandinavian journal of gastroenterology. 230 (230): 35–9. PMID 10499460.
- Cohen S, Booth GH (1975). "Gastric acid secretion and lower-esophageal-sphincter pressure in response to coffee and caffeine". The New England Journal of Medicine. 293 (18): 897–9. doi:10.1056/NEJM197510302931803. PMID 1177987.
- Sherwood, Lauralee; Kell, Robert (2009). Human Physiology: From Cells to Systems (1st Canadian ed.). Nelsen. pp. 613–9. ISBN 0-17-644107-7.
- Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K, Jéquier E (1980). "Caffeine and coffee: Their influence on metabolic rate and substrate utilization in normal weight and obese individuals". The American Journal of Clinical Nutrition. 33 (5): 989–97. PMID 7369170.
- Dulloo AG, Geissler CA, Horton T, Collins A, Miller DS (1989). "Normal caffeine consumption: Influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers". The American Journal of Clinical Nutrition. 49 (1): 44–50. PMID 2912010.
- Koot P, Deurenberg P (1995). "Comparison of changes in energy expenditure and body temperatures after caffeine consumption". Annals of Nutrition and Metabolism. 39 (3): 135–42. doi:10.1159/000177854. PMID 7486839.
- "Caffeine in the diet". MedlinePlus, US National Library of Medicine. 30 April 2013. Retrieved 2 January 2015.
- Rapuri PB, Gallagher JC, Kinyamu HK, Ryschon KL (2001). "Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes". The American Journal of Clinical Nutrition. 74 (5): 694–700. PMID 11684540.
- Maughan RJ, Griffin J (2003). "Caffeine ingestion and fluid balance: a review". J Hum Nutr Diet. 16 (6): 411–20. doi:10.1046/j.1365-277X.2003.00477.x. PMID 19774754.
- Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism Am. J. Physiol. Renal Physiol. 1 July 2008 295:F35-F36
- Anahad O'connor (4 March 2008). "Really? The claim: caffeine causes dehydration". New York Times. Retrieved 3 August 2009.
- Armstrong LE, Casa DJ, Maresh CM, Ganio MS (2007). "Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance". Exerc Sport Sci Rev. 35 (3): 135–40. doi:10.1097/jes.0b013e3180a02cc1. PMID 17620932.
- Welsh EJ, Bara A, Barley E, Cates CJ (2010). Welsh EJ, ed. "Caffeine for asthma". Cochrane Database of Systematic Reviews (1): CD001112. doi:10.1002/14651858.CD001112.pub2. PMID 20091514.
- Tarnopolsky MA (2010). "Caffeine and creatine use in sport". Ann. Nutr. Metab. 57 Suppl 2: 1–8. doi:10.1159/000322696. PMID 21346331.
- Winston AP (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment. 11 (6): 432–439. doi:10.1192/apt.11.6.432.
- Vilarim MM, Rocha Araujo DM, Nardi AE (2011). "Caffeine challenge test and panic disorder: A systematic literature review". Expert Review of Neurotherapeutics. 11 (8): 1185–95. doi:10.1586/ern.11.83. PMID 21797659.
- Smith A (September 2002). "Effects of caffeine on human behavior". Food Chem. Toxicol. 40 (9): 1243–55. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
- Bruce MS, Lader M (February 1989). "Caffeine abstention in the management of anxiety disorders". Psychol Med. 19 (1): 211–4. doi:10.1017/S003329170001117X. PMID 2727208.
- Smith A (2002). "Effects of caffeine on human behavior". Food and Chemical Toxicology. 40 (9): 1243–55. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
- Lara DR (2010). "Caffeine, mental health, and psychiatric disorders". J. Alzheimers Dis. 20 Suppl 1: S239–48. doi:10.3233/JAD-2010-1378. PMID 20164571.
- Brent RL, Christian MS, Diener RM (2011). "Evaluation of the reproductive and developmental risks of caffeine". Birth Defects Res. B Dev. Reprod. Toxicol. 92 (2): 152–87. doi:10.1002/bdrb.20288. PMC . PMID 21370398.
- Kuczkowski KM (2009). "Caffeine in pregnancy". Arch. Gynecol. Obstet. 280 (5): 695–8. doi:10.1007/s00404-009-0991-6. PMID 19238414.
- Jahanfar S, Sharifah H (2009). Jahanfar S, ed. "Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome". Cochrane Database Syst Rev (2): CD006965. doi:10.1002/14651858.CD006965.pub2. PMID 19370665.
- "Food Standards Agency publishes new caffeine advice for pregnant women". Retrieved 3 August 2009.
- Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (1999). "Actions of caffeine in the brain with special reference to factors that contribute to its widespread use". Pharmacol. Rev. 51 (1): 83–133. PMID 10049999.
