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coffee with the caffeine removed (同)decaf

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/13 16:36:34」(JST)

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Caffeine (/kæˈfiːn, ˈkæfiːn, ˈkæfiːɪn/) is a central nervous system (CNS) stimulant of the methylxanthine class of psychoactive drugs.^[8] 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. It is a bitter, white crystalline purine, a methylxanthine alkaloid, and thus closely related chemically to the adenine and guanine contained in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, nuts, or leaves of a number of plants native to South America and East Asia. The most well known source of caffeine is the seed (commonly incorrectly referred to as the "bean") of Coffea plants. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to increase one's energy level. Caffeine is extracted from the plant part containing it for making beverages by steeping it in water, a process called infusion. These beverages are very popular; in North America, 90% of adults consume caffeine daily.^[9]

Caffeine is classified by the Food and Drug Administration as "generally recognized as safe" (GRAS). Toxic doses, over 10 grams per day for an adult, are much higher than typical dose of under 500 milligrams per day. A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used and how it is prepared (e.g. drip, percolation, or espresso). Thus it requires roughly 50–100 ordinary cups of coffee to reach a lethal dose. However pure powdered caffeine, which is widely available as a dietary supplement, can be lethal in tablespoon-sized amounts. There are several known mechanisms of action to explain the effects of caffeine. The most prominent is to reversibly block the action of adenosine on its receptor, which blocks the onset of drowsiness induced by adenosine. Caffeine also stimulates selected portions of the autonomic nervous system.

Caffeine can have both positive and negative health effects. It can be used to treat bronchopulmonary dysplasia of prematurity, and to prevent apnea of prematurity: caffeine citrate was placed on the WHO Model List of Essential Medicines in 2007.^[10] It may confer a modest protective effect against some diseases,^[11] including Parkinson's disease^[12] and certain types of cancer. One meta-analysis concluded that cardiovascular disease such as coronary artery disease and stroke is less likely with 3–5 cups of non-decaffeinated coffee per day but more likely with over 5 cups per day.^[13] Some people experience insomnia or sleep disruption if they consume caffeine, especially during the evening hours, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit consumption to the equivalent of two cups of coffee per day or less.^[14]^[15] Whether or not caffeine is an addictive drug depends on how an addiction is defined. It can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake.^[1]^[3]^[16] Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).^{[citation needed]}

Caffeine confers a survival advantage on the plant containing it in three ways. First, if it is ingested by an insect feeding on and potentially damaging or killing the plant, caffeine functions as a natural pesticide which can paralyze and kill the insect. Second, droppings from the plant infuse the surrounding soil with caffeine, which can inhibit the growth of and kill competing seedlings (and potentially its own progeny and itself). Third, caffeine can enhance the reward memory of pollinators such as honey bees, thus increasing the numbers of its progeny.

1 Uses
- 1.1 Medical
- 1.2 Enhancing performance
2 Side effects
- 2.1 Pregnancy risk
- 2.2 Reinforcement disorders
  - 2.2.1 Addiction
  - 2.2.2 Dependence and withdrawal
  - 2.2.3 Tolerance
- 2.3 Risk of other diseases
3 Overdose
4 Pharmacology
- 4.1 Pharmacodynamics
  - 4.1.1 Receptor and ion channel targets
  - 4.1.2 Enzyme targets
  - 4.1.3 Performance enhancing mechanism
  - 4.1.4 Metabolite pharmacodynamics
- 4.2 Pharmacokinetics
5 Physical and chemical properties
- 5.1 Biosynthesis
- 5.2 Detection in body fluids
- 5.3 Analogs
6 Natural occurrence
7 Products
- 7.1 Beverages
  - 7.1.1 Coffee
  - 7.1.2 Tea
  - 7.1.3 Soft drinks and energy drinks
  - 7.1.4 Other beverages
- 7.2 Chocolate
- 7.3 Tablets
- 7.4 Other oral products
- 7.5 Inhalants
- 7.6 Combinations with other drugs
8 Decaffeination
9 History
- 9.1 Discovery and spread of use
- 9.2 Chemical identification, isolation, and synthesis
10 Society and culture
- 10.1 Consumption
- 10.2 Governments
- 10.3 Religions
11 Other organisms
12 References
13 Bibliography
14 External links

Uses

Medical

Caffeine is used in

bronchopulmonary dysplasia in premature infants for both prevention^[17] and treatment.^[18] It may improve weight gain during therapy^[19] and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay.^[20]^[21] On the other hand, subtle long-term side effects are possible.^[22]
apnea of prematurity as a primary treatment,^[23] but not prevention.^[24]^[25]
orthostatic hypotension treatment.^[25]^[26]

