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a bitter alkaloid found in coffee and tea that is responsible for their stimulating effects (同)caffein
someone addicted to caffeine (同)caffein addict

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カフェイン(コーヒー・茶に含まれている刺激性物質)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/02 14:31:26」(JST)

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This article is about the stimulant drug. For other uses, see Caffeine (disambiguation).

Caffeine 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 maté, 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.^[5]

Part of the reason caffeine is classified by the Food and Drug Administration as GRAS (generally recognized as safe) is that toxic doses (over 10 grams) are much higher than typically used doses (less than 500 milligrams). Ordinary consumption can have low health risks, even when carried on for years – there may be a modest protective effect against some diseases, including Parkinsons Disease, and certain types of cancer. Caffeine can have both positive and negative effects on anxiety disorders.^{[citation needed]} 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, but some authorities have concluded that prudent advice is for pregnant women to limit consumption to the equivalent of two cups of coffee per day or less.^[6] 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.^[7] 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. The degree to which caffeine can produce clinically significant physical and mental dependence remains a subject of controversy in the medical literature.

1 Health effects
- 1.1 Stimulant effects
- 1.2 Physical effects
- 1.3 Psychological effects
- 1.4 Caffeine toxicity
- 1.5 Addiction and tolerance
- 1.6 Withdrawal
- 1.7 Other animals
2 Sources and consumption
3 Chemical properties and biosynthesis
4 Pharmacology
- 4.1 Mechanism of action
  - 4.1.1 Caffeine metabolites
- 4.2 Metabolism
5 Detection in biological fluids
6 Decaffeination
7 History
- 7.1 Discovery
- 7.2 Legality
8 Religion
9 See also
10 References
11 Bibliography
12 External links

Health effects

Main article: Health effects of caffeine

Stimulant effects

Caffeine is a central nervous system and metabolic stimulant,^[8] 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.^[9] 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.^[9]

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.^[10] In shift workers it leads to fewer mistakes caused by tiredness.^[11] In athletics, moderate doses of caffeine can improve sprint,^[12] endurance,^[13] and team sports performance,^[14] but the improvements are usually not very large. Interestingly, some evidence suggests that coffee does not produce the ergogenic effects observed in other caffeine sources.^[15] High doses of caffeine, however, can impair athletic performance by interfering with coordination.^[16] Evidence shows that, contrary to common advice, caffeine may be helpful at high altitude.^[17]

Physical effects

Consumption of large amounts of caffeine – usually more than 250 mg per day – can lead to 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.^[18]

Coffee consumption is associated with a lower overall risk of cancer.^[19] 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.^[20] 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.^[20] On the other hand, caffeine has been shown to inhibit cellular DNA repair mechanisms.,^[2] but only at extreme high concentrations (which would be lethal in humans).^[21] There is little or no evidence that caffeine consumption increases the risk of cardiovascular disease, and it may somewhat reduce the risk of type 2 diabetes.^[22] 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.^[23] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.^[24] It may protect people from liver cirrhosis.^[25] There is no evidence that coffee stunts a child's growth.^[26] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.^[27] Similarly, intravenous caffeine is often used in hospitals to provide temporary pain relief for headaches associated 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.^[28] However as the data supporting this conclusion is of poor quality some suggest limiting caffeine consumption during pregnancy.^[29]^[30] 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.^[31] 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.^[7] 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).^[32]

On the positive side, caffeine is the primary treatment of the breathing disorders apnea of prematurity^[33] and may also be effective in preventing bronchopulmonary dysplasia in premature infants.^[34] The only short-term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy,^[35] and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.^[36] While some authors have raised the possibility of subtle long-term problems,^[37] 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.^[38]^[39]

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.^[40] Because of this diuretic effect, some authorities have recommended that athletes or airline passengers avoid caffeine in order to reduce the risk of dehydration.^[40] 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,^[40] and studies have generally failed to support the notion that ordinary consumption of caffeinated beverages contributes significantly to dehydration, even in athletes.^[41]^[42]^[43]

Caffeine has been demonstrated to increase muscle performance: Coso et al. found that a caffeine dose of at least 3 mg/kg in the form of an energy drink improved half-squat and bench-press maximal muscle power.^[44]

Psychological effects

The US National Institutes of Health states:

[Too] 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.^[45]

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).^[46] The DSM-IV defines 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.^[46] As of 2010 the effect of caffeine on people with ADHD is not known.^[47] However anecdotal evidence suggests that many individuals with ADHD already use caffeine to self-medicate themselves or their dependants, and they find that it has the opposite effect than it normally does, such as inducing a “calm-down” effect that encourages sleep instead of making them more active and stimulated.^[48] Some studies have however found a modest protective against Alzheimer disease, but the evidence is inconclusive.^[49]^[50]^[51]

Caffeine can have both negative^[52] and positive^{[citation needed]} effects on anxiety disorders. A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder.^[53]^[54]^[55] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety^[56] or, rarely, trigger mania or psychosis. In moderate doses caffeine may reduce symptoms of depression and lower suicide risk.^[47] In moderate doses caffeine typically does not affect learning or memory,^[57] and can improve cognitive functions, especially in people who are fatigued, possibly due to its effect on alertness.^[58]^[59]^[60] However anxiety sufferers can have high caffeine sensitivity.^[61]^[62]^[63]^[64] For some people, anxiety can be very much reduced by discontinuing caffeine use.^[65]

