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; in 2005, 90% of North
American adults consumed caffeine daily.
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
WHO Model List of Essential Medicines . It
may confer a modest protective effect against some diseases,
including Parkinson\'s disease . Some people experience insomnia or
sleep disruption if they consume caffeine, especially during the
evening hours, but others show little disturbance. Evidence of a risk
during pregnancy is equivocal; some authorities recommend that
pregnant women limit consumption to the equivalent of two cups of
coffee per day or less.
Caffeine can produce a mild form of drug
dependence – associated with withdrawal symptoms such as sleepiness,
headache, and irritability – when an individual stops using caffeine
after repeated daily intake. Tolerance to the autonomic effects of
increased blood pressure and heart rate, and increased urine output,
develops with chronic use (i.e., these symptoms become less pronounced
or do not occur following consistent use).
Caffeine is classified by the 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 Use
* 1.1 Medical
* 1.2 Enhancing performance
* 1.2.1 Cognitive
* 1.2.2 Physical
* 1.3 Specific populations
* 1.3.1 Adults
* 1.3.2 Children
* 1.3.3 Adolescents
* 1.3.4 Pregnancy and breastfeeding
* 2 Side effects
* 2.1 Physical
* 2.2 Psychological
* 2.3 Reinforcement disorders
* 2.3.2 Dependence and withdrawal
* 2.4 Risk of other diseases
* 3 Overdose
* 4 Interactions
* 4.3 Oral birth control
* 4.4 Medications
* 5 Pharmacology
* 5.1 Pharmacodynamics
* 5.1.1 Receptor and ion channel targets
* 18.104.22.168 Effects on striatal dopamine
* 5.1.3 Off-target effects
* 6 Chemistry
* 6.1 Synthesis
* 6.3 Detection in body fluids
* 6.4 Analogs
* 7 Natural occurrence
* 8 Products
* 8.1.3 Soft drinks and energy drinks
* 8.1.4 Other beverages
* 8.3 Tablets
* 8.4 Other oral products
* 8.5 Inhalants
* 8.6 Combinations with other drugs
* 9 History
* 9.1 Discovery and spread of use
* 9.2 Chemical identification, isolation, and synthesis
* 9.3 Historic regulations
* 10 Society and culture
* 10.1 Regulations
* 10.2 Consumption
* 10.3 Religions
* 11 Other organisms
* 12 Research
* 13 See also
* 14 References
* 15 Bibliography
* 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 prevention.
Orthostatic hypotension treatment.
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
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 power output.
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 limits:
MAXIMUM RECOMMENDED DAILY CAFFEINE INTAKE
45 mg (slightly more than in 12 oz of a typical soft drink)
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 (ACOG) concluded in 2010 that
caffeine consumption is safe up to 200 mg per day in pregnant women.
For women who breastfeed, are pregnant, or may become pregnant, Health
Canada recommends a maximum daily caffeine intake of no more than 300
mg, or a little over two 8 oz (237 mL) cups of coffee.
The evidence for or against the importance of limiting caffeine
intake during pregnancy is insufficient and of low quality. There are
conflicting reports in the scientific literature about caffeine
consumption during pregnancy. A 2011 risk analysis review found that
caffeine consumption during pregnancy does not appear to increase the
risk of congenital malformations , miscarriage or growth retardation
even when consumed in moderate to high amounts. There is some
evidence that the hormonal changes during pregnancy slow the metabolic
clearance of caffeine from the system, causing a given dose to have
longer-lasting effects (as long as 15 hours in the third trimester).
There is 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 vasoconstriction .
Long-term consumption at sufficiently high doses has been associated
with chronic arterial stiffness.
Coffee and caffeine can affect
gastrointestinal motility and gastric acid secretion.
low doses may cause weak bronchodilation for up to four hours in
Caffeine increases basal metabolic rate in adults. In
postmenopausal women, high caffeine consumption can accelerate bone
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
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.
In moderate doses, caffeine may reduce symptoms of depression and
lower suicide risk.
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
ICD-10 , include a classification of caffeine addiction
under a broader diagnostic model. Some state that certain users can
become addicted and therefore unable to decrease use even though they
know there are negative health effects.
Caffeine does not appear to be a reinforcing stimulus, and some
degree of aversion may actually occur, with people preferring placebo
over caffeine in a study on drug abuse liability published in an NIDA
research monograph. Some state that research does not provide support
for an underlying biochemical mechanism for caffeine addiction.
Other research states it can affect the reward system.