Enhancing performance

Health effects of caffeine

Caffeine is a central nervous system and metabolic stimulant,^[8] and is used to reduce physical fatigue and to prevent or treat drowsiness. It produces increased wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination.^[27] The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance. Desired effects begin less than an hour after consumption, and a moderate dose usually subsides in about five hours.^[27]

Caffeine has the desired effect of delaying/preventing sleep, but does not affect all people in the same way. It also improves performance during sleep deprivation.^[28] In shift workers it leads to fewer mistakes caused by drowsiness.^[29]

In athletes, moderate doses of caffeine can improve sprint,^[30] endurance,^[31] and team sports performance,^[32] but the improvements are usually not substantial. Some evidence suggests that coffee does not produce the performance enhancing effects observed in other caffeine sources.^[33]

Side effects

Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common, and include mild anxiety, jitteriness, insomnia, and interference with co-ordination in athletes.^[34] The caffeine-induced disorders recognized in the The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) are: caffeine-induced anxiety disorder, caffeine-induced sleep disorder, caffeine intoxication, caffeine withdrawal and caffeine-related disorder not otherwise specified.^[35] Caffeine in low doses may cause weak bronchodilation for up to four hours in asthmatics: it should therefore be avoided prior to having any lung function test performed.^[36]

Caffeine can have negative effects on anxiety disorders.^[37] A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder.^[38]^[39] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety^[40] or, rarely, trigger mania or psychosis. In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk.^[41] Caffeine does not improve memory or learning,^[42] but can improve cognitive functions in people who are fatigued, possibly due to its effect on alertness.^[43] For some people, discontinuing caffeine use can significantly reduce anxiety.^[44]

Caffeine increases urine output acutely, but not chronically. When doses of caffeine equivalent to 2–3 cups of coffee are administered to people who have not consumed caffeine during prior days, it results in a mild increase in urinary output.^[45] This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); and is mediated via proximal tubular adenosine receptor blockade.^[46] Because of this effect, some authorities have recommended that athletes and airline passengers avoid caffeine to reduce the risk of dehydration, i.e. hypernatremia, and the risk of extracellular fluid volume depletion. However, chronic users of caffeine develop a tolerance to these effects, and have no chronic increase in urinary output.^[47]^[48]

Pregnancy risk

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.^[49] However, as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy.^[50]^[51] 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.^[52] 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.^[15] Although the evidence that caffeine may be harmful during pregnancy is equivocal, there is some evidence that the hormonal changes during pregnancy slow the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting effects (as long as 15 hours in the third trimester).^[53]

Reinforcement disorders

Addiction

Whether or not caffeine can result in an addictive disorder depends on how addiction is defined. Some diagnostic models, such as the ICDM-9 and ICD-10, include a classification of caffeine addiction under a broader diagnostic model.^[54] Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.^[55]^[56]

Research does not provide support for an underlying biochemical mechanism for caffeine addiction,^[1]^[57]^[58]^[59] although it does appear to affect the rewarding properties of other stimuli.^[60]

"Caffeine addiction" was added to the ICDM-9 and ICD-10; however, its addition was contested with claims that this diagnostic model of caffeine addiction is not supported by evidence.^[1]^[2]^[61] The American Psychiatric Association's DSM-5 does not include the diagnosis of a caffeine addiction but propose criteria for the disorder for more study.^[62]^[63]

Dependence and withdrawal

Mild physical dependence or psychological dependence may occur with repeated daily intake;^[1] the associated physical or psychological withdrawal state may involve symptoms such as fatigue, headache, irritability, inability to concentrate, sleepiness or drowsiness, stomach pain, and joint pain.^[1]^[16] Withdrawal headaches are experienced by roughly half of those who stop consuming caffeine for two days following an average daily intake of 235 mg.^[64]

The ICD-10 includes a diagnostic model for caffeine dependence, but the DSM-5 does not.^[3]^[61] The APA, which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of this disorder is unclear.^[3] The DSM-5 instead lists "caffeine use disorder" in the emerging models section of the manual.^[3]

Tolerance

Tolerance to the desired effect of alertness does not occur following repeated use. Tolerance to some undesired effects, particularly to caffeine's autonomic effects, develops quickly, especially among heavy coffee and energy drink consumers.^[65] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.^[53]

