Caffeine - wikipedia Caffeine This article is about the stimulant drug. For other uses, see Caffeine ( disambiguation ). Caffeine Clinical data Pronunciation / kæˈfiːn, ˈkæfiːn / Synonyms Guaranine Methyltheobromine 1, 3, 7 - Trimethylxanthine Theine AHFS / Drugs.com Monograph Pregnancy category AU : A US : C ( Risk not ruled out ) Dependence liability Physical : low -- moderate Psychological : low Addiction liability Low / None Routes of administration By mouth, insufflation, enema, rectal, intravenous Drug class Stimulant ATC code N06BC01 ( WHO ) Legal status Legal status In general : unscheduled 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 ~ 1 hour Biological half - life Adults : 3 -- 7 hours Infants : 65 -- 130 hours Duration of action 3 -- 4 hours Excretion Urine ( 100 % ) Identifiers IUPAC name 1, 3, 7 - Trimethylpurine - 2, 6 - dione CAS Number 58 - 08 - 2 PubChem CID 2519 IUPHAR / BPS 407 DrugBank DB00201 ChemSpider 2424 UNII 3G6A5W338E KEGG D00528 ChEBI CHEBI : 27732 ChEMBL CHEMBL113 PDB ligand CFF ( PDBe, RCSB PDB ) ECHA InfoCard 100.000. 329 Chemical and physical data Formula Molar mass 194.19 g / mol 3D model ( JSmol ) Interactive image Density 1.23 g / cm Melting point 235 to 238 ° C ( 455 to 460 ° F ) ( anhydrous ) 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 See also : data page Caffeine is a central nervous system ( CNS ) stimulant of the methylxanthine class. It is the world 's most widely consumed psychoactive drug. Unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. There are several known mechanisms of action to explain the effects of caffeine. The most prominent is that it reversibly blocks the action of adenosine on its receptor and consequently prevents the onset of drowsiness induced by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system. Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guanine bases of 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 and helps to protect them against predator insects and to prevent germination of nearby seeds. The most well known source of caffeine is the coffee bean, a misnomer for the seed of Coffea plants. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to improve performance. To make these drinks, caffeine is extracted by steeping the plant product in water, a process called infusion. Caffeine - containing drinks, such as coffee, tea, and cola, are very popular ; as of 2014, 85 % of American adults consumed some form of caffeine daily, consuming 164 mg on average. Caffeine can have both positive and negative health effects. It can treat and prevent the premature infant breathing disorders bronchopulmonary dysplasia of prematurity and apnea of prematurity. Caffeine citrate is on the WHO Model List of Essential Medicines. It may confer a modest protective effect against some diseases, including Parkinson 's disease. 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. Caffeine 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. 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 ). Caffeine is classified by the US 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 doses 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 available as a dietary supplement, can be lethal in tablespoon - sized amounts. Contents 1 Use 1.1 Medical 1.2 Enhancing performance 1.2. 1 Cognitive 1.2. 2 Physical 1.3 Specific populations 1.3. 1 Adults 1.3. 2 Children 1.3. 3 Adolescents 1.3. 4 Pregnancy and breastfeeding 2 Side effects 2.1 Physical 2.2 Psychological 2.3 Reinforcement disorders 2.3. 1 Addiction 2.3. 2 Dependence and withdrawal 2.4 Risk of other diseases 3 Overdose 4 Interactions 4.1 Alcohol 4.2 Tobacco 4.3 Birth control 4.4 Medications 5 Pharmacology 5.1 Pharmacodynamics 5.1. 1 Receptor and ion channel targets 5.1. 1.1 Effects on striatal dopamine 5.1. 2 Enzyme targets 5.1. 3 Off - target effects 5.2 Pharmacokinetics 6 Chemistry 6.1 Synthesis 6.2 Decaffeination 6.3 Detection in body fluids 6.4 Analogs 6.5 Precipitation of tannins 7 Natural occurrence 8 Products 8.1 Beverages 8.1. 1 Coffee 8.1. 2 Tea 8.1. 3 Soft drinks and energy drinks 8.1. 4 Other beverages 8.2 Chocolate 8.3 Tablets 8.4 Other oral products 8.5 Inhalants 8.6 Combinations with other drugs 9 History 9.1 Discovery and spread of use 9.2 Chemical identification, isolation, and synthesis 9.3 Historic regulations 10 Society and culture 10.1 Regulations 10.2 Consumption 10.3 Religions 11 Other organisms 12 Research 13 See also 14 References 15 Bibliography 16 External links Use Medical Caffeine is used in : Bronchopulmonary dysplasia in premature infants for both prevention and treatment. It may improve weight gain during therapy and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay. On the other hand, subtle long - term side effects are possible. Apnea of prematurity as a primary treatment, but not prevention. Orthostatic hypotension treatment. Enhancing performance Cognitive Caffeine is a central nervous system stimulant that reduces fatigue and drowsiness. At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination. The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance. The desired effects arise approximately one hour after consumption, and the desired effects of a moderate dose usually subside after about three or four hours. Caffeine can delay or prevent sleep, and improves task performance during sleep deprivation. Shift workers who use caffeine make fewer mistakes due to drowsiness. A systematic review and meta - analysis from 2014 found that concurrent caffeine and L - theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching ; these effects are most pronounced during the first hour post-dose. Physical Caffeine is a proven ergogenic aid in humans. Caffeine improves athletic performance in aerobic ( especially endurance sports ) and anaerobic conditions. Moderate doses of caffeine ( around 5 mg / kg ) can improve sprint performance, cycling and running time trial performance, endurance ( i.e., it delays the onset of muscle fatigue and central fatigue ), and cycling power output. Specific populations Adults For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg. Children In healthy children, caffeine intake produces effects that are `` modest and typically innocuous ''. There is no evidence that coffee stunts a child 's growth. For children age 12 and under, Health Canada recommends a maximum daily caffeine intake of no more than 2.5 milligrams per kilogram of body weight. Based on average body weights of children, this translates to the following age - based intake limits : Age range Maximum recommended daily caffeine intake 4 -- 6 45 mg ( slightly more than in 12 oz of a typical soft drink ) 7 -- 9 62.5 mg 10 -- 12 85 mg ( about 1⁄2 cup of coffee ) Adolescents Health Canada has not developed advice for adolescents because of insufficient data. However, they suggest that daily caffeine intake for this age group be no more than 2.5 mg / kg body weight. This is because the maximum adult caffeine dose may not be appropriate for light weight adolescents or for younger adolescents who are still