- Chen, Ling-Wei; Wu, Yi; Neelakantan, Nithya; Chong, Mary Foong-Fong; Pan, An; van Dam, Rob M (19 September 2014). "Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis". BMC Medicine. 12 (1). doi:10.1186/s12916-014-0174-6.
- Budney, AJ; Emond, JA (November 2014). "Caffeine addiction? Caffeine for youth? Time to act!". Addiction (Abingdon, England). 109 (11): 1771–2. doi:10.1111/add.12594. PMID 24984891.
Academics and clinicians, however, have not yet reached consensus about the potential clinical importance of caffeine addiction (or 'use disorder')
- Meredith, SE; Juliano, LM; Hughes, JR; Griffiths, RR (September 2013). "Caffeine Use Disorder: A Comprehensive Review and Research Agenda.". Journal of caffeine research. 3 (3): 114–130. doi:10.1089/jcr.2013.0016. PMID 24761279.
- Riba, edited by Allan Tasman, Jerald Kay, Jeffrey A. Lieberman, Michael B. First, Michelle B. (2014). Psychiatry (Fourth ed.). p. 1446. ISBN 9781118753361.
- Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci. 15 (4): 431–443. PMC . PMID 24459410.
DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement
- Miller PM (2013). "Chapter III: Types of Addiction". Principles of addiction comprehensive addictive behaviors and disorders (1st ed.). Elsevier Academic Press. p. 784. ISBN 9780123983619. Retrieved 11 July 2015.
Astrid Nehlig and colleagues present evidence that in animals caffeine does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. A single photon emission computed tomography (SPECT) assessment of brain activation in humans showed that caffeine activates regions involved in the control of vigilance, anxiety, and cardiovascular regulation but did not affect areas involved in reinforcement and reward.
- Nehlig A, Armspach JP, Namer IJ (2010). "SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence". Dialogues Clin Neurosci. 12 (2): 255–263. PMC . PMID 20623930.
Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. ... these earlier data plus the present data reflect that caffeine at doses representing about two cups of coffee in one sitting does not activate the circuit of dependence and reward and especially not the main target area, the nucleus accumbens. ,, ... Therefore, caffeine appears to be different from drugs of dependence like cocaine, amphetamine, morphine, and nicotine, and does not fulfil the common criteria or the scientific definitions to be considered an addictive substance.42
- Temple, JL (June 2009). "Caffeine use in children: what we know, what we have left to learn, and why we should worry.". Neuroscience and biobehavioral reviews. 33 (6): 793–806. doi:10.1016/j.neubiorev.2009.01.001. PMID 19428492.
Through these interactions, caffeine is able to directly potentiate dopamine neurotransmission, thereby modulating the rewarding and addicting properties of nervous system stimuli.
- "ICD-10 Version:2015". World Health Organization. 2015. Retrieved 10 July 2015.
F15 Mental and behavioural disorders due to use of other stimulants, including caffeine ...
.2 Dependence syndrome
A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.
The dependence syndrome may be present for a specific psychoactive substance (e.g. tobacco, alcohol, or diazepam), for a class of substances (e.g. opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:]
- Addicott, MA (September 2014). "Caffeine Use Disorder: A Review of the Evidence and Future Implications.". Current addiction reports. 1 (3): 186–192. doi:10.1007/s40429-014-0024-9. PMID 25089257.
- Association, American Psychiatry (2013). Diagnostic and statistical manual of mental disorders : DSM-5 (5th ed.). Washington [etc.]: American Psychiatric Publishing. pp. 792–795. ISBN 0890425558.
- "Information about caffeine dependence". Caffeinedependence.org. John Hopkins Medicine. 9 July 2003. Archived from the original on 23 May 2012. Retrieved 25 May 2012.
- Silverman K, Evans SM, Strain EC, Griffiths RR (October 1992). "Withdrawal syndrome after the double-blind cessation of caffeine consumption". N. Engl. J. Med. 327 (16): 1109–14. doi:10.1056/NEJM199210153271601. PMID 1528206.
- Day-Tasevski, Erica (6 April 2010). Genetic Determinants of the Acute Effects and Withdrawal Symptoms of Caffeine (MSc Thesis). University of Toronto. hdl:1807/24245.[page needed]
- Nkondjock A (May 2009). "Coffee consumption and the risk of cancer: an overview". Cancer Lett. 277 (2): 121–5. doi:10.1016/j.canlet.2008.08.022. PMID 18834663.
- Arab L (2010). "Epidemiologic evidence on coffee and cancer". Nutrition and cancer. 62 (3): 271–83. doi:10.1080/01635580903407122. PMID 20358464.
- Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N (2010). "Caffeine intake and dementia: systematic review and meta-analysis". J. Alzheimers Dis. 20 Suppl 1: S187–204. doi:10.3233/JAD-2010-091387. PMID 20182026.
