Caffeine is a bitter, white crystalline
purine, a methylxanthine
alkaloid, and is chemically related to the
deoxyribonucleic acid (DNA) and
ribonucleic acid (RNA). It is found in the seeds, fruits, nuts, or leaves of a number of plants native to Africa, East Asia and South America, and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds, as well as encouraging consumption by select animals such as
honey bees. The best-known source of caffeine is the
coffee bean, the seed of the Coffea plant. People may drink
beverages containing caffeine to relieve or prevent drowsiness and to improve cognitive performance. To make these drinks, caffeine is extracted by
steeping the plant product in water, a process called
infusion. Caffeine-containing drinks, such as
cola, are consumed globally in high volumes. In 2020, almost 10 million tonnes of coffee beans were consumed globally. Caffeine is the world's most widely consumed
psychoactive drug. Unlike most other psychoactive substances, caffeine remains largely unregulated and legal in nearly all parts of the world. Caffeine is also an outlier as its use is seen as socially acceptable in most cultures and even encouraged in others.
Caffeine has both positive and negative health effects. It can treat and prevent the premature infant breathing disorders
bronchopulmonary dysplasia of prematurity and
apnea of prematurity.
Caffeine citrate is on the
WHO Model List of Essential Medicines. It may confer a modest protective effect against some diseases, including
Parkinson's disease. Some people experience
sleep disruption or anxiety if they consume caffeine, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit caffeine 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 US
Food and Drug Administration as
generally recognized as safe. Toxic doses, over 10 grams per day for an adult, are much higher than the typical dose of under 500 milligrams per day. The
European Food Safety Authority reported that up to 400 mg of caffeine per day (around 5.7 mg/kg of body mass per day) does not raise safety concerns for non-pregnant adults, while intakes up to 200 mg per day for pregnant and lactating women do not raise safety concerns for the fetus or the breast-fed infants. A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used, how it is roasted (darker roasts have less caffeine), and how it is prepared (e.g.,
espresso). Thus it requires roughly 50–100 ordinary cups of coffee to reach the toxic dose. However, pure powdered caffeine, which is available as a
dietary supplement, can be lethal in tablespoon-sized amounts.
Some people use caffeine-containing beverages such as coffee or tea to try to treat their
asthma. Evidence to support this practice is poor. It appears that caffeine in low doses improves airway function in people with asthma, increasing
forced expiratory volume (FEV1) by 5% to 18%, with this effect lasting for up to four hours.
The addition of caffeine (100–130 mg) to commonly prescribed pain relievers such as
ibuprofen modestly improves the proportion of people who achieve
Consumption of caffeine after abdominal surgery shortens the time to recovery of normal bowel function and shortens length of hospital stay.
Caffeine was formerly used as a second-line treatment for
ADHD. It is considered less effective than
amphetamine but more so than placebo for children with ADHD. Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of
Caffeine improves muscular strength and power, and may enhance muscular endurance. Caffeine also enhances performance on anaerobic tests. Caffeine consumption before constant load exercise is associated with reduced perceived exertion. While this effect is not present during exercise-to-exhaustion exercise, performance is significantly enhanced. This is congruent with caffeine reducing perceived exertion, because exercise-to-exhaustion should end at the same point of fatigue. Caffeine also improves power output and reduces time to completion in aerobic time trials, an effect positively (but not exclusively) associated with longer duration exercise.
For the general population of healthy adults,
Health Canada advises a daily intake of no more than 400 mg. This limit was found to be safe by a 2017 systematic review on caffeine toxicology.
In healthy children, moderate caffeine intake under 400 mg produces effects that are "modest and typically innocuous". As early as six months old, infants can metabolize caffeine at the same rate as that of adults. Higher doses of caffeine (>400 mg) can cause physiological, psychological and behavioral harm, particularly for children with psychiatric or cardiac conditions. There is no evidence that coffee stunts a child's growth. The
American Academy of Pediatrics recommends that caffeine consumption is not appropriate for children and adolescents and should be avoided. This recommendation is based on a clinical report released by American Academy of Pediatrics in 2011 with a review of 45 publications from 1994 to 2011 and includes inputs from various stakeholders (Pediatricians, Committee on nutrition, Canadian Pediatric Society,
Centers for Disease Control & Prevention,
Food and Drug Administration, Sports Medicine & Fitness committee, National Federations of High School Associations). 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:
Maximum recommended daily caffeine intake
45 mg (slightly more than in 355 ml (12 fl. oz) of a typical caffeinated soft drink)
85 mg (about 1⁄2 cup of coffee)
Health Canada has not developed advice for adolescents because of insufficient data. However, 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 experiencing adverse effects.
