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Caffeine

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For other uses, see Caffeine (disambiguation).
Caffeine
Caffeine Caffeine
General
Systematic name 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
Other names 1,3,7-trimethylxanthine
trimethylxanthine
theine
mateine
guaranine
methyltheobromine
Molecular formula C8H10N4O2
SMILES O=C1C2=C(N=CN2C)N(C(=O)N1C)C
Molar mass 194.19 g/mol
Appearance Odorless, white needles or powder
CAS number [58-08-2]
Properties
Density and phase 1.2 g/cm3, solid
Solubility in water Slightly soluble
Melting point 237 °C
Boiling point 178 °C (sublimes)
Acidity (pKa) 10.4 (40°)
Hazards
MSDS External MSDS
Main hazards May be fatal if inhaled, swallowed
or absorbed through the skin.
NFPA 704
NFPA 704
safety square
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability (yellow): no hazard codeSpecial hazards (white): no code
2
1
Flash point N/A
RTECS number EV6475000
Except where noted otherwise, data are given for
materials in their standard state (at 25 °C, 100 kPa)
Infobox disclaimer and references

Caffeine (sometimes called guaranine when found in guarana [1], mateine when found in mate [2] [3], and theine when found in tea [4]) is a xanthine alkaloid found in the leaves and beans of the coffee plant, in tea, yerba mate, guarana berries, and in small quantities in cocoa, the kola nut and the Yaupon holly. Overall, caffeine is found in the beans, leaves, and fruit of over 60 plants, where it acts as a natural pesticide that paralyzes and kills many insects feeding upon them.[5] Its name is derived from Italian caffè ("coffee") plus the alkaloid suffix -ine.

Caffeine is a central nervous system (CNS) stimulant, having the effect of warding off drowsiness and restoring alertness.[6] Beverages containing caffeine — such as coffee, tea, soft drinks and energy drinks — enjoy popularity great enough to make caffeine the world's most widely consumed psychoactive substance. In North America 90% of all adults consume caffeine daily.[7]

In nature, caffeine is found with widely varying concentrations of the other xanthine alkaloids theophylline and theobromine, which are cardiac stimulants. When caffeine appears to have different effects depending on the source, it is due primarily to varying concentrations of other stimulants and absorption rates of the mixture.

Sources

Caffeine is the most widely used psychoactive substance in the world.

Caffeine is a plant alkaloid, found in numerous plant varieties, the most commonly used of which are coffee, tea, and to some extent cocoa. Other, less commonly used, sources of caffeine include the plants yerba mate and guaraná, which are sometimes used in the preparation of teas and, more recently, energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these plants.

The world's primary source of caffeine is the coffee bean (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the variety of coffee bean and the method of preparation used, but in general one serving of coffee ranges from about 40 milligrams for a single shot (30 milliliters) of arabica variety espresso to about 100 milligrams for strong drip coffee. Generally, dark roast coffee has less caffeine than lighter roasts since the roasting process reduces caffeine content of the bean. Arabica coffee normally contains less caffeine content than the Robusta variety. Coffee also contains trace amounts of theophylline, but no theobromine.[8]

Tea is another common source of caffeine in many cultures. Tea contains somewhat less caffeine per serving than coffee, usually about half as much, depending on the strength of the brew, though certain types of tea, such as black and oolong, contain somewhat more caffeine than most other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee.

Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 milligrams to 50 milligrams of caffeine per serving. By contrast, energy drinks such as Red Bull contain as much as 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.[9]

Chocolate derived from cocoa is a weak stimulant, mostly due to its content of theobromine and theophylline, but it also contains a small amount of caffeine.[10] However, chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with coffee. A typical 28 g serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee.

Finally, caffeine may also be purchased in most areas in the form of pills that contain from 50 milligrams to 200 milligrams. Caffeine pills are regulated differently by different nations.

Caffeine equivalents

In general, each of the following contains approximately 200 milligrams of caffeine:

Caffeine content is highly unpredictable in coffee and tea drinks, especially in tea. Preparation has a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the green Japanese Gyokuro, for example, contain far more caffeine than much darker teas like Lapsang Souchong, which has very little.

History of use

Main articles: History of cocoa, History of coffee, Origin and early history of tea

Caffeine has been in use since the Stone Age. Early peoples found that chewing the seeds, bark, or leaves of many plants had the effects of easing fatigue, to stimulating awareness, and elevating the mood. Only much later was it found that by steeping such plants in hot water one could get greater effects; many cultures have legends that attribute the discovery of such plants to people living many thousands of years ago.