Caffeine addiction" was added to the ICDM-9 and ICD-10. However, its
addition was contested with claims that this diagnostic model of
caffeine addiction is not supported by evidence. The American
Psychiatric Association 's
DSM-5 does not include the diagnosis of a
caffeine addiction but proposes criteria for the disorder for more
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 withdrawal .
Caffeine dependence can
involve withdrawal symptoms such as fatigue, headache, irritability,
depressed mood, reduced contentedness, inability to concentrate,
sleepiness or drowsiness, stomach pain , and joint pain . Withdrawal
headaches are experienced by roughly half of those who stop consuming
caffeine for two days following an average daily intake of 235 mg.
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.
intraocular pressure in those with glaucoma but does not appear to
affect normal individuals. It may protect people from liver cirrhosis
Caffeine may lessen the severity of acute mountain sickness if
taken a few hours prior to attaining a high altitude.
Primary symptoms of caffeine intoxication
Consumption of 1–1.5 grams per day is associated with a condition
known as caffeinism. Caffeinism usually combines caffeine dependency
with a wide range of unpleasant symptoms including nervousness,
irritability, restlessness, insomnia, headaches, and palpitations
after caffeine use.
Caffeine overdose can result in a state of central nervous system
over-stimulation called caffeine intoxication (
DSM-IV 305.90). This
syndrome typically occurs only after ingestion of large amounts of
caffeine, well over the amounts found in typical caffeinated beverages
and caffeine tablets (e.g., more than 400–500 mg at a time). The
symptoms of caffeine intoxication are comparable to the symptoms of
overdoses of other stimulants : they may include restlessness,
fidgeting, anxiety, excitement, insomnia, flushing of the face,
increased urination, gastrointestinal disturbance, muscle twitching, a
rambling flow of thought and speech, irritability, irregular or rapid
heart beat, and psychomotor agitation . In cases of much larger
overdoses, mania , depression , lapses in judgment, disorientation ,
disinhibition , delusions, hallucinations, or psychosis may occur, and
rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.
Massive overdose can result in death. The LD50 of caffeine in
humans is dependent on individual sensitivity, but is estimated to be
150 to 200 milligrams per kilogram of body mass (75–100 cups of
coffee for a 70 kilogram adult). A number of fatalities have been
caused by overdoses of readily available powdered caffeine
supplements, for which the estimated lethal amount is less than a
tablespoon. The lethal dose is lower in individuals whose ability to
metabolize caffeine is impaired due to genetics or chronic liver
disease A death was reported in a man with liver cirrhosis who
overdosed on caffeinated mints.
Treatment of mild caffeine intoxication is directed toward symptom
relief; severe intoxication may require peritoneal dialysis ,
hemodialysis , or hemofiltration .
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 consumed. Alcohol
consumption alone reduces both inhibitory and activational aspects of
Caffeine antagonizes the activational aspect of
behavioral control, but has no effect on the inhibitory behavioral
Smoking tobacco increases caffeine clearance by 56%.
ORAL BIRTH CONTROL
Consumption of caffeine while orally administering birth control can
extend the half-life of caffeine; therefore, greater attention should
be taken during caffeine consumption.
Caffeine may increase the effectiveness of some medications including
ones used to treat headaches .
STRUCTURE OF A TYPICAL CHEMICAL SYNAPSE
Axon terminal Synaptic cleft
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 a receptor antagonist at all adenosine receptor subtypes
(A1 , A2A , A2B , and A3 receptors). Antagonism at these receptors
stimulates the medullary vagal, vasomotor, and respiratory centers ,
which increases respiratory rate, reduces heartrate, and constricts
Adenosine receptor antagonism also promotes
neurotransmitter release (e.g., monoamines and acetylcholine ), which
endows caffeine with its stimulant effects; adenosine acts as an
inhibitory neurotransmitter that suppresses activity in the central
nervous system. Heart palpitations are caused by blockade of the
adenosine A1 receptor.
Because caffeine is both water- and lipid-soluble, it readily crosses
the blood–brain barrier that separates the bloodstream from the
interior of the brain. Once in the brain, the principal mode of action
is as a nonselective antagonist of adenosine receptors (in other
words, an agent that reduces the effects of adenosine). The caffeine
molecule is structurally similar to adenosine, and is capable of
binding to adenosine receptors on the surface of cells without
activating them, thereby acting as a competitive antagonist .