Pregnancy and breastfeeding
The metabolism of caffeine is reduced in pregnancy, especially in the third trimester, and the half-life of caffeine during pregnancy can be increased up to 15 hours (as compared to 2.5 to 4.5 hours in non-pregnant adults). Current evidence regarding the effects of caffeine on pregnancy and for breastfeeding are inconclusive. There is limited primary and secondary advice for, or against, caffeine use during pregnancy and its effects on the fetus or newborn.
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. For women who breastfeed, are pregnant, or may become pregnant, 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. A 2017 systematic review on caffeine toxicology found evidence supporting that caffeine consumption up to 300 mg/day for pregnant women is generally not associated with adverse reproductive or developmental effect.
There are conflicting reports in the scientific literature about caffeine use during pregnancy. A 2011 review found that caffeine during pregnancy does not appear to increase the risk of
growth retardation even when consumed in moderate to high amounts. Other reviews, however, concluded that there is some evidence that higher caffeine intake by pregnant women may be associated with a higher risk of giving birth to a
low birth weight baby, and may be associated with a higher risk of pregnancy loss. A systematic review, analyzing the results of observational studies, suggests that women who consume large amounts of caffeine (greater than 300 mg/day) prior to becoming pregnant may have a higher risk of experiencing pregnancy loss.
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.
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 may induce anxiety and panic disorders in people with
Parkinson's disease. 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.
In moderate doses, caffeine has been associated with reduced symptoms of
depression and lower
suicide risk. Two reviews indicate that increased consumption of coffee and caffeine may reduce the risk of depression.
Some textbooks state that caffeine is a mild euphoriant, while others state that it is not a euphoriant.
Whether caffeine can result in an addictive disorder depends on how addiction is defined. Compulsive caffeine consumption under any circumstances has not been observed, and caffeine is therefore not generally considered addictive. However, 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 does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, with people preferring placebo over caffeine in a study on drug abuse liability published in an
NIDA research monograph. Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction. Other research states it can affect the reward system.
"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.
Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. The frequency at which this occurs is self-reported at 11%, but in lab tests only half of the people who report withdrawal actually experience it, casting doubt on many claims of dependence. Mild
physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day, although these symptoms last no longer than a day. Some symptoms associated with
psychological dependence may also occur during withdrawal. The diagnostic criteria for caffeine withdrawal require a previous prolonged daily use of caffeine. Following 24 hours of a marked reduction in consumption, a minimum of 3 of these signs or symptoms is required to meet withdrawal criteria: difficulty concentrating,
fatigue. Additionally, the signs and symptoms must disrupt important areas of functioning and are not associated with effects of another condition.
The ICD-11 includes
caffeine dependence as a distinct diagnostic category, which closely mirrors the
DSM-5's proposed set of criteria for "caffeine-use disorder". Caffeine use disorder refers to dependence on caffeine characterized by failure to control caffeine consumption despite negative physiological consequences. 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 the disorder is unclear. Due to this inconclusive evidence on clinical significance, the DSM-5 classifies caffeine-use disorder as a "condition for further study".
Tolerance to the effects of caffeine occurs for caffeine-induced elevations in
blood pressure and the subjective feelings of nervousness.
Sensitization, the process whereby effects become more prominent with use, occurs for positive effects such as feelings of alertness and wellbeing. 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 (170 g) cup of coffee or two to three 12 oz (340 g) 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.
The DSM-5 also includes other caffeine-induced disorders consisting of caffeine-induced anxiety disorder, caffeine-induced sleep disorder and unspecified caffeine-related disorders. The first two disorders are classified under "Anxiety Disorder" and "Sleep-Wake Disorder" because they share similar characteristics. Other disorders that present with significant distress and impairment of daily functioning that warrant clinical attention but do not meet the criteria to be diagnosed under any specific disorders are listed under "Unspecified Caffeine-Related Disorders".