Contrary to popular belief, some research suggests that caffeine does not increase motivation in humans, and may even decrease motivation in some.^[66]

Caffeine toxicity

Primary symptoms of caffeine intoxication^[67]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90),.^[46] 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 per 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.^[67] 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.^[68]^[69]

Extreme overdose can result in death.^[70]^[71] 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.^[4] Though achieving lethal dose with caffeine would be difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine.^{[citation needed]} An exception to this would be taking a drug such as fluvoxamine or levofloxacin, which blocks the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine five-fold.^[69]^[70]^[71]^[72] 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.^[67]

Addiction and tolerance

Main article: Caffeine addiction

With repetitive use, physical dependence or addiction may occur. 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.^[73] Some coffee drinkers develop tolerance to its sleep-disrupting effects, but others apparently do not.^[32]

Withdrawal

Main article: Caffeine withdrawal

Withdrawal symptoms – including headache, 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.^[74] 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.^[75] In prolonged caffeine drinkers, symptoms such as increased depression and anxiety, nausea, vomiting, physical pains and intense desire for caffeine containing beverages 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).^[76] Previous versions of the manual included "caffeine intoxication" but not caffeine withdrawal.

Other animals

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

See also: Effect of psychoactive drugs on animals

While safe in humans, caffeine is considerably toxic to various animals, such as dogs and birds.^[77]^[78] The increased toxicity of caffeine in some animals is at least partly due to a poorer ability to metabolize the compound.^[79] Caffeine also has a pronounced effect on mollusks, various insects, and spiders.^[80]

Sources and consumption

Chemical properties and biosynthesis

Caffeine biosynthesis^[106]

Caffeine laboratory synthesis^[107]^[108]

Caffeine is an achiral molecule^[109] without stereoisomers.^[110]

The two amide groups of caffeine exist predominately as zwitterionic resonance structures where the nitrogen and carbon atoms are double bonded to each other so that both of these nitrogen atoms are essentially planar (in sp² orbital hybridization). The fused ring system therefore contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.^{[citation needed]}

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.^[111]

Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized chemically.^[112] If desired, it may be synthesized from dimethylurea and malonic acid.^[107]^[108]^[113]

Pure anhydrous caffeine is a white colorless powder with a melting point of 227–228 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL).^[114] It is also moderately soluble in ethanol (1.5 g/100 mL).^[114] It is weakly basic (pK_a = ~0.6) requiring strong acid to protonate it.^[3]

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.^[115]

Mechanism of action

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

Adenosine acts as an inhibitor neurotransmitter that suppresses activity in the central nervous system. Consumption of caffeine antagonizes adenosine and increases activity in neurotransmission including acetylcholine, epinephrine, dopamine, serotonin, glutamate, norepinephrine, cortisol, and in higher doses, endorphins which explains the analgesic effect to some users. At very high doses (exceeding 500 milligrams) caffeine inhibits GABA neurotransmission. This evidence explains why caffeine causes anxiety, insomnia, rapid heart and respiration rate.^{[citation needed]}

Because caffeine is both water-soluble 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.^[116]

Adenosine is found in every part of the body, because it plays a role in the fundamental adenosine triphosphate (ATP) related energy producing mechanism and is also needed for RNA synthesis, but it has additional functions in the brain. The evidence indicates that brain adenosine acts to protect the brain by suppressing neural activity and by increasing blood flow via receptors located on vascular smooth muscle.^[117] Brain adenosine levels are increased by various types of metabolic stress, including lack of oxygen and interruption of blood flow. There is evidence that adenosine functions as a synaptically released neurotransmitter in some parts of the brain; however, stress-related adenosine increases appear to be produced mainly by extracellular metabolism of ATP. Unlike most neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in a voltage-controlled manner, but the possibility of such a mechanism has not been ruled out fully.^[117]

Several classes of adenosine receptors have been described, with different anatomical distributions. A₁ receptors are widely distributed, and act to inhibit calcium uptake. A_2A receptors are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lower densities. There is evidence that A _2A receptors interact with the dopamine system, which is involved in reward and arousal. (A_2A receptors can also be found on arterial walls and blood cell membranes.)^[118]

Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be more specifically involved in control of the sleep-wake cycle. Robert McCarley and his colleagues have argued that accumulation of adenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that the effects may be mediated both by inhibition of wake-promoting neurons via A₁ receptors, and activation of sleep-promoting neurons via indirect effects on A_2A receptors.^[118] More recent studies have provided additional evidence for the importance of A_2A, but not A₁, receptors.^[119]

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.^[120] A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine.^[121] 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.^[122]

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.^[123]

Metabolism

Caffeine 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.^[124] Peak blood concentration is reached within one hour.^[125] It is eliminated by first-order kinetics.^[126] Caffeine can also be absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine)^[127] and chlorobutanol and caffeine (for the treatment of hyperemesis).^[128]

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 has been measured with a range of results. Some measures get 4.9 hours,^[129] and others are at around 6 hours.^[130] 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.^[32] 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.^[129]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,^[131] each of which has its own effects on the body:

Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.
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.^{[citation needed]}

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.^[132]

Some quinolone antibiotics exert an inhibitory effect on CYP1A2, thereby reducing clearance of caffeine and thus increasing blood levels.^[133]

A 2011 analysis published by PLoS Genetics reviewed five studies covering more than 47,000 subjects of European descent. Researchers determined that habitual caffeine intake is associated with variations in two genes that regulate how quickly the body processes caffeine. Subjects who had a high-intake mutation of either gene on both chromosomes consumed 40 mg more caffeine per day (equivalent to a can of cola) than people who did not.^[134]

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.^[135]

Decaffeination

Fibrous crystals of purified caffeine. Dark field light microscope image, the image covers an area of approx. 11 by 7 mm.

