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 helps to protect them against predator
insects and to prevent germination of nearby seeds. The most well
known source of caffeine is the coffee bean, a misnomer for the seed
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; as of 2014, 85% of American
adults consumed some form of caffeine daily, consuming 164 mg on
Caffeine can have 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 consumption to the
equivalent of two cups of coffee per day or less.
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
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.
1.2 Enhancing performance
1.3 Specific populations
1.3.4 Pregnancy and breastfeeding
2 Adverse effects
2.3 Reinforcement disorders
2.3.2 Dependence and withdrawal
2.4 Risk of other diseases
4.3 Birth control
5.1.1 Receptor and ion channel targets
220.127.116.11 Effects on striatal dopamine
5.1.3 Off-target effects
6.3 Detection in body fluids
6.5 Precipitation of tannins
7 Natural occurrence
8.1.3 Soft drinks and energy drinks
8.1.4 Other beverages
8.4 Other oral products
8.6 Combinations with other drugs
9.1 Discovery and spread of use
9.2 Chemical identification, isolation, and synthesis
9.3 Historic regulations
10 Society and culture
11 Other organisms
13 See also
16 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
Orthostatic hypotension treatment.
In moderate doses, caffeine may reduce symptoms of depression and
lower suicide risk.
Caffeine is a central nervous system stimulant that reduces fatigue
and drowsiness. At normal doses, caffeine has variable effects on
learning and memory, but it generally improves reaction time,
wakefulness, concentration, and motor coordination. The amount
of caffeine needed to produce these effects varies from person to
person, depending on body size and degree of tolerance. The
desired effects arise approximately one hour after consumption, and
the desired effects of a moderate dose usually subside after about
three or four hours.
Caffeine can delay or prevent sleep and improves task performance
during sleep deprivation. Shift workers who use caffeine make
fewer mistakes due to drowsiness.
A systematic review and meta-analysis from 2014 found that concurrent
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.
Caffeine is a proven ergogenic aid in humans.
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
Caffeine increases basal metabolic rate in
For 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". There is no evidence that coffee stunts
a child's growth. 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
Maximum recommended daily caffeine intake
45 mg (slightly more than in 12 oz of a typical caffeinated soft
85 mg (about ½ 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 suffering adverse effects.
Pregnancy and breastfeeding
Food Standards Agency
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
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
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.
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 congenital
malformations, miscarriage or 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.
Caffeine can increase blood pressure and cause
Coffee and caffeine can affect
gastrointestinal motility and gastric acid secretion.
Caffeine in low doses may cause weak bronchodilation for up to four
hours in asthmatics. In postmenopausal women, high caffeine
consumption can accelerate bone loss.
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.
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
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.
Some textbooks state that caffeine is a mild euphoriant,
others state that it is not a euphoriant, and one states that
it is and is not a euphoriant.
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 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
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. 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 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
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.
ICD-10 includes a diagnostic model for caffeine dependence, but
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.
Risk of other diseases
Coffee § Health and pharmacology
A protective effect of caffeine against
Alzheimer's disease is
possible, but the evidence is inconclusive. Caffeine
increases intraocular pressure in those with glaucoma but does not
appear to affect normal individuals. It may protect people from
Caffeine may lessen the severity of acute
mountain sickness if taken a few hours prior to attaining a high
Primary symptoms of caffeine intoxication
Consumption of 1–1.5 grams (0.035–0.053 oz) 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 (
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 150–200 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.
Treatment of mild caffeine intoxication is directed toward symptom
relief; severe intoxication may require peritoneal dialysis,
hemodialysis, or hemofiltration.
See also: Caffeinated alcoholic energy drink
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
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%.
Birth control pills can extend the half-life of caffeine, requiring
greater attention to caffeine consumption.
Caffeine sometimes increases the effectiveness of some medications,
such as those for headaches.
Structure of a typical chemical synapse
Caffeine's primary mechanism of action is as an antagonist of
adenosine receptors in the brain
In the absence of caffeine and when a person is awake and alert,
little adenosine is present in (CNS) neurons. With a continued wakeful
state, over time it accumulates in the neuronal synapse, in turn
binding to and activating adenosine receptors found on certain CNS
neurons; when activated, these receptors produce a cellular response
that ultimately increases drowsiness. When caffeine is consumed, it
antagonizes adenosine receptors; in other words, caffeine prevents
adenosine from activating the receptor by blocking the location on the
receptor where adenosine binds to it. As a result, caffeine
temporarily prevents or relieves drowsiness, and thus maintains or
Receptor and ion channel targets
Caffeine is an antagonist at all four adenosine receptor subtypes (A1,
A2A, A2B, and A3), although with varying potencies. The
affinity (KD) values of caffeine for the human adenosine receptors are
12 μM at A1, 2.4 μM at A2A, 13 μM at A2B, and
80 μM at A3.
Knockout mouse studies have specifically
implicated antagonism of the A2A receptor as responsible for the
wakefulness-promoting effects of caffeine. Antagonism of
adenosine receptors by caffeine stimulates the medullary vagal,
vasomotor, and respiratory centers, which increases respiratory rate,
reduces heart rate, 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 A1
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 trisphosphate 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
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
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.
affects the cholinergic system where it inhibits the enzyme
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 is metabolized in the liver into three primary metabolites:
paraxanthine (84%), theobromine (12%), and theophylline (4%)
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
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.
Smoking 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
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
1,3,7-Trimethyluric acid is a minor caffeine metabolite. Each of
these metabolites is further metabolized and then excreted in the
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 of conjugate base = ~0.6) requiring strong acid to
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.
One biosynthetic route of caffeine, as performed by
One laboratory synthesis of caffeine
The biosynthesis of caffeine is an example of convergent evolution
among different species.