This section needs expansion with: practical management of overdose, see
PMID30893206. You can help by
adding to it. (November 2019)
Consumption of 1–1.5 grams (1,000–1,500 mg) 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 overstimulation known as caffeine intoxication, a clinically significant temporary condition that develops during, or shortly after, the consumption of caffeine. 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). According to the DSM-5, caffeine intoxication may be diagnosed if five (or more) of the following symptoms develop after recent consumption of caffeine: restlessness, nervousness, excitement, insomnia, flushed face,
diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech,
tachycardia or cardiac
arrhythmia, periods of inexhaustibility, and
According to the International Classification of Diseases (ICD-11), cases of very high caffeine intake (e.g. > 5 g) may result in caffeine intoxication with symptoms including mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations or psychosis, and
High caffeine consumption in energy drinks (at least 1 liter or 320 mg of caffeine) was associated with short-term cardiovascular side effects including hypertension, prolonged
QT interval, and heart palpitations. These cardiovascular side effects were not seen with smaller amounts of caffeine consumption in energy drinks (less than 200 mg).
As of 2007 there is no known antidote or reversal agent for caffeine intoxication. Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require
hemofiltration.Intralipid infusion therapy is indicated in cases of imminent risk of cardiac arrest in order to scavenge the free serum caffeine.
Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications. In 2016, 3702 caffeine-related exposures were reported to Poison Control Centers in the United States, of which 846 required treatment at a medical facility, and 16 had a major outcome; and several caffeine-related deaths are reported in case studies. The
LD50 of caffeine in rats is 192 milligrams per kilogram, the fatal dose in humans is estimated to be 150–200 milligrams per kilogram (2.2 lb) of body mass (75–100 cups of coffee for a 70 kg (150 lb) adult). There are cases where doses as low as 57 milligrams per kilogram have been fatal. 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 2013 of a man with
liver cirrhosis who overdosed on caffeinated mints.
Caffeine is a substrate for
CYP1A2, and interacts with many substances through this and other mechanisms.
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. The
Dietary Guidelines for Americans recommend avoidance of concomitant consumption of alcohol and caffeine, as this may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.
Smoking tobacco increases caffeine clearance by 56%. Cigarette smoking induces the cytochrome P450 1A2 enzyme that breaks down caffeine, which may lead to increased caffeine tolerance and coffee consumption for regular smokers.
Caffeine sometimes increases the effectiveness of some medications, such as those for
headaches. Caffeine was determined to increase the potency of some over-the-counter
analgesic medications by 40%.
The pharmacological effects of adenosine may be blunted in individuals taking large quantities of
methylxanthines like caffeine. Some other examples of methylxanthines include the medications
aminophylline, which are prescribed to relieve symptoms of asthma or
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 adenosine 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.
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
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
heterodimer (this is a receptor complex with 1 adenosine A1 receptor and 1 dopamine D1 receptor) and the
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.
Urinary metabolites of caffeine in humans at 48 hours post-dose
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
ergotaminetartrate and caffeine (for the relief of
migraine) and of
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.
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 and 7 hours. The half-life is decreased by 30-50% in adult male
smokers, approximately doubled in women taking
oral contraceptives, and prolonged in the
last trimester of pregnancy. 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.
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.
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 of
conjugate acid = ~0.6) requiring strong acid to protonate it. Caffeine does not contain any
stereogenic centers and hence is classified as an
xanthine core of caffeine contains two fused rings, a
imidazole. The pyrimidinedione in turn contains two
amide functional groups that exist predominantly in a
zwitterionicresonance 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 sp2hybridized and planar. The imidazole ring also has a
resonance. Therefore, the fused 5,6 ring core of caffeine contains a total of ten
pi electrons and hence according to
Hückel's rule is
Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using a number of solvents. Following are 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 "
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
charcoaladsorption (as above) or by
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
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.
Around thirty plant species are known to contain caffeine. Common sources are the "beans" (seeds) of the two cultivated coffee plants, Coffea arabica and Coffea canephora (the quantity varies, but 1.3% is a typical value); and of the cocoa plant, Theobroma cacao; the leaves of the
tea plant; and
kola nuts. Other sources include the leaves of
yaupon holly, South American holly
yerba mate, and Amazonian holly
guayusa; and seeds from Amazonian maple
guarana berries. 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. Caffeine is stored in tea leaves in two places. Firstly, in the cell
vacuoles where it is complexed with
polyphenols. This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles. Caffeine in nectar may improve the reproductive success of the
pollen producing plants by enhancing the reward memory of pollinators such as
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
methylxanthinealkaloids, including the
theobromine, and polyphenols that can form insoluble complexes with caffeine.
Products containing caffeine include coffee, tea,
soft drinks ("colas"),
energy drinks, other beverages,
chocolate, caffeine tablets, other oral products, and inhalation products. According to a 2020 study in the United States, coffee is the major source of caffeine intake in middle-aged adults, while soft drinks and tea are the major sources in adolescents. Energy drinks are more commonly consumed as a source of caffeine in adolescents as compared to adults.