Risk of other diseases

Coffee consumption is associated with a lower overall risk of cancer.^[66] 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.^[67] 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.^[67] A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.^[68]^[69]^[70] Moderate coffee consumption may decrease the risk of cardiovascular disease,^[13] and it may somewhat reduce the risk of type 2 diabetes.^[71] 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.^[72] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.^[73] It may protect people from liver cirrhosis.^[74] There is no evidence that coffee stunts a child's growth.^[75] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.^[76] Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.^[77]

Overdose

Primary symptoms of caffeine intoxication^[78]

Consumption of 1000–1500 mg per day is associated with a condition known as caffeinism.^[79] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.^[80]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90).^[81] 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.^[78] 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.^[82]^[83]

Massive overdose can result in death.^[84]^[85] The LD₅₀ of caffeine in humans is dependent on individual sensitivity, but is estimated to be 150 to 200 milligrams per kilogram of body mass (75–100 cups of coffee for a 70 kilogram adult).^[86] A number of fatalities have been caused by overdoses of readily available powdered caffeine supplements, for which the estimated lethal amount is less than a tablespoon.^[87] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease^[88] A death was reported in a man with liver cirrhosis who overdosed on caffeinated mints.^[89]^[90]^[91]

Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration.^[78]

Pharmacology

Pharmacodynamics

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

In the absence of caffeine and when a person is awake and alert, little adenosine is present in (CNS) neurons. With a continued wakeful state, over time it accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes adenosine receptors; in other words, caffeine prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.^[4]

Receptor and ion channel targets

Caffeine is a receptor antagonist at all adenosine receptor subtypes (A1, A2A, A2B, and A3 receptors).^[4] Antagonism at these receptors stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heartrate, and constricts blood vessels.^[4] Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;^[4]^[92] adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Increased heart rate is caused by blockade of the adenosine A1 receptor.^[4]

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.^[93]

In addition to its activity at adenosine receptors, caffeine is an inositol triphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3).^[94] It is also a competitive antagonist of the ionotropic glycine receptor.^[95]

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.^[96] As a competitive nonselective phosphodiesterase inhibitor,^[97] caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha^[98]^[99] and leukotriene^[100] synthesis, and reduces inflammation and innate immunity.^[100] Caffeine is also significantly implicated in cholinergic system where it e.g. inhibits enzyme acetylcholinesterase.^[101]

Performance enhancing mechanism

A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine.^[102] 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.^[103]

Metabolite pharmacodynamics

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 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.^[104]

Pharmacokinetics

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 distributed throughout all bodily tissues.^[5] Peak blood concentration is reached within 1–2 hours.^{[citation needed]} It is eliminated by first-order kinetics.^[105] Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine)^[106] and chlorobutanol and caffeine (for the treatment of hyperemesis).^[107]

Caffeine's biological half-life – the time required for the body to eliminate one-half of a dose – varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for caffeine metabolism) and age. In healthy adults, caffeine's half-life is between 3–7 hours.^[4] Nicotine decreases the half-life by 30–50%,^[53] while oral contraceptives can double it^[53] and pregnancy can raise it to as much as 15 hours during the last trimester.^[53] In newborns the half-life can be 80 hours or more, dropping very rapidly with age, possibly to less than the adult value by age 6 months.^[53] The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and increases its elimination half-life more than tenfold; from 4.9 hours to 56 hours.^[108]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,^[109] each of which has its own effects on the body:

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

1,3,7-Trimethyluric acid is a minor caffeine metabolite.^[4] 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.^[110]

A 2011 review found that increased caffeine intake was associated with a variation in two genes that increase the rate of caffeine catabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more caffeine per day than others.^[111] This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene "forces" people to drink coffee.

Physical and chemical properties

Pure anhydrous caffeine is a white odorless powder with a melting point of 235–238 °C.^[6]^[7] Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL).^[112] It is also moderately soluble in ethanol (1.5 g/100 mL).^[112] It is weakly basic (pK_a = ~0.6) requiring strong acid to protonate it.^[113] Caffeine does not contain any stereogenic centers^[114] and hence is classified as an achiral molecule.^[115]

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp² hybridized and planar. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.^[116]

Biosynthesis

Caffeine may be synthesized from dimethylurea and malonic acid,^[117]^[118]^[119] but is rarely obtained from synthesis since it is readily available as a byproduct of decaffeination.^[120]

Caffeine biosynthesis^[121]

Caffeine laboratory synthesis^[117]^[118]

Detection in body fluids

Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.^[122]

Analogs

Some analog substances have been created which mimic caffeine's properties with either function or structure or both, one of the latter is the drug DMPX.^[123]

Natural occurrence

Around sixty plant species are known to contain caffeine.^[124] Common sources are the "bean" (seed) of the coffee plant (the quantity varies, but 1.3% is a typical value^[125]); in the leaves of the tea bush; and in kola nuts. Other sources include yaupon holly leaves, South American holly yerba mate leaves, seeds from Amazonian maple guarana berries, and Amazonian holly guayusa leaves. Temperate climates around the world have produced unrelated caffeine containing plants.

Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant:^[126] high caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.^[127] In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival.^[128]

The differing perceptions in the effects of ingesting beverages made from various plants containing caffeine could be explained by the fact that these beverages also contain varying mixtures of other methylxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.^[129]^{[clarification needed]}

Products

Caffeine Content in Select Food and Drugs^[130]^[131]^[132]^[133]^[134]
Product	Serving size	Caffeine per serving (mg)	Caffeine (mg/L)
Caffeine tablet (regular-strength)	1 tablet	7002100000000000000♠100	—
Caffeine tablet (extra-strength)	1 tablet	7002200000000000000♠200	—
Excedrin tablet	1 tablet	7001650000000000000♠65	—
Hershey's Special Dark (45% cacao content)	1 bar (43 g or 1.5 oz)	7001310000000000000♠31	—
Hershey's Milk Chocolate (11% cacao content)	1 bar (43 g or 1.5 oz)	7001100000000000000♠10	—
Percolated coffee	207 mL (7.0 US fl oz)	7001800000000000000♠80–135	7002386000000000000♠386–652
Drip coffee	207 mL (7.0 US fl oz)	7002115000000000000♠115–175	7002555000000000000♠555–845
Coffee, decaffeinated	207 mL (7.0 US fl oz)	7000500000000000000♠5–15	7001240000000000000♠24–72
Coffee, espresso	44–60 mL (1.5–2.0 US fl oz)	7002100000000000000♠100	7003169100000000000♠1,691–2,254
Tea – black, green, and other types, – steeped for 3 min.	177 millilitres (6.0 US fl oz)	7001220000000000000♠22–74^[133]^[134]	7002124000000000000♠124–418
Guayakí yerba mate (loose leaf)	6 g (0.21 oz)	7001850000000000000♠85^[135]	7002358000000000000♠approx. 358
Coca-Cola Classic	355 mL (12.0 US fl oz)	7001340000000000000♠34	7001960000000000000♠96
Mountain Dew	355 mL (12.0 US fl oz)	7001540000000000000♠54	7002154000000000000♠154
Pepsi Max	355 mL (12.0 US fl oz)	7001690000000000000♠69	7002194000000000000♠194
Guaraná Antarctica	350 mL (12 US fl oz)	7001300000000000000♠30	7002100000000000000♠100
Jolt Cola	695 mL (23.5 US fl oz)	7002280000000000000♠280	7002403000000000000♠403
Red Bull	250 mL (8.5 US fl oz)	7001800000000000000♠80	7002320000000000000♠320

Products containing caffeine are coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,^[136] caffeine tablets, other oral products, and inhalation.

Beverages

Coffee

The world's primary source 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;^[137] 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.^[138]^[139] Arabica coffee typically contains half the caffeine of the robusta variety.^[137] In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount.^[138]^[139]

Tea

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed more weakly than coffee. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, certain types of tea may contain somewhat more caffeine than other teas.^[140]

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.^[140]

Soft drinks and energy drinks

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain 10 to 69 milligrams of caffeine per 12 ounce serving.^{[citation needed]} 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.^[141]

Other beverages

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

Chocolate

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.^[142] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount caffeine as coffee: 80–160 mg per 100 g.^[131]

Tablets

No-Doz 100 mg caffeine tablets

Tablets offer the advantages over coffee and tea of convenience, known dosage, and avoiding concomitant fluid intake. Manufacturers of caffeine tablets claim that using caffeine of pharmaceutical quality improves mental alertness.^{[citation needed]} These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.^[143]

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.^[144] Another unusual intake route is SpazzStick, a caffeinated lip balm.^[145] Alert Energy Caffeine Gum was introduced in the United States in 2013, but was voluntarily withdrawn after an announcement of an investigation by the FDA of the health effects of added caffeine in foods.^[146]

Inhalants

Taking caffeine by inhalation was under scrutiny by some U.S. lawmakers in 2011.^[147]

Combinations with other drugs

Ethanol and caffeine have been combined into one beverage. This beverage is considered unsafe, and is not approved by the FDA.^[148]
Ya ba contains a combination of methamphetamine and caffeine.