In addition to its activity at adenosine receptors, caffeine is an
inositol trisphosphate receptor 1 antagonist and a voltage-independent
activator of the ryanodine receptors (
RYR2 , and
RYR3 ). It is
also a competitive antagonist of the ionotropic glycine receptor .
Effects On Striatal Dopamine
While caffeine does not directly bind to any dopamine receptors , it
influences the binding activity of dopamine at its receptors in the
striatum by binding to adenosine receptors that have formed GPCR
heteromers with dopamine receptors, specifically the A1 –D1 receptor
heterodimer (this is a receptor complex with 1 adenosine A1 receptor
and 1 dopamine D1 receptor) and the A2A –D2 receptor heterotetramer
(this is a receptor complex with 2 adenosine A2A receptors and 2
dopamine D2 receptors). The A2A–D2 receptor heterotetramer has
been identified as a primary pharmacological target of caffeine,
primarily because it mediates some of its psychostimulant effects and
its pharmacodynamic interactions with dopaminergic psychostimulants.
Caffeine also causes the release of dopamine in the dorsal striatum
and nucleus accumbens core (a substructure within the ventral striatum
), but not the nucleus accumbens shell , by antagonizing A1 receptors
in the axon terminal of dopamine neurons and A1 –A2A heterodimers (a
receptor complex composed of 1 adenosine A1 receptor and 1 adenosine
A2A receptor) in the axon terminal of glutamate neurons. During
chronic caffeine use, caffeine-induced dopamine release within the
nucleus accumbens core is markedly reduced due to drug tolerance .
Caffeine, like other xanthines , also acts as a phosphodiesterase
inhibitor . As a competitive nonselective phosphodiesterase inhibitor
, caffeine raises intracellular cAMP , activates protein kinase A ,
inhibits TNF-alpha and leukotriene synthesis, and reduces
inflammation and innate immunity .
Caffeine also affects the
cholinergic system where it inhibits the enzyme acetylcholinesterase .
Caffeine antagonizes adenosine A2A receptors in the ventrolateral
preoptic area (VLPO), thereby reducing inhibitory GABA
neurotransmission to the tuberomammillary nucleus , a histaminergic
projection nucleus that activation-dependently promotes arousal.
Disinhibition of the tuberomammillary nucleus is the chief mechanism
by which caffeine produces wakefulness-promoting effects.
Caffeine 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
Caffeine from coffee or other beverages is absorbed by the small
intestine within 45 minutes of ingestion and distributed throughout
all bodily tissues. Peak blood concentration is reached within 1–2
hours. It is eliminated by first-order kinetics .
Caffeine can also
be absorbed rectally, evidenced by suppositories of ergotamine
tartrate and caffeine (for the relief of migraine ) and chlorobutanol
and caffeine (for the treatment of hyperemesis ). However, rectal
absorption is less efficient than oral: the maximum concentration
(Cmax ) and total amount absorbed (AUC ) are both about 30% (i.e.
1/3.5) of the oral amounts.
Caffeine's biological half-life – the time required for the body to
eliminate one-half of a dose – varies widely among individuals
according to factors such as pregnancy, other drugs, liver enzyme
function level (needed for caffeine metabolism) and age. In healthy
adults, caffeine's half-life is between 3–7 hours. 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
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
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 protonate it.
Caffeine does not contain any
stereogenic centers and hence is classified as an achiral molecule.
The xanthine core of caffeine contains two fused rings, a
pyrimidinedione and imidazole . The pyrimidinedione in turn contains
two amide functional groups that exist predominately in a zwitterionic
resonance the location from which the nitrogen atoms are double bonded
to their adjacent amide carbons atoms. Hence all six of the atoms
within the pyrimidinedione ring system are sp2 hybridized and planar.
Therefore, the fused 5,6 ring core of caffeine contains a total of ten
pi electrons and hence according to Hückel\'s rule is aromatic .
One biosynthetic route of caffeine, as performed by
Coffea species. 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 .
Commercial supplies of caffeine are not usually manufactured
synthetically because the chemical it is readily available as a
byproduct of decaffeination.
Decaffeination Fibrous crystals of purified
Dark field light microscope image, the image covers an area
of approx. 7 x 11mm.
Extraction of caffeine from coffee, to produce caffeine and
decaffeinated coffee, can be performed using a number of solvents.
Benzene , chloroform , trichloroethylene , and dichloromethane have
all been used over the years but for reasons of safety, environmental
impact, cost, and flavor, they have been superseded by the following
* WATER EXTRACTION:
Coffee beans are soaked in water. The water,
which contains many other compounds in addition to caffeine and
contributes to the flavor of coffee, is then passed through activated
charcoal , which removes the caffeine. The water can then be put back
with the beans and evaporated dry, leaving decaffeinated coffee with
its original flavor.
