Caffeine

Caffeine
Caffeine
General
IUPAC nomenclature	3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-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
Hazards
MSDS	External MSDS
Main hazards	May be fatal if inhaled, swallowed or absorbed through the skin.
NFPA 704	1 2 0
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 is a chemical compound that was first made naturally only by certain plants. At present, there are 63 different types of plants known to contain caffeine, which include those plants from which we make coffee,tea and cocoa. Historically the most popular source of caffeine in the human diet has been from coffee and tea. Today, beverages containing added caffeine — such as colas and energy drinks — enjoy popularity great enough to make caffeine the world's most popular psychoactive drug.

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.

Caffeine is classified as a methylxanthine alkaloid. In its pure form it is a white powder that is odorless with a slightly bitter taste.

In nature, caffeine is found in widely varying concentrations with other xanthine alkaloids such as theophylline and theobromine, which are also cardiac stimulants.

Sources of caffeine

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

The world's primary source of caffeine is the coffee bean (the seed of the coffee plant), from which coffee is brewed. More than 80 species of the genus Coffea are known. Caffeine content in coffee varies widely depending on the variety of coffee bean and the method of preparation used, but in general, one 8 oz. serving of coffee has about 100 mg of caffeine. Dark roast coffee has less caffeine than lighter roasts, since the roasting process reduces the caffeine content of the bean. Arabica coffee beans average 24 mg/g of caffeine wheras the Robusta variety averages 13 mg/g (Casal et al. 2000).

Tea is another common source of caffeine ,produced by brewing leaves of the tea plant. There are hundreds of varieties of this single species of tea,Camellia sinensis. The amount of oxidation that each variety undergoes determines whether it is classed as white,green,oolong or black,where white has the least amount of oxidation of the leaf and black tea has the most. More oxidation results in higher levels of caffeine. In black tea caffeine was found to be 25 mg/g of tea leaf whereas in green tea the caffeine level was 15 mg/g of leaf (Khokhar et al.2002).

Guarana beverages are made from seeds of the plant Paullinia cupana that have been roasted, ground to a paste and dissolved in water. This paste is also used to make medicines or flavor foods. The guarana seeds contain larger amounts of caffeine than do coffee beans, with reported levels as high as 80 mg per gram of seed.

One of the most delicious sources of caffeine is chocolate. This is obtained from the cacao plant, Theobroma cacao. This plant produces seeds which are the source of cocoa, chocolate and cocoa butter. Cacao seeds have only a small amount of caffeine ,with 2.5 mg/gram. A typical serving of a milk chocolate bar (28g) has about 20 mg of caffeine.

Cola (kola) nuts are a natural source of caffeine that were once used as the sole source of caffeine in the first Coca-Cola beverages. There are about 40 species of the cola plant,with Cola nitida,and C.acuminata being the most common commercial species. Cola nuts contain up to 25 mg of caffeine per gram.

Yerba mate' (Ilex paraguensis )is a tree which grows in South America and its leaves are used to make a caffeine-containing tea. The flavor and aroma of the leaves of the wild trees is said to be much better than the cultivated ones. The level of caffeine in the leaves is less than 20 mg per gram of leaves.

Purified caffeine is now a common additive of many soft drinks. Some sports or energy drinks have very high levels. Red Bull has about 100 mg of caffeine per serving. Soft drinks like Coca-Cola contain 23 mg per 8oz ,and Pepsi One contains 36 mg per 8oz. The U.S. Food and Drug Administration (F.D.A.) allows caffeine to be added to cola-type beverages up to 0.02 % and it must appear on the label as an ingredient. The European Union requires that a warning be placed on the packaging of any food whose caffeine content exceeds 150 mg per litre.

History of caffeine use

Coffee beans are indigenous to the land of Ethiopia, and by the fourth century AD, were introduced into Arabia and the rest of the East.In the 15th century the Sufis of Yemen used coffee to stay awake during prayers. In the 16th century there were coffee houses in Istanbul, Cairo and Mecca, and in the mid-17th century coffee houses opened in Europe.

