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    * Caffeine *

    کافئین


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    (Wikipedia) - Caffeine This article is about the stimulant drug. For other uses, see Caffeine (disambiguation). Caffeine Systematic (IUPAC) name Clinical data AHFS/Drugs.com Pregnancy cat. Legal status Dependence liability Routes Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion Identifiers CAS number ATC code PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Synonyms PDB ligand ID Chemical data Formula Mol. mass Physical data Density Melt. point Boiling point
    1,3,7-Trimethylpurine-2,6-dione
    monograph
    • AU: A
    • US: C
    • AU: Unscheduled
    • UK: GSL
    • US: OTC
    Low–moderate No addiction liability
    oral, insufflation, enema, rectal, intravenous
    99%
    25–36%
    Primarily CYP1A2; Other enzymes: CYP2E1, CYP2C8, CYP2C9, CYP3A4
    Adults: 3–7 hours Neonates: 65–130 hours
    urine (100%)
    58-08-2 Y
    N06BC01
    CID 2519
    407
    DB00201
    2424 Y
    3G6A5W338E Y
    D00528 Y
    CHEBI:27732 Y
    CHEMBL113 Y
    Methyltheobromine
    CFF (PDBe, RCSB PDB)
    C8H10N4O2 
    194.19 g/mol
    SMILES
    • Canonical CN1C=NC2=C1C(=O)N(C(=O)N2C)C
    InChI
    • InChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3 Key:RYYVLZVUVIJVGH-UHFFFAOYSA-N Y

    1.23 g/cm³
    235–238 °C (455–460 °F) (anhydrous)
    178 °C (352 °F) (sublimes)

    Caffeine (/kæˈfiːn, ˈkæfiːn, ˈkæfiːɪn/) is a bitter, white crystalline xanthine alkaloid and a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants, as well as enhancing the reward memory of pollinators. It is most commonly consumed by humans in infusions extracted from the seed of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut. Other sources include yerba mate, guarana berries, guayusa, and the yaupon holly.

    In humans, caffeine acts as a central nervous system stimulant, temporarily warding off drowsiness and restoring alertness. It is the world''s most widely consumed psychoactive drug, but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks, enjoy great popularity. In North America, 90% of adults consume caffeine daily.

    Part of the reason caffeine is classified by the Food and Drug Administration as generally recognized as safe is that toxic doses (over 10 grams for an average adult) are much higher than typically used doses (fewer than 500 milligrams). Ordinary consumption has low health risks, even when carried on for years – there may be a modest protective effect against some diseases, including Parkinson''s disease, heart disease, and certain types of cancer. Some people experience sleep disruption if they consume caffeine, especially during the evening hours, but others show little disturbance and the effect of caffeine on sleep is highly variable.

    Evidence of a risk to pregnancy is equivocal, with some authorities concluding that it is wise for pregnant women to limit consumption to the equivalent of two cups of coffee per day or less. Caffeine has pressor and mild diuretic effects when administered to people who are not used to it, but regular users develop a tolerance to this effect, and studies have generally failed to support the common notion that ordinary consumption contributes significantly to dehydration. With heavy use, tolerance develops rapidly to autonomic effects such as elevated heart rate and muscle twitching, but not to the cognitive or arousal effects of caffeine. Chronic use can result in a mild state of caffeine dependence.

    ContentsStimulant effects

    Caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It produces increased wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination. The amount of caffeine needed to produce effects varies from person to person, depending on body size and degree of tolerance. Effects begin less than an hour after consumption, and a moderate dose usually wears off in about five hours.

    Caffeine has a number of effects on sleep, but does not affect all people in the same way. It improves performance during sleep deprivation but may lead to subsequent insomnia. In shift workers it leads to fewer mistakes caused by tiredness. In athletics, moderate doses of caffeine can improve sprint, endurance, and team sports performance, but the improvements are usually not very large. Some evidence suggests that coffee does not produce the ergogenic effects observed in other caffeine sources. High doses of caffeine, however, can impair athletic performance by interfering with coordination. There is also evidence that caffeine may be helpful at high altitude.

    Side effects Main article: Health effects of caffeineHealth effects of caffeinePhysical effects

    Consumption of 1000–1500 mg per day is associated with a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and mental conditions including nervousness, irritability, restlessness, insomnia, headaches, and heart palpitations after caffeine use.

    Coffee consumption is associated with a lower overall risk of cancer. This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer. There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer. Moderate coffee consumption may decrease the risk of cardiovascular disease, and it may somewhat reduce the risk of type 2 diabetes. Drinking four or more cups of coffee per day does not affect the risk of hypertension compared to drinking little or no coffee. However those who drink 1–3 cups per day may be at a slightly increased risk. Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals. It may protect people from liver cirrhosis. There is no evidence that coffee stunts a child''s growth. Caffeine may increase the effectiveness of some medications including ones used to treat headaches. Similarly, intravenous caffeine is often used in hospitals to provide temporary pain relief for headaches caused by low cerebrospinal fluid pressure.