Caffeine may be synthesized in the lab starting with dimethylurea and
malonic acid.[clarification needed]
Commercial supplies of caffeine are not usually manufactured
synthetically because the chemical is readily available as a byproduct
Main article: Decaffeination
Fibrous crystals of purified caffeine.
Dark-field microscopy image,
about 7 mm × 11 mm
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
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
Coffee manufacturers recover the caffeine and resell
it for use in soft drinks and over-the-counter caffeine tablets.
Supercritical carbon dioxide
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
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
"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
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
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
Some other caffeine analogs:
Precipitation of tannins
Caffeine, as do other alcaloids such as cinchonine, quinine or
strychnine, precipitates polyphenols and tannins.This property can be
used in a quantitation method.
Roasted coffee beans
Around sixty 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); in the leaves of the tea plant; 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
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
Caffeine in nectar may improve the reproductive
success of the pollen producing plants by enhancing the reward memory
of pollinators such as honeybees.
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]
See also: Caffeinated drink
Caffeine content in select food and drugs
Caffeine per serving (mg)
Caffeine tablet (regular-strength)
Caffeine tablet (extra-strength)
Hershey's Special Dark
Hershey's Special Dark (45% cacao content)
1 bar (43 g or 1.5 oz)
Chocolate (11% cacao content)
1 bar (43 g or 1.5 oz)
207 mL (7.0 US fl oz)
207 mL (7.0 US fl oz)
207 mL (7.0 US fl oz)
44–60 mL (1.5–2.0 US fl oz)
Tea – black, green, and other types, – steeped for 3
177 millilitres (6.0 US fl oz)
Guayakí yerba mate (loose leaf)
6 g (0.21 oz)
355 mL (12.0 US fl oz)
355 mL (12.0 US fl oz)
355 mL (12.0 US fl oz)
350 mL (12 US fl oz)
695 mL (23.5 US fl oz)
250 mL (8.5 US fl oz)
Products containing caffeine are coffee, tea, soft drinks ("colas"),
energy drinks, other beverages, chocolate, caffeine tablets,
other oral products, and inhalation.
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,
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 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
Guaraná seeds ("beans") are used in making the commercially sold
Guaraná Antarctica, which originated in Brazil and is
currently the fifteenth most popular soft drink in the world.[citation
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 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
No-Doz 100 mg caffeine tablets
Tablets offer the advantages over coffee and tea of convenience, known
dosage, and avoiding concomitant sugar, acid and 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
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.
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
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.
Painkillers such as propyphenazone/paracetamol/caffeine combine
caffeine with an analgesic.
Discovery and spread of use
Coffeehouse in Palestine, circa 1900
Main articles: History of chocolate, History of coffee, History of
tea, and History of yerba mate
According to Chinese legend, the Chinese emperor Shennong, reputed to
have reigned in about 3000 BCE, accidentally discovered tea when he
noted that when certain leaves fell into boiling water, a fragrant and
restorative drink resulted.
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
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.
Kola nut use appears to have ancient origins. It is chewed in many
West African cultures, individually or in a social setting, to restore
vitality and ease hunger pangs.
The earliest evidence of cocoa bean use comes from residue found in an
ancient Mayan pot dated to 600 BCE. Also, chocolate was consumed in a
bitter and spicy drink called xocolatl, often seasoned with vanilla,
chile pepper, and achiote. Xocolatl was believed to fight fatigue, a
belief probably attributable to the theobromine and caffeine content.
Chocolate was an important luxury good throughout pre-Columbian
Mesoamerica, and cocoa beans were often used as currency.[citation
Xocolatl was introduced to
Europe by the Spaniards, and became a
popular beverage by 1700. The Spaniards also introduced the cacao tree
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
Pierre Joseph Pelletier
In 1819, the German chemist
Friedlieb Ferdinand Runge
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 ...
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 it was later
proved by Mulder and by Carl Jobst that theine was actually
In 1895, German chemist
Hermann Emil Fischer
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
Mecca and in the
Ottoman Empire made coffee illegal for
Charles II of England
Charles II of England tried to ban it in
Frederick II of Prussia
Frederick II of Prussia banned it in 1777,
and coffee was banned in
Sweden at various times between 1756 and
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
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.
Society and culture
Food and Drug Administration
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
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,
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
Caffeine effects on spider webs
See also: Effect of psychoactive drugs on animals
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
Caffeine has also been found to enhance the reward
memory of honeybees.
Caffeine has been used to double chromosomes in haploid wheat.
^ a b c d e f g 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 978-0-07-148127-4. 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.
^ a b c Karch SB (2009). Karch's pathology of drug abuse (4th ed.).
Boca Raton: CRC Press. pp. 229–230.
ISBN 978-0-8493-7881-2. 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
^ a b c d e f
American Psychiatric Association
American 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
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
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
^ a b Introduction to Pharmacology (third ed.). Abingdon: CRC Press.
2007. pp. 222–223. ISBN 978-1-4200-4742-4.
^ a b c d Juliano LM, Griffiths RR (October 2004). "A critical review
of caffeine withdrawal: empirical validation of symptoms and signs,
incidence, severity, and associated features" (PDF).
Psychopharmacology. 176 (1): 1–29. doi:10.1007/s00213-004-2000-x.
PMID 15448977. Archived from the original (PDF) 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.
^ a b c d e f g h i j k l m n o "Caffeine". DrugBank. University of
Alberta. 16 September 2013. Retrieved 8 August 2014.
^ a b c d Poleszak 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. doi:10.1016/j.pharep.2015.06.138.
^ a b "Caffeine". Pubchem Compound. NCBI. Retrieved 16 October 2014.
178 °C (sublimes)
238 DEG C (ANHYD)
^ a b "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
^ a b Nehlig A, Daval JL, Debry G (1992). "
Caffeine and the central
nervous system: mechanisms of action, biochemical, metabolic and
psychostimulant effects". Brain Research. Brain Research Reviews. 17
(2): 139–70. doi:10.1016/0165-0173(92)90012-B.
