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(i) (i)

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
Caffeine
also stimulates certain portions of the autonomic nervous system .

Caffeine
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 of Coffea
Coffea
plants. Beverages
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
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
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
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.

CONTENTS

* 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

* 2.3.1 Addiction
Addiction
* 2.3.2 Dependence and withdrawal

* 2.4 Risk of other diseases

* 3 Overdose

* 4 Interactions

* 4.1 Alcohol
Alcohol
* 4.2 Tobacco
Tobacco
* 4.3 Oral birth control * 4.4 Medications

* 5 Pharmacology

* 5.1 Pharmacodynamics

* 5.1.1 Receptor and ion channel targets

* 5.1.1.1 Effects on striatal dopamine

* 5.1.2 Enzyme
Enzyme
targets * 5.1.3 Off-target effects

* 5.2 Pharmacokinetics
Pharmacokinetics

* 6 Chemistry

* 6.1 Synthesis * 6.2 Decaffeination
Decaffeination
* 6.3 Detection in body fluids * 6.4 Analogs

* 7 Natural occurrence

* 8 Products

* 8.1 Beverages
Beverages

* 8.1.1 Coffee
Coffee
* 8.1.2 Tea
Tea
* 8.1.3 Soft drinks and energy drinks * 8.1.4 Other beverages

* 8.2 Chocolate
Chocolate
* 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

USE

MEDICAL

Caffeine
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
Orthostatic hypotension
treatment.

ENHANCING PERFORMANCE

Cognitive

Caffeine
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
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 caffeine and L-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching ; these effects are most pronounced during the first hour post-dose.

Physical

Caffeine
Caffeine
is a proven ergogenic aid in humans. Caffeine
Caffeine
improves athletic performance in aerobic (especially endurance sports ) and anaerobic conditions. Moderate doses of caffeine (around 5 mg/kg ) can improve sprint performance, cycling and running time trial performance, endurance (i.e., it delays the onset of muscle fatigue and central fatigue ), and cycling power output.

SPECIFIC POPULATIONS

Adults

For the general population of healthy adults, Health Canada
Health Canada
advises a daily intake of no more than 400 mg.

Children

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:

AGE RANGE MAXIMUM RECOMMENDED DAILY CAFFEINE INTAKE

4–6 45 mg (slightly more than in 12 oz of a typical soft drink)

7–9 62.5 mg

10–12 85 mg (about ½ cup of coffee)

Adolescents

Health Canada
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

The UK 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.

SIDE EFFECTS

PHYSICAL

Caffeine
Caffeine
can increase blood pressure and cause vasoconstriction . Long-term consumption at sufficiently high doses has been associated with chronic arterial stiffness. Coffee
Coffee
and caffeine can affect gastrointestinal motility and gastric acid secretion. Caffeine
Caffeine
in low doses may cause weak bronchodilation for up to four hours in asthmatics. Caffeine
Caffeine
increases basal metabolic rate in adults. 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.

PSYCHOLOGICAL

Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common, and include mild anxiety, jitteriness, insomnia, increased sleep latency, and reduced coordination. Caffeine
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.

REINFORCEMENT DISORDERS

Addiction

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
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
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

Main article: Caffeine dependence

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.

The ICD-10 includes a diagnostic model for caffeine dependence , but the DSM-5 does not. The APA , which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of this disorder is unclear. The DSM-5 instead lists "caffeine use disorder" in the emerging models section of the manual.

Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine (750 to 1200 mg/day spread throughout the day) have been shown to produce complete tolerance to some, but not all of the effects of caffeine. Doses as low as 100 mg/day, such as a 6 oz cup of coffee or two to three 12 oz servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption. Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.

RISK OF OTHER DISEASES

See also: Coffee
Coffee
§ Health and pharmacology

A protective effect of caffeine against Alzheimer\'s disease is possible, but the evidence is inconclusive. Caffeine
Caffeine
increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals. It may protect people from liver cirrhosis . Caffeine
Caffeine
may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.

OVERDOSE

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
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 .

INTERACTIONS

ALCOHOL

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 consumed. Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine
Caffeine
antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.

TOBACCO

Smoking
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.