Main article: Decaffeination

Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an important industrial process and can be performed using a number of different 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:

Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.^[136]
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.^[136]
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.^[136]

'Decaffeinated' coffees do in fact contain caffeine, although only about 10 mg per cup as opposed to 85 mg per cup from regular.^[137]

History

Coffeehouse in Palestine, circa 1900

Main articles: History of chocolate, History of coffee, History of tea, and History of yerba mate

Caffeine was first isolated from coffee in 1820 by the German chemist Friedlieb Ferdinand Runge, and then independently in 1821 by French chemists Pierre Robiquet, Pierre Pelletier, and Joseph Caventou. Pelletier coined the word "cafeine" from the French word for coffee (café), and this term became the English word "caffeine".

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.^[138] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.^[139]

The history of coffee has been recorded as far back as the ninth century. During that time, coffee beans were available only in their place of origin, Ethiopia. Legends trace the discovery of coffee either to a Sufi dervish named Omar, or to a goatherder named Kaldi, who observed goats become elated and sleepless at night after grazing on coffee shrubs and, upon trying the berries the goats had been eating, experienced the same vitality.^[140] The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th-century Persian physician al-Razi.^[140]^:11 The first reliable record of the use of coffee outside Ethiopia comes from Aden, in 1451.^[140]^:16 The appreciation of coffee as a beverage in Europe dates from the 17th century. The first coffee house in Venice opened some time in the late 1640s.^[140]^:127 In Britain, the first coffee house was opened in Oxford in 1650.^[140]^:41 They soon became popular throughout Western Europe, and played a significant role in social relations in the 17th and 18th centuries.^[141]

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".^[142] 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.^[143]^{[unreliable source?]}

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.^{[citation needed]}

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".^{[citation needed]}

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".^[144] Archaeologists have found evidence of this use stretch back far into antiquity,^[145] possibly dating to Late Archaic times.^[144]

Discovery

Pierre 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).^[146] In 1821, caffeine was isolated both by 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 the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work.^[147] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:^[148] "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." According to Runge, he did this at the behest of Johann Wolfgang von Goethe.^[149]^[150]

Pelletier's article on caffeine was the first to use the term in print (in the French form Caféine).^[151] It corroborates Berzelius's account:

Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Mssrs. 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^[152] while Pelletier was the first to perform an elemental analysis.^[153]

In 1827, M. Oudry isolated "théine" from tea,^[154] but it was later proved by Mulder^[155] and by Carl Jobst^[156] that theine was actually caffeine.^[150]

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.^[157] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.^[158]

Legality

Today, caffeine is legal and available in many forms in all jurisdictions.^{[citation needed]}

Historically, coffee and thus caffeine was illegal for some classes in Mecca in parts of the 16th century,^[159] and in the Ottoman empire.^[160]^[161] Charles II of England tried to ban it in 1676,^[162]^[163] Frederic II of Prussia banned it in 1777,^[164]^[165] and coffee was banned in Sweden in the years 1756–1769, 1794–1796, 1799–1802, and 1817–1823. The bans on coffee have often had religious, economic, or political reasons rather than being based on concerns for the well-being of the population.^{[citation needed]}

Religion

Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine.^{[citation needed]} 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."^[166]

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.^{[citation needed]}

People who refrain from consuming caffeine, for religious or other reasons, may instead use a substitute that performs a culturally similar role to coffee.^{[citation needed]}

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.^[167]^[168]