^ Mitchell, Diane C.; Knight, Carol A.; Hockenberry, Jon; Teplansky,
Robyn; Hartman, Terryl J. (1 January 2014). "Beverage caffeine intakes
in the U.S." Food and Chemical Toxicology. 63: 136–142.
WHO Model List of Essential Medicines
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.
^ Qi H, Li S (April 2014). "Dose-response meta-analysis on coffee, tea
and caffeine consumption with risk of Parkinson's disease". Geriatrics
& Gerontology International. 14 (2): 430–9.
doi:10.1111/ggi.12123. PMID 23879665.
Mayo Clinic staff. "Pregnancy Nutrition: Foods to avoid during
pregnancy". Mayo Clinic. Retrieved 15 April 2012.
^ a b American 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.
doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.
^ Robertson D, Wade D, Workman R, Woosley RL, Oates JA (April 1981).
"Tolerance to the humoral and hemodynamic effects of caffeine in man".
The Journal of Clinical Investigation. 67 (4): 1111–7.
doi:10.1172/JCI110124. PMC 370671 . PMID 7009653.
^ Kugelman A, Durand M (December 2011). "A comprehensive approach to
the prevention of bronchopulmonary dysplasia". Pediatric Pulmonology.
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
Caffeine for Apnea of Prematurity (CAP) trial". Biology
of the Neonate. 88 (3): 208–13. doi:10.1159/000087584.
^ Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A,
Solimano A, Tin W (May 2006). "
Caffeine therapy for apnea of
prematurity". The New England Journal of Medicine. 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". The New England Journal of
Medicine. 357 (19): 1893–902. doi:10.1056/NEJMoa073679.
^ 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 (November 2009). "Losing sleep over the caffeination of
prematurity". The Journal of Physiology. 587 (Pt 22): 5299–300.
doi:10.1113/jphysiol.2009.182303. PMC 2793860 .
^ Mathew OP (May 2011). "Apnea of prematurity: pathogenesis and
management strategies". Journal of Perinatology. 31 (5): 302–10.
doi:10.1038/jp.2010.126. PMID 21127467.
^ Henderson-Smart DJ, De Paoli AG (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.
^ a b "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.
^ Lara DR (2010). "Caffeine, mental health, and psychiatric
disorders". Journal of Alzheimer's Disease. 20 Suppl 1: S239–48.
doi:10.3233/JAD-2010-1378. PMID 20164571.
^ a b c Bolton S (1981). "Caffeine: Psychological Effects, Use and
Abuse" (PDF). Orthomolecular Psychiatry. 10 (3): 202–211.
^ Nehlig A (2010). "Is caffeine a cognitive enhancer?". Journal of
Alzheimer's Disease. 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.
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.
^ Snel J, Lorist MM (2011). "Effects of caffeine on sleep and
cognition". Progress in Brain Research. 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 (May 2010). Ker
K, ed. "
Caffeine for the prevention of injuries and errors in shift
workers". The Cochrane Database of Systematic Reviews (5): CD008508.
doi:10.1002/14651858.CD008508. PMC 4160007 .
^ a b 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): 507–22.
doi:10.1111/nure.12120. PMID 24946991.
^ a b c d e f Pesta DH, Angadi SS, Burtscher M, Roberts CK (December
2013). "The effects of caffeine, nicotine, ethanol, and
tetrahydrocannabinol on exercise performance". Nutrition &
Metabolism. 10 (1): 71. doi:10.1186/1743-7075-10-71.
PMC 3878772 . 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
^ Bishop D (December 2010). "Dietary supplements and team-sport
performance". Sports Medicine. 40 (12): 995–1017.
doi:10.2165/11536870-000000000-00000. PMID 21058748.
^ Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (February 2011).
"Does caffeine added to carbohydrate provide additional ergogenic
benefit for endurance?". International Journal of Sport Nutrition and
Exercise Metabolism. 21 (1): 71–84. doi:10.1123/ijsnem.21.1.71.
^ Liddle DG, Connor DJ (June 2013). "Nutritional supplements and
ergogenic AIDS". Primary 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)
• 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
^ Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K,
Jéquier E (May 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. doi:10.1093/ajcn/33.5.989. PMID 7369170.
^ 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.
doi:10.1093/ajcn/49.1.44. PMID 2912010.
^ Koot P, Deurenberg P (1995). "Comparison of changes in energy
expenditure and body temperatures after caffeine consumption". Annals
of Nutrition & Metabolism. 39 (3): 135–42.
doi:10.1159/000177854. PMID 7486839.
^ a b c d "It's Your Health – Caffeine". Health Canada. March
2010. Retrieved 8 November 2010.
^ Castellanos FX, Rapoport JL (2002). "Effects of caffeine on
development and behavior in infancy and childhood: A review of the
published literature". Food and Chemical Toxicology. 40 (9):
^ Levounis P, Herron AJ (2014). The
Addiction Casebook. American
Psychiatric Pub. p. 49. ISBN 978-1-58562-458-4.
Food Standards Agency
Food Standards Agency publishes new caffeine advice for pregnant
women". Retrieved 3 August 2009.
^ Kuczkowski KM (November 2009). "
Caffeine in pregnancy". Archives of
Gynecology and Obstetrics. 280 (5): 695–8.
doi:10.1007/s00404-009-0991-6. PMID 19238414.
^ Brent RL, Christian MS, Diener RM (April 2011). "Evaluation of the
reproductive and developmental risks of caffeine". Birth Defects
Research. Part B, Developmental and Reproductive Toxicology. 92 (2):
152–87. doi:10.1002/bdrb.20288. PMC 3121964 .
^ Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM (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): 174.
doi:10.1186/s12916-014-0174-6. PMC 4198801 .
^ Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM (May
2016). "Maternal caffeine intake during pregnancy and risk of
pregnancy loss: a categorical and dose-response meta-analysis of
prospective studies". Public Health Nutrition. 19 (7): 1233–44.
doi:10.1017/S1368980015002463. PMID 26329421.
^ Lassi ZS, Imam AM, Dean SV, Bhutta ZA (September 2014).
"Preconception care: caffeine, smoking, alcohol, drugs and other
environmental chemical/radiation exposure". Reproductive Health. 11
Suppl 3: S6. doi:10.1186/1742-4755-11-S3-S6. PMC 4196566 .
^ Daniels JW, Molé PA, Shaffrath JD, Stebbins CL (July 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.
^ Bracco D, Ferrarra JM, Arnaud MJ, Jéquier E, Schutz Y (October
1995). "Effects of caffeine on energy metabolism, heart rate, and
methylxanthine metabolism in lean and obese women". The American
Journal of Physiology. 269 (4 Pt 1): E671–8.
^ Mahmud A, Feely J (August 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. Supplement. 230 (230):
35–9. PMID 10499460.
^ Cohen S, Booth GH (October 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 L, Kell R (2009). Human Physiology: From Cells to Systems
(1st Canadian ed.). Nelsen. pp. 613–9.
^ a b Welsh EJ, Bara A, Barley E, Cates CJ (January 2010). Welsh EJ,
Caffeine for asthma". The Cochrane Database of Systematic Reviews
(1): CD001112. doi:10.1002/14651858.CD001112.pub2.
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 (November 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.
^ a b Maughan RJ, Griffin J (December 2003). "
Caffeine ingestion and
fluid balance: a review". Journal of Human Nutrition and Dietetics. 16
(6): 411–20. doi:10.1046/j.1365-277X.2003.00477.x.
^ 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 (July 2007). "Caffeine,
fluid-electrolyte balance, temperature regulation, and exercise-heat
tolerance". Exercise and Sport Sciences Reviews. 35 (3): 135–40.
doi:10.1097/jes.0b013e3180a02cc1. PMID 17620932.
^ Tarnopolsky MA (2010). "
Caffeine and creatine use in sport". Annals
of Nutrition & Metabolism. 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.
^ Vilarim MM, Rocha Araujo DM, Nardi AE (August 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 and Chemical Toxicology. 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". Psychological Medicine. 19 (1):
211–4. doi:10.1017/S003329170001117X. PMID 2727208.
^ Kohn R, Keller M (2015). "Chapter 34 Emotions". In Tasman A, Kay J,
Lieberman JA, First MB, Riba M. Psychiatry, 2 Volume Set. Volume 1.
New York: John Wiley & Sons. pp. 557–558.
ISBN 978-1-118-84547-9. Table 34-12...
Caffeine Intoxication –
^ Hrnčiarove J, Barteček R (2017). "8. Substance Dependence". In
Hosák L, Hrdlička M, et al. Psychiatry and Pedopsychiatry. Prague:
Karolinum Press. pp. 153–154. ISBN 9788024633787. At a
high dose, caffeine shows a euphoric effect.
^ Schulteis G (2010). "Brain stimulation and addiction". In Koob GF,
Le Moal M, Thompson RF. Encyclopedia of Behavioral Neuroscience.
Elsevier. p. 214. ISBN 978-0-08-091455-8. 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
^ Salerno BB, Knights EK (2010). Pharmacology for health professionals
(3rd ed.). Chatswood, N.S.W.: Elsevier Australia. p. 433.
ISBN 978-0-7295-3929-6. 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. ISBN 978-1-118-38578-4. 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
^ Rang HP, Ritter JM, Flower RJ, Henderson G (2014). Rang & Dale's
Pharmacology E-Book (8th ed.). Elsevier Health Sciences. pp. 453,
594. ISBN 978-0-7020-5497-6. By comparison with amphetamines,
methylxanthines produce less locomotor stimulation and do not induce
euphoria, stereotyped behaviour patterns or a psychotic state, but
their effects on fatigue and mental function are similar.
Table 37.2 ... Psychomotor stimulants ... Drugs that cause wakefulness
and euphoria ... Amphetamines, cocaine, methylphenidate,
^ Budney AJ, Emond JA (November 2014). "
Caffeine addiction? Caffeine
for youth? Time to act!". Addiction. 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".
Caffeine Research. 3 (3): 114–130.
doi:10.1089/jcr.2013.0016. PMC 3777290 .
^ Riba A, Tasman J, Kay JA, Lieberman MB, First MB (2014). Psychiatry
(Fourth ed.). p. 1446. ISBN 978-1-118-75336-1.
^ Fishchman N, Mello N. Testing for Abuse Liability of Drugs in Humans
(PDF). 5600 Fishers Lane Rockville, MD 20857: U.S. Department of
Health and Human Services Public Health Service Alcohol, Drug Abuse,
and Mental Health Administration National Institute on Drug Abuse.
p. 179. Archived from the original (PDF) on 22 December
^ Nestler EJ (December 2013). "Cellular basis of memory for
addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–43.
PMC 3898681 . 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 978-0-12-398361-9.
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
^ 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.
PMC 3181952 . 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
^ 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. PMC 2699625 .
PMID 19428492. Through these interactions, caffeine is able to
directly potentiate dopamine neurotransmission, thereby modulating the
rewarding and addicting properties of nervous system stimuli.
^ a b "
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. PMC 4115451 .
^ Association American Psychiatry (2013). Diagnostic and statistical
manual of mental disorders :
DSM-5 (5th ed.). Washington [etc.]:
American Psychiatric Publishing. pp. 792–795.
^ 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. PMC 2699625 .
^ a b c "Information about caffeine dependence".