growing. The daily dose of 2.5 mg / kg body weight would not cause adverse health effects in the majority of adolescent caffeine consumers. This is a conservative suggestion since older and heavier weight adolescents may be able to consume adult doses of caffeine without suffering adverse effects. Pregnancy and breastfeeding The UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day -- the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee. The American Congress of Obstetricians and Gynecologists ( ACOG ) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. For women who breastfeed, are pregnant, or may become pregnant, Health Canada recommends a maximum daily caffeine intake of no more than 300 mg, or a little over two 8 oz ( 237 mL ) cups of coffee. The evidence for or against the importance of limiting caffeine intake during pregnancy is insufficient and of low quality. There are conflicting reports in the scientific literature about caffeine consumption during pregnancy. A 2011 risk analysis review found that 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. 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 ). There is some evidence that higher caffeine intake by pregnant women may be associated with a higher risk of giving birth to a low birth weight baby, and may be associated with a higher risk of pregnancy loss. A systematic review, analyzing the results of observational studies, suggests that women who consume large amounts of caffeine ( greater than 300 mg / day ) prior to becoming pregnant may have a higher risk of experiencing pregnancy loss. Side effects Physical Caffeine can increase blood pressure and cause vasoconstriction. Coffee and caffeine can affect gastrointestinal motility and gastric acid secretion. Caffeine in low doses may cause weak bronchodilation for up to four hours in asthmatics. Caffeine increases basal metabolic rate in adults. In postmenopausal women, high caffeine consumption can accelerate bone loss. Doses of caffeine equivalent to the amount normally found in standard servings of tea, coffee and carbonated soft drinks appear to have no diuretic action. However, acute ingestion of caffeine in large doses ( at least 250 -- 300 mg, equivalent to the amount found in 2 -- 3 cups of coffee or 5 -- 8 cups of tea ) results in a short - term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks. This increase is due to both a diuresis ( increase in water excretion ) and a natriuresis ( increase in saline excretion ) ; it is mediated via proximal tubular adenosine receptor blockade. The acute increase in urinary output may increase the risk of dehydration. However, chronic users of caffeine develop a tolerance to this effect, and experience no increase in urinary output. Psychological Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common, and include mild anxiety, jitteriness, insomnia, increased sleep latency, and reduced coordination. Caffeine can have negative effects on anxiety disorders. According to a 2011 literature review, caffeine use is positively associated with anxiety and panic disorders. At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety. For some people, discontinuing caffeine use can significantly reduce anxiety. In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk. Some textbooks state that caffeine is a mild euphoriant, others state that it is not a euphoriant, and one states that it is and is not a euphoriant. 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. Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects. Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, with people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA research monograph. Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction. Other research states it can affect the reward system. `` 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. The American Psychiatric Association 's DSM - 5 does not include the diagnosis of a caffeine addiction but proposes criteria for the disorder for more study. Dependence and withdrawal Main article : Caffeine dependence Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. The frequency at which this occurs is self reported at 11 %, but in lab tests only half of the people who report withdrawal actually experience it, casting doubt on many claims of dependence. Mild to increasingly severe physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day ; some symptoms associated with psychological dependence may also occur during withdrawal. Caffeine dependence can involve withdrawal symptoms such as fatigue, headache, irritability, depressed mood, reduced contentedness, inability to concentrate, sleepiness or drowsiness, stomach pain, and joint pain. Withdrawal headaches are experienced by roughly half of those who stop consuming caffeine for two days following an average daily intake of 235 mg. The ICD - 10 includes a diagnostic model for caffeine dependence, but the DSM - 5 does not. 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. The DSM - 5 instead lists `` caffeine use disorder '' in the emerging models section of the manual. Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine ( 750 to 1200 mg / day spread throughout the day ) have been shown to produce complete tolerance to some, but not all of the effects of caffeine. Doses as low as 100 mg / day, such as a 6 oz cup of coffee or two to three 12 oz servings of caffeinated soft - drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption. Some coffee drinkers develop tolerance to its undesired sleep - disrupting effects, but others apparently do not. Risk of other diseases See also : Coffee § Health and pharmacology A protective effect of caffeine against Alzheimer 's disease is possible, but the evidence is inconclusive. Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals. It may protect people from liver cirrhosis. Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude. Overdose Primary symptoms of caffeine intoxication Consumption of 1 -- 1.5 grams per day is associated with a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use. Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication ( DSM - IV 305.90 ). This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets ( e.g., more than 400 -- 500 mg at a time ). The symptoms of caffeine intoxication are comparable to the symptoms of overdoses of other stimulants : they may include restlessness, fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, or psychosis may occur, and rhabdomyolysis ( breakdown of skeletal muscle tissue ) can be provoked. Massive overdose can result in death. The LD 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 ). 