Decaffeination

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

Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using a number of solvents. Benzene, 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.^[149]
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.^[149]
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.^[149]

"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.^[150]

History

Discovery and spread of use

Coffeehouse in Palestine, circa 1900

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.^[151] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.^[152]

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.^[153] 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.^[154]

Kola nut use appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs.

The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. Also, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.^{[citation 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".^[155] Archaeologists have found evidence of this use far into antiquity,^[156] possibly dating to Late Archaic times.^[155]

Chemical identification, isolation, and synthesis

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).^[157] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.^[158]^[159] 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.^[160] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:^[161] "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).^[162] It corroborates Berzelius's account:

Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Messrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ...

Robiquet was one of the first to isolate and describe the properties of pure caffeine,^[163] whereas Pelletier was the first to perform an elemental analysis.^[164]

In 1827, M. Oudry isolated "théine" from tea,^[165] but it was later proved by Mulder^[166] and by Carl Jobst^[167] that theine was actually caffeine.^[159]

In 1895, German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from its chemical components (i.e. a "total synthesis"), and two years later, he also derived the structural formula of the compound.^[168] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.^[169]

Society and culture

Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.^[170]

Governments

Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca and in the Ottoman Empire made coffee illegal for some classes.^[171]^[172]^[173] Charles II of England tried to ban it in 1676,^[174]^[175] Frederick II of Prussia banned it in 1777,^[176]^[177] and coffee was banned in Sweden at various times between 1756 and 1823.

In 1911, caffeine became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".^[178] 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.^[179]^{[unreliable source?]} The Food and Drug Administration (FDA) in the United States currently allows only beverages containing less than 0.02% caffeine;[161] but caffeine powder, which is sold as a dietary supplement, is unregulated.[162]

Religions

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."^[180]

Gaudiya Vaishnavas generally also abstain from caffeine, because they believe it clouds the mind and over-stimulates the senses. To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.^{[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.^[181]^[182]

Other organisms

Caffeine effects on spider webs

Pseudomonas putida CBB5 can live on pure caffeine, and can cleave caffeine into carbon dioxide and ammonia.^[183]

Caffeine is toxic to birds^[184] and to dogs and cats,^[185] and has a pronounced adverse effect on mollusks, various insects, and spiders.^[186] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.^[187] Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the pollen producing plants.^[188]

References

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Boiling Point
178 deg C (sublimes)
Melting Point
238 DEG C (ANHYD)
^ ^a ^b "Caffeine". ChemSpider. Royal Society of Chemistry. Retrieved 16 October 2014. Experimental Melting Point:
234–236 °C Alfa Aesar
237 °C Oxford University Chemical Safety Data
238 °C LKT Labs [C0221]
237 °C Jean-Claude Bradley Open Melting Point Dataset 14937
238 °C Jean-Claude Bradley Open Melting Point Dataset 17008, 17229, 22105, 27892, 27893, 27894, 27895
235.25 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
236 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
235 °C Jean-Claude Bradley Open Melting Point Dataset 6603
234–236 °C Alfa Aesar A10431, 39214
Experimental Boiling Point:
178 °C (Sublimes) Alfa Aesar
178 °C (Sublimes) Alfa Aesar 39214
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^ ^a ^b "ICD-10 Version:2015". World Health Organization. 2015. Retrieved 10 July 2015.
F15 Mental and behavioural disorders due to use of other stimulants, including caffeine ...

.2 Dependence syndrome
A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.
The dependence syndrome may be present for a specific psychoactive substance (e.g. tobacco, alcohol, or diazepam), for a class of substances (e.g. opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:]
Chronic alcoholism
Dipsomania
Drug addiction
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^ For more information, see Alejandro Lopez-Ortiz. "Frequently Asked Questions about Coffee and Caffeine".
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^ Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. pp. 3–4. ISBN 978-0-415-92723-9.
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^ 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. Retrieved 8 January 2014.
^ In 1819, Runge was invited to show Goethe how belladonna caused dilation of the pupil, which Runge did, using a cat as an experimental subject. Goethe was so impressed with the demonstration that: "Nachdem Goethe mir seine größte Zufriedenheit sowol über die Erzählung des durch scheinbaren schwarzen Staar Geretteten, wie auch über das andere ausgesprochen, übergab er mir noch eine Schachtel mit Kaffeebohnen, die ein Grieche ihm als etwas Vorzügliches gesandt. "Auch diese können Sie zu Ihren Untersuchungen brauchen," sagte Goethe. Er hatte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein." (After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. "You can also use these in your investigations," said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.)
This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was 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 Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. ISBN 978-0-415-92723-9. ^{[page needed]}
^ 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 JJ (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual Report on the Progress of the Physical Sciences by Jacob Berzelius] (in German) 7. p. 270. From page 270: "Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen 1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zusammenkunft der Societé de Pharmacie in Paris die erste mündliche Mittheilung darüber gab." (However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris.)
^ Pelletier, Pierre Joseph (1822). "Cafeine". Dictionnaire de Médecine (in French) 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 3 March 2011.
^ Robiquet, Pierre Jean (1823). "Cafe". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French) 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 3 March 2011.
^ Dumas 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.
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^ Jobst, Carl (1838). "Thein identisch mit Caffein" [Theine is identical to caffeine]. Liebig's Annalen der Chemie und Pharmacie 25: 63–66. doi:10.1002/jlac.18380250106.
^ Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.
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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