- Marques S, Batalha VL, Lopes LV, Outeiro TF (2011). "Modulating Alzheimer's disease through caffeine: a putative link to epigenetics". J. Alzheimers Dis. 24 (2): 161–71. doi:10.3233/JAD-2011-110032. PMID 21427489.
- Arendash GW, Cao C (2010). "Caffeine and coffee as therapeutics against Alzheimer's disease". J. Alzheimers Dis. 20 Suppl 1: S117–26. doi:10.3233/JAD-2010-091249. PMID 20182037.
- van Dam RM (2008). "Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer". Applied Physiology, Nutrition, and Metabolism. 33 (6): 1269–1283. doi:10.1139/H08-120. PMID 19088789.
- Zhang Z, Hu G, Caballero B, Appel L, Chen L (June 2011). "Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies". Am. J. Clin. Nutr. 93 (6): 1212–9. doi:10.3945/ajcn.110.004044. PMID 21450934.
- Li M, Wang M, Guo W, Wang J, Sun X (March 2011). "The effect of caffeine on intraocular pressure: a systematic review and meta-analysis". Graefes Arch. Clin. Exp. Ophthalmol. 249 (3): 435–42. doi:10.1007/s00417-010-1455-1. PMID 20706731.
- Muriel P, Arauz J (2010). "Coffee and liver diseases". Fitoterapia. 81 (5): 297–305. doi:10.1016/j.fitote.2009.10.003. PMID 19825397.
- O'Connor A (2007). Never shower in a thunderstorm : surprising facts and misleading myths about our health and the world we live in (1st ed.). New York: Times Books. p. 144. ISBN 978-0-8050-8312-5. Retrieved 15 January 2014.
- Gilmore B, Michael M (February 2011). "Treatment of acute migraine headache". Am Fam Physician. 83 (3): 271–80. PMID 21302868.
- Hackett PH (2010). "Caffeine at high altitude: java at base Camp". High Alt. Med. Biol. 11 (1): 13–7. doi:10.1089/ham.2009.1077. PMID 20367483.
- "Caffeine (Systemic)". MedlinePlus. 25 May 2000. Archived from the original on 23 February 2007. Retrieved 3 August 2009.
- Winston AP, Hardwick E, Jaberi N (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment. 11 (6): 432–439. doi:10.1192/apt.11.6.432. Retrieved 19 December 2013.
- Iancu I, Olmer A, Strous RD (2007). "Caffeinism: History, clinical features, diagnosis, and treatment". In Smith BD, Gupta U, Gupta BS. Caffeine and Activation Theory: Effects on Health and Behavior. CRC Press. pp. 331–344. ISBN 978-0-8493-7102-8. Retrieved 15 January 2014.
- American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). American Psychiatric Association. ISBN 0-89042-062-9.
- "Caffeine overdose". MedlinePlus. 4 April 2006. Retrieved 3 August 2009.
- Verkhratsky A (January 2005). "Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons". Physiol. Rev. 85 (1): 201–79. doi:10.1152/physrev.00004.2004. PMID 15618481.
- Holmgren P, Nordén-Pettersson L, Ahlner J (2004). "Caffeine fatalities – four case reports". Forensic Science International. 139 (1): 71–3. doi:10.1016/j.forsciint.2003.09.019. PMID 14687776.
- "FDA Consumer Advice on Powdered Pure Caffeine". FDA. Retrieved 20 August 2014.
- Peters JM (1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature". The Journal of Clinical Pharmacology and the Journal of New Drugs. 7 (3): 131–141. doi:10.1002/j.1552-4604.1967.tb00034.x.
- Murray Carpenter. "Caffeine powder poses deadly risks". New York Times. Retrieved 18 May 2015.
- Rodopoulos N, Wisén O, Norman A (May 1995). "Caffeine metabolism in patients with chronic liver disease". Scand. J. Clin. Lab. Invest. 55 (3): 229–42. doi:10.3109/00365519509089618. PMID 7638557.
- Cheston P, Smith L (11 October 2013). "Man died after overdosing on caffeine mints". The Independent. Retrieved 13 October 2013.
- Prynne M (11 October 2013). "Warning over caffeine sweets after father dies from overdose". The Telegraph. Retrieved 13 October 2013.
- Fricker M (12 October 2013). "John Jackson: Family of dad who died from caffeine overdose after eating MINTS want them removed from sale". Daily Mirror. Retrieved 13 October 2013.
- MacKay M, Tiplady B, Scholey AB (2002). "Interactions between alcohol and caffeine in relation to psychomotor speed and accuracy". Human psychopharmacology. 17 (3): 151–6. doi:10.1002/hup.371. PMID 12404692.