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^ Janknegt R (1990). "Drug interactions with quinolones". J. Antimicrob. Chemother. 26 Suppl D: 7–29. doi:10.1093/jac/26.suppl_D.7. PMID 2286594.
^ Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, Berndt SI, Boerwinkle E, Chanock S, Chatterjee N, Couper D, Curhan G, Heiss G, Hu FB, Hunter DJ, Jacobs K, Jensen MK, Kraft P, Landi MT, Nettleton JA, Purdue MP, Rajaraman P, Rimm EB, Rose LM, Rothman N, Silverman D, Stolzenberg-Solomon R, Subar A, Yeager M, Chasman DI, van Dam RM, Caporaso NE (April 2011). "Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption". In Gibson, Greg. PLoS Genet. 7 (4): e1002033. doi:10.1371/journal.pgen.1002033. PMC 3071630. PMID 21490707.
^ Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 236–9. ISBN 0-931890-08-X.
^ ^a ^b ^c Senese F (2005-09-20). "How is coffee decaffeinated?". General Chemistry Online. Retrieved 2009-08-03.
^ http://news.ufl.edu/2006/10/10/decaf
^ John C. Evans (1992). Tea in China: The History of China's National Drink. Greenwood Press. p. 2. ISBN 0-313-28049-5.
^ Yu L (1995). The Classic of Tea: Origins & Rituals. Ecco Pr. ISBN 0-88001-416-4.
^ ^a ^b ^c ^d ^e Ukers WH (1922). All About Coffee. New York: The Tea and Coffee Trade Journal Company. pp. 13–15. ISBN 0-8103-4092-5.
^ <Please add first missing authors to populate metadata.> (1911). "Coffee". Encyclopædia Britannica.
^ Benjamin LT, Rogers AM, Rosenbaum A (1991). "Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911". J Hist Behav Sci 27 (1): 42–55. doi:10.1002/1520-6696(199101)27:1<42::AID-JHBS2300270105>3.0.CO;2-1. PMID 2010614.
^ The Rise and Fall of Cocaine Cola. Lewrockwell.com. Retrieved on 2012-05-25.
^ ^a ^b Fairbanks, Charles H. (2004). "The function of black drink among the Creeks". In Hudson, Charles M.. Black Drink. University of Georgia Press. p. 123. ISBN 978-0-8203-2696-2.
^ Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T (August 2012). "Ritual Black Drink consumption at Cahokia". Proc. Natl. Acad. Sci. U.S.A. 109 (35): 13944–13949. doi:10.1073/pnas.1208404109. PMC 3435207. PMID 22869743.
^ Runge, Friedlieb Ferdinand (1820). Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie [Latest phytochemical discoveries for the founding of a scientific phytochemistry]. Berlin: G. Reimer. pp. 144–159.
^ Berzelius, Jöns Jakob (1825). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual report on the progress of the physical sciences by Jacob Berzelius] (in German) 4. p. 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 is a material in coffee, which was discovered at the same time, 1821, by Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known about it in the press.)
^ Berzelius, Jöns Jacob (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius (in German) 7. p. 270.
^ 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 hattte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein." (After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. "You can also use these in your investigations," said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.)
This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was 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.
^ ^a ^b Weinberg BA, Bealer BK (2001). The World of Caffeine. Routledge. ISBN 0-415-92722-6.
^ Pelletier, Pierre Joseph (1822). "Cafeine". Dictionnaire de Médecine (in French) 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 2011-03-03.
^ Robiquet, Pierre Jean (1823). "Cafe". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French) 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 2011-03-03.
^ Dumas and Pelletier (1823). "Recherches sur la composition élémentaire et sur quelques propriétés caractéristiques des bases salifiables organiques" [Studies into the elemental composition and some characteristic properties of organic bases]. Annales de Chimie et de Physique (in French) 24: 163–191.
^ Oudry M (1827). "Note sur la Théine". Nouvelle bibliothèque médicale (in French) 1: 477–479.
^ Mulder, G. J. (1838). "Ueber Theïn und Caffeïn" [Concerning theine and caffeine]. Journal für Praktische Chemie 15: 280–284. doi:10.1002/prac.18380150124.
^ Jobst, Carl (1838). "Thein identisch mit Caffein" [Theine is identical to caffeine)]. Liebig's Annalen der Chemie und Pharmacie 25: 63–66.
^ 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.
- Emil Fischer (1881a) "Ueber das Caffeïn" (On caffeine), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 14 : 637-644.
- Emil Fischer (1881b) "Ueber das Caffeïn. Zweite Mitteilung." (On caffeine. Second communication.), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 14 : 1905-1915.
- Emil Fischer (1882) "Ueber das Caffeïn. Dritte Mitteilung." (On caffeine. Third communication.), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 15 : 29-33.
- Emil Fischer and Lorenz Ach (1895) "Synthese des Caffeïns" (Synthesis of caffeine), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 28 : 3135-3143.
- Emil Fischer (1897) "Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen" (On the constitution of caffeine, xanthin, hypoxanthin, and related bases), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 30 : 549-559.
^ Hj. Théel (1902). "Nobel Prize Presentation Speech". Retrieved 2009-08-03.
^ Brown, Daniel W (2004). A new introduction to Islam. Chichester, West Sussex: Wiley-Blackwell. pp. 149–51. ISBN 1-4051-5807-7.
^ Ágoston, Gábor; Masters, Bruce (2009). Encyclopedia of the Ottoman Empire. ISBN 978-1-4381-1025-7.
^ Hopkins, Kate (2006-03-24). "Food Stories: The Sultan's Coffee Prohibition". Accidental Hedonist. Retrieved January 3, 2010.
^ "By the King. A PROCLAMATION FOR THE Suppression of Coffee-Houses". Retrieved 2012-03-18.
^ Pendergrast 2001, p. 13
^ Pendergrast 2001, p. 11
^ Bersten 1999, p. 53
^ Doctrine and Covenants Student Manual: Religion 324 and 325. Salt Lake City: LDS Church. 2001. p. 209.
^ Juan Eduardo Campo (1 January 2009). Encyclopedia of Islam. Infobase Publishing. pp. 154–. ISBN 978-1-4381-2696-8. Retrieved 1 November 2012.
^ Daniel W. Brown (24 August 2011). A New Introduction to Islam. John Wiley & Sons. pp. 149–. ISBN 978-1-4443-5772-1. Retrieved 2 November 2012.