MEDICATIONS

Caffeine
Caffeine
may increase the effectiveness of some medications including ones used to treat headaches .

PHARMACOLOGY

PHARMACODYNAMICS

STRUCTURE OF A TYPICAL CHEMICAL SYNAPSE

Postsynaptic density Voltage- gated Ca++ channel Synaptic vesicle Neurotransmitter transporter Receptor Neurotransmitter Axon terminal Synaptic cleft Dendrite
Dendrite

Caffeine's primary mechanism of action is as an antagonist of adenosine receptors in the brain

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

Receptor And Ion Channel Targets

Caffeine
Caffeine
is a receptor antagonist at all adenosine receptor subtypes (A1 , A2A , A2B , and A3 receptors). Antagonism at these receptors stimulates the medullary vagal, vasomotor, and respiratory centers , which increases respiratory rate, reduces heartrate, and constricts blood vessels. Adenosine
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 ( RYR1 , RYR2 , and RYR3 ). It is also a competitive antagonist of the ionotropic glycine receptor .

Effects On Striatal Dopamine

While caffeine does not directly bind to any dopamine receptors , it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1 –D1 receptor heterodimer (this is a receptor complex with 1 adenosine A1 receptor and 1 dopamine D1 receptor) and the A2A –D2 receptor heterotetramer (this is a receptor complex with 2 adenosine A2A receptors and 2 dopamine D2 receptors). The A2A–D2 receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.

Caffeine
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 .

Enzyme
Enzyme
Targets

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
Caffeine
also affects the cholinergic system where it inhibits the enzyme acetylcholinesterase .

Off-target Effects

Caffeine
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.

PHARMACOKINETICS

Caffeine
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
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
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
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
Paraxanthine
(84%): Increases lipolysis , leading to elevated glycerol and free fatty acid levels in blood plasma . * Theobromine
Theobromine
(12%): Dilates blood vessels and increases urine volume. Theobromine
Theobromine
is also the principal alkaloid in the cocoa bean (chocolate ). * Theophylline
Theophylline
(4%): Relaxes smooth muscles of the bronchi , and is used to treat asthma . The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

1,3,7-Trimethyluric acid is a minor caffeine metabolite. Each of these metabolites is further metabolized and then excreted in the urine. Caffeine
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.

CHEMISTRY

Pure anhydrous caffeine is a bitter-tasting white odorless powder with a melting point of 235–238 °C. Caffeine
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
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 .

SYNTHESIS

One biosynthetic route of caffeine, as performed by Camellia
Camellia
and Coffea
Coffea
species. One laboratory synthesis of caffeine

The biosynthesis of caffeine is an example of convergent evolution among different species.

Caffeine
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

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

Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using a number of solvents. Benzene
Benzene
, chloroform , trichloroethylene , and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost, and flavor, they have been superseded by the following main methods:

* WATER EXTRACTION: Coffee
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
Coffee
manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets. * SUPERCRITICAL CARBON DIOXIDE EXTRACTION: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm . Under these conditions, CO2 is in a "supercritical " state : It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation , recrystallization , or reverse osmosis . * EXTRACTION BY ORGANIC SOLVENTS: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.

"Decaffeinated" coffees do in fact contain caffeine in many cases – some commercially available decaffeinated coffee products contain considerable levels. One study found that decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of caffeine per cup for regular coffee.

DETECTION IN BODY FLUIDS

Caffeine
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.

ANALOGS

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:

* Dipropylcyclopentylxanthine * 8-Cyclopentyl-1,3-dimethylxanthine
8-Cyclopentyl-1,3-dimethylxanthine
* 8-Phenyltheophylline
8-Phenyltheophylline

NATURAL OCCURRENCE

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
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
Caffeine
in plants acts as a natural pesticide : it can paralyze and kill predator insects feeding on the plant. High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection. In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival. Caffeine
Caffeine
is stored in tea leaves in two places. Firstly, in the cell vacuoles where it is complexed with polyphenols . This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles. Caffeine
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.