- Liguori A, Robinson JH (2001). "Caffeine antagonism of alcohol-induced driving impairment". Drug and Alcohol Dependence. 63 (2): 123–9. doi:10.1016/s0376-8716(00)00196-4. PMID 11376916.
- Marczinski CA, Fillmore MT (2003). "Dissociative antagonistic effects of caffeine on alcohol-induced impairment of behavioral control". Experimental and clinical psychopharmacology. 11 (3): 228–36. doi:10.1037/1064-12184.108.40.206. PMID 12940502.
- Zevin & Benowitz (1999). "Drug Interactions with Tobacco Smoking". Clin Pharmacokinet. 6 (6): 425–438.
- Benowitz NL (1990). "Clinical pharmacology of caffeine". Annual Review of Medicine. 41: 277–88. doi:10.1146/annurev.me.41.020190.001425. PMID 2184730.
- "World of Caffeine". World of Caffeine. 15 June 2013. Retrieved 19 December 2013.
- Fisone G, Borgkvist A, Usiello A (2004). "Caffeine as a psychomotor stimulant: mechanism of action". Cell. Mol. Life Sci. 61 (7–8): 857–72. doi:10.1007/s00018-003-3269-3. PMID 15095008.
- "Caffeine". IUPHAR. International Union of Basic and Clinical Pharmacology. Retrieved 2 November 2014.
- Duan L, Yang J, Slaughter MM (August 2009). "Caffeine inhibition of ionotropic glycine receptors". J. Physiol. (Lond.). 587 (Pt 16): 4063–75. doi:10.1113/jphysiol.2009.174797. PMC . PMID 19564396.
- Ferré S (2010). "Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine". J. Alzheimers Dis. 20 Suppl 1: S35–49. doi:10.3233/JAD-2010-1400. PMID 20182056.
By targeting A1-A2A receptor heteromers in striatal glutamatergic terminals and A1 receptors in striatal dopaminergic terminals (presynaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A-D2 and A1-D1 receptor heteromers.
- Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, Lluís C, Casadó V, Volkow ND (2015). "Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer". Neuropharmacology. doi:10.1016/j.neuropharm.2015.05.028. PMID 26051403.
- Bonaventura J, Navarro G, Casadó-Anguera V, Azdad K, Rea W, Moreno E, Brugarolas M, Mallol J, Canela EI, Lluís C, Cortés A, Volkow ND, Schiffmann SN, Ferré S, Casadó V (2015). "Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer". Proc. Natl. Acad. Sci. U.S.A. 112 (27): E3609–18. doi:10.1073/pnas.1507704112. PMC . PMID 26100888.
Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R.
- Ferré S (2016). "Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders". Psychopharmacology (Berl.). doi:10.1007/s00213-016-4212-2. PMID 26786412.
The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants.
- Ferré S (2008). "An update on the mechanisms of the psychostimulant effects of caffeine". J. Neurochem. 105 (4): 1067–1079. doi:10.1111/j.1471-4159.2007.05196.x. PMID 18088379.
On the other hand, our 'ventral shell of the nucleus accumbens' very much overlaps with the striatal compartment simply described by De Luca et al. (2007) as 'nucleus accumbens shell,' where both studies show that caffeine does not modify the extracellular levels of dopamine. Therefore, the results of both experimental groups are basically the same and point to differential effects of caffeine in different striatal subcompartments. In fact, analyzing the effects of the intrastriatal perfusion of an A1 receptor antagonist in several other striatal compartments showed striking differences compared with the shell of the nucleus accumbens. Thus, A1 receptor blockade signiﬁcantly increased the extracellular concentration of dopamine, but not glutamate, in the core of the nucleus accumbens and in the caudate–putamen and the effect was more pronounced in the most medial compartments (Boryczet al. 2007). In summary, a subregional difference in the A1 receptor-mediated control of glutamate and dopamine release exists in the striatum ... A2A receptors play a crucial role in the sleep-promoting effects of adenosine and the arousal-enhancing effects of caffeine (Huang et al. 2007; Ferre´ et al. 2007a). Those A2A receptors are localized in the ventrolateral pre-optic area of the hypothalamus and their stimulation promotes sleep by inducing GABA release in the histaminergic tuberomammillary nucleus, thereby inhibiting the histaminergic arousal system ... chronic caffeine exposure counteracts both motor activation and dopamine release in the nucleus accumbens induced by caffeine or an A1 receptor antagonist ... An additional factor that might play a signiﬁcant role in caffeine tolerance is the signiﬁcant increase in plasma and extracellular concentrations of adenosine with chronic caffeine exposure ... The existence of an A1 receptor-mediated glutamate-independent modulation of dopamine release suggested the presence of functional A1 receptors in striatal dopaminergic terminals. ... In the SSM, adenosine acts pre- and post-synaptically through multiple mechanisms, which depend on heteromerization of A1 and A2A receptors among themselves and with D1 and D2 receptors, respectively. Caffeine produces its motor and reinforcing effects by releasing the pre- and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission in the SSM. By releasing the pre-synaptic brake, caffeine induces glutamate-dependent and glutamate-independent release of dopamine.