Bibliography

Bersten, Ian (1999). Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria. Sydney: Helian Books. ISBN 0-9577581-0-3.
Pendergrast, Mark (2001) [1999]. Uncommon Grounds: The History of Coffee and How It Transformed Our World. London: Texere. ISBN 1-58799-088-1.

External links

Look up caffeine in Wiktionary, the free dictionary.

Wikinews has related news: Alzheimer's disease reversed in mice using caffeine

Caffeine bound to proteins in the PDB
The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
Caffeine: ChemSub Online
Mayo Clinic staff (October 3, 2009). "Caffeine content for coffee, tea, soda and more". Mayo Clinic. Retrieved 2010-11-08.
Caffeine at The Periodic Table of Videos (University of Nottingham)
eMedicine Caffeine-Related Psychiatric Disorders
Caffeine International Chemical Safety Cards

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. カフェインおよびカフェイン含有飲料の利益とリスク benefits and risks of caffeine and caffeinated beverages
2. カフェインの心血管系への影響 cardiovascular effects of caffeine
3. 生殖能力および妊娠転帰におよぼすカフェインの影響 the effects of caffeine on fertility and on pregnancy outcomes
4. 早産児における無呼吸の管理 management of apnea of prematurity
5. 腰椎穿刺後頭痛 post lumbar puncture headache

English Journal

Caffeine electrochemical sensor using imprinted film as recognition element based on polypyrrole, sol-gel, and gold nanoparticles hybrid nanocomposite modified pencil graphite electrode.

Rezaei B1, Khalili Boroujeni M2, Ensafi AA2.
Biosensors & bioelectronics.Biosens Bioelectron.2014 Oct 15;60:77-83. doi: 10.1016/j.bios.2014.03.028. Epub 2014 Apr 13.
In the present study, a novel sensitive and selective nanocomposite imprinted electrochemical sensor for the indirect determination of caffeine has been prepared. The imprinted sensor was fabricated on the surface of pencil graphite electrode (PGE) via one-step electropolymerization of the imprinted
PMID 24769451

Influence of molecular weight on in vitro immunostimulatory properties of instant coffee.

Passos CP1, Cepeda MR2, Ferreira SS2, Nunes FM3, Evtuguin DV4, Madureira P5, Vilanova M5, Coimbra MA2.
Food chemistry.Food Chem.2014 Oct 15;161:60-6. doi: 10.1016/j.foodchem.2014.03.119. Epub 2014 Apr 2.
Instant coffee was prepared and fractionated into higher (>100kDa), medium (5-10, 10-30, 30-100kDa) and lower (1-5, <1kDa) molecular weight fractions. Sugars and linkage composition characteristics of arabinogalactans and galactomannans were recovered in all fractions. Also, amino acid analysi
PMID 24837922

Simultaneous determination of caffeine, caramel and riboflavin in cola-type and energy drinks by synchronous fluorescence technique coupled with partial least squares.

Ziak L1, Májek P1, Hroboňová K1, Cacho F1, Sádecká J2.
Food chemistry.Food Chem.2014 Sep 15;159:282-6. doi: 10.1016/j.foodchem.2014.03.034. Epub 2014 Mar 17.
The aim of this work was to develop a multivariate method for the rapid determination of caffeine and Class IV caramel in cola-type soft drinks and of caffeine, Class III caramel and riboflavin in energy drinks using synchronous fluorescence spectra. The synchronous fluorescence spectra were recorde
PMID 24767056

Japanese Journal

From JSCR (Journal of Strength and Conditioning Research) カフェインの一時的摂取が短時間の高強度エクササイズのパフォーマンスに及ぼす効果 : 系統的レビュー

Astorino Todd A.,Roberson Daniel W.
Strength & conditioning journal : 日本ストレングス&コンディショニング協会機関誌 19(4), 50-57, 2012-05
NAID 40019315670

Caffeine Increases the Antitumor Effect of Cisplatin in Human Hepatocellular Carcinoma Cells

Kawano Yohei,Nagata Masashi,他 [Takafumi@@Kohno]
Biological & pharmaceutical bulletin 35(3), 400-407, 2012-03
NAID 40019161969

Related Pictures

★リンクテーブル★

リンク元	「薬物濫用」「メチルキサンチン」「カフェイン」「中枢神経興奮薬」「anhydrous caffeine」
拡張検索	「caffeine and sodium benzoate」「antipyrine caffeine citrate」「caffeine sensitivity test」「caffeine use disorders」「caffeine-related disorder」