Tea has been consumed in China for thousands of years, where it has been purported to have been discovered by the Chinese Emperor Shen Nung in 2737 B.C.E. Traditional stories tell that monks drank tea to stay awake during meditation practice.

Guarana and yerba mate' are plants indigenous to South America and it is presumed that the use of both of these plants by ancient peoples such as the Guarani tribesmen,from whom the guarana plant was named, started before any recorded history of this area.

Cola nuts are indigenous to West Africa and have been chewed by local people possibly for thousands of years. It has been traded to other countries as a valuable commodity since probably before the 14th century ; and it has been used as a stimulant by Islamic people who use it to replace alcohol, which is forbidden.

In 1519, Hernando Cortes entered Mexico and reported that cocoa was being consumed in large quantities by the Aztec leader Montezuma. Here again, it is probable that the cacao plant has been consumed by the native people of Mexico for more than one thousand years.

Preparation of Pure Caffeine

In 1821, relatively pure caffeine was isolated for the first time by the German chemist Friedlieb Ferdinand Runge. According to legend, he did this at the instigation of Johann Wolfgang von Goethe (Weinberg & Bealer 2001). He called this substance "kafein" , which means ,something found in coffee. Caffeine was not synthesized until 61 years later - in 1882, by the brilliant German chemist,Emil Fischer .(Merck Index 2001)

Purified caffeine powder can be synthesized from a variety of starting materials, such as urea,xanthine,theophylline and theobromine. The high demand for decaffeinated products and the ease of purification of caffeine from the decaffeination liquid ,makes synthesis more expensive than purification.

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 and carbon dioxide.

In the water method,green coffee beans are soaked in water. The water extract,which contains not only caffeine but also many flavor compounds ,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 is an excellent nonpolar solvent for caffeine and is safer than the organic solvents that have been 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 atmospheres. Under these conditions, CO₂ is said to be 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 activated carbon or by other standard methods.

Caffeine's toxicity to humans

There has been extensive research on caffeine and this drug’s effect on the health of human beings . The Food and Drug Administration (F.D.A.) concluded in 1958 that caffeine is recognized as safe for consumption. A recent review claims to have found no signs or evidence that caffeine’s use in carbonated beverages would produce unhealthy effects on the consumer.

The American Medical Association (AMA) also views caffeine as being safe for consumption. They state that moderate coffee and tea drinkers probably don’t need to have concern for their health in regards to caffeine consumption.

The minimum amount of caffeine needed to cause death to human beings is estimated to be 150-200 mg/kg of body weight . Symptoms of acute toxicity,including nausea,vomiting,diarrhea,cramps and possibly seizures (Sauer 1994), may be observed after taking sublethal doses of caffeine. There have been many reported deaths from intentional overdosing on caffeine pills. Periodically, caffeine pills come under media fire in connection with the death of a college student due to a overdose of caffeine. One example is the death of a twenty-year old North Carolina student, Jason Warren Allen, who swallowed almost 90 pills on a dare ,equivalent to about 250 cups of coffee. A few other deaths by caffeine overdose have been known, almost always in the case of excessive pill consumption.

Too much caffeine, especially over an extended period of time, can lead to a number of physical and mental conditions. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) states: "The four caffeine-induced psychiatric disorders include caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS)."

An overdose of caffeine can result in a state termed caffeine intoxication or caffeine poisoning. Its symptoms are both physiological and psychological. Symptoms of caffeine intoxication include: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, muscle twitching, rambling , cardiac arrhythmia or tachycardia, and psychomotor agitation, gastrointestinal complaints, increased blood pressure, rapid pulse, vasoconstriction (tightening or constricting of superficial blood vessels) sometimes resulting in cold hands or fingers, increased amounts of fatty acids in the blood, and an increased production of gastric acid. In extreme cases mania, depression, lapses in judgment, disorientation, loss of social inhibition, delusions, hallucinations and psychosis may occur.