Coffee manufacturers recover the caffeine and
resell it for use in soft drinks and over-the-counter caffeine
* SUPERCRITICAL CARBON DIOXIDE EXTRACTION: Supercritical carbon
dioxide is an excellent nonpolar solvent for caffeine, and is safer
than the organic solvents that are otherwise used. The extraction
process is simple: CO2 is forced through the green coffee beans at
temperatures above 31.1 °C and pressures above 73 atm . Under these
conditions, CO2 is in a "supercritical " state : It has gaslike
properties that allow it to penetrate deep into the beans but also
liquid-like properties that dissolve 97–99% of the caffeine. The
caffeine-laden CO2 is then sprayed with high pressure water to remove
the caffeine. The caffeine can then be isolated by charcoal adsorption
(as above) or by distillation , recrystallization , or reverse osmosis
* EXTRACTION BY ORGANIC SOLVENTS: Certain organic solvents such as
ethyl acetate present much less health and environmental hazard than
chlorinated and aromatic organic solvents used formerly. Another
method is to use triglyceride oils obtained from spent coffee grounds.
"Decaffeinated" coffees do in fact contain caffeine in many cases –
some commercially available decaffeinated coffee products contain
considerable levels. One study found that decaffeinated coffee
contained 10 mg of caffeine per cup, compared to approximately 85 mg
of caffeine per cup for regular coffee.
DETECTION IN BODY FLUIDS
Caffeine can be quantified in blood, plasma, or serum to monitor
therapy in neonates, confirm a diagnosis of poisoning, or facilitate a
medicolegal death investigation. Plasma caffeine levels are usually in
the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates
receiving treatment for apnea, and 40–400 mg/L in victims of acute
overdosage. Urinary caffeine concentration is frequently measured in
competitive sports programs, for which a level in excess of 15 mg/L is
usually considered to represent abuse.
Some analog substances have been created which mimic caffeine's
properties with either function or structure or both. Of the latter
group are the xanthines
DMPX and 8-chlorotheophylline , which is an
ingredient in dramamine . Members of a class of nitrogen substituted
xanthines are often proposed as potential alternatives to caffeine.
Many other xanthine analogues constituting the adenosine receptor
antagonist class have also been elucidated.
Some other caffeine analogs:
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 C. canephora (the quantity varies, but 1.3% is a
typical value ); in the leaves of the tea bush ; and in kola nuts .
Other sources include yaupon holly leaves, South American holly yerba
mate leaves, seeds from Amazonian maple guarana berries, and Amazonian
holly guayusa leaves. Temperate climates around the world have
produced unrelated caffeine containing plants.
Caffeine in plants acts as a natural pesticide : it can paralyze and
kill predator insects feeding on the plant. High caffeine levels are
found in coffee seedlings when they are developing foliage and lack
mechanical protection. In addition, high caffeine levels are found in
the surrounding soil of coffee seedlings, which inhibits seed
germination of nearby coffee seedlings, thus giving seedlings with the
highest caffeine levels fewer competitors for existing resources for
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.
Caffeine content in select food and drugs
CAFFEINE PER SERVING (MG )
CAFFEINE (MG/L )
Caffeine tablet (regular-strength)
Caffeine tablet (extra-strength)
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 min.
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.
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
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
slow-release excipient .
* Mate is a drink popular in many parts of South America. Its
preparation consists of filling a gourd with the leaves of the South
American holly yerba mate , pouring hot but not boiling water over the
leaves, and drinking with a straw, the bombilla, which acts as a
filter so as to draw only the liquid and not the yerba leaves.
Guaraná seeds ("beans") are used in making the commercially sold
Guaraná Antarctica , which originated in Brazil and is
currently the fifteenth most popular soft drink in the world.
* The leaves of
Ilex guayusa , the Ecuadorian holly tree, are placed
in boiling water to make a guayusa tea, which is both brewed locally
and sold commercially throughout the world.
Chocolate derived from cocoa beans contains a small amount of
caffeine. The weak stimulant effect of chocolate may be due to a
combination of theobromine and theophylline, as well as caffeine. A
typical 28-gram serving of a milk chocolate bar has about as much
caffeine as a cup of decaffeinated coffee. By weight, dark chocolate
has one to two times the amount of caffeine as coffee: 80–160 mg per
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
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.