「薬物濫用」

Caffeine
Systematic (IUPAC) name
	1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione; 3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
Clinical data
AHFS/Drugs.com	monograph
Pregnancy cat.	C(US)
Legal status	Unscheduled (AU) GSL (UK) OTC (US)
Dependence liability	Moderate
Routes	Oral, insufflation, enema
Pharmacokinetic data
Bioavailability	99%
Protein binding	17% to 36%
Metabolism	demethylation by CYP1A2
Half-life	5 hours
Excretion	urine (100%)
Identifiers
CAS number	58-08-2
ATC code	N06BC01
PubChem	CID 2519
DrugBank	DB00201
ChemSpider	2424
UNII	3G6A5W338E
KEGG	D00528
ChEBI	CHEBI:27732
ChEMBL	CHEMBL113
Chemical data
Formula	C8H10N4O2
Mol. mass	194.19 g/mol
SMILES	eMolecules & PubChem
	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 ;
Properties:
Molecular formula	C8H10N4O2
Molar mass	194.19 g mol−1
Exact mass	194.080376 u
Appearance	Odorless, white needles or powder
Density	1.23 g/cm3, solid
Melting point	235–238 °C, 500–501 K (anhydrous); 234–235 °C, 507–508 K (monohydrate)
Boiling point	178 °C, 451 K, 352 °F (subl.)
Solubility in water	2.17 g/100 mL (25 °C); 18.0 g/100 mL (80 °C); 67.0 g/100 mL (100 °C)
Solubility	ethanol 15 g/L
Acidity (pKa)	-0.13–1.22 protonated caffeine
Dipole moment	3.64 D (calculated)
Hazards:
MSDS	ICSC 0405
EU Index	613-086-00-5
EU classification	Harmful (Xn)
R-phrases	R22
S-phrases	(S2)
NFPA 704	0 2 0
LD50	192 mg/kg (rat, oral)

　　[★]

英: drug abuse, substance abuse
同: 薬物乱用
関: 薬物依存、薬物嗜癖、物質乱用、物質依存症、薬物使用、接着剤吸引

薬物使用が身体に及ぼす効果

濫用 substance abuse：a pattern of abnormal substance use that leads to impairment of occupational, physical, or social functioning(BBS.73)
依存 substance dependence：ub stance abuse puls withdrawal symptoms, tolerance, or a pattern of repetitive use(BBS.73)
離脱 withdrawal：the development of physical or pschological symptoms after the reduction or cessation of intake of a substance(BBS.73)
耐性 tolerance：the need for increased amounts of the substance to achieve the same positive psychological effect(BBS.73)
交差耐性 cross-tolerance：the development of tolerance to one substance as the result of using another substance(BBS.73)

薬物

1. 中枢神経興奮薬(覚醒剤を含む) stimulants　　身体依存はないとされている

カフェイン caffeine
ニコチン nicotine
amphetamines　精神依存有り。身体依存無し

アンフェタミン amphetamine　精神依存有り。身体依存無し。耐性は連用で出現
デキストロアンフェタミン dextroamphetamine Dexedrine
メタンフェタミン methamphetamine Desoxyn speed ice ヒロポン　精神依存有り。身体依存無し。耐性は連用で出現　　←　以前、日本で多く使われた
メチルフェニデート methylphenidate Ritalin
methylene dioxymethamphetamine MDMA ecstasy

コカイン cocaine crack freebase　精神依存有り。身体依存無し　精神依存生じやすい。耐性発現殆ど無し　コカ

2. sedatives

alcohol　　精神依存有り。身体依存有り。
barbiturates
benzodiazepines

⇔flumazenil Mazicon Romazicon

3. opioids

morphine　精神依存・身体依存有り　けし
heroin　精神依存・身体依存が強い。耐性発現早い。離脱症状激しい
codeine
pethidine
fentanyl
methadone
l-alpha-acetylmethadol acetate LAMM
buprenorphine Temgesic

4. hallucinogens and related agents

cannabis(marijuana(tetrahydrocannabinol THC,hashish)　精神依存有り。身体依存無し　精神依存軽度。耐性は長期使用で軽度出現　大麻草
lysergic acid diethylamide LSD
phencyclidine PCP angel dust
psilocybin
mescaline

精神依存、身体依存

	精神依存	身体依存
コカイン、アンフェタミン類(アンフェタミン、メチルフェタミン)、大麻	○
麻薬(モルヒネ、ヘロイン、コデイン)、バルビツール酸系(フェノバルビタール、チオペンタール)、アルコール	○	○

「メチルキサンチン」

　　[★]

英: methylxanthine
関

概念

ホスホジエステラーゼ阻害作用を有する化合物の一群

誘導体

構造

メチルキサンチン系

作用機序 (SPC.211)

飲料として摂取した場合血中濃度は<50μM

血中濃度	作用
0.5-1.0mM	[Ca²⁺]_i↑
>50μM	ホスホジエステラーゼの阻害
<50μM	アデノシン受容体の拮抗

cAMP↑－(+cAMP)→ホルモン受容体↑、(+cAMP)βアドレナリン受容体↑
アデノシン受容体の非特異的拮抗、細胞内Ca2+遊離

薬理作用 (SPC.211,212)

中枢作用　　　：眠気消失、知的活動↑、興奮、不眠、振戦、神経過敏、けいれん、胃腸障害
心血管系作用　：陽性変力作用、陽性変時作用
気管支拡張作用：気管支平滑筋の弛緩
利尿作用
高濃度：SRからCa²⁺を放出→骨格筋拘縮、胃酸分泌促進

	カフェイン	テオフィリン	テオブロミン
中枢作用	◎	○	△
心血管系作用	○	◎	△
気管支拡張作用	△	◎	○
利尿作用	○	◎	△

副作用

肝臓で代謝されるので肝不全では中毒症状を呈する

「カフェイン」

　　[★]