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 less of the product is used as compared to an equivalent serving of coffee. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, teas contain varying amounts of caffeine.
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 (350 mL) 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
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 is a soft drink originating in Brazil made from the seeds of the
The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea.
The leaves of Ilex vomitoria, the yaupon holly tree, are placed in boiling water to make a yaupon tea.
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 of caffeine as coffee: 80–160 mg per 100 g. Higher percentages of cocoa such as 90% amount to 200 mg per 100 g approximately and thus, a 100-gram 85% cocoa chocolate bar contains about 195 mg caffeine.
No-Doz 100 mg caffeine tablets
Tablets offer several advantages over coffee, tea, and other caffeinated beverages, including convenience, known dosage, and avoidance of concomitant intake of sugar, acids, and fluids. A use of caffeine in this form is said to improve 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.
There are several products being marketed that offer inhalers that deliver proprietary blends of supplements, with caffeine being a key ingredient. In 2012, the FDA sent a warning letter to one of the companies marketing these inhalers, expressing concerns for the lack of safety information available about inhaled caffeine.
According to Chinese legend, the
Chinese emperorShennong, reputed to have reigned in about 3000 BCE, inadvertently 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 plant appears in the middle of the fifteenth century, in the
Sufi monasteries of the
Yemen in 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,
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.
Kola nut use appears to have ancient origins. It is chewed in many
West African cultures, in both private and social settings, to restore vitality and ease hunger pangs.
The earliest evidence of
cocoa bean use comes from residue found in an
ancient Mayan pot dated to 600 BCE. Also,
chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with
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-ColumbianMesoamerica, and cocoa beans were often used as currency.
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.[a] 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 ...
Robiquet was one of the first to isolate and describe the properties of pure caffeine, whereas Pelletier was the first to perform an
In 1827, M. Oudry isolated "théine" from tea, but in 1838 it was proved by
Mulder and by Carl Jobst that theine was actually the same as caffeine.
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.
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.,
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 an average of one serving of a caffeinated beverage for every person every day. The consumption of caffeine has remained stable between 1997 and 2015. Coffee, tea and soft drinks are the most important caffeine sources, with energy drinks contributing little to the total caffeine intake across all age groups.
Until recently, the
Seventh-day Adventist Church asked for its members to "abstain from caffeinated drinks", but has removed this from
baptismal vows (while still recommending abstention as policy). 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 overstimulates 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.
Recently discovered bacteria Pseudomonas putida CBB5 can live on pure caffeine and can cleave caffeine into carbon dioxide and ammonia.
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
^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.").
abcdefMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 375.
ISBN978-0-07-148127-4. 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.
abcKarch SB (2009).
Karch's pathology of drug abuse (4th ed.). Boca Raton: CRC Press. pp. 229–230.
ISBN978-0-8493-7881-2. 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
abcAmerican Psychiatric Association (2013).
"Substance-Related and Addictive Disorders"(PDF). American Psychiatric Publishing. pp. 1–2. Archived from
the original(PDF) on 15 August 2015. 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.
abcJuliano LM, Griffiths RR (October 2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features". Psychopharmacology. 176 (1): 1–29.
S2CID5572188. 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.
abcdPoleszak E, Szopa A, Wyska E, Kukuła-Koch W, Serefko A, Wośko S, Bogatko K, Wróbel A, Wlaź P (February 2016). "Caffeine augments the antidepressant-like activity of mianserin and agomelatine in forced swim and tail suspension tests in mice". Pharmacological Reports. 68 (1): 56–61.
^Institute of Medicine (US) Committee on Military Nutrition Research (2001). "2, Pharmacology of Caffeine".
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ab"Caffeine". Pubchem Compound. NCBI. Retrieved 16 October 2014. Boiling Point 178 °C (sublimes) Melting Point 238 DEG C (ANHYD)
ab"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
^Camfield DA, Stough C, Farrimond J, Scholey AB (August 2014). "Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis". Nutrition Reviews. 72 (8): 507–522.
abcJahanfar S, Jaafar SH, et al. (Cochrane Pregnancy and Childbirth Group) (June 2015). "Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes". The Cochrane Database of Systematic Reviews (6): CD006965.
abAmerican College of Obstetricians and Gynecologists (August 2010). "ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstetrics and Gynecology. 116 (2 Pt 1): 467–8.
^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". Biology of the Neonate. 88 (3): 208–13.
^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". The New England Journal of Medicine. 357 (19): 1893–902.