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. The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease A death was reported in a man with liver cirrhosis who overdosed on caffeinated mints. Treatment of mild caffeine intoxication is directed toward symptom relief ; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration. Interactions Alcohol See also : Caffeinated alcoholic energy drink According to DSST, alcohol provides a reduction in performance and caffeine has a significant improvement in performance. When alcohol and caffeine are consumed jointly, the effects produced by caffeine are affected, but the alcohol effects remain the same. For example, when additional caffeine is added, the drug effect produced by alcohol is not reduced. However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed. Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control. Tobacco Smoking tobacco increases caffeine clearance by 56 %. Birth control Birth control pills can extend the half - life of caffeine, requiring greater attention to caffeine consumption. Medications Caffeine sometimes increases the effectiveness of some medications, such as those for headaches. Pharmacology Pharmacodynamics Structure of a typical chemical synapse Postsynaptic density Voltage - gated Ca channel Synaptic vesicle Neurotransmitter transporter Receptor Neurotransmitter Axon terminal Synaptic cleft Dendrite 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. Receptor and ion channel targets Caffeine is an antagonist at all four adenosine receptor subtypes ( A, A, A, and A ), although with varying potencies. The affinity ( K ) values of caffeine for the human adenosine receptors are 12 μM at A, 2.4 μM at A, 13 μM at A, and 80 μM at A. Knockout mouse studies have specifically implicated antagonism of the A receptor as responsible for the wakefulness - promoting effects of caffeine. Antagonism of adenosine receptors by caffeine stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heart rate, and constricts blood vessels. Adenosine receptor antagonism also promotes neurotransmitter release ( e.g., monoamines and acetylcholine ), which endows caffeine with its stimulant effects ; adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the A receptor. 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 antagonist. In addition to its activity at adenosine receptors, caffeine is an inositol trisphosphate receptor 1 antagonist and a voltage - independent activator of the ryanodine receptors ( RYR1, RYR2, and RYR3 ). It is also a competitive antagonist of the ionotropic glycine receptor. Effects on striatal dopamine While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A -- D receptor heterodimer ( this is a receptor complex with 1 adenosine A receptor and 1 dopamine D receptor ) and the A -- D receptor heterotetramer ( this is a receptor complex with 2 adenosine A receptors and 2 dopamine D receptors ). The A -- D receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants. Caffeine also causes the release of dopamine in the dorsal striatum and nucleus accumbens core ( a substructure within the ventral striatum ), but not the nucleus accumbens shell, by antagonizing A receptors in the axon terminal of dopamine neurons and A -- A heterodimers ( a receptor complex composed of 1 adenosine A receptor and 1 adenosine A receptor ) in the axon terminal of glutamate neurons. During chronic caffeine use, caffeine - induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance. Enzyme targets Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. As a competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF - alpha and leukotriene synthesis, and reduces inflammation and innate immunity. Caffeine also affects the cholinergic system where it inhibits the enzyme acetylcholinesterase. Off - target effects Caffeine antagonizes adenosine A2A receptors in the ventrolateral preoptic area ( VLPO ), thereby reducing inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation - dependently promotes arousal. Disinhibition of the tuberomammillary nucleus is the chief mechanism by which caffeine produces wakefulness - promoting effects. Pharmacokinetics Caffeine is metabolized in the liver into three primary metabolites : paraxanthine ( 84 % ), theobromine ( 12 % ), and theophylline ( 4 % ) Urinary metabolites of caffeine in humans at 48 hours post-dose. Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues. Peak blood concentration is reached within 1 -- 2 hours. It is eliminated by first - order kinetics. Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine ( for the relief of migraine ) and chlorobutanol and caffeine ( for the treatment of hyperemesis ). However, rectal absorption is less efficient than oral : the maximum concentration ( C ) and total amount absorbed ( AUC ) are both about 30 % ( i.e., 1 / 3.5 ) of the oral amounts. 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. Smoking decreases the half - life by 30 -- 50 %, while oral contraceptives can double it and pregnancy can raise it to as much as 15 hours during the last trimester. 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. 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. Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethyl xanthines, 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. 1, 3, 7 - Trimethyluric acid is a minor caffeine metabolite. 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. 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. This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation. Chemistry Pure anhydrous caffeine is a bitter - tasting white odorless powder with a melting point of 235 -- 238 ° C. Caffeine is moderately soluble in water at room temperature ( 2 g / 100 mL ), but very soluble in boiling water ( 66 g / 100 mL ). It is also moderately soluble in ethanol ( 1.5 g / 100 mL ). It is weakly basic ( pK of conjugate base = ~ 0.6 ) requiring strong acid to protonate it. Caffeine does not contain any stereogenic centers and hence is classified as an achiral molecule. The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance 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 sp 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. Synthesis One biosynthetic route of caffeine, as performed by Camellia and Coffea species. One laboratory synthesis of caffeine The biosynthesis of caffeine is an example of convergent evolution among different species. Caffeine may be synthesized in the lab starting with dimethylurea and malonic acid. Commercial supplies of caffeine are not usually manufactured synthetically because the chemical is readily available as a byproduct of decaffeination. Decaffeination Main article : 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. 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 : CO is forced through the green coffee beans at temperatures above 31.1 ° C and pressures above 73 atm. Under these conditions, CO 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 CO 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. 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. `` 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. 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. Analogs Some analog substances have been created which mimic caffeine 's properties with either function or structure or both. Of the latter group are the xanthines DMPX and 8 - chlorotheophylline, which is an ingredient in dramamine. Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine. Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated. Some other caffeine analogs : Dipropylcyclopentylxanthine 8 - Cyclopentyl - 1, 3 - dimethylxanthine 8 - Phenyltheophylline Precipitation of tannins. Caffeine, as do other alcaloids such as cinchonine, quinine or strychnine, precipitates polyphenols and tannins. This property can be used in a quantitation method. Natural occurrence Roasted coffee beans Around sixty plant species are known to contain caffeine. Common sources are the `` beans '' ( seeds ) of the two cultivated coffee plants, Coffea arabica and Coffea canephora ( the quantity varies, but 1.3 % is a typical value ) ; 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. High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection. 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. Caffeine is stored in tea leaves in two places. Firstly, in the cell vacuoles where it is complexed with polyphenols. This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles. Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honeybees. 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. Products See also : Caffeinated drink Caffeine content in select food and drugs Product Serving size Caffeine per serving ( mg ) Caffeine ( mg / L ) Caffeine tablet ( regular - strength ) 1 tablet 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 7002124000000000000 ♠ 124 -- 418 Guayakí yerba mate ( loose leaf ) 6 g ( 0.21 oz ) 7001850000000000000 ♠ 85 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, caffeine tablets, other oral products, and inhalation. Beverages Coffee 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 type of coffee bean and the method of preparation used ; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot ( 30 milliliters ) of arabica - variety espresso, to approximately 100 -- 125 milligrams for a cup ( 120 milliliters ) of drip coffee. Arabica coffee typically contains half the caffeine of the robusta variety. In general, dark - roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount. 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, teas contain varying amounts of caffeine. 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. 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 0 to 55 milligrams of caffeine per 12 ounce serving. By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow - release excipient. 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. 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. The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea, which is both brewed locally and sold commercially throughout the world. 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. 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 of caffeine as coffee : 80 -- 160 mg per 100 g. Higher percentages of cocoa such as 90 % amount to 200 mg per 100g approximately and thus, a 100 gram 85 % cocoa chocolate bar contains about 195 mg caffeine. Tablets No - Doz 100 mg caffeine tablets Tablets offer the advantages over coffee and tea of convenience, known dosage, and avoiding concomitant sugar, acid and fluid intake. Manufacturers of caffeine tablets claim that using caffeine of pharmaceutical quality improves mental alertness. These tablets are commonly used by students studying for their exams and by people who work or drive for long hours. Other oral products One U.S. company is marketing oral dissolvable caffeine strips. Another intake route is SpazzStick, a caffeinated lip balm. 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. Inhalants There are several products being marketed that offer inhalers that deliver proprietary blends of supplements, with caffeine being a key ingredient. In 2012, the FDA sent a warning letter to one of the companies marketing these inhalers, expressing concerns for the lack of safety information available about inhaled caffeine. Combinations with other drugs Some beverages combine alcohol with caffeine to create a caffeinated alcoholic drink. The stimulant effects of caffeine may mask the depressant effects of alcohol, potentially reducing the user 's awareness of their level of intoxication. Such beverages have been the subject of bans due to safety concerns. In particular, United States Food and Drug Administration has classified caffeine added to malt liquor beverages as an `` unsafe food additive ''. Ya ba contains a combination of methamphetamine and caffeine. History Discovery and spread of use Coffeehouse in Palestine, circa 1900 Main articles : History of chocolate, History of coffee, History of tea, and History of yerba mate According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted. Shennong is also mentioned in Lu Yu 's Cha Jing, a famous early work on the subject of tea. The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern Arabia. From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas. 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. Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as `` black bean ''. The leaves and stems of the yaupon holly ( Ilex vomitoria ) were used by Native Americans to brew a tea called asi or the `` black drink ''. Archaeologists have found evidence of this use far into antiquity, possibly dating to Late Archaic times. 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 ). According to Runge, he did this at the behest of Johann Wolfgang von Goethe. In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre - Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge 's or each other 's work. However, Berzelius later acknowledged Runge 's priority in the extraction of caffeine, stating : `` However, at this point, it should not remain unmentioned that Runge ( in his Phytochemical Discoveries, 1820, pages 146 -- 147 ) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris. '' Pelletier 's article on caffeine was the first to use the term in print ( in the French form Caféine from the French word for coffee : café ). It corroborates Berzelius 's account : Caffeine, noun ( feminine ). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period -- while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona ( 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, whereas Pelletier was the first to perform an elemental analysis. In 1827, M. Oudry isolated `` théine '' from tea, but it was later proved by Mulder and by Carl Jobst that theine was actually caffeine. In 1895, German chemist Hermann Emil Fischer ( 1852 -- 1919 ) first synthesized caffeine from its chemical components ( i.e. a `` total synthesis '' ), and two years later, he also derived the structural formula of the compound. This was part of the work for which Fischer was awarded the Nobel Prize in 1902. Historic Regulations 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. Charles II of England tried to ban it in 1676, Frederick II of Prussia banned it in 1777, 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 ''. 