It is commonly assumed that only a small proportion of people exposed to caffeine develop symptoms of caffeine intoxication. However, because it mimics organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia, a growing number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated. Shannon et al. (1998) point out that:

"Caffeine-induced psychosis, whether it be delirium, manic depression, schizophrenia, or merely an anxiety syndrome, in most cases will be hard to differentiate from other organic or non-organic psychoses....The treatment for caffeine-induced psychosis is to withhold further caffeine." A study in the British Journal of Addiction declared that "although infrequently diagnosed, caffeinism is thought to afflict as many as one person in ten of the population" ( James and Stirling 1983).

Because caffeine increases the production of stomach acid and tends to relax the gastro-esophageal sphincter (Drug Facts and Comparisons 2001),which controls the passage of materials between the stomach and esophagus, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease. Furthermore, it can also lead to nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, heart palpitations and hyperreflexia.

It is suggested that "slow metabolizers" who carry a variant of polymorphic cytochrome P450 1A2 (CYP1A2) enzyme have an increased risk of nonfatal myocardial infarction .

Effects of caffeine

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

Caffeine is a central nervous system stimulant, and is used both recreationally and medically to restore mental alertness when unusual weakness or drowsiness occurs. Doses of 100-200 mg result in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination. It also results in restlessness, a loss of fine motor control, headaches, and dizziness. It is important to note, however, that caffeine cannot replace sleep, and should be used only occasionally as an alertness aid.

Thus caffeine causes an increase in blood flow to the kidneys and an increase in the production of urine. It also decreases the tubular reabsorption of sodium and water ,resulting in a more dilute urine. In the brain, caffeine causes blood vessels to constrict,but among the peripheral blood vessels caffeine causes dilation. Caffeine causes a brief increase in heart rate , cardiac output and the force of contraction. At doses greater than 250 mg it may cause extra beats, rapid heart rate (tachycardia) and/or major ventricular arrhythmias (Drug Facts Comparisons 2001).

Caffeine stimulates skeletal muscle by increasing the strength of contraction and decreasing fatigue.

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.

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.

Caffeine metabolism

Caffeine is easily absorbed when taken orally,with 99% absorption occurring within 15-120 minutes. A dose of 250 mg produced a peak plasma level of 5-25 micrograms per ml. In order for caffeine to be effective it must reach plasma levels of 6-13 micrograms/ml (Drug Facts and Comparisons 2001). After ingestion, caffeine has a physiological half-life in adults of three to seven hours, with much longer values in neonates and pregnant women. It is rapidly distributed to all body compartments,including the placenta and blood-brain barrier. Small amounts will also enter breast milk.

Continued consumption of caffeine can lead to drug tolerance. Upon withdrawal, the body becomes oversensitive to adenosine, causing the blood pressure to drop dramatically, which leads to headaches and other symptoms.

Caffeine is metabolized in the liver,through demethylation and oxidation, by a cytochrome P450 enzyme system known as 1A2 or CYP1A2. In the first stage it forms three dimethylxanthines:

• 1,7-dimethylxanthine at 80-84%
• 3,7-dimethylxanthine (theobromine)at 10-12%
• 1,3-dimethylxanthine (theophylline)at 4%

Each of these metabolites is further metabolised and then excreted in the urine,primarily as methylated urates and methylated xanthines. About 1 % of caffeine enters the urine unchanged.

Mechanism of action

It is believed that the main action of caffeine is to block adenosine receptors (A₁ and A_2a) on the surfaces of cells. Adenosine is composed of adenine plus ribose,a five carbon sugar. Since the caffeine molecule is structurally similar to adenine it is able to bind to adenosine receptors without activating them and thus prevent their activation by adenosine. Adenosine is a neuromodulator and modifies the release of neurotransmitters in nerve cells. When caffeine blocks adenosine receptors ,the cells act as if the receptor is empty.