PRODUCTS

See also: Caffeinated drink

Caffeine
Caffeine
content in select food and drugs

PRODUCT SERVING SIZE CAFFEINE PER SERVING (MG ) CAFFEINE (MG/L )

Caffeine
Caffeine
tablet (regular-strength) 1 tablet 7002100000000000000♠100 —

Caffeine
Caffeine
tablet (extra-strength) 1 tablet 7002200000000000000♠200 —

Excedrin tablet 1 tablet 7001650000000000000♠65 —

Hershey\'s Special
Special
Dark (45% cacao content) 1 bar (43 g or 1.5 oz) 7001310000000000000♠31 —

Hershey\'s Milk Chocolate
Chocolate
(11% cacao content) 1 bar (43 g or 1.5 oz) 7001100000000000000♠10 —

Percolated coffee 207 mL (7.0 US fl oz ) 7001800000000000000♠80–135 7002386000000000000♠386–652

Drip coffee 207 mL (7.0 US fl oz) 7002115000000000000♠115–175 7002555000000000000♠555–845

Coffee, decaffeinated 207 mL (7.0 US fl oz) 7000500000000000000♠5–15 7001240000000000000♠24–72

Coffee, espresso 44–60 mL (1.5–2.0 US fl oz) 7002100000000000000♠100 7003169100000000000♠1,691–2,254

Tea
Tea
– black, green, and other types , – steeped for 3 min. 177 millilitres (6.0 US fl oz) 7001220000000000000♠22–74 7002124000000000000♠124–418

Guayakí yerba mate (loose leaf) 6 g (0.21 oz) 7001850000000000000♠85 7002358000000000000♠approx. 358

Coca- Cola
Cola
Classic 355 mL (12.0 US fl oz) 7001340000000000000♠34 7001960000000000000♠96

Mountain Dew
Mountain Dew
355 mL (12.0 US fl oz) 7001540000000000000♠54 7002154000000000000♠154

Pepsi Max 355 mL (12.0 US fl oz) 7001690000000000000♠69 7002194000000000000♠194

Guaraná Antarctica 350 mL (12 US fl oz) 7001300000000000000♠30 7002100000000000000♠100

Jolt Cola
Cola
695 mL (23.5 US fl oz) 7002280000000000000♠280 7002403000000000000♠403

Red Bull
Red Bull
250 mL (8.5 US fl oz) 7001800000000000000♠80 7002320000000000000♠320

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

BEVERAGES

Coffee

The world's primary source of caffeine is the coffee "bean" (the seed of the coffee plant ), from which coffee is brewed. Caffeine
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

Tea
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
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
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
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 .

Other Beverages

* Mate is a drink popular in many parts of South America. Its preparation consists of filling a gourd with the leaves of the South American holly yerba mate , pouring hot but not boiling water over the leaves, and drinking with a straw, the bombilla, which acts as a filter so as to draw only the liquid and not the yerba leaves. * Guaraná seeds ("beans") are used in making the commercially sold beverage Guaraná Antarctica , which originated in Brazil and is currently the fifteenth most popular soft drink in the world. * The leaves of Ilex guayusa , the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea, which is both brewed locally and sold commercially throughout the world.

CHOCOLATE

Chocolate
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.

TABLETS

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 Energy Caffeine
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.

INHALANTS

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
Ya ba
contains a combination of methamphetamine and caffeine.

HISTORY

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

The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears in the middle of the fifteenth century, in the Sufi
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
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
Chocolate
was an important luxury good throughout pre-Columbian Mesoamerica
Mesoamerica
, and cocoa beans were often used as currency.

Xocolatl was introduced to Europe
Europe
by the Spaniards , and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies
West Indies
and the Philippines
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 caffeine.

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.

HISTORIC REGULATIONS

Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca
Mecca
and in the Ottoman Empire
Ottoman Empire
made coffee illegal for some classes. 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
Sweden
at various times between 1756 and 1823.

In 1911, caffeine became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca- Cola
Cola
syrup in Chattanooga, Tennessee
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

REGULATIONS

The 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.

CONSUMPTION

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.

RELIGIONS

Some Seventh-day Adventists , Church of God (Restoration) adherents, and Christian Scientists
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
Muslims
today. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws .

OTHER ORGANISMS

Caffeine
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
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
Caffeine
has also been found to enhance the reward memory of honeybees .