- Ribeiro JA, Sebastião AM (2010). "Caffeine and adenosine". J. Alzheimers Dis. 20 Suppl 1: S3–15. doi:10.3233/JAD-2010-1379. PMID 20164566.
- Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". J. Allergy Clin. Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.
- Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics (Sao Paulo). 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC . PMID 18568240.
- Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
- Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–94. doi:10.4049/jimmunol.174.2.589. PMID 15634873.
- Pohanka, M (2014). "The effects of caffeine on the cholinergic system.". Mini Reviews in Medicinal Chemistry. 14 (6): 543–549. doi:10.2174/1389557514666140529223436. PMID 24873820.
- Liguori A, Hughes JR, Grass JA (1997). "Absorption and subjective effects of caffeine from coffee, cola and capsules". Pharmacol. Biochem. Behav. 58 (3): 721–6. doi:10.1016/S0091-3057(97)00003-8. PMID 9329065.
- Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID (1981). "Plasma and salivary pharmacokinetics of caffeine in man". Eur. J. Clin. Pharmacol. 21 (1): 45–52. doi:10.1007/BF00609587. PMID 7333346.
- Graham JR (1954). "Rectal use of ergotamine tartrate and caffeine alkaloid for the relief of migraine". N. Engl. J. Med. 250 (22): 936–8. doi:10.1056/NEJM195406032502203. PMID 13165929.
- Brødbaek HB, Damkier P (2007). "The treatment of hyperemesis gravidarum with chlorobutanol-caffeine rectal suppositories in Denmark: practice and evidence". Ugeskrift for Læger (in Danish). 169 (22): 2122–3. PMID 17553397.
- Teekachunhatean, Supanimit; et al. (8 January 2013). "Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects". ISRN Pharmacology. Hindawi Publishing Corporation. 2013 (147238). doi:10.1155/2013/147238. Retrieved 8 August 2016.
- "Drug Interaction: Caffeine Oral and Fluvoxamine Oral". Medscape Multi-Drug Interaction Checker.
- "Caffeine". The Pharmacogenetics and Pharmacogenomics Knowledge Base. Retrieved 25 October 2010.
- Verbeeck RK (2008). "Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction". Eur. J. Clin. Pharmacol. 64 (12): 1147–61. doi:10.1007/s00228-008-0553-z. PMID 18762933.
- Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, Berndt SI, Boerwinkle E, Chanock S, Chatterjee N, Couper D, Curhan G, Heiss G, Hu FB, Hunter DJ, Jacobs K, Jensen MK, Kraft P, Landi MT, Nettleton JA, Purdue MP, Rajaraman P, Rimm EB, Rose LM, Rothman N, Silverman D, Stolzenberg-Solomon R, Subar A, Yeager M, Chasman DI, van Dam RM, Caporaso NE (April 2011). Gibson G, ed. "Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption". PLoS Genet. 7 (4): e1002033. doi:10.1371/journal.pgen.1002033. PMC . PMID 21490707.
- Susan Budavari, ed. (1996). The Merck Index (12th ed.). Whitehouse Station, NJ: Merck & Co., Inc. p. 1674.
- This is the pKa for protonated caffeine, given as a range of values included in Harry G. Brittain; Richard J. Prankerd (2007). Profiles of Drug Substances, Excipients and Related Methodology, volume 33: Critical Compilation of pKa Values for Pharmaceutical Substances. Academic Press. p. 15. ISBN 0-12-260833-X. Retrieved 15 January 2014.
- Klosterman L (2006). The Facts About Caffeine (Drugs). Benchmark Books (NY). p. 43. ISBN 0-7614-2242-0.
- Vallombroso T (2001). Organic Chemistry Pearls of Wisdom. Boston Medical Publishing Corp. p. 43. ISBN 1-58409-016-2.
- Keskineva N. "Chemistry of Caffeine" (PDF). Chemistry Department, East Stroudsburg University. Retrieved 2 January 2014.
- Temple NJ, Wilson T (2003). Beverages in Nutrition and Health. Totowa, NJ: Humana Press. p. 172. ISBN 1-58829-173-1.
- US patent 2785162, Swidinsky J, Baizer MM, "Process for the formylation of a 5-nitrouracil", published 12 March 1957, assigned to New York Quinine and Chemical Works, Inc.
- Zajac MA, Zakrzewski AG, Kowal MG, Narayan S (2003). "A Novel Method of Caffeine Synthesis from Uracil" (PDF). Synthetic Communications. 33 (19): 3291–3297. doi:10.1081/SCC-120023986.