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 (adrenaline) and norepinephrine released via the hypothalamic-pituitary-adrenal axis Epinephrine, the natural endocrine system 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.

It has been reported that caffeine acts as a competitive inhibitor of the enzyme cyclic AMP-phosphodiesterase. However, the levels of caffeine in blood required to produce an increase in blood pressure are well below those required for inhibition of cyclic AMP-phosphodiesterase (Chawla et al. 2006). Therefore inhibition of this enzyme can not explain caffeine's therapeutic effects.

The metabolites of caffeine may contribute to caffeine's effects. Theobromine dilates the blood vessels which increases the flow of blood and thus leads to an increase in 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 the bronchioles and also acts to increase heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for the breakdown of triglycerides which results in an increase in the release of glycerol and fatty acids into the blood to be used as a source of fuel by the muscles (Dews et al. 1984).

With these effects, caffeine is increases 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 (Ivy et al. 1979). 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 (Graham & Spriet 1991). 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 (Trice & Hayes 1995).

Withdrawal

Individuals who consume caffeine regularly develop a reduction in sensitivity to caffeine; when such individuals reduce their caffeine intake, their body becomes oversensitive to adenosine, with the result that blood pressure drops dramatically, leading to an excess of blood in the head (though not necessarily on the brain), causing a headache. Other symptoms may include nausea, fatigue, drowsiness, anxiety and irritability; in extreme cases symptoms may include depression, inability to concentrate and diminished motivation to initiate or to complete daily tasks at home or at work.

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. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.

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

Effects on fetuses and newborn children

There is some evidence that caffeine may be dangerous for fetuses and newborn children. In a 1985 study conducted by scientists of Carleton University, children born by mothers who had consumed more than 300 mg per day of caffeine were found to have, on the average, lower birth weight and head circumference than the children of mothers who had consumed little or no caffeine. In addition, use of large amounts of caffeine by the mother during pregnancy may cause problems with the heart rhythm of the fetus. For these reasons, some doctors recommend that women largely discontinue caffeine consumption during pregnancy and possibly also after birth until the newborn child is weaned.

The negative effects of caffeine on the developing fetus can be attributed to the ability of caffeine to inhibit two DNA damage response proteins known as Ataxia-Telangiectasia Mutated (ATM) or ATM-Rad50 Related (ATR). These proteins control much of the cells' ability to stop the cell cycle in the presence of DNA damage, such as DNA single/double strand breaks and nucleotide dimerization. DNA damage can occur relatively frequently in actively dividing cells, such as those in the developing fetus. Caffeine is used in laboratory setting as an inhibitor to these proteins and it has been shown in a study ( Lawson et al. 2004) that women who use caffeine during pregnancy have a higher likelihood of miscarriage than those who do not. Since the dosage rate of self-administration is difficult to control and the effects of caffeine on the fetus are related to random occurrence (DNA damage), a minimal toxic dose to the fetus has yet to be established.

Global consumption of caffeine is estimated to be 76 mg per person per day. In the U.S.A. the average is 238 mg per person per day .

References

ISBN links support NWE through referral fees

• Casal,S.,Oliveira,M.B.P.P.,Alves,M.R.,and Ferreira,M.A. 2000. Discriminate analysis of roasted coffee varieties for trigonelline,nicotinic acid and caffeine content.Journal of Agricultural and Food Chemistry48:3420-3424
• Chawla,J.,Suleman,A.,Lorenzo,N. 2006. Neurologic effects of caffeine.(http://www.emedicine.com/neuro/topic666.htm)
• Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction JAMA. 2006 Mar 8;295(10):1135-41 PMID 16522833
• Dews, P.B. (1984). "Caffeine: Perspectives from Recent Research". Berlin: Springer-Valerag.
• Drug Facts and Comparisons, 2001. ISBN :1-57439-073-2
• Hughes JR, McHugh P, Holtzman S. "Caffeine and schizophrenia." Psychiatr Serv 1998;49:1415-7. Fulltext. PMID 9826240.
• Ivy, J., Costill, D., Fink, W. et al. (1979). "Influence of caffeine and carbohydrate feedings on endurance performance". Medical Science Sports Journal (Vol. 11). 6-11.
• James,J.E. and Stirling,K.P., "Caffeine: A Summary of Some of the Known and Suspected Deleterious Habits of Habitual Use," British Journal of Addiction, 1983;78:251-58.