英: caffeine
ラ: coffeinum
同: メチルテオブロミン methyltheobromine, 1,3,7-トリメチルキサンチン 1,3,7-trimethylxanthine
商: PL配合、無水カフェイン、LL配合シロップ小児用、アンナカ、カフェイン水和物、キョーリンAP2配合、クリアミン配合、サラザック配合、セラピナ配合、セラピナ配合、トーワチーム配合、ネオアムノール配合、ヒダントールD配合、ピーエイ配合、ピーエイ配合、ピーエイ配合、ピーエイ配合、ペレックス配合、マリキナ配合、マリキナ配合、ミグレニン、ラコールNF配合、ラコール配合、安息香酸ナトリウムカフェイン、幼児用PL配合
関: メチルキサンチン、安息香酸ナトリウムカフェイン

概念

メチルキサンチン誘導体
中枢作用が強い

「中枢神経興奮薬」

　　[★]

英: cerntral nervous system stimulant, CNS stimulant
同: 中枢興奮薬
関: 薬理学

中枢神経系の機能を亢進する薬物の総称

中枢神経興奮薬

メチルキサンチン誘導体(methylxanthine)

覚醒アミン

「anhydrous caffeine」

　　[★]

無水カフェイン

関: caffeine、caffeine and sodium benzoate

「caffeine and sodium benzoate」

　　[★]

安息香酸ナトリウムカフェイン

関: anhydrous caffeine、caffeine

caffeine、sodium benzoate

「antipyrine caffeine citrate」

　　[★] クエン酸カフェインアンチピリン

「caffeine sensitivity test」

　　[★] カフェイン感受性検査

「caffeine use disorders」

　　[★] カフェイン使用障害

「caffeine-related disorder」

　　[★] カフェイン関連障害

[1] Caffeine, International Occupational Safety and Health Information Centre (CIS)

[sigmaaldrich1-2] Caffeine (anhydrous). sigmaaldrich.com

[pKa-3] This is the pK_a for protonated caffeine, given as a range of values included in Harry G. Brittain, Richard J. Prankerd (2007). Profiles of Drug Substances, Excipients and Related Methodology, volume 33: Critical Compilation of pK_a Values for Pharmaceutical Substances. Academic Press. ISBN 0-12-260833-X.

[ld50-4] Peters JM (1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature". The Journal of Clinical Pharmacology and the Journal of New Drugs 7 (7): 131–141. doi:10.1002/j.1552-4604.1967.tb00034.x.

[demon_drink-5] Lovett R (2005-09-24). "Coffee: The demon drink?". New Scientist (2518). Retrieved 2009-08-03. (subscription required)

[MayoPreg2-6] Mayo Clinic staff. "Pregnancy Nutrition: Foods to avoid during pregnancy". Mayo Clinic. Retrieved 2012-04-15.

[ACOG_policy_462_caffeine-7] American College of Obstetricians and Gynecologists (August 2010). "ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstet Gynecol 116 (2 Pt 1): 467–8. doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.

[pmid1356551-8] Nehlig A, Daval JL, Debry G (1992). "Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects". Brain Res. Brain Res. Rev. 17 (2): 139–70. doi:10.1016/0165-0173(92)90012-B. PMID 1356551.

[effects-9] Bolton S (1981). "Caffeine: Psychological Effects, Use and Abuse". Orthomolecular Psychiatry 10 (3): 202–211.

[pmid21531247-10] Snel J, Lorist MM (2011). "Effects of caffeine on sleep and cognition". Prog. Brain Res. Progress in Brain Research 190: 105–17. doi:10.1016/B978-0-444-53817-8.00006-2. ISBN 978-0-444-53817-8. PMID 21531247.

[pmid20464765-11] Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I (2010). "Caffeine for the prevention of injuries and errors in shift workers". In Ker, Katharine. Cochrane Database Syst Rev (5): CD008508. doi:10.1002/14651858.CD008508. PMID 20464765.

[pmid21058748-12] Bishop D (2010). "Dietary supplements and team-sport performance". Sports Med 40 (12): 995–1017. doi:10.2165/11536870-000000000-00000. PMID 21058748.

[pmid21411838-13] Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (2011). "Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance?". Int J Sport Nutr Exerc Metab 21 (1): 71–84. PMID 21411838.

[pmid19924012-14] Astorino TA, Roberson DW (2010). "Efficacy of acute caffeine ingestion for short-term high-intensity exercise performance: a systematic review". J Strength Cond Res 24 (1): 257–65. doi:10.1519/JSC.0b013e3181c1f88a. PMID 19924012.

[pmid9729561-15] Graham TE, Hibbert E, Sathasivam P (September 1998). "Metabolic and exercise endurance effects of coffee and caffeine ingestion". J. Appl. Physiol. 85 (3): 883–9. PMID 9729561.

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[141] <Please add first missing authors to populate metadata.> (1911). "Coffee". Encyclopædia Britannica.

[pmid2010614-142] Benjamin LT, Rogers AM, Rosenbaum A (1991). "Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911". J Hist Behav Sci 27 (1): 42–55. doi:10.1002/1520-6696(199101)27:1<42::AID-JHBS2300270105>3.0.CO;2-1. PMID 2010614.

[143] The Rise and Fall of Cocaine Cola. Lewrockwell.com. Retrieved on 2012-05-25.

[Fairbanks-144] Fairbanks, Charles H. (2004). "The function of black drink among the Creeks". In Hudson, Charles M.. Black Drink. University of Georgia Press. p. 123. ISBN 978-0-8203-2696-2.