Caffeinedependence.org. Johns 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". The New England Journal of Medicine. 327 (16):
1109–14. doi:10.1056/NEJM199210153271601. PMID 1528206.
^ a b c d e Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE
(March 1999). "Actions of caffeine in the brain with special reference
to factors that contribute to its widespread use". Pharmacological
Reviews. 51 (1): 83–133. PMID 10049999.
^ Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N (2010).
Caffeine intake and dementia: systematic review and meta-analysis".
Journal of Alzheimer's Disease. 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".
Journal of Alzheimer's Disease. 24 Suppl 2 (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". Journal of Alzheimer's Disease. 20 Suppl
1: S117–26. doi:10.3233/JAD-2010-091249. PMID 20182037.
^ 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 = Albrecht Von Graefes Archiv Fur Klinische Und
Experimentelle Ophthalmologie. 249 (3): 435–42.
doi:10.1007/s00417-010-1455-1. PMID 20706731.
^ Muriel P, Arauz J (July 2010). "
Coffee and liver diseases".
Fitoterapia. 81 (5): 297–305. doi:10.1016/j.fitote.2009.10.003.
^ Hackett PH (2010). "
Caffeine at high altitude: java at base cAMP".
High Altitude Medicine & Biology. 11 (1): 13–7.
doi:10.1089/ham.2009.1077. PMID 20367483.
^ a b c "
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
American Psychiatric Association
American Psychiatric Association (1994). Diagnostic and Statistical
Manual of Mental Disorders (4th ed.). American Psychiatric
Association. ISBN 978-0-89042-062-1.
Caffeine overdose". MedlinePlus. 4 April 2006. Retrieved 3 August
^ Verkhratsky A (January 2005). "Physiology and pathophysiology of the
calcium store in the endoplasmic reticulum of neurons". Physiological
Reviews. 85 (1): 201–79. doi:10.1152/physrev.00004.2004.
^ Holmgren P, Nordén-Pettersson L, Ahlner J (January 2004). "Caffeine
fatalities – four case reports". Forensic Science International. 139
(1): 71–3. doi:10.1016/j.forsciint.2003.09.019.
^ "FDA Consumer Advice on Powdered Pure Caffeine". FDA. Retrieved 20
^ 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. Archived from the original on
12 January 2012.
^ 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". Scandinavian Journal of Clinical
and Laboratory Investigation. 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
^ 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 (April 2002). "Interactions between
alcohol and caffeine in relation to psychomotor speed and accuracy".
Human Psychopharmacology. 17 (3): 151–6. doi:10.1002/hup.371.
^ a b c Liguori A, Robinson JH (July 2001). "
Caffeine antagonism of
alcohol-induced driving impairment". Drug and
Alcohol Dependence. 63
(2): 123–9. doi:10.1016/s0376-8716(00)00196-4.
^ Marczinski CA, Fillmore MT (August 2003). "Dissociative antagonistic
effects of caffeine on alcohol-induced impairment of behavioral
control". Experimental and Clinical Psychopharmacology. 11 (3):
228–36. doi:10.1037/1064-1218.104.22.168. PMID 12940502.
^ Zevin S, Benowitz NL (June 1999). "Drug interactions with tobacco
smoking. An update". Clinical Pharmacokinetics. 36 (6): 425–38.
doi:10.2165/00003088-199936060-00004. PMID 10427467.
^ Benowitz NL (1990). "Clinical pharmacology of caffeine". Annual
Review of Medicine. 41: 277–88.
doi:10.1146/annurev.me.41.020190.001425. PMID 2184730.
^ Gilmore B, Michael M (February 2011). "Treatment of acute migraine
headache". American Family Physician. 83 (3): 271–80.
^ a b c Froestl W, Muhs A, Pfeifer A (2012). "Cognitive enhancers
(nootropics). Part 1: drugs interacting with receptors". J. Alzheimers
Dis. 32 (4): 793–887. doi:10.3233/JAD-2012-121186.
^ "World of Caffeine". World of Caffeine. 15 June 2013. Retrieved 19
^ Fisone G, Borgkvist A, Usiello A (April 2004). "
Caffeine as a
psychomotor stimulant: mechanism of action". Cellular and Molecular
Life Sciences. 61 (7–8): 857–72. doi:10.1007/s00018-003-3269-3.
^ "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". The Journal of Physiology. 587 (Pt 16):
4063–75. doi:10.1113/jphysiol.2009.174797. PMC 2756438 .
^ a b c Ferré S (2010). "Role of the central ascending
neurotransmitter systems in the psychostimulant effects of caffeine".
Journal of Alzheimer's Disease. 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
^ a b Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés
A, Lluís C, Casadó V, Volkow ND (May 2016). "Allosteric mechanisms
within the adenosine A2A-dopamine D2 receptor heterotetramer".
Neuropharmacology. 104: 154–60.
doi:10.1016/j.neuropharm.2015.05.028. PMID 26051403.
^ a b 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 (July 2015). "Allosteric
interactions between agonists and antagonists within the adenosine A2A
receptor-dopamine D2 receptor heterotetramer". Proceedings of the
National Academy of Sciences of the United States of America. 112
(27): E3609–18. doi:10.1073/pnas.1507704112. PMC 4500251 .
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.
^ a b Ferré S (2016). "Mechanisms of the psychostimulant effects of
caffeine: implications for substance use disorders".
Psychopharmacology. 233 (10): 1963–79.
doi:10.1007/s00213-016-4212-2. PMC 4846529 .
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.
^ a b c d 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; Ferré 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
^ Ribeiro JA, Sebastião AM (2010). "
Caffeine and adenosine". Journal
of Alzheimer's Disease. 20 Suppl 1: S3–15.
doi:10.3233/JAD-2010-1379. PMID 20164566.
^ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases".
The Journal of Allergy and Clinical Immunology. 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. 63 (3): 321–8.
doi:10.1590/S1807-59322008000300006. PMC 2664230 .