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. Society and Culture Regulations The Food and Drug Administration ( FDA ) in the United States currently allows only beverages containing less than 0.02 % caffeine ; but caffeine powder, which is sold as a dietary supplement, is unregulated. It is a regulatory requirement that the label of most prepackaged foods must declare a list of ingredients, including food additives such as caffeine, in descending order of proportion. However, there is no regulatory provision for mandatory quantitative labeling of caffeine, ( e.g., milligrams caffeine per stated serving size ). There are a number of food ingredients that naturally contain caffeine. These ingredients must appear in food ingredient lists. However, as is the case for `` food additive caffeine '', there is no requirement to identify the quantitative amount of caffeine in composite foods containing ingredients that are natural sources of caffeine. While coffee or chocolate are broadly recognized as caffeine sources, some ingredients ( e.g., guarana, yerba maté ) are likely less recognized as caffeine sources. For these natural sources of caffeine, there is no regulatory provision requiring that a food label identify the presence of caffeine nor state the amount of caffeine present in the food. 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. Religions Some Seventh - day Adventists, Church of God ( Restoration ) adherents, and Christian Scientists do not consume caffeine. Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter - day Saints has said the following with regard to caffeinated beverages : ``... the Church revelation spelling out health practices ( Doctrine and Covenants 89 ) does not mention the use of caffeine. The Church 's health guidelines prohibit alcoholic drinks, smoking or chewing of tobacco, and ' hot drinks ' -- taught by Church leaders to refer specifically to tea and coffee. '' 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. Caffeinated beverages are widely consumed by Muslims today. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden `` intoxicating beverages '' under Islamic dietary laws. Other organisms Caffeine effects on spider webs See also : Effect of psychoactive drugs on animals Recently discovered bacteria Pseudomonas putida CBB5 can live on pure caffeine, and can cleave caffeine into carbon dioxide and ammonia. Caffeine is toxic to birds and to dogs and cats, and has a pronounced adverse effect on mollusks, various insects, and spiders. This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight. Caffeine has also been found to enhance the reward memory of honeybees. Research Caffeine has been used to double chromosomes in haploid wheat. See also Wakefulness - promoting agent Nootropic References ^ Jump up to : 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 978 - 0 - 07 - 148127 - 4. 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. ^ Jump up to : Karch SB ( 2009 ). Karch 's pathology of drug abuse ( 4th ed. ). Boca Raton : CRC Press. pp. 229 -- 230. ISBN 978 - 0 - 8493 - 7881 - 2. 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 ^ Jump up to : American Psychiatric Association ( 2013 ). `` Substance - Related and Addictive Disorders '' ( PDF ). American Psychiatric Publishing. pp. 1 -- 2. Archived from the original ( PDF ) on 15 August 2015. 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. ^ Jump up to : Introduction to Pharmacology ( third ed. ). Abingdon : CRC Press. 2007. pp. 222 -- 223. ISBN 978 - 1 - 4200 - 4742 - 4. ^ Jump up to : Juliano LM, Griffiths RR ( October 2004 ). `` A critical review of caffeine withdrawal : empirical validation of symptoms and signs, incidence, severity, and associated features '' ( PDF ). Psychopharmacology. 176 ( 1 ) : 1 -- 29. doi : 10.1007 / s00213 - 004 - 2000 - x. PMID 15448977. Archived ( PDF ) from the original on 29 January 2012. Results : Of 49 symptom categories identified, the following 10 fulfilled validity criteria : headache, fatigue, decreased energy / activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy / not clearheaded. In addition, flu - like symptoms, nausea / vomiting, and muscle pain / stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50 % and the incidence of clinically significant distress or functional impairment was 13 %. Typically, onset of symptoms occurred 12 -- 24 h after abstinence, with peak intensity at 20 -- 51 h, and for a duration of 2 -- 9 days. ^ Jump up to : `` Caffeine ''. DrugBank. University of Alberta. 16 September 2013. Retrieved 8 August 2014. ^ Jump up to : Poleszak E, Szopa A, Wyska E, Kukuła - Koch W, Serefko A, Wośko S, Bogatko K, Wróbel A, Wlaź P ( February 2016 ). `` Caffeine augments the antidepressant - like activity of mianserin and agomelatine in forced swim and tail suspension tests in mice ''. Pharmacological Reports. 68 ( 1 ) : 56 -- 61. doi : 10.1016 / j. pharep. 2015.06. 138. PMID 26721352. ^ Jump up to : `` Caffeine ''. Pubchem Compound. NCBI. Retrieved 16 October 2014. Boiling Point 178 ° C ( sublimes ) Melting Point 238 DEG C ( ANHYD ) ^ Jump up to : `` 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 ^ Jump up to : Nehlig A, Daval JL, Debry G ( 1992 ). `` Caffeine and the central nervous system : mechanisms of action, biochemical, metabolic and psychostimulant effects ''. Brain Research. Brain Research Reviews. 17 ( 2 ) : 139 -- 70. doi : 10.1016 / 0165 - 0173 ( 92 ) 90012 - B. PMID 1356551. Jump up ^ Mitchell, Diane C. ; Knight, Carol A. ; Hockenberry, Jon ; Teplansky, Robyn ; Hartman, Terryl J. ( 1 January 2014 ). `` Beverage caffeine intakes in the U.S ''. Food and Chemical Toxicology. 63 : 136 -- 142. doi : 10.1016 / j. fct. 2013.10. 042. Jump up ^ WHO Model List of Essential Medicines ( PDF ) ( 18th ed. ). World Health Organization. October 2013 ( April 2013 ). p. 34 ( p. 38 of pdf ). Retrieved 23 December 2014. Jump up ^ Cano - Marquina A, Tarín JJ, Cano A ( May 2013 ). `` The impact of coffee on health ''. Maturitas. 75 ( 1 ) : 7 -- 21. doi : 10.1016 / j. maturitas. 2013.02. 002. PMID 23465359. Jump up ^ Qi H, Li S ( April 2014 ). `` Dose - response meta - analysis on coffee, tea and caffeine consumption with risk of Parkinson 's disease ''. Geriatrics & Gerontology International. 14 ( 2 ) : 430 -- 9. doi : 10.1111 / ggi. 12123. PMID 23879665. Jump up ^ Mayo Clinic staff. `` Pregnancy Nutrition : Foods to avoid during pregnancy ''. Mayo Clinic. 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The Cochrane Database of Systematic Reviews ( 12 ) : CD000432. doi : 10.1002 / 14651858. CD000432. pub2. PMID 21154344. ^ Jump up to : `` Caffeine : Summary of Clinical Use ''. IUPHAR Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 13 February 2015. Jump up ^ Gupta V, Lipsitz LA ( October 2007 ). `` Orthostatic hypotension in the elderly : diagnosis and treatment ''. The American Journal of Medicine. 120 ( 10 ) : 841 -- 7. doi : 10.1016 / j. amjmed. 2007.02. 023. PMID 17904451. ^ Jump up to : Bolton S ( 1981 ). `` Caffeine : Psychological Effects, Use and Abuse '' ( PDF ). Orthomolecular Psychiatry. 10 ( 3 ) : 202 -- 211. Jump up ^ Nehlig A ( 2010 ). `` Is caffeine a cognitive enhancer ? ''. Journal of Alzheimer 's Disease. 