According to one popular Chinese legend, Shennong, the Emperor of China and inventor of agriculture and Chinese medicine, reputed to have reigned about 5,000 years ago, accidentally discovered that when some leaves fell into boiling water, a fragrant and restorative drink resulted.[12] Shennong is also mentioned in Lu Yu's Cha Jing, famous early work on the subject.[13]

The early history of coffee is involved in considerable obscurity, but a popular myth traces its discovery to Ethiopia, from where coffea arabica originates. According to this myth, a goatherder named Kaldi observed goats that became elated and sleepless at night after browsing on coffee shrubs and, upon trying the berries that the goats had been eating, experienced the same vitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th century CE physician Razi. In 1587 Mala-ye Jaziri compiled a work tracing the history and legal controversies of coffee entitled "Umdat al safwa fi hill al-qahwa", and in this work, Jaziri recorded that one Sheikh, Jamal-al-Din al-Dhabhani, mufti of Aden, was the first to adopt the use of coffee in 1454, and that in the 15th century the Sufis of Yemen routinely used coffee to stay awake during prayers.

Towards the close of the 16th century the use of coffee was recorded by a European resident in Egypt, and about this time it came into general use in the Near East. The appreciation of coffee as a beverage in Europe dates from the 17th century, during which time "coffee houses" were instituted, the first being opened in Constantinople and Venice. The first coffee houses was opened in London in St Michael's Alley, Cornhill in 1652. They soon became popular throughout Western Europe, and played a significant role in the social life of the 17th and 18th centuries.[14]

The kola nut, like coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West African cultures, individually or in a group setting, to restore vitality and ease hunger pangs. Kola was originally used to make cola soft drinks, though today most of these mass-produced beverages use artificial flavourings and caffeine obtained by the decaffeination of coffee.

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, alledging that the caffeine in its drink was "injurious to health".[15] On March 13, 1911, the government initiated "The United States vs. Forty Barrels and Twenty Kegs of Coca-Cola", hoping to force Coca-Cola to remove caffeine from its formula by making exaggerated claims, such as that the excessive use of Coca-Cola at one girl’s school led to "wild nocturnal freaks, violations of college rules and female proprieties, and even immoralities." [16] Although the judge ruled in Coca-Cola’s favor, two bills were introduced to the U.S House in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of 'habit-forming' and 'deleterious' substances which must be listed on a product's label.

The earliest evidence of cocao comes from residue found in an ancient Mayan pot dated to 2,600 years ago. In the New World, chocolate was consumed in a bitter and spicy drink called xocoatl, often seasoned with vanilla, chile pepper, and achiote. Xocoatl was believed to fight fatigue, a belief that is 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.

Chocolate was introduced to Europe by the Spaniards and became a popular beverage by 1700. They 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.

In 1819, relatively pure caffeine was isolated for the first time by the German chemist Friedrich Ferdinand Runge. According to the legend, he did this at the instigation of Johann Wolfgang von Goethe [17]

As of today, global consumption of caffeine has been estimated to be 120,000 tonnes per annum.[18] This number equates to one serving of one caffeine oriented beverage per person on the planet per day.

Effects

Caffeine has a significant effect on spiders, which is reflected in their web construction.

Caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination .[19] The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. Consumption of caffeine does not eliminate the need for sleep: it only temporarily reduces the sensation of being tired.

Caffeine is sometimes administered in combination with medicines to increase their effectiveness, such as with ergotamine in the treatment of migraine and cluster headaches, or with certain pain relievers such as aspirin or acetaminophen. Caffeine may also be used to overcome the drowsiness caused by antihistamines. Breathing problems (apnea) in premature infants are sometimes treated with citrated caffeine, which is available only by prescription in many countries.[20]

While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on spiders, for example, than most other drugs do.[21]

Overuse

Caffeine is a drug that in large amounts, especially over an extended period of time, can lead to a condition termed "caffeinism". Caffeinism usually combines physical addiction with a wide range of physical and mental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, heart palpitations and hyperreflexia. [22] Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease.[23] However, since both "regular" and decaffeinated coffees have also been shown to stimulate the gastric mucosa and increase stomach acid secretion, caffeine is probably not the only component of coffee responsible.[24]

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, defines four caffeine-induced psychiatric disorders: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS)."

Caffeine intoxication

An acute overdose of caffeine, usually in excess of 250 milligrams (more than 2-3 cups of brewed coffee), can result in a state of central nervous system overstimulation called caffeine intoxication. The symptoms of caffeine intoxication may include restlessness, nervousness, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irregular or rapid heart beat, and psychomotor agitation. Cite error: A <ref> tag is missing the closing </ref> (see the help page). [25]

In cases of extreme overdose, death can result. The LD50 of caffeine is 192 mg/kg in rats.[26] The LD50 of caffeine is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kg of body mass, roughly 140 to 180 cups of coffee for an average adult taken within a limited timeframe that is dependent on half-life. Though achieving lethal dose with coffee would be exceptionally difficult with regular coffee, there have been many reported deaths from intentional overdosing on caffeine pills.[27] [28] [29] [30]

Treatment of severe caffeine intoxication is may simply be supportive treament of the immediate symptoms [31] [32], but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemoperfusion may be required.[33]

Anxiety and sleep disorders

Long-term overuse of caffeine can elicit a number of psychiatric disturbances. Two such disorders recognised by the APA are caffeine-induced sleep disorder and caffeine-induced anxiety disorder.