    Caffeine consumption during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts. However as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy. For example the UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee. The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. Although the evidence that caffeine may be harmful during pregnancy is equivocal, there is some evidence that the hormonal changes associated with 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).

    Caffeine is a weak bronchodilator. In clinical tests on adults with asthma, at fairly low doses (5 mg/kg of body weight), caffeine has been shown to provide a small improvement in lung function, such that it needs to be controlled for in diagnostic tests. Caffeine is the primary treatment of the breathing disorders apnea of prematurity and may also be effective in preventing bronchopulmonary dysplasia in premature infants. The only short-term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine. While some authors have raised the possibility of subtle long-term problems, follow-up neurological data at 18 months and at five years after neonatal caffeine treatment revealed the opposite; treatment appears to be neuroprotective, as caffeine-treated children were significantly less likely to have cerebral palsy and had reduced rates of language and cognitive delay.

    When doses of caffeine equivalent to 2–3 cups of coffee are administered to people who have not consumed caffeine during prior days, they produce a mild increase in urinary output. Because of this diuretic effect, some authorities have recommended that athletes or airline passengers avoid caffeine to reduce the risk of dehydration. Most people who consume caffeine, however, ingest it daily. Regular users of caffeine have been shown to develop a strong tolerance to the diuretic effect, and studies have generally failed to support the notion that ordinary consumption of caffeinated beverages contributes significantly to dehydration, even in athletes.

    Psychological effects

    The US National Institutes of Health states: " much caffeine can make you restless, anxious, and irritable. It may also keep you from sleeping well and cause headaches, abnormal heart rhythms, or other problems. If you stop using caffeine, you could get withdrawal symptoms. Some people are more sensitive to the effects of caffeine than others. They should limit their use of caffeine. So should pregnant and nursing women."

    Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA) including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety disorder and caffeine-related disorder not otherwise specified (NOS). The DSM-IV defines a person with caffeine-induced sleep disorder as an individual who regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. As of 2010 the effect of caffeine on people with ADHD is not known. Some studies have however found modest protective effect against Alzheimer disease, but the evidence is inconclusive.

    Caffeine can have negative effects on anxiety disorders. A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder. At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety or, rarely, trigger mania or psychosis. In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk. In moderate doses, caffeine typically does not affect learning or memory, and can improve cognitive functions, especially in people who are fatigued, possibly due to its effect on alertness. For some people, anxiety can be very much reduced by discontinuing caffeine use.

    OverdosePrimary symptoms of caffeine intoxicationToxicity

    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.

    Extreme overdose can result in death. The median lethal dose (LD50) given orally is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or roughly 80 to 100 cups of coffee for an average adult. Though achieving lethal dose of caffeine would be difficult with regular coffee, it is easier to reach high doses with caffeine pills, and the lethal dose can be lower in individuals whose ability to metabolize caffeine is impaired. Chronic liver disease is one factor that can slow the metabolism of caffeine. There has been a reported death of a man who had liver cirrhosis overdosing on caffeinated mints. Drugs such as fluvoxamine or levofloxacin can have a similar effect by blocking the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine five-fold. The exact cause of death in such cases is uncertain, but may result from cardiac arrhythmia leading to cardiac arrest.

    Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine, then peritoneal dialysis, hemodialysis, or hemofiltration may be required.

    Dependence and tolerance Main article: Caffeine dependence

    With repetitive use, physical dependence may occur. Caffeine has no addiction liability. Also, some effects of caffeine, particularly the autonomic effects, decrease over time, a phenomenon known as a tolerance. Tolerance develops quickly to some (but not all) effects of caffeine, especially among heavy coffee and energy drink consumers. Some coffee drinkers develop tolerance to its sleep-disrupting effects, but others apparently do not.

    Withdrawal

    Withdrawal symptoms – including headaches, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints – may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days. Withdrawal headaches are experienced by 52% of people who stopped consuming caffeine for two days after an average of 235 mg caffeine per day prior to that. In prolonged caffeine users, symptoms such as increased depression and anxiety, nausea, vomiting, physical pains and intense desire for caffeine are also reported. Peer knowledge, support and interaction may aid withdrawal.

    Caffeine withdrawal is categorized as a mental disorder in the DSM-5 (the 5th edition of the Diagnostic and Statistical Manual published by the American Psychiatric Association). Previous versions of the manual included "caffeine intoxication" but not caffeine withdrawal.