[145] Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T (August 2012). "Ritual Black Drink consumption at Cahokia". Proc. Natl. Acad. Sci. U.S.A. 109 (35): 13944–13949. doi:10.1073/pnas.1208404109. PMC 3435207. PMID 22869743.

[146] Runge, Friedlieb Ferdinand (1820). Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie [Latest phytochemical discoveries for the founding of a scientific phytochemistry]. Berlin: G. Reimer. pp. 144–159.

[147] Berzelius, Jöns Jakob (1825). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual report on the progress of the physical sciences by Jacob Berzelius] (in German) 4. p. 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 is a material in coffee, which was discovered at the same time, 1821, by Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known about it in the press.)

[148] Berzelius, Jöns Jacob (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius (in German) 7. p. 270.

[149] 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 hattte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein." (After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. "You can also use these in your investigations," said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.)
This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was 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-150] Weinberg BA, Bealer BK (2001). The World of Caffeine. Routledge. ISBN 0-415-92722-6.

[151] Pelletier, Pierre Joseph (1822). "Cafeine". Dictionnaire de Médecine (in French) 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 2011-03-03.

[152] Robiquet, Pierre Jean (1823). "Cafe". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French) 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 2011-03-03.

[153] Dumas and Pelletier (1823). "Recherches sur la composition élémentaire et sur quelques propriétés caractéristiques des bases salifiables organiques" [Studies into the elemental composition and some characteristic properties of organic bases]. Annales de Chimie et de Physique (in French) 24: 163–191.

[154] Oudry M (1827). "Note sur la Théine". Nouvelle bibliothèque médicale (in French) 1: 477–479.

[155] Mulder, G. J. (1838). "Ueber Theïn und Caffeïn" [Concerning theine and caffeine]. Journal für Praktische Chemie 15: 280–284. doi:10.1002/prac.18380150124.

[156] Jobst, Carl (1838). "Thein identisch mit Caffein" [Theine is identical to caffeine)]. Liebig's Annalen der Chemie und Pharmacie 25: 63–66.

[157] 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.

Emil Fischer (1881a) "Ueber das Caffeïn" (On caffeine), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 14 : 637-644.

Emil Fischer (1881b) "Ueber das Caffeïn. Zweite Mitteilung." (On caffeine. Second communication.), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 14 : 1905-1915.

Emil Fischer (1882) "Ueber das Caffeïn. Dritte Mitteilung." (On caffeine. Third communication.), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 15 : 29-33.

Emil Fischer and Lorenz Ach (1895) "Synthese des Caffeïns" (Synthesis of caffeine), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 28 : 3135-3143.

Emil Fischer (1897) "Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen" (On the constitution of caffeine, xanthin, hypoxanthin, and related bases), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 30 : 549-559.

[158] Emil Fischer (1881a) "Ueber das Caffeïn" (On caffeine), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 14 : 637-644.

[159] Emil Fischer (1881b) "Ueber das Caffeïn. Zweite Mitteilung." (On caffeine. Second communication.), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 14 : 1905-1915.

[160] Emil Fischer (1882) "Ueber das Caffeïn. Dritte Mitteilung." (On caffeine. Third communication.), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 15 : 29-33.

[161] Emil Fischer and Lorenz Ach (1895) "Synthese des Caffeïns" (Synthesis of caffeine), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 28 : 3135-3143.

[162] Emil Fischer (1897) "Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen" (On the constitution of caffeine, xanthin, hypoxanthin, and related bases), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 30 : 549-559.

[158] Hj. Théel (1902). "Nobel Prize Presentation Speech". Retrieved 2009-08-03.

[159] Brown, Daniel W (2004). A new introduction to Islam. Chichester, West Sussex: Wiley-Blackwell. pp. 149–51. ISBN 1-4051-5807-7.

[agostonmasters2009-160] Ágoston, Gábor; Masters, Bruce (2009). Encyclopedia of the Ottoman Empire. ISBN 978-1-4381-1025-7.

[hopkins2006-161] Hopkins, Kate (2006-03-24). "Food Stories: The Sultan's Coffee Prohibition". Accidental Hedonist. Retrieved January 3, 2010.

[162] "By the King. A PROCLAMATION FOR THE Suppression of Coffee-Houses". Retrieved 2012-03-18.

[Pendergrast13-163] Pendergrast 2001, p. 13

[Pendergrast11-164] Pendergrast 2001, p. 11

[165] Bersten 1999, p. 53

[166] Doctrine and Covenants Student Manual: Religion 324 and 325. Salt Lake City: LDS Church. 2001. p. 209.

[Campo2009-167] Juan Eduardo Campo (1 January 2009). Encyclopedia of Islam. Infobase Publishing. pp. 154–. ISBN 978-1-4381-2696-8. Retrieved 1 November 2012.

[Brown2011-168] Daniel W. Brown (24 August 2011). A New Introduction to Islam. John Wiley & Sons. pp. 149–. ISBN 978-1-4443-5772-1. Retrieved 2 November 2012.

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^[84]^[85]	7002124000000000000124–416
Guayakí yerba mate (loose leaf)	6 g (200 US fl oz)	700185000000000000085^[86]	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
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

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caffeine