20 Suppl 1 : S85 -- 94. doi : 10.3233 / JAD - 2010 - 091315. PMID 20182035. Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively ; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on this, and caffeine appears to improve memory performance under suboptimal alertness. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long - term memory... Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties. Jump up ^ Snel J, Lorist MM ( 2011 ). `` Effects of caffeine on sleep and cognition ''. Progress in Brain Research. Progress in Brain Research. 190 : 105 -- 17. doi : 10.1016 / B978 - 0 - 444 - 53817 - 8.00006 - 2. ISBN 978 - 0 - 444 - 53817 - 8. PMID 21531247. Jump up ^ Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I ( May 2010 ). Ker K, ed. `` Caffeine for the prevention of injuries and errors in shift workers ''. The Cochrane Database of Systematic Reviews ( 5 ) : CD008508. doi : 10.1002 / 14651858. CD008508. PMC 4160007. PMID 20464765. ^ Jump up to : Camfield DA, Stough C, Farrimond J, Scholey AB ( August 2014 ). `` Acute effects of tea constituents L - theanine, caffeine, and epigallocatechin gallate on cognitive function and mood : a systematic review and meta - analysis ''. Nutrition Reviews. 72 ( 8 ) : 507 -- 22. doi : 10.1111 / nure. 12120. PMID 24946991. ^ Jump up to : Pesta DH, Angadi SS, Burtscher M, Roberts CK ( December 2013 ). `` The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance ''. Nutrition & Metabolism. 10 ( 1 ) : 71. doi : 10.1186 / 1743 - 7075 - 10 - 71. PMC 3878772. PMID 24330705. Caffeine - induced increases in performance have been observed in aerobic as well as anaerobic sports ( for reviews, see ( 26, 30, 31 ) ). Trained athletes seem to benefit from a moderate dose of 5 mg / kg ( 32 ), however, even lower doses of caffeine ( 1.0 -- 2.0 mg / kg ) may improve performance ( 33 ). Some groups found significantly improved time trial performance ( 34 ) or maximal cycling power ( 35 ), most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively. Theophylline, a metabolite of caffeine, seems to be even more effective in doing so ( 36 ). The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities ( 37 )... For both caffeine - naïve as well as caffeine - habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise ( 61 )... In summary, caffeine, even at physiological doses ( 3 -- 6 mg / kg ), as well as coffee are proven ergogenic aids and as such -- in most exercise situations, especially in endurance - type events -- clearly work - enhancing ( 26 ). It most likely has a peripheral effect targeting skeletal muscle metabolism as well as a central effect targeting the brain to enhance performance, especially during endurance events ( see Table 1 ). Also for anaerobic tasks, the effect of caffeine on the CNS might be most relevant... Muendel et al. ( 93 ) found a 17 % improvement in time to exhaustion after nicotine patch application compared to a placebo without affecting cardiovascular and respiratory parameters or substrate metabolism. In this sense, nicotine seems to exert similar effects as caffeine by delaying the development of central fatigue as impaired central drive is an important factor contributing to fatigue during exercise... The physiological effects of the above mentioned substances are well established. However, the ergogenic effect of some of the discussed drugs may be questioned and one has to consider the cohort tested for every specific substance. However, only caffeine has enough strength of evidence to be considered an ergogenic aid. Jump up ^ Bishop D ( December 2010 ). `` Dietary supplements and team - sport performance ''. Sports Medicine. 40 ( 12 ) : 995 -- 1017. doi : 10.2165 / 11536870 - 000000000 - 00000. PMID 21058748. Jump up ^ Conger SA, Warren GL, Hardy MA, Millard - Stafford ML ( February 2011 ). `` Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance ? ''. International Journal of Sport Nutrition and Exercise Metabolism. 21 ( 1 ) : 71 -- 84. doi : 10.1123 / ijsnem. 21.1. 71. PMID 21411838. Jump up ^ Liddle DG, Connor DJ ( June 2013 ). `` Nutritional supplements and ergogenic AIDS ''. Primary Care. 40 ( 2 ) : 487 -- 505. doi : 10.1016 / j. pop. 2013.02. 009. PMID 23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training... Physiologic and performance effects Amphetamines increase dopamine / norepinephrine release and inhibit their reuptake, leading to central nervous system ( CNS ) stimulation Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40 Improved reaction time Increased muscle strength and delayed muscle fatigue Increased acceleration Increased alertness and attention to task ^ Jump up to : `` It 's Your Health -- Caffeine ''. Health Canada. March 2010. 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Volume 1. New York : John Wiley & Sons. pp. 557 -- 558. ISBN 978 - 1 - 118 - 84547 - 9. Table 34 - 12... Caffeine Intoxication -- Euphoria Jump up ^ Hrnčiarove J, Barteček R ( 2017 ). `` 8. Substance Dependence ''. In Hosák L, Hrdlička M, et al. Psychiatry and Pedopsychiatry. Prague : Karolinum Press. pp. 153 -- 154. ISBN 9788024633787. At a high dose, caffeine shows a euphoric effect. Jump up ^ Schulteis G ( 2010 ). `` Brain stimulation and addiction ''. In Koob GF, Le Moal M, Thompson RF. Encyclopedia of Behavioral Neuroscience. Elsevier. p. 214. ISBN 978 - 0 - 08 - 091455 - 8. Therefore, caffeine and other adenosine antagonists, while weakly euphoria - like on their own, may potentiate the positive hedonic efficacy of acute drug intoxication and reduce the negative hedonic consequences of drug withdrawal. Jump up ^ Salerno BB, Knights EK ( 2010 ). Pharmacology for health professionals ( 3rd ed. ). Chatswood, N.S.W. : Elsevier Australia. p. 433. ISBN 978 - 0 - 7295 - 3929 - 6. In contrast to the amphetamines, caffeine does not cause euphoria, stereotyped behaviors or psychoses. Jump up ^ Ebenezer I ( 2015 ). Neuropsychopharmacology and Therapeutics. John Wiley & Sons. p. 18. ISBN 978 - 1 - 118 - 38578 - 4. However, in contrast to other psychoactive stimulants, such as amphetamine and cocaine, caffeine and the other methylxanthines do not produce euphoria, stereotyped behaviors or psychotic like symptoms in large doses. Jump up ^ Rang HP, Ritter JM, Flower RJ, Henderson G ( 2014 ). Rang & Dale 's Pharmacology E-Book ( 8th ed. ). Elsevier Health Sciences. pp. 453, 594. ISBN 978 - 0 - 7020 - 5497 - 6. By comparison with amphetamines, methylxanthines produce less locomotor stimulation and do not induce euphoria, stereotyped behaviour patterns or a psychotic state, but their effects on fatigue and mental function are similar. Table 37.2... Psychomotor stimulants... Drugs that cause wakefulness and euphoria... Amphetamines, cocaine, methylphenidate, caffeine Jump up ^ Budney AJ, Emond JA ( November 2014 ). `` Caffeine addiction ? Caffeine for youth ? Time to act ! ''. Addiction. 