    Sources and consumption See also: Caffeinated drink Caffeine Content in Select Food and Drugs Product Serving size Caffeine per serving (mg) Caffeine (mg/L)
    Caffeine tablet (regular-strength) 1 tablet 7002100000000000000100
    Caffeine tablet (extra-strength) 1 tablet 7002200000000000000200
    Excedrin tablet 1 tablet 700165000000000000065
    Hershey''s Special Dark (45% cacao content) 1 bar (43 g or 1.5 oz) 700131000000000000031
    Hershey''s Milk Chocolate (11% cacao content) 1 bar (43 g or 1.5 oz) 700110000000000000010
    Percolated coffee 207 mL (7.0 US fl oz) 700180000000000000080–135 7002386000000000000386–652
    Drip coffee 207 mL (7.0 US fl oz) 7002115000000000000115–175 7002555000000000000555–845
    Coffee, decaffeinated 207 mL (7.0 US fl oz) 70005000000000000005–15 700124000000000000024–72
    Coffee, espresso 44–60 mL (1.5–2.0 US fl oz) 7002100000000000000100 70031691000000000001,691–2,254
    Tea – black, green, and other types, – steeped for 3 min. 177 millilitres (6.0 US fl oz) 700122000000000000022–74 7002124000000000000124–416
    Guayakí yerba mate (loose leaf) 6 g (0.21 oz) 700185000000000000085 7002358000000000000approx. 358
    Coca-Cola Classic 355 mL (12.0 US fl oz) 700134000000000000034 700196000000000000096
    Mountain Dew 355 mL (12.0 US fl oz) 700154000000000000054 7002154000000000000154
    Pepsi Max 355 mL (12.0 US fl oz) 700169000000000000069 7002194000000000000194
    Guaraná Antarctica 350 mL (12 US fl oz) 700130000000000000030 7002100000000000000100
    Jolt Cola 695 mL (23.5 US fl oz) 7002280000000000000280 7002403000000000000403
    Red Bull 250 mL (8.5 US fl oz) 700180000000000000080 7002320000000000000320

    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.

    Caffeine is found in many plant species, where it acts as a natural pesticide, with high caffeine levels being observed in seedlings still developing foliage but lacking mechanical protection; caffeine paralyzes and kills certain insects feeding on the plant. High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine is understood to have a natural function as both a natural pesticide and an inhibitor of seed germination of other nearby coffee seedlings, thus giving it a better chance of survival. Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the plant.

    Common sources of caffeine are coffee, tea, soft drinks and energy drinks, caffeine supplements, and (to a lesser extent) chocolate derived from cocoa beans. Less commonly used sources of caffeine include the yerba mate, guarana and ilex guayusa plants, which are sometimes used in the preparation of teas and energy drinks. Two of caffeine''s alternative names, mateine and guaranine, are derived from the names of these plants.

    The disparity in experience and effects between the various natural caffeine sources could be because plant sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as polyphenols that can form insoluble complexes with caffeine.

    One of the world''s primary sources of caffeine is the coffee "bean" (which is the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee. Arabica coffee typically contains half the caffeine of the robusta variety.

    In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces a small amount of the bean''s caffeine content.

    Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed much weaker. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, certain types of tea may contain somewhat more caffeine than other teas.

    Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.

    No-Doz 100 mg caffeine tablets

    Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per 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.

    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, although dark chocolate has about the same caffeine as coffee by weight. Some dark chocolate currently in production contains as much as 160 mg per 100 g – which is double the caffeine content of the highest caffeinated drip coffee by weight.

    Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness. These effects have been borne out by research that shows caffeine use (whether in tablet form or not) results in decreased fatigue and increased attentiveness.

    These tablets are commonly used by students studying for their exams and by people who work or drive for long hours. One U.S. company is also marketing dissolving caffeine strips as an alternative to energy drinks. Another unusual intake route is SpazzStick, a caffeinated lip balm. As of 2013, a number of innovative caffeinated products such as Alert Energy Caffeine Gum, a Wrigley product, had been introduced in the United States, but were under scrutiny; after announcement of an investigation by the FDA of the health effects of added caffeine in foods, Alert Energy Caffeine Gum was voluntarily withdrawn from sale.

    As of 2011, inhaled caffeine is a distribution method under scrutiny by some U.S. lawmakers.

    Chemical properties and biosynthesisCaffeine biosynthesisCaffeine laboratory synthesis

    Pure anhydrous caffeine is a white odorless powder with a melting point of 225–228 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL). It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.

    Caffeine does not contain any stereogenic centers and hence is classified as an achiral molecule.

    The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance form where 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.

    Caffeine is synthesized in plants from the purine nucleotides AMP, GMP, and IMP. These in turn are transformed into xanthosine and then theobromine, the latter being the penultimate precursor of caffeine. Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized chemically. If desired, it may be synthesized from dimethylurea and malonic acid.