- Simon Tilling. "Crystalline Caffeine". Bristol University. Retrieved 3 August 2009.
- "Caffeine biosynthesis". The Enzyme Database. Trinity College Dublin. Retrieved 24 September 2011.
- Senese F (20 September 2005). "How is coffee decaffeinated?". General Chemistry Online. Retrieved 3 August 2009.
- McCusker RR, Fuehrlein B, Goldberger BA, Gold MS, Cone EJ (October 2006). "Caffeine content of decaffeinated coffee". J Anal Toxicol. 30 (8): 611–3. doi:10.1093/jat/30.8.611. PMID 17132260. Lay summary – University of Florida News.
- Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 236–9. ISBN 0-931890-08-X.
- "3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs.". Life Sci. 43: 1671–84. 1988. doi:10.1016/0024-3205(88)90478-x. PMID 3193854.
- Kennerly, Jason (22 September 1995). "N Substituted Xanthines: A Caffeine Analog Information File". Retrieved 6 November 2015.
- Müller, Christa E.; Jacobson, Kenneth A. (19 August 2010). Fredholm, Bertil B., ed. "Xanthines as Adenosine Receptor Antagonists". Handbook of Experimental Pharmacology. 200. Springer Berlin Heidelberg: 151–199. doi:10.1007/978-3-642-13443-2_6. ISSN 0171-2004. PMC . PMID 20859796.
- "Which Plants Contain Caffeine?". medscape.com.
- For more information, see Alejandro Lopez-Ortiz. "Frequently Asked Questions about Coffee and Caffeine".
- Nathanson JA (1984). "Caffeine and related methylxanthines: possible naturally occurring pesticides". Science. 226 (4671): 184–7. doi:10.1126/science.6207592. PMID 6207592.
- Frischknecht PM, Ulmer-Dufek J, Baumann TW (1986). "Purine alkaloid formation in buds and developing leaflets of Coffea arabica: Expression of an optimal defence strategy?". Phytochemistry. 25 (3): 613–6. doi:10.1016/0031-9422(86)88009-8.
- Baumann TW (1984). "Metabolism and excretion of caffeine during germination of Coffea arabica L". Plant and Cell Physiology. 25 (8): 1431–6.
- Balentine D. A.; Harbowy M. E.; Graham H. N. (1998). G Spiller, ed. Tea: the Plant and its Manufacture; Chemistry and Consumption of the Beverage. Caffeine.[clarification needed]
- "Caffeine Content of Food and Drugs". Nutrition Action Health Newsletter. Center for Science in the Public Interest. 1996. Archived from the original on 14 June 2007. Retrieved 3 August 2009.
- "Caffeine Content of Beverages, Foods, & Medications". The Vaults of Erowid. 7 July 2006. Retrieved 3 August 2009.
- "Caffeine Content of Drinks". Caffeine Informer. Retrieved 8 December 2013.
- Chin JM, Merves ML, Goldberger BA, Sampson-Cone A, Cone EJ (October 2008). "Caffeine content of brewed teas". J Anal Toxicol. 32 (8): 702–4. doi:10.1093/jat/32.8.702. PMID 19007524.
- Richardson, Bruce (2009). "Too Easy to be True. De-bunking the At-Home Decaffeination Myth". Elmwood Inn. Retrieved 12 January 2012.
- "Traditional Yerba Mate in Biodegradable Bag". Guayaki Yerba Mate. Retrieved 17 July 2010.
- Matissek R (1997). "Evaluation of xanthine derivatives in chocolate: nutritional and chemical aspects". European Food Research and Technology. 205 (3): 175–84. doi:10.1007/s002170050148. INIST:2861730.
- "Caffeine". International Coffee Organization. Retrieved 1 August 2009.
- "Coffee and Caffeine FAQ: Does dark roast coffee have less caffeine than light roast?". Retrieved 2 August 2009.
- "All About Coffee: Caffeine Level". Jeremiah's Pick Coffee Co. Archived from the original on 18 March 2008. Retrieved 3 August 2009.
- Hicks MB, Hsieh YH, Bell LN (1996). "Tea preparation and its influence on methylxanthine concentration". Food Research International. 29 (3–4): 325–330. doi:10.1016/0963-9969(96)00038-5.
- "Nutrition and healthy eating". Mayo Clinic. Retrieved 18 November 2015.
- Bempong DK, Houghton PJ, Steadman K (1993). "The xanthine content of guarana and its preparations". Int J Pharmacog. 31 (3): 175–181. doi:10.3109/13880209309082937. ISSN 0925-1618.