^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February
Pentoxifylline inhibits TNF-alpha production from human
alveolar macrophages". American Journal of Respiratory and Critical
Care Medicine. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085.
^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005).
"Leukotrienes: underappreciated mediators of innate immune responses".
Journal of Immunology. 174 (2): 589–94.
doi:10.4049/jimmunol.174.2.589. PMID 15634873.
^ Arnaud, M. J. (2011). "
Metabolism of Natural
Methylxanthines in Animal and Man. In: Methylxanthines". Handbook of
Experimental Pharmacology. 200. doi:10.1007/978-3-642-13443-2_3.
^ Liguori A, Hughes JR, Grass JA (November 1997). "Absorption and
subjective effects of caffeine from coffee, cola and capsules".
Pharmacology Biochemistry and Behavior. 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".
European Journal of Clinical Pharmacology. 21 (1): 45–52.
doi:10.1007/BF00609587. PMID 7333346.
^ Graham JR (June 1954). "Rectal use of ergotamine tartrate and
caffeine alkaloid for the relief of migraine". The New England Journal
of Medicine. 250 (22): 936–8. doi:10.1056/NEJM195406032502203.
^ Brødbaek HB, Damkier P (May 2007). "[The treatment of hyperemesis
gravidarum with chlorobutanol-caffeine rectal suppositories in
Denmark: practice and evidence]". Ugeskrift for Laeger (in Danish).
169 (22): 2122–3. PMID 17553397.
^ Teekachunhatean S, Tosri N, Rojanasthien N, Srichairatanakool S,
Sangdee C (8 January 2013). "
Caffeine following a
Single Administration of
Coffee Enema versus Oral
in Healthy Male Subjects". ISRN Pharmacology. Hindawi Publishing
Corporation. 2013 (147238): 147238. doi:10.1155/2013/147238.
PMC 3603218 . PMID 23533801.
^ "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 (December 2008). "
Pharmacokinetics and dosage adjustment
in patients with hepatic dysfunction". European Journal of Clinical
Pharmacology. 64 (12): 1147–61. doi:10.1007/s00228-008-0553-z.
^ 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 Genetics. 7 (4):
e1002033. doi:10.1371/journal.pgen.1002033. PMC 3071630 .
^ a b 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 Brittain HG, Prankerd RJ (2007). Profiles of Drug
Substances, Excipients and Related Methodology, volume 33: Critical
Compilation of pKa Values for Pharmaceutical Substances. Academic
Press. p. 15. ISBN 978-0-12-260833-9. Retrieved 15 January
^ 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.
^ Keskineva N. "Chemistry of Caffeine" (PDF). Chemistry Department,
East Stroudsburg University. Archived from the original (PDF) on 2
January 2014. Retrieved 2 January 2014.
Caffeine biosynthesis". The
Enzyme Database. Trinity College
Dublin. Retrieved 24 September 2011.
^ "MetaCyc Pathway: caffeine biosynthesis I". MetaCyc database. SRI
International. Retrieved 12 July 2017.
^ a b Temple NJ, Wilson T (2003).
Beverages in Nutrition and Health.
Totowa, NJ: Humana Press. p. 172.
^ a b US patent 2785162, Swidinsky J, Baizer MM, "Process for the
formylation of a 5-nitrouracil", published 12 March 1957, assigned to
Quinine and Chemical Works, Inc.
^ Denoeud F, Carretero-Paulet L, Dereeper A, Droc G, Guyot R,
Pietrella M, Zheng C, Alberti A, Anthony F, Aprea G, Aury JM, Bento P,
Bernard M, Bocs S, Campa C, Cenci A, Combes MC, Crouzillat D, Da Silva
C, Daddiego L, De Bellis F, Dussert S, Garsmeur O, Gayraud T, Guignon
V, Jahn K, Jamilloux V, Joët T, Labadie K, Lan T, Leclercq J,
Lepelley M, Leroy T, Li LT, Librado P, Lopez L, Muñoz A, Noel B,
Pallavicini A, Perrotta G, Poncet V, Pot D, Rigoreau M, Rouard M,
Rozas J, Tranchant-Dubreuil C, VanBuren R, Zhang Q, Andrade AC, Argout
X, Bertrand B, de Kochko A, Graziosi G, Henry RJ, Ming R, Nagai C,
Rounsley S, Sankoff D, Giuliano G, Albert VA, Wincker P, Lashermes P
(September 2014). "The coffee genome provides insight into the
convergent evolution of caffeine biosynthesis". Science. 345 (6201):
1181–4. doi:10.1126/science.1255274. PMID 25190796.
^ Huang R, O'Donnell AJ, Barboline JJ, Barkman TJ (September 2016).
Convergent evolution of caffeine in plants by co-option of exapted
ancestral enzymes". Proceedings of the National Academy of Sciences of
the United States of America. 113 (38): 10613–8.
doi:10.1073/pnas.1602575113. PMC 5035902 .
^ Williams R (September 21, 2016). "How Plants Evolved Different Ways
to Make Caffeine".
^ Zajac MA, Zakrzewski AG, Kowal MG, Narayan S (2003). "A Novel Method
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.
^ a b c 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
Caffeine content of decaffeinated coffee". Journal of
Analytical Toxicology. 30 (8): 611–3. doi:10.1093/jat/30.8.611.
PMID 17132260. Lay summary – University of Florida News.
^ Baselt R (2017). Disposition of Toxic Drugs and Chemicals in Man
(11th ed.). Seal Beach, CA: Biomedical Publications. pp. 335–8.
^ Seale TW, Abla KA, Shamim MT, Carney JM, Daly JW (1988).
"3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo
antagonist of adenosine analogs". Life Sciences. 43 (21): 1671–84.
doi:10.1016/0024-3205(88)90478-x. PMID 3193854.