109 ( 11 ) : 1771 -- 2. doi : 10.1111 / add. 12594. PMID 24984891. Academics and clinicians, however, have not yet reached consensus about the potential clinical importance of caffeine addiction ( or ' use disorder ' ) Jump up ^ 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. doi : 10.1089 / jcr. 2013.0016. PMC 3777290. PMID 24761279. Jump up ^ Riba A, Tasman J, Kay JA, Lieberman MB, First MB ( 2014 ). Psychiatry ( Fourth ed. ). p. 1446. ISBN 978 - 1 - 118 - 75336 - 1. Jump up ^ Fishchman N, Mello N. Testing for Abuse Liability of Drugs in Humans ( PDF ). 5600 Fishers Lane Rockville, MD 20857 : U.S. Department of Health and Human Services Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse. p. 179. Jump up ^ Nestler EJ ( December 2013 ). `` Cellular basis of memory for addiction ''. Dialogues in Clinical Neuroscience. 15 ( 4 ) : 431 -- 43. 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 Jump up ^ Miller PM ( 2013 ). `` Chapter III : Types of Addiction ''. Principles of addiction comprehensive addictive behaviors and disorders ( 1st ed. ). Elsevier Academic Press. p. 784. ISBN 978 - 0 - 12 - 398361 - 9. 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. Jump up ^ Nehlig A, Armspach JP, Namer IJ ( 2010 ). `` SPECT assessment of brain activation induced by caffeine : no effect on areas involved in dependence ''. Dialogues in Clinical Neuroscience. 12 ( 2 ) : 255 -- 63. 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... 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. 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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 Jump up ^ Addicott MA ( September 2014 ). `` Caffeine Use Disorder : A Review of the Evidence and Future Implications ''. 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Alzheimers Dis. 32 ( 4 ) : 793 -- 887. doi : 10.3233 / JAD - 2012 - 121186. PMID 22886028. Jump up ^ `` World of Caffeine ''. World of Caffeine. 15 June 2013. Retrieved 19 December 2013. Jump up ^ Fisone G, Borgkvist A, Usiello A ( April 2004 ). `` Caffeine as a psychomotor stimulant : mechanism of action ''. Cellular and Molecular Life Sciences. 61 ( 7 -- 8 ) : 857 -- 72. doi : 10.1007 / s00018 - 003 - 3269 - 3. PMID 15095008. Jump up ^ `` Caffeine ''. IUPHAR. International Union of Basic and Clinical Pharmacology. Retrieved 2 November 2014. Jump up ^ Duan L, Yang J, Slaughter MM ( August 2009 ). `` Caffeine inhibition of ionotropic glycine receptors ''. The Journal of Physiology. 587 ( Pt 16 ) : 4063 -- 75. doi : 10.1113 / jphysiol. 2009.174797. PMC 2756438. PMID 19564396. ^ Jump up to : Ferré S ( 2010 ). `` Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine ''. Journal of Alzheimer 's Disease. 20 Suppl 1 : S35 -- 49. doi : 10.3233 / JAD - 2010 - 1400. PMID 20182056. By targeting A1 - A2A receptor heteromers in striatal glutamatergic terminals and A1 receptors in striatal dopaminergic terminals ( presynaptic brake ), caffeine induces glutamate - dependent and glutamate - independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A - D2 and A1 - D1 receptor heteromers. ^ Jump up to : Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, Lluís C, Casadó V, Volkow ND ( May 2016 ). `` Allosteric mechanisms within the adenosine A2A - dopamine D2 receptor heterotetramer ''. Neuropharmacology. 104 : 154 -- 60. doi : 10.1016 / j. neuropharm. 2015.05. 028. 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On the other hand, our ' ventral shell of the nucleus accumbens ' very much overlaps with the striatal compartment simply described by De Luca et al. ( 2007 ) as ' nucleus accumbens shell, ' where both studies show that caffeine does not modify the extracellular levels of dopamine. Therefore, the results of both experimental groups are basically the same and point to differential effects of caffeine in different striatal subcompartments. In fact, analyzing the effects of the intrastriatal perfusion of an A1 receptor antagonist in several other striatal compartments showed striking differences compared with the shell of the nucleus accumbens. Thus, A1 receptor blockade significantly increased the extracellular concentration of dopamine, but not glutamate, in the core of the nucleus accumbens and in the caudate -- putamen and the effect was more pronounced in the most medial compartments ( Boryczet al. 2007 ). In summary, a subregional difference in the A1 receptor - mediated control of glutamate and dopamine release exists in the striatum... A2A receptors play a crucial role in the sleep - promoting effects of adenosine and the arousal - enhancing effects of caffeine ( Huang et al. 2007 ; Ferré et al. 2007a ). Those A2A receptors are localized in the ventrolateral pre-optic area of the hypothalamus and their stimulation promotes sleep by inducing GABA release in the histaminergic tuberomammillary nucleus, thereby inhibiting the histaminergic arousal system... chronic caffeine exposure counteracts both motor activation and dopamine release in the nucleus accumbens induced by caffeine or an A1 receptor antagonist... An additional factor that might play a significant role in caffeine tolerance is the significant increase in plasma and extracellular concentrations of adenosine with chronic caffeine exposure... The existence of an A1 receptor - mediated glutamate - independent modulation of dopamine release suggested the presence of functional A1 receptors in striatal dopaminergic terminals... In the SSM, adenosine acts pre - and post-synaptically through multiple mechanisms, which depend on heteromerization of A1 and A2A receptors among themselves and with D1 and D2 receptors, respectively. Caffeine produces its motor and reinforcing effects by releasing the pre - and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission in the SSM. By releasing the pre-synaptic brake, caffeine induces glutamate - dependent and glutamate - independent release of dopamine. Jump up ^ Ribeiro JA, Sebastião AM ( 2010 ). `` Caffeine and adenosine ''. Journal of Alzheimer 's Disease. 20 Suppl 1 : S3 -- 15. doi : 10.3233 / JAD - 2010 - 1379. PMID 20164566. Jump up ^ Essayan DM ( November 2001 ). `` Cyclic nucleotide phosphodiesterases ''. 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Tea : the Plant and its Manufacture ; Chemistry and Consumption of the Beverage. Caffeine. Jump up ^ `` Caffeine Content of Food and Drugs ''. Nutrition Action Health Newsletter. Center for Science in the Public Interest. 1996. Archived from the original on 14 June 2007. Retrieved 3 August 2009. ^ Jump up to : `` Caffeine Content of Beverages, Foods, & Medications ''. The Vaults of Erowid. 7 July 2006. Retrieved 3 August 2009. Jump up ^ `` Caffeine Content of Drinks ''. Caffeine Informer. Retrieved 8 December 2013. ^ Jump up to : Chin JM, Merves ML, Goldberger BA, Sampson - Cone A, Cone EJ ( October 2008 ). `` Caffeine content of brewed teas ''. Journal of Analytical Toxicology. 32 ( 8 ) : 702 -- 4. doi : 10.1093 / jat / 32.8. 702. PMID 19007524. ^ Jump up to : Richardson B ( 2009 ). `` Too Easy to be True. De-bunking the At - Home Decaffeination Myth ''. Elmwood Inn. Retrieved 12 January 2012. Jump up ^ `` Traditional Yerba Mate in Biodegradable Bag ''. Guayaki Yerba Mate. 