In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. [34]

In some individuals, the large amounts of caffeine can induce anxiety severe enough to necessitate clinical attention. This caffeine-induced anxiety disorder can take many forms, from generalized anxiety, to panic attacks, obsessive-compulsive symptoms, or even phobic symptoms. [34] Because this condition can mimic organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, or even schizophrenia, a growing number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced psychosis would simply be to withhold further caffeine.[35] A Study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten in the general population.[36]

Metabolism

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

Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion, It is widely distributed in total body water and is eliminated by apparent first-order kinetics.

The half-life of caffeine — the time required for the body to eliminate one-half of the total amount of caffeine consumed — varies widely among individuals according to such factors as age, liver diseases, pregnancy, some medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is about 3-4 hours. In woman taking oral contraceptives this is increased to around 13 hours, and in pregnant women the half-life is 18-20 hours. Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours.[37] In infants and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30 hours. Other factors, such as smoking can shorten caffeine's half-life.[38]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines, [39] which each have their own effects on the body:

Each of these metabolites is further metabolised and then excreted in the urine.

Mechanism of action

Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain. They are presented here side by side for comparison.

The principal mode of action of caffeine [40] is as an antagonist of adenosine receptors in the brain. The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (a "false transmitter" method of antagonism). The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also increase levels of epinephrine [41], possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood.

The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to constrict preferentially the afferent arterioles of the glomerulus, its inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine or adrenaline and norepinephrine released via the hypothalamic-pituitary-adrenal axis[42] Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs and a release of glucose by the liver.

Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in the messaging cascade produced by cells in response to stimulation by epinephrine, so by blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate.

The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, 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.[43]

With these effects, caffeine is an ergogenic: increasing the capacity for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who consumed caffeine compared to control tests.[44] Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight.[45] The extensive boost shown in the runners is not an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.[46]

Tolerance and withdrawal

Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary results. [47] First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation.

Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users. [47]

Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks at home or at work; in extreme cases it may cause mild depression.

Withdrawal symptoms may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually lasts from one to five days; this amount of time is largely explained by the long time it takes for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.[48] Most effective is a combination of both an analgesic and a small amount of caffeine; caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief.[49] For this reason, many over the counter headache drugs include caffeine in their formula.

Currently caffeine withdrawal is recognized as meriting further study by the DSM-IV, although recent research demonstrating its clinical significance means that it will likely be included as an Axis-1 disorder in the DSM-V [50]

Extraction of pure caffeine

Anhydrous (dry) USP grade Caffeine

It is very difficult to know the exact amount of caffeine in a particular drink that is not automatically prepared. The amount of caffeine in a single serving of coffee varies considerably due to many variables. Concentration can vary from bean to bean within a given bush; preparation of the raw bean will affect concentration, as well as multiple variables involved in brewing.

Caffeine extraction 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 flavour, they have been superseded by two main methods:

Water extraction

Coffee beans are soaked in water. The water—which contains not only caffeine but also many other compounds which contribute to the flavour 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 a good flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and medicines.

Supercritical carbon dioxide extraction

Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds) but is safer than the organic solvents that are used for caffeine extraction. 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 which allow it to penetrate deep into the beans but also liquid-like properties which 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.

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  46. ^ Trice, I (Mar 1995). "Effects of caffeine ingestion on exercise-induced changes during high-intensity, intermittent exercise". Int J Sport Nutr. 5 (1): 37–44. PMID 7749424. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  47. ^ a b Green, RM (Jan 1986). "Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex". J Clin Invest. 77 (1): 222–227. PMID 3003150. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  48. ^ Sawynok, J (Jan 1995). "Pharmacological rationale for the clinical use of caffeine". Drugs. 49 (1): 37–50. PMID 7705215. {{cite journal}}: |access-date= requires |url= (help)
  49. ^ "Headache Triggers: Caffeine". WebMD. June 2004. Retrieved 2006-08-14.
  50. ^ Kirchheimer, Sid (Sept. 30, 2004). "Caffeine Withdrawal Is Real". CBS News. Retrieved 2006-08-14. {{cite news}}: Check date values in: |date= (help)
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