DISCOVERY AND SPREAD OF USE
Coffeehouse in Palestine , circa 1900 Main articles: History
of chocolate ,
History of coffee ,
History of tea , and History of
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
Chocolate was an important luxury good throughout
Mesoamerica , and cocoa beans were often used as
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
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
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 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
elemental analysis .
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 1676,
Frederick II of Prussia
Frederick II of Prussia banned it in 1777, and coffee was banned in
Sweden at various times between 1756 and 1823.
In 1911, caffeine became the focus of one of the earliest documented
health scares, when the US government seized 40 barrels and 20 kegs of
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
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 the food.
Global consumption of caffeine has been estimated at 120,000 tonnes
per year, making it the world's most popular psychoactive substance.
This amounts to one serving of a caffeinated beverage for every person
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 unit weight.
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
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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.,
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
(2013). "Substance-Related and Addictive Disorders" (PDF). American
Psychiatric Publishing. pp. 1–2. Archived from the original (PDF) on
15 August 2015. Retrieved 10 July 2015. Substance use disorder in
DSM-5 combines the
DSM-IV categories of substance abuse and substance
dependence into a single disorder measured on a continuum from mild to
severe. ... Additionally, the diagnosis of dependence caused much
confusion. Most people link dependence with "addiction" when in fact
dependence can be a normal body response to a substance. ... DSM-5
will not include caffeine use disorder, although research shows that
as little as two to three cups of coffee can trigger a withdrawal
effect marked by tiredness or sleepiness. There is sufficient evidence
to support this as a condition, however it is not yet clear to what
extent it is a clinically significant disorder.
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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.
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178 °C (sublimes)
238 DEG C (ANHYD)
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Retrieved 16 October 2014. Experimental Melting Point:
234–236 °C Alfa Aesar
237 °C Oxford University Chemical Safety Data
238 °C LKT Labs
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,
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,
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Caffeine does not usually affect
performance in learning and memory tasks, although caffeine may
occasionally have facilitatory or inhibitory effects on memory and
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.
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have been observed in aerobic as well as anaerobic sports (for
reviews, see ). Trained athletes seem to benefit from a moderate dose
of 5 mg/kg , however, even lower doses of caffeine (1.0–2.0 mg/kg)
may improve performance . Some groups found significantly improved
time trial performance or maximal cycling power , most likely related
to a greater reliance on fat metabolism and decreased neuromuscular
fatigue, respectively. Theophylline, a metabolite of caffeine, seems
to be even more effective in doing so . The effect of caffeine on fat
oxidation, however, may only be significant during lower exercise
intensities and may be blocked at higher intensities . ... For both
caffeine-naïve as well as caffeine-habituated subjects, moderate to
high doses of caffeine are ergogenic during prolonged moderate
intensity exercise . ... In summary, caffeine, even at physiological
doses (3–6 mg/kg), as well as coffee are proven ergogenic aids and
as such – in most exercise situations, especially in endurance-type
events – clearly work-enhancing . It most likely has a peripheral
effect targeting skeletal muscle metabolism as well as a central
effect targeting the brain to enhance performance, especially during
endurance events (see Table 1). Also for anaerobic tasks, the effect
of caffeine on the CNS might be most relevant. ... Muendel et al.
found a 17% improvement in time to exhaustion after nicotine patch
application compared to a placebo without affecting cardiovascular and
respiratory parameters or substrate metabolism. In this sense,
nicotine seems to exert similar effects as caffeine by delaying the
development of central fatigue as impaired central drive is an
important factor contributing to fatigue during exercise. ... The
physiological effects of the above mentioned substances are well
established. However, the ergogenic effect of some of the discussed
drugs may be questioned and one has to consider the cohort tested for
every specific substance. However, only caffeine has enough strength
of evidence to be considered an ergogenic aid.
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Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit
their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic
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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
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GABA release in the histaminergic tuberomammillary
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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
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presence of functional A1 receptors in striatal dopaminergic
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through multiple mechanisms, which depend on heteromerization of A1
and A2A receptors among themselves and with D1 and D2 receptors,
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dopaminergic neurotransmission in the SSM. By releasing the
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durch scheinbaren schwarzen Staar Geretteten, wie auch über das
andere ausgesprochen, übergab er mir noch eine Schachtel mit
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entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt
Caffeine is a material in coffee, which was discovered at
the same time, 1821, by
Robiquet and Pelletier and Caventou, by whom
however nothing was made known about it in the press.)
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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
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