- Smit HJ, Gaffan EA, Rogers PJ (November 2004). "Methylxanthines are the psycho-pharmacologically active constituents of chocolate". Psychopharmacology (Berl.). 176 (3–4): 412–9. doi:10.1007/s00213-004-1898-3. PMID 15549276.
- Bennett Alan Weinberg; Bonnie K. Bealer (2001). The World of caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. p. 195. ISBN 978-0-415-92723-9. Retrieved 15 January 2014.
- "LeBron James Shills for Sheets Caffeine Strips, a Bad Idea for Teens, Experts Say". Abcnews.go.com. ABC News. 10 June 2011. Retrieved 25 May 2012.
- Nancy Shute (15 April 2007). "Over The Limit:Americans young and old crave high-octane fuel, and doctors are jittery". US News and World Reports. Archived from the original on 8 January 2014.
- "F.D.A. Inquiry Leads Wrigley to Halt 'Energy Gum' Sales". New York Times. Associated Press. 8 May 2013. Retrieved 9 May 2013.
- http://www.washingtonpost.com/business/controversy-over-inhaled-caffeine-grows-as-as-sen-schumer-calls-for-fda-probe/2011/12/22/gIQAjQaVDP_story.html[dead link]
- "Food Additives & Ingredients > Caffeinated Alcoholic Beverages". fda.gov. Food and Drug Administration. 17 November 2010. Retrieved 24 January 2014.
- John C. Evans (1992). Tea in China: The History of China's National Drink. Greenwood Press. p. 2. ISBN 0-313-28049-5.
- Yu L (1995). The Classic of Tea: Origins & Rituals. Ecco Pr. ISBN 0-88001-416-4.[page needed]
- Bennett Alan Weinberg; Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. pp. 3–4. ISBN 978-0-415-92723-9.
- Meyers, Hannah (7 March 2005). ""Suave Molecules of Mocha" – Coffee, Chemistry, and Civilization". New Partisan. Archived from the original on 9 March 2005. Retrieved 3 February 2007.
- Fairbanks, Charles H. (2004). "The function of black drink among the Creeks". In Hudson, Charles M. Black Drink. University of Georgia Press. p. 123. ISBN 978-0-8203-2696-2.
- Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T (August 2012). "Ritual Black Drink consumption at Cahokia". Proc. Natl. Acad. Sci. U.S.A. 109 (35): 13944–13949. doi:10.1073/pnas.1208404109. PMC . PMID 22869743.
- Runge, Friedlieb Ferdinand (1820). Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie [Latest phytochemical discoveries for the founding of a scientific phytochemistry]. Berlin: G. Reimer. pp. 144–159. Retrieved 8 January 2014.
- 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.
- Bennett Alan Weinberg; Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. pp. xvii–xxi. ISBN 978-0-415-92723-9.
- Berzelius, Jöns Jakob (1825). "Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius" [Annual report on the progress of the physical sciences by Jacob Berzelius] (in German). 4: 180. From page 180: "Caféin ist eine Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und Pelletier und Caventou entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt machte." (Caffeine is a material in coffee, which was discovered at the same time, 1821, by Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known about it in the press.)
- Berzelius JJ (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual Report on the Progress of the Physical Sciences by Jacob Berzelius] (in German). 7. p. 270. From page 270: "Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen 1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zusammenkunft der Societé de Pharmacie in Paris die erste mündliche Mittheilung darüber gab." (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, Pierre Joseph (1822). "Cafeine". Dictionnaire de Médecine (in French). 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 3 March 2011.
- Robiquet, Pierre Jean (1823). "Café". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French). 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 3 March 2011.
- Dumas; Pelletier (1823). "Recherches sur la composition élémentaire et sur quelques propriétés caractéristiques des bases salifiables organiques" [Studies into the elemental composition and some characteristic properties of organic bases]. Annales de Chimie et de Physique (in French). 24: 163–191.
- Oudry M (1827). "Note sur la Théine". Nouvelle bibliothèque médicale (in French). 1: 477–479.
- Mulder, G. J. (1838). "Ueber Theïn und Caffeïn" [Concerning theine and caffeine]. Journal für Praktische Chemie. 15: 280–284. doi:10.1002/prac.18380150124.
- Jobst, Carl (1838). "Thein identisch mit Caffein" [Theine is identical to caffeine]. Liebig's Annalen der Chemie und Pharmacie. 25: 63–66. doi:10.1002/jlac.18380250106.
- Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.
- Fischer E (1881). "Ueber das Caffeïn" [On caffeine]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 14: 637–644. doi:10.1002/cber.188101401142.
- Fischer E (1881). "Ueber das Caffeïn. Zweite Mitteilung" [On caffeine. Second communication.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 14 (2): 1905–1915. doi:10.1002/cber.18810140283.