GMD MS Spectrum
The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
Caffeine: ChemSub Online
Caffeine at The Periodic Table of Videos (University of Nottingham)
Caffeine International Chemical Safety Cards
Mayo Clinic staff (3 October 2009). "Caffeine content for coffee, tea, soda and more". Mayo Clinic. Retrieved 8 November 2010.

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. カフェインおよびカフェイン含有飲料の心血管系への影響 cardiovascular effects of caffeine and caffeinated beverages
3. 女性の生殖能力におよぼすカフェインの影響 the effects of caffeine on reproductive outcomes in women
4. 突然の心停止および心突然死の概要 overview of sudden cardiac arrest and sudden cardiac death
5. 早産児における無呼吸のマネージメント management of apnea of prematurity

English Journal

Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-Results from the EPIC cohort study.

Dik VK1, Bueno-de-Mesquita HB, Van Oijen MG, Siersema PD, Uiterwaal CS, Van Gils CH, Van Duijnhoven FJ, Cauchi S, Yengo L, Froguel P, Overvad K, Bech BH, Tjønneland A, Olsen A, Boutron-Ruault MC, Racine A, Fagherazzi G, Kühn T, Campa D, Boeing H, Aleksandrova K, Trichopoulou A, Peppa E, Oikonomou E, Palli D, Grioni S, Vineis P, Tumino R, Panico S, Peeters PH, Weiderpass E, Engeset D, Braaten T, Dorronsoro M, Chirlaque MD, Sánchez MJ, Barricarte A, Zamora-Ros R, Argüelles M, Jirström K, Wallström P, Nilsson LM, Ljuslinder I, Travis RC, Khaw KT, Wareham N, Freisling H, Licaj I, Jenab M, Gunter MJ, Murphy N, Romaguera-Bosch D, Riboli E.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Jul 15;135(2):401-12. doi: 10.1002/ijc.28655. Epub 2013 Dec 21.
Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotype
PMID 24318358

Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case-control study.

Ferrucci LM1, Cartmel B, Molinaro AM, Leffell DJ, Bale AE, Mayne ST.
European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP).Eur J Cancer Prev.2014 Jul;23(4):296-302. doi: 10.1097/CEJ.0000000000000037.
Tea and coffee are hypothesized to play a protective role in skin carcinogenesis through bioactive components, such as caffeine, yet the epidemiologic evidence is mixed. Existing data support an inverse association with basal cell carcinoma (BCC), more so than for melanoma or squamous cell carcinoma
PMID 24841641

Young adolescents' perceptions, patterns, and contexts of energy drink use. A focus group study.

Costa BM1, Hayley A2, Miller P2.
Appetite.Appetite.2014 May 20. pii: S0195-6663(14)00215-3. doi: 10.1016/j.appet.2014.05.013. [Epub ahead of print]
Caffeinated energy drinks (EDs) are purported to increase energy and improve performance, but have been associated with adverse health effects and death. EDs are popular among adolescents and young adults, yet little is known about their use among young adolescents. This study explored perceptions,
PMID 24852220

Japanese Journal

耳朶脈波分析による静的作業時の休憩効果とその際に飲用するカフェイン含有コーヒーの効用について

山田貴代,山下淳,苗鉄軍
農作業研究 44(1), 11-19, 2009-03-16
NAID 10029876236

The Effect of Coffee Drinking on the Bowel Movement Frequency in Young Japanese Women

Sato Nobuko,Ejima Kazue,Kasada Tomomi,Shingaki Yoriko,Murakami Yayoi,Kanazawa Ayako
熊本大学教育学部紀要. 自然科学 57, 93-97, 2008-12-19
… From the result, it is indicated that stool frequency of young Japanese women was increased by coffee drinking, possibly by caffeinated coffee. …
NAID 110006991126