RESEARCH

Caffeine
Caffeine
has been used to double chromosomes in haploid wheat .

SEE ALSO

* Wakefulness-promoting agent * Nootropic
Nootropic

REFERENCES

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Caffeine
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Caffeine
facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine
Caffeine
facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on this, and caffeine appears to improve memory performance under suboptimal alertness. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. ... Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties. * ^ Snel J, Lorist MM (2011). "Effects of caffeine on sleep and cognition". Progress in Brain Research. Progress in Brain Research. 190: 105–17. ISBN 978-0-444-53817-8 . PMID 21531247 . doi :10.1016/B978-0-444-53817-8.00006-2 . * ^ Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I (May 2010). Ker K, ed. " Caffeine
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* ^ Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care. 40 (2): 487–505. PMID 23668655 . doi :10.1016/j.pop.2013.02.009 . Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ... Physiologic and performance effects • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40 • Improved reaction time • Increased muscle strength and delayed muscle fatigue • Increased acceleration • Increased alertness and attention to task * ^ A B C D "It\'s Your Health – Caffeine". Health Canada
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* ^ 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, caffeine * ^ Budney AJ, Emond JA (November 2014). "Caffeine addiction? Caffeine
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is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. ... these earlier data plus the present data reflect that caffeine at doses representing about two cups of coffee in one sitting does not activate the circuit of dependence and reward and especially not the main target area, the nucleus accumbens. ,, ... Therefore, caffeine appears to be different from drugs of dependence like cocaine, amphetamine, morphine, and nicotine, and does not fulfil the common criteria or the scientific definitions to be considered an addictive substance.42 * ^ Temple JL (June 2009). " Caffeine
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* ^ 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. Chronic alcoholism Dipsomania Drug addiction * ^ Addicott MA (September 2014). " Caffeine
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* ^ 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 rescued by apparent "black star" 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 ) of 1866. It was reprinted in: Johann Wolfgang von Goethe with F.W. von Biedermann, ed., Goethes Gespräche, vol. 10: Nachträge, 1755–1832 (Leipzig, (Germany): F.W. v. Biedermann, 1896), pages 89–96; see especially page 95. * ^ 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" (in German). 4: 180. From page 180: "Caféin ist eine Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und Pelletier und Caventou entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt machte." ( Caffeine
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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.) * ^ Berzelius JJ (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius (in German). 7. p. 270. From page 270: "Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen 1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zusammenkunft der Societé de Pharmacie in Paris die erste mündliche Mittheilung darüber gab." (However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris.) * ^ Pelletier, Pierre Joseph (1822). "Cafeine". Dictionnaire de Médecine (in French). 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 3 March 2011. * ^ Robiquet, Pierre Jean (1823). "Café". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French). 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 3 March 2011. * ^ Dumas; Pelletier (1823). "Recherches sur la composition élémentaire et sur quelques propriétés caractéristiques des bases salifiables organiques" . 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" . Journal für Praktische Chemie. 15: 280–284. doi :10.1002/prac.18380150124 .

* ^ Jobst, Carl (1838). "Thein identisch mit Caffein" . Liebig's Annalen der Chemie und Pharmacie. 25: 63–66. doi :10.1002/jlac.18380250106 .

* ^ Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.

* Fischer E (1881). "Ueber das Caffeïn" . Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 14: 637–644. doi :10.1002/cber.188101401142 . * Fischer E (1881). "Ueber das Caffeïn. Zweite Mitteilung" . Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 14 (2): 1905–1915. doi :10.1002/cber.18810140283 . * Fischer E (1882). "Ueber das Caffeïn. Dritte Mitteilung" . Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 15: 29–33. doi :10.1002/cber.18820150108 . * Fischer E, Ach L (1895). "Synthese des Caffeïns" . 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" . Berichte der Deutschen chemischen Gesellschaft zu Berlin (in German). 30: 549–559. doi :10.1002/cber.189703001110 .

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* ^ Paul L. "Why Caffeine
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BIBLIOGRAPHY

* Bersten I (1999). Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria. Sydney: Helian Books. ISBN 978-0-9577581-0-0 . * Pendergrast M (2001) . Uncommon Grounds: The History of Coffee
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staff (3 October 2009). " Caffeine
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