- Fischer E (1882). "Ueber das Caffeïn. Dritte Mitteilung" [On caffeine. Third communication.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 15: 29–33. doi:10.1002/cber.18820150108.
- Fischer E, Ach L (1895). "Synthese des Caffeïns" [Synthesis of caffeine]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 28 (3): 3135–3143. doi:10.1002/cber.189502803156.
- Fischer E (1897). "Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen" [On the constitution of caffeine, xanthin, hypoxanthin, and related bases.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 30: 549–559. doi:10.1002/cber.189703001110.
- Hj. Théel (1902). "Nobel Prize Presentation Speech". Retrieved 3 August 2009.
- Brown, Daniel W (2004). A new introduction to Islam. Chichester, West Sussex: Wiley-Blackwell. pp. 149–51. ISBN 1-4051-5807-7.
- Ágoston, Gábor; Masters, Bruce (2009). Encyclopedia of the Ottoman Empire. p. 138. ISBN 978-1-4381-1025-7.
- Hopkins, Kate (24 March 2006). "Food Stories: The Sultan's Coffee Prohibition". Accidental Hedonist. Retrieved 3 January 2010.
- "By the King. A PROCLAMATION FOR THE Suppression of Coffee-Houses". Retrieved 18 March 2012.
- Pendergrast 2001, p. 13
- Pendergrast 2001, p. 11
- Bersten 1999, p. 53
- Benjamin LT, Rogers AM, Rosenbaum A (1991). "Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911". J Hist Behav Sci. 27 (1): 42–55. doi:10.1002/1520-6696(199101)27:1<42::AID-JHBS2300270105>3.0.CO;2-1. PMID 2010614.
- "The Rise and Fall of Cocaine Cola". Lewrockwell.com. Retrieved 25 May 2012.[unreliable source?]
- "CFR - Code of Federal Regulations Title 21". U.S. Food and Drug Administration. 21 August 2015. Retrieved 23 November 2015.
- Sanner, Ann (19 July 2014). "Sudden death of Ohio teen highlights dangers of caffeine powder". The Globe and Mail. Columbus, Ohio: Phillip Crawley. The Associated Press. Retrieved 23 November 2015.
- Reissig CJ, Strain EC, Griffiths RR (2009). "Caffeinated energy drinks – a growing problem". Drug and Alcohol Dependence. 99 (1–3): 1–10. doi:10.1016/j.drugalcdep.2008.08.001. PMC . PMID 18809264. Lay summary – ScienceDaily (25 September 2008).
- Geoffrey Burchfield (1997). Meredith Hopes, ed. "What's your poison: caffeine". Australian Broadcasting Corporation. Retrieved 15 January 2014.
- "Mormonism in the News: Getting It Right August 29". The Church of Jesus Christ of Latter-Day Saints. 2012. Retrieved 17 April 2016.
- Juan Eduardo Campo (1 January 2009). Encyclopedia of Islam. Infobase Publishing. p. 154. ISBN 978-1-4381-2696-8. Retrieved 1 November 2012.
- Daniel W. Brown (24 August 2011). A New Introduction to Islam. John Wiley & Sons. p. 149. ISBN 978-1-4443-5772-1.
- "Newly Discovered acteria Lives on Caffeine". Blogs.scientificamerican.com. 24 May 2011. Retrieved 19 December 2013.
- Paul, Dr. Lisa. "Why Caffeine is Toxic to Birds". HotSpot for Birds. Advin Systems. Retrieved 29 February 2012.
- "Caffeine". Retrieved 12 September 2014.
- Noever R, Cronise J, Relwani RA (29 April 1995). "Using spider-web patterns to determine toxicity". NASA Tech Briefs. New Scientist magazine. 19 (4): 82.
- Arnaud MJ (2011). "Pharmacokinetics and metabolism of natural methylxanthines in animal and man". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 200 (200): 33–91. doi:10.1007/978-3-642-13443-2_3. ISBN 978-3-642-13442-5. PMID 20859793.
- Wright GA, Baker DD, Palmer MJ, Stabler D, Mustard JA, Power EF, Borland AM, Stevenson PC (March 2013). "Caffeine in floral nectar enhances a pollinator's memory of reward". Science. 339 (6124): 1202–4. Bibcode:2013Sci...339.1202W. doi:10.1126/science.1228806. PMC . PMID 23471406.
- Thomas J, Chen Q, Howes N (1997). "Chromosome doubling of haploids of common wheat with caffeine.". Genome. 40 (4): 552–558. doi:10.1139/g97-072. PMID 18464846.
- 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) . Uncommon Grounds: The History of Coffee and How It Transformed Our World. London: Texere. ISBN 1-58799-088-1.
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- Mayo Clinic staff (3 October 2009). "Caffeine content for coffee, tea, soda and more". Mayo Clinic. Retrieved 8 November 2010.