Related Pictures

★リンクテーブル★

リンク元	「caffeination」「カフェイン添加」
拡張検索	「decaffeinated」

「caffeination」

Structure of a typical chemical synapse
	Postsynaptic; density Voltage-; gated Ca++; channel Synaptic; vesicle Neurotransmitter; transporter Receptor Neurotransmitter Axon terminal Synaptic cleft Dendrite

Caffeine
Systematic (IUPAC) name
	1,3,7-Trimethylpurine-2,6-dione
Clinical data
AHFS/Drugs.com	monograph
Pregnancy; category	AU: A; US: C (Risk not ruled out);
Legal status	AU: Unscheduled; CA: Unscheduled; NZ: Unscheduled; UK: Unscheduled; US: Unscheduled; UN: Unscheduled; EU: Unscheduled;
Dependence; liability	Physical: low–moderate; Psychological: trivial–low
Routes of; administration	oral, insufflation, enema, rectal, intravenous
Pharmacokinetic data
Bioavailability	99%
Protein binding	25–36%
Metabolism	Primary: CYP1A2; Minor: CYP2E1, CYP3A4, CYP2C8, CYP2C9
Metabolites	Paraxanthine (84%); Theobromine (12%); Theophylline (4%)
Onset of action	Up to 45 minutes
Biological half-life	Adults: 3–7 hours; Neonates: 65–130 hours
Excretion	urine (100%)
Identifiers
CAS Registry Number	58-08-2
ATC code	N06BC01
PubChem	CID: 2519
IUPHAR/BPS	407
DrugBank	DB00201
ChemSpider	2424
UNII	3G6A5W338E
KEGG	D00528
ChEBI	CHEBI:27732
ChEMBL	CHEMBL113
Synonyms	Guaranine; Methyltheobromine; 1,3,7-Trimethylxanthine; Theine
PDB ligand ID	CFF (PDBe, RCSB PDB)
Chemical data
Formula	C8H10N4O2
Molecular mass	194.19 g/mol
	SMILES 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 ;
Physical data
Density	1.23 g/cm3
Melting point	235 to 238 °C (455 to 460 °F) (anhydrous)
See also: data page

　　[★]

カフェイン添加

関: caffeinated

「カフェイン添加」

　　[★]

英: caffeination、caffeinated

「decaffeinated」

　　[★]

カフェイン除去した

関: decaffeination

[Nestler_caffeine_dependence-addiction-1] ^ ^a ^b ^c ^d ^e ^f Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 375. ISBN 9780071481274. Long-term caffeine use can lead to mild physical dependence. A withdrawal syndrome characterized by drowsiness, irritability, and headache typically lasts no longer than a day. True compulsive use of caffeine has not been documented.

[Clinical_addiction_.26_dependence-2] Karch SB (2009). Karch's pathology of drug abuse (4th ed.). Boca Raton: CRC Press. pp. 229–230. ISBN 9780849378812. The suggestion has also been made that a caffeine dependence syndrome exists ... In one controlled study, dependence was diagnosed in 16 of 99 individuals who were evaluated. The median daily caffeine consumption of this group was only 357 mg per day (Strain et al., 1994).
Since this observation was first published, caffeine addiction has been added as an official diagnosis in ICDM 9. This decision is disputed by many and is not supported by any convincing body of experimental evidence. ... All of these observations strongly suggest that caffeine does not act on the dopaminergic structures related to addiction, nor does it improve performance by alleviating any symptoms of withdrawal

[DSM-5_definitions_.2B_addiction-dependence_distinction_.2B_Caffeine_use_disorder-3] ^ ^a ^b ^c ^d ^e ^f American Psychiatric Association (2013). "Substance-Related and Addictive Disorders" (PDF). American Psychiatric Publishing. pp. 1–2. Retrieved 10 July 2015. Substance use disorder in DSM-5 combines the DSM-IV categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe. ... Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with “addiction” when in fact dependence can be a normal body response to a substance. ... DSM-5 will not include caffeine use disorder, although research shows that as little as two to three cups of coffee can trigger a withdrawal effect marked by tiredness or sleepiness. There is sufficient evidence to support this as a condition, however it is not yet clear to what extent it is a clinically significant disorder.

[Drugbank-Caffeine-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o "Caffeine". DrugBank. University of Alberta. 16 September 2013. Retrieved 8 August 2014.

[pmid9329065-5] Liguori A, Hughes JR, Grass JA (1997). "Absorption and subjective effects of caffeine from coffee, cola and capsules". Pharmacol. Biochem. Behav. 58 (3): 721–6. doi:10.1016/S0091-3057(97)00003-8. PMID 9329065.