• Khokhar,S. and Magnusdottir,S.G.M. 2002. Total phenol,catechin,and caffeine contents of teas commonly consumed in the United Kingdom.Journal of Agricultural and Food Chemistry50:565-570.

• Sauer,A.H.1994. Caffeine.Clinical Toxicology Review 17(2).
• Shannon MW, Haddad LM, Winchester JF. Clinical Management of Poisoning and Drug Overdose, 3rd ed.. 1998. ISBN 0721664091.
• Diagnostic and Statistical Manual of Mental Disorders ISBN 0890420610
• Tarnopolsky, M. A. (1994). "Caffeine and endurance performances". Sports Medicine (Vol. 18 Ed. 2): 109 – 125.

• Trice, I., and Haymes, E. (1995). "Effects of caffeine ingestion on exercise-induced changes during high intensity, intermittent exercise". International Journal of Sports Nutrition. 37-44.

• Weinberg BA, Bealer BK. The world of caffeine. New York & London: Routledge, 2001. ISBN 0-415-92722-6.

External links

• Merck Index,13th edition,2001.NY :Merck and Co.,Inc.US National Library of Medicine: MedlinePlus® Drug Information: Caffeine

Caffeine Chemistry

• Is Caffeine a Health Hazard?
• The Caffeine FAQ
• The Physician and Sportsmedicine (Vol 25 - No. 11 - November 97) Caffeine: A User's Guide
• Center for Science in the Public Interest (CSPI) article Caffeine: The Inside Scoop
• CSPI article Caffeine Content of Foods
• Images of webs spun by spiders after eating flies laced with LSD, mescaline, hashish and caffeine
• The Caffeine Database
• Mass Spectrometry - Caffeine Effects
• Caffeine: Psychological Effects, Use & Abuse
• Caffeine: How Stuff Works
• Caffeine 3D view and pdb-file
• Erowid Vaults

Caffeine toxicity

• Johns Hopkins University Caffeine Dependence Study
• eMedicine Caffeine-Related Psychiatric Disorders
• The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
• L Tondo and N Rudas, "The course of a seasonal bipolar disorder influenced by caffeine," Journal of Affective Disorders, 1991;22 (4):249-251 Abstract
• DC Mackay and JW Rollins, "Caffeine and caffeinism," Journal of the Royal Naval Medical Service, 1989;75(2):65-7. Abstract
• K Gilliland and D Andress, "Ad lib caffeine consumption, symptoms of caffeinism, and academic performance," American Journal of Psychiatry, 1981; 138:512-514 Abstract
• American Psychiatric Association, 158th annual meeting. Abstract #NR45. "First Graders' Behavior Problems Linked to Caffeinated Cola." Fulltext
• Whalen R, "Caffeine-Induced Anaphylaxis, A Progressive Toxic Dementia" Fulltext
• JA Sours, "Case reports of anorexia nervosa and caffeinism," American Journal of Psychiatry, 1983; 140:235-236 Abstract

Stimulants (N06 and others) -
Caffeine | Nicotine | Modafinil/Armodafinil | Adrafinil | Fenethylline
Sympathomimetic amines (R01, A08, and others) - 4-methylaminorex | Benzylpiperazine | Cathinone | Chlorphentermine | Cocaine | CFT | Diethylpropion | Ephedrine | Fenfluramine | Mazindol | Methylone | Methylphenidate | Pemoline | Phendimetrazine | Phenmetrazine | Phentermine | Phenylephrine | Propylhexedrine | Pseudoephedrine | Sibutramine | Synephrine See also amphetamines

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