^ Kennerly J (22 September 1995). "N Substituted Xanthines: A Caffeine
Analog Information File". Retrieved 6 November 2015.
^ Müller CE, Jacobson KA (19 August 2010). Fredholm BB, ed.
"Xanthines as adenosine receptor antagonists". Handbook of
Experimental Pharmacology. Handbook of Experimental Pharmacology.
Springer Berlin Heidelberg. 200 (200): 151–99.
doi:10.1007/978-3-642-13443-2_6. PMC 3882893 .
^ Plant Polyphenols: Synthesis, Properties, Significance. Richard W.
Hemingway,Peter E. Laks,Susan J. Branham (page 263)
^ "Which Plants Contain Caffeine?". medscape.com.
^ For more information, see Alejandro Lopez-Ortiz. "Frequently Asked
Coffee and Caffeine".
^ Nathanson JA (October 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). "
formation in buds and developing leaflets of
Expression of an optimal defence strategy?". Phytochemistry. 25 (3):
^ Baumann TW (1984). "
Metabolism and excretion of caffeine during
Coffea arabica L". Plant and Cell Physiology. 25 (8):
^ van Breda, Shane V.; van der Merwe, Chris F.; Robbertse, Hannes;
Apostolides, Zeno (10 November 2012). "Immunohistochemical
localization of caffeine in young
Camellia sinensis (L.) O. Kuntze
(tea) leaves". Planta. 237 (3): 849–858.
^ a b 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 4521368 . PMID 23471406.
^ Balentine DA, Harbowy ME, Graham HN (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.
^ a b "
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
^ a b Chin JM, Merves ML, Goldberger BA, Sampson-Cone A, Cone EJ
(October 2008). "
Caffeine content of brewed teas". Journal of
Analytical Toxicology. 32 (8): 702–4. doi:10.1093/jat/32.8.702.
^ a b Richardson B (2009). "Too Easy to be True. De-bunking the
Decaffeination Myth". Elmwood Inn. Archived from the original
on 27 December 2011. 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.
^ a b "Caffeine". International
Coffee Organization. Archived from the
original on 27 March 2009. Retrieved 1 August 2009.
^ a b "
Caffeine FAQ: Does dark roast coffee have less
caffeine than light roast?". Retrieved 2 August 2009.
^ a b "All About Coffee:
Caffeine Level". Jeremiah's Pick
Archived from the original on 18 March 2008. Retrieved 3 August
^ a b Hicks MB, Hsieh YH, Bell LN (1996). "
Tea preparation and its
influence on methylxanthine concentration". Food Research
International. 29 (3–4): 325–330.
^ "Nutrition and healthy eating". Mayo Clinic. Retrieved 18 November
^ 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. 176 (3–4): 412–9.
doi:10.1007/s00213-004-1898-3. PMID 15549276.
^ Weinberg BA, Bealer BK (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.
^ "Some Common Questions". Eagle Energy. Retrieved 2017-05-22.
^ "2012 - Breathable Foods, Inc. 3/5/12". www.fda.gov. Retrieved
^ "Food Additives & Ingredients > Caffeinated Alcoholic
Beverages". fda.gov. Food and Drug Administration. 17 November 2010.
Retrieved 24 January 2014.
^ Evans JC (1992).
Tea in China: The History of China's National
Drink. Greenwood Press. p. 2. ISBN 978-0-313-28049-8.
^ Yu L (1995). The Classic of Tea: Origins & Rituals. Ecco Pr.
ISBN 978-0-88001-416-8. [page needed]
^ Weinberg BA, Bealer BK (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 H (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.
^ a b Fairbanks CH (2004). "The function of black drink among the
Creeks". In Hudson MC. 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". Proceedings of the
National Academy of Sciences of the United States of America. 109
(35): 13944–9. doi:10.1073/pnas.1208404109. PMC 3435207 .
^ Runge FF (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
Johann Wolfgang von Goethe
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
^ Weinberg BA, Bealer BK (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
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
^ 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
^ 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.
^ Jobst, Carl (1838). "Thein identisch mit Caffein" [Theine is
identical to caffeine]. Liebig's Annalen der Chemie und Pharmacie. 25:
^ 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:
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.
Fischer E (1882). "Ueber das Caffeïn. Dritte Mitteilung" [On
caffeine. Third communication.]. Berichte der Deutschen chemischen
Gesellschaft zu Berlin (in German). 15: 29–33.
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.
^ Hj. Théel (1902). "Nobel Prize Presentation Speech". Retrieved 3
^ Brown DW (2004). A new introduction to Islam. Chichester, West
Sussex: Wiley-Blackwell. pp. 149–51.
^ Ágoston, Gábor; Masters, Bruce (2009). Encyclopedia of the Ottoman
Empire. p. 138. ISBN 978-1-4381-1025-7.
^ Hopkins K (24 March 2006). "Food Stories: The Sultan's Coffee
Prohibition". Accidental Hedonist. Archived from the original on 20
November 2012. 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 (January 1991). "Coca-Cola,
caffeine, and mental deficiency: Harry Hollingworth and the
Chattanooga trial of 1911". Journal of the History of the Behavioral
Sciences. 27 (1): 42–55.
^ "The Rise and Fall of
Cocaine Cola". Lewrockwell.com. Retrieved 25
^ "CFR – Code of Federal Regulations Title 21". U.S. Food and Drug
Administration. 21 August 2015. Retrieved 23 November 2015.
^ Sanner A (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
^ Reissig CJ, Strain EC, Griffiths RR (January 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 2735818 . 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
^ "Mormonism in the News: Getting It Right August 29". The Church of
Jesus Christ of Latter-Day Saints. 2012. Retrieved 17 April
^ Juan Eduardo Campo (1 January 2009). Encyclopedia of Islam. Infobase
Publishing. p. 154. ISBN 978-1-4381-2696-8. Retrieved 1
^ Daniel W. Brown (24 August 2011). A New Introduction to Islam. John
Wiley & Sons. p. 149. ISBN 978-1-4443-5772-1.