[Pubchem_properties-6] "Caffeine". Pubchem Compound. NCBI. Retrieved 16 October 2014.
Boiling Point
178 deg C (sublimes)
Melting Point
238 DEG C (ANHYD)

[ChemSpider-7] "Caffeine". ChemSpider. Royal Society of Chemistry. Retrieved 16 October 2014. Experimental Melting Point:
234–236 °C Alfa Aesar
237 °C Oxford University Chemical Safety Data
238 °C LKT Labs [C0221]
237 °C Jean-Claude Bradley Open Melting Point Dataset 14937
238 °C Jean-Claude Bradley Open Melting Point Dataset 17008, 17229, 22105, 27892, 27893, 27894, 27895
235.25 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
236 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
235 °C Jean-Claude Bradley Open Melting Point Dataset 6603
234–236 °C Alfa Aesar A10431, 39214
Experimental Boiling Point:
178 °C (Sublimes) Alfa Aesar
178 °C (Sublimes) Alfa Aesar 39214

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[55] Meredith, SE; Juliano, LM; Hughes, JR; Griffiths, RR (September 2013). "Caffeine Use Disorder: A Comprehensive Review and Research Agenda.". Journal of caffeine research 3 (3): 114–130. PMID 24761279.

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[Cellular_basis-57] Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci 15 (4): 431–443. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement

[Human-caffeine_NAcc_neuroimaging-58] Miller PM (2013). "Chapter III: Types of Addiction". Principles of addiction comprehensive addictive behaviors and disorders (1st ed.). Elsevier Academic Press. p. 784. ISBN 9780123983619. Retrieved 11 July 2015. Astrid Nehlig and colleagues present evidence that in animals caffeine does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. A single photon emission computed tomography (SPECT) assessment of brain activation in humans showed that caffeine activates regions involved in the control of vigilance, anxiety, and cardiovascular regulation but did not affect areas involved in reinforcement and reward.

[Paper_cited_by_preceding_book_ref-59] Nehlig A, Armspach JP, Namer IJ (2010). "SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence". Dialogues Clin Neurosci 12 (2): 255–263. PMC 3181952. PMID 20623930. Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. ... these earlier data plus the present data reflect that caffeine at doses representing about two cups of coffee in one sitting does not activate the circuit of dependence and reward and especially not the main target area, the nucleus accumbens. [10],[11],[12] ... Therefore, caffeine appears to be different from drugs of dependence like cocaine, amphetamine, morphine, and nicotine, and does not fulfil the common criteria or the scientific definitions to be considered an addictive substance.⁴²

[60] Temple, JL (June 2009). "Caffeine use in children: what we know, what we have left to learn, and why we should worry.". Neuroscience and biobehavioral reviews 33 (6): 793–806. PMID 19428492. Through these interactions, caffeine is able to directly potentiate dopamine neurotransmission, thereby modulating the rewarding and addicting properties of nervous system stimuli.

[ICD-10_F15.2-61] "ICD-10 Version:2015". World Health Organization. 2015. Retrieved 10 July 2015.
F15 Mental and behavioural disorders due to use of other stimulants, including caffeine ...

.2 Dependence syndrome
A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.
The dependence syndrome may be present for a specific psychoactive substance (e.g. tobacco, alcohol, or diazepam), for a class of substances (e.g. opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:]
Chronic alcoholism
Dipsomania
Drug addiction

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[157] 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. Retrieved 8 January 2014.

[158] In 1819, Runge was invited to show Goethe how belladonna caused dilation of the pupil, which Runge did, using a cat as an experimental subject. Goethe was so impressed with the demonstration that: "Nachdem Goethe mir seine größte Zufriedenheit sowol über die Erzählung des durch scheinbaren schwarzen Staar Geretteten, wie auch über das andere ausgesprochen, übergab er mir noch eine Schachtel mit Kaffeebohnen, die ein Grieche ihm als etwas Vorzügliches gesandt. "Auch diese können Sie zu Ihren Untersuchungen brauchen," sagte Goethe. Er hatte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein." (After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. "You can also use these in your investigations," said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.)
This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was 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-159] Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. ISBN 978-0-415-92723-9. ^{[page needed]}

[160] 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.)

[161] Berzelius JJ (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual Report on the Progress of the Physical Sciences by Jacob Berzelius] (in German) 7. p. 270. From page 270: "Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen 1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zusammenkunft der Societé de Pharmacie in Paris die erste mündliche Mittheilung darüber gab." (However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris.)

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[168] 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.

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