^Grimes LM, Kennedy AE, Labaton RS, Hine JF, Warzak WJ (2015). "Caffeine as an Independent Variable in Behavioral Research: Trends from the Literature Specific to ADHD". Journal of Caffeine Research. 5 (3): 95–104.
^Nehlig A (2010).
"Is caffeine a cognitive enhancer?"(PDF). Journal of Alzheimer's Disease. 20 (Suppl 1): S85–94.
S2CID17392483. Archived from
the original(PDF) on 31 January 2021. 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.
abCamfield DA, Stough C, Farrimond J, Scholey AB (August 2014). "Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis". Nutrition Reviews. 72 (8): 507–22.
^Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care. 40 (2): 487–505.
PMID23668655. 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
^Dulloo AG, Geissler CA, Horton T, Collins A, Miller DS (January 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.
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^Wang L, Shen X, Wu Y, Zhang D (March 2016). "Coffee and caffeine consumption and depression: A meta-analysis of observational studies". The Australian and New Zealand Journal of Psychiatry. 50 (3): 228–42.
^Grosso G, Micek A, Castellano S, Pajak A, Galvano F (January 2016). "Coffee, tea, caffeine and risk of depression: A systematic review and dose-response meta-analysis of observational studies". Molecular Nutrition & Food Research. 60 (1): 223–34.
^Kohn R, Keller M (2015).
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ISBN978-1-118-84547-9. Table 34-12... Caffeine Intoxication – Euphoria
^Hrnčiarove J, Barteček R (2017).
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ISBN9788024633787. At a high dose, caffeine shows a euphoric effect.
^Schulteis G (2010).
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ISBN978-0-08-091455-8. Therefore, caffeine and other adenosine antagonists, while weakly euphoria-like on their own, may potentiate the positive hedonic efficacy of acute drug intoxication and reduce the negative hedonic consequences of drug withdrawal.
^Salerno BB, Knights EK (2010). Pharmacology for health professionals (3rd ed.). Chatswood, N.S.W.: Elsevier Australia. p. 433.
ISBN978-0-7295-3929-6. In contrast to the amphetamines, caffeine does not cause euphoria, stereotyped behaviors or psychoses.
^Ebenezer I (2015). Neuropsychopharmacology and Therapeutics. John Wiley & Sons. p. 18.
ISBN978-1-118-38578-4. However, in contrast to other psychoactive stimulants, such as amphetamine and cocaine, caffeine and the other methylxanthines do not produce euphoria, stereotyped behaviors or psychotic like symptoms in large doses.
^Nestler EJ, Hymen SE, Holtzmann DM, Malenka RC. "16". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). McGraw-Hill Education. True compulsive use of caffeine has not been documented, and, consequently, these drugs are not considered addictive.
^Budney AJ, Emond JA (November 2014). "Caffeine addiction? Caffeine for youth? Time to act!". Addiction. 109 (11): 1771–2.
PMID24984891. Academics and clinicians, however, have not yet reached consensus about the potential clinical importance of caffeine addiction (or 'use disorder')
^Fishchman N, Mello N.
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^Nestler EJ (December 2013).
"Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–43.
PMID24459410. 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.
ISBN978-0-12-398361-9. 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 in Clinical Neuroscience. 12 (2): 255–63.
PMID20623930. 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
^"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:] Chronic alcoholism Dipsomania Drug addiction
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^Jiang X, Zhang D, Jiang W (February 2014). "Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies". European Journal of Nutrition. 53 (1): 25–38.
S2CID5566177. Dose-response analysis suggested that incidence of T2DM decreased ...14% [0.86 (0.82-0.91)] for every 200 mg/day increment in caffeine intake.
^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". Graefe's Archive for Clinical and Experimental Ophthalmology. 249 (3): 435–42.
^Desk reference to the diagnostic criteria from DSM-5. American Psychiatric Publishing. Washington, DC: American Psychiatric Association. 2013.
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^This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was reprinted in: Johann Wolfgang von Goethe with F.W. von Biedermann, ed., Goethes Gespräche, vol. 10: Nachträge, 1755–1832 (Leipzig, (Germany): F.W. v. Biedermann, 1896), pages 89–96; see especially
^Berzelius JJ (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). Vol. 4. p. 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). Vol. 7. p. 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.
^Pelletier PJ (1822).
"Cafeine". Dictionnaire de Médecine (in French). Vol. 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 3 March 2011.
^Robiquet PJ (1823).
"Café". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French). Vol. 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 3 March 2011.
^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.