    Pharmacology

    Inside the body, caffeine acts through several mechanisms, but its most important effect is to counteract a substance called adenosine that naturally circulates at high levels throughout the body, and especially in the nervous system. In the brain, adenosine plays a generally protective role, part of which is to reduce neural activity levels – for example, there is some evidence that adenosine helps to induce torpor in animals that seasonally hibernate.

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

    Caffeine is a receptor antagonist at all adenosine receptor subtypes (A1, A2A, A2B, and A3 receptors). Antagonism at these receptors stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heartrate, and constricts blood vessels. Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects; adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system.

    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 inhibitor.

    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 is also significantly implicated in cholinergic system where it e.g. inhibits enzyme acetylcholinesterase.

    A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine. In the classic, or metabolic theory, caffeine may increase fat utilization and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or intramuscular triglycerides by increasing circulating epinephrine levels. The increased availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby enhancing endurance performance. In the nervous system, caffeine may reduce the perception of effort by lowering the neuron activation threshold, making it easier to recruit the muscles for exercise.

    Caffeine metabolites

    Metabolites of caffeine also contribute to caffeine''s effects. Paraxanthine is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and force of contraction. 1,3,7-Trimethyluric acid is a minor caffeine metabolite.

    MetabolismCaffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)

    Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body. Peak blood concentration is reached within 1–2 hours. It is eliminated by first-order kinetics. Caffeine can also be absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and chlorobutanol and caffeine (for the treatment of hyperemesis).

    The biological half-life of caffeine – the time required for the body to eliminate one-half of the total amount of caffeine – varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. It can also be significantly altered by drugs or hormonal states. In healthy adults, caffeine''s half-life is roughly 3–7 hours. Heavy cigarette smokers show a decrease in half-life of 30–50%, oral contraceptives can double it, and pregnancy can raise it even more, to as much as 15 hours during the last trimester. In newborn infants the half-life can be 80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by the age of 6 months. The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and prolongs 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:

    Each of these metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.

    Some quinolone antibiotics exert an inhibitory effect on CYP1A2, thereby reducing clearance of caffeine and thus increasing blood levels.

    A 2011 review found that habitual caffeine intake was associated with a variation in two genes that regulate how quickly the body processes caffeine. Subjects who had a high-intake mutation on both chromosomes consumed 40 mg more caffeine per day than people who did not.

    Detection in biological 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.

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

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

    "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.

    HistoryCoffeehouse in Palestine, circa 1900Main articles: History of chocolate, History of coffee, History of tea and History of yerba mate

    According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted. Shennong is also mentioned in Lu Yu''s Cha Jing, a famous early work on the subject of tea.

    The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern Arabia. From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.

    Use of the kola nut, like the coffee berry and tea leaf, 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. In 1911, kola became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health". Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product''s label.

    The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. In the New World, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.

    Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as "black bean".

    The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink". Archaeologists have found evidence of this use stretch back far into antiquity, possibly dating to Late Archaic times.

    DiscoveryPierre Joseph Pelletier

    In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the first time; he called it "Kaffebase" (i.e. a base that exists in coffee). According to Runge, he did this at the behest of Johann Wolfgang von Goethe. In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge''s or each other''s work. However, Berzelius later acknowledged Runge''s priority in the extraction of caffeine, stating: "However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris."

    Pelletier''s article on caffeine was the first to use the term in print (in the French form Caféine from the French word for coffee: café). It corroborates Berzelius''s account:

    Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona 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 (1852–1919) first synthesized caffeine from raw materials (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.

    Legality

    Because caffeine is a psychoactive drug, it is often regulated. In the United States, the Food and Drug Administration (FDA) restricts beverages to containing less than 0.02% caffeine. Caffeine powder, which is sold as a dietary supplement, is unregulated.

    Historically, coffee and thus caffeine was illegal for some classes in Mecca in parts of the 16th century, and in the Ottoman empire. Charles II of England tried to ban it in 1676, Frederick II of Prussia banned it in 1777, and coffee was banned in Sweden in the years 1756–1769, 1794–1796, 1799–1802, and 1817–1823. The bans on coffee have often been motivated by religious, economic, or political reasons rather than by concerns for the well-being of the population.

    Religion

    Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine. Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: "With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided."

    Gaudiya Vaishnavas generally also abstain from caffeine, as it is alleged to cloud the mind and over-stimulate the senses. To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.

    People who refrain from consuming caffeine, for religious or other reasons, may instead use a substitute that performs a culturally similar role to coffee.

    Caffeinated beverages are widely consumed by Muslims today; in the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.

    Other organisms Other animalsCaffeine has a significant effect on spiders, which is illustrated here in the erratic construction of their webs.

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