^ "Newly Discovered Bacteria Lives on Caffeine".
Blogs.scientificamerican.com. 24 May 2011. Retrieved 19 December
^ Paul L. "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". Handbook of Experimental
Pharmacology. Handbook of Experimental Pharmacology. 200 (200):
33–91. doi:10.1007/978-3-642-13443-2_3. ISBN 978-3-642-13442-5.
^ Thomas J, Chen Q, Howes N (August 1997). "Chromosome doubling of
haploids of common wheat with caffeine". Genome. 40 (4): 552–8.
doi:10.1139/g97-072. PMID 18464846.
Bersten I (1999). Coffee, Sex & Health: A history of anti-coffee
crusaders and sexual hysteria. Sydney: Helian Books.
Pendergrast M (2001) . Uncommon Grounds: The History of Coffee
and How It Transformed Our World. London: Texere.
Wikimedia Commons has media related to Caffeine.
Wikinews has related news:
Alzheimer's disease reversed in mice using
GMD MS Spectrum
The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1
Caffeine: ChemSub Online
The Periodic Table of Videos
The Periodic Table of Videos (University of Nottingham)
Caffeine International Chemical Safety Cards
Mayo Clinic staff (3 October 2009). "
Caffeine content for coffee, tea,
soda and more". Mayo Clinic. Retrieved 8 November 2010.
List of countries by coffee production
Species and varieties
Coffee Pot Control Protocol
List of coffee dishes
Cà phê sữa đá
Café au lait
Café de olla
Café con leche
Café com Cheirinho
Greek frappé coffee
Indian filter coffee
Ipoh white coffee
Viennese coffee house
Roasted grain drink
Coffee and doughnuts
Coffee cup sleeve
Tasse à café
Coffee leaf rust
King Gustav's twin experiment
Coffee vending machine
Single-serve coffee container
Third wave of coffee
Amphetamine (Dextroamphetamine, Levoamphetamine)
DOPA (Dextrodopa, Levodopa)
Fenfluramine (Dexfenfluramine, Levofenfluramine)
Methamphetamine (Dextromethamphetamine, Levomethamphetamine)
CFT (WIN 35,428)
Troparil (β-CPT, WIN 35,065-2)
ATC code: N06B
Acetylcholine metabolism and transport modulators
Inhibitors: Reversible: Carbamates: Aldicarb
Thiofanox; Stigmines: Distigmine
Terestigmine; Others: Acotiamide
Irreversible: Organophosphates: Acephate
Dimethyl 4-(methylthio)phenyl phosphate
VX; Others: Demecarium
Fasciculins (green mamba toxins) (1, 2, 3, 4)
Onchidal (Onchidella binneyi)
Reactivators: Asoxime chloride
Many of the other AChE inhibitors listed above
Botulinum toxin (A, C, E)
Botulinum toxin (B, D, F, G)
Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)
LPHN agonists: α-Latrotoxin
Atracotoxin (e.g., robustoxin, versutoxin)
See also: Receptor/signaling modulators • Muscarinic acetylcholine
receptor modulators • Nicotinic acetylcholine receptor modulators
Glycine receptor modulators
Positive modulators: Alcohols (e.g., brometone, chlorobutanol
(chloretone), ethanol (alcohol), tert-butanol (2M2P), tribromoethanol,
Barbiturates (e.g., pentobarbital, sodium thiopental)
Dihydropyridines (e.g., nicardipine)
Ginseng constituents (e.g., ginsenosides (e.g., ginsenoside-Rf))
Glutamic acid (glutamate)
Neuroactive steroids (e.g., alfaxolone, pregnenolone (eltanolone),
pregnenolone acetate, minaxolone, ORG-20599)
Tropeines (e.g., atropine, bemesetron, cocaine, LY-278584,
Volatiles/gases (e.g., chloral hydrate, chloroform, desflurane,
diethyl ether (ether), enflurane, halothane, isoflurane,
methoxyflurane, sevoflurane, toluene, trichloroethane (methyl
Endocannabinoids (e.g., 2-AG, anandamide (AEA))
Quinolines (e.g., 4-hydroxyquinoline, 4-hydroxyquinoline-3-carboxylic
acid, 5,7-CIQA, 7-CIQ, 7-TFQ, 7-TFQA)
Negative modulators: Amiloride
Benzodiazepines (e.g., bromazepam, clonazepam, diazepam,
Dihydropyridines (e.g., nicardipine, nifedipine, nitrendipine)
Ginkgo constituents (e.g., bilobalide, ginkgolides (e.g., ginkgolide
A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M))
Neuroactive steroids (e.g., 3α-androsterone sulfate, 3β-androsterone
sulfate, deoxycorticosterone, DHEA sulfate, pregnenolone sulfate,
Opioids (e.g., codeine, dextromethorphan, dextrorphan, levomethadone,
levorphanol, morphine, oripavine, pethidine, thebaine)
Picrotoxin (i.e., picrotin and picrotoxinin)
Tropeines (e.g., bemesetron, LY-278584, tropisetron, zatosetron)
See here instead.
GABA receptor modulators
GABAA receptor positive modulators
Ionotropic glutamate receptor modulators
See also: Receptor/signaling modulators
Purine receptor modulators
SDZ WAG 994
Emodin (Rheum officinale)
Puerarin (Radix puerariae)
Sodium ferulate (Angelica sinensis, Ligusticum wallichii)
Tetramethylpyrazine (ligustrazine) (Ligusticum wallichii)
See also: Receptor/signaling modulators
Pharmacy and Pharmacology portal