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Jump up ^ Meyers H ( 7 March 2005 ). `` '' Suave Molecules of Mocha '' -- Coffee, Chemistry, and Civilization ``. New Partisan. Archived from the original on 9 March 2005. Retrieved 3 February 2007. ^ Jump up to : Fairbanks CH ( 2004 ). `` The function of black drink among the Creeks ''. In Hudson MC. Black Drink. University of Georgia Press. p. 123. ISBN 978 - 0 - 8203 - 2696 - 2. Jump up ^ Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T ( August 2012 ). `` Ritual Black Drink consumption at Cahokia ''. Proceedings of the National Academy of Sciences of the United States of America. 109 ( 35 ) : 13944 -- 9. doi : 10.1073 / pnas. 1208404109. PMC 3435207. PMID 22869743. Jump up ^ Runge FF ( 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. Jump up ^ 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. Jump up ^ Weinberg BA, Bealer BK ( 2001 ). The World of Caffeine : The Science and Culture of the World 's Most Popular Drug. Routledge. pp. xvii -- xxi. ISBN 978 - 0 - 415 - 92723 - 9. Jump up ^ 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 : 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. ) Jump up ^ 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. ) Jump up ^ Pelletier, Pierre Joseph ( 1822 ). `` Cafeine ''. Dictionnaire de Médecine ( in French ). 4. Paris : Béchet Jeune. pp. 35 -- 36. Retrieved 3 March 2011. Jump up ^ Robiquet, Pierre Jean ( 1823 ). `` Café ''. Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers ( in French ). 4. Paris : Thomine et Fortic. pp. 50 -- 61. Retrieved 3 March 2011. Jump up ^ Dumas ; 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. Jump up ^ Oudry M ( 1827 ). `` Note sur la Théine ''. Nouvelle bibliothèque médicale ( in French ). 1 : 477 -- 479. Jump up ^ Mulder, G.J. ( 1838 ). `` Ueber Theïn und Caffeïn '' ( Concerning theine and caffeine ). Journal für Praktische Chemie. 15 : 280 -- 284. doi : 10.1002 / prac. 18380150124. Jump up ^ 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. Jump up ^ 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. Fischer E ( 1881 ). `` Ueber das Caffeïn '' ( On caffeine ). Berichte der Deutschen chemischen Gesellschaft zu Berlin ( in German ). 14 : 637 -- 644. doi : 10.1002 / cber. 188101401142. Fischer E ( 1881 ). `` Ueber das Caffeïn. Zweite Mitteilung '' ( On caffeine. Second communication. ). Berichte der Deutschen chemischen Gesellschaft zu Berlin ( in German ). 14 ( 2 ) : 1905 -- 1915. doi : 10.1002 / cber. 18810140283. Fischer E ( 1882 ). `` Ueber das Caffeïn. Dritte Mitteilung '' ( On caffeine. Third communication. ). Berichte der Deutschen chemischen Gesellschaft zu Berlin ( in German ). 15 : 29 -- 33. doi : 10.1002 / cber. 18820150108. Fischer E, Ach L ( 1895 ). `` Synthese des Caffeïns '' ( Synthesis of caffeine ). Berichte der Deutschen chemischen Gesellschaft zu Berlin ( in German ). 28 ( 3 ) : 3135 -- 3143. doi : 10.1002 / cber. 189502803156. Fischer E ( 1897 ). `` Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen '' ( On the constitution of caffeine, xanthin, hypoxanthin, and related bases. ). Berichte der Deutschen chemischen Gesellschaft zu Berlin ( in German ). 30 : 549 -- 559. doi : 10.1002 / cber. 189703001110. Jump up ^ Hj. Théel ( 1902 ). `` Nobel Prize Presentation Speech ''. Retrieved 3 August 2009. Jump up ^ Brown DW ( 2004 ). A new introduction to Islam. Chichester, West Sussex : Wiley - Blackwell. pp. 149 -- 51. ISBN 978 - 1 - 4051 - 5807 - 7. Jump up ^ Ágoston, Gábor ; Masters, Bruce ( 2009 ). Encyclopedia of the Ottoman Empire. p. 138. ISBN 978 - 1 - 4381 - 1025 - 7. Jump up ^ Hopkins K ( 24 March 2006 ). `` Food Stories : The Sultan 's Coffee Prohibition ''. Accidental Hedonist. Archived from the original on 20 November 2012. Retrieved 3 January 2010. Jump up ^ `` By the King. A PROCLAMATION FOR THE Suppression of Coffee - Houses ''. Retrieved 18 March 2012. 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Jump up ^ Reissig CJ, Strain EC, Griffiths RR ( January 2009 ). `` Caffeinated energy drinks -- a growing problem ''. Drug and Alcohol Dependence. 99 ( 1 -- 3 ) : 1 -- 10. doi : 10.1016 / j. drugalcdep. 2008.08. 001. PMC 2735818. PMID 18809264. Lay summary -- ScienceDaily ( 25 September 2008 ). Jump up ^ Geoffrey Burchfield ( 1997 ). Meredith Hopes, ed. `` What 's your poison : caffeine ''. Australian Broadcasting Corporation. Retrieved 15 January 2014. Jump up ^ `` Mormonism in the News : Getting It Right August 29 ''. The Church of Jesus Christ of Latter - Day Saints. 2012. Retrieved 17 April 2016. Jump up ^ Juan Eduardo Campo ( 1 January 2009 ). Encyclopedia of Islam. Infobase Publishing. p. 154. ISBN 978 - 1 - 4381 - 2696 - 8. Retrieved 1 November 2012. Jump up ^ Daniel W. Brown ( 24 August 2011 ). A New Introduction to Islam. John Wiley & Sons. p. 149. ISBN 978 - 1 - 4443 - 5772 - 1. Jump up ^ `` Newly Discovered Bacteria Lives on Caffeine ''. Blogs.scientificamerican.com. 24 May 2011. Retrieved 19 December 2013. Jump up ^ Paul L. `` Why Caffeine is Toxic to Birds ''. HotSpot for Birds. Advin Systems. Retrieved 29 February 2012. Jump up ^ `` Caffeine ''. Retrieved 12 September 2014. Jump up ^ Noever R, Cronise J, Relwani RA ( 29 April 1995 ). `` Using spider - web patterns to determine toxicity ''. NASA Tech Briefs. New Scientist magazine. 19 ( 4 ) : 82. Jump up ^ Arnaud MJ ( 2011 ). `` Pharmacokinetics and metabolism of natural methylxanthines in animal and man ''. Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology. 200 ( 200 ) : 33 -- 91. doi : 10.1007 / 978 - 3 - 642 - 13443 - 2_3. ISBN 978 - 3 - 642 - 13442 - 5. PMID 20859793. Jump up ^ Thomas J, Chen Q, Howes N ( August 1997 ). `` Chromosome doubling of haploids of common wheat with caffeine ''. Genome. 40 ( 4 ) : 552 -- 8. doi : 10.1139 / g97 - 072. PMID 18464846. Bibliography Bersten I ( 1999 ). Coffee, Sex & Health : A history of anti-coffee crusaders and sexual hysteria. Sydney : Helian Books. ISBN 978 - 0 - 9577581 - 0 - 0. Pendergrast M ( 2001 ) ( 1999 ). Uncommon Grounds : The History of Coffee and How It Transformed Our World. London : Texere. ISBN 1 - 58799 - 088 - 1. External links Wikimedia Commons has media related to Caffeine. Wikinews has related news : Alzheimer 's disease reversed in mice using caffeine 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. 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Coffee and doughnuts Coffee cup Coffee cup sleeve Demitasse Tasse à café Coffee leaf rust King Gustav 's twin experiment Coffee vending machine Demitasse spoon Single - serve coffee container Third wave of coffee Coffee portal Category : Coffee Stimulants Adamantanes Adapromine Amantadine Bromantane Memantine Rimantadine Adenosine antagonists 8 - Chlorotheophylline 8 - Cyclopentyltheophylline 8 - Phenyltheophylline Aminophylline Caffeine CGS - 15943 Dimethazan Paraxanthine SCH - 58261 Theobromine Theophylline Alkylamines Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Levopropylhexedrine Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane Ampakines CX - 516 CX - 546 CX - 614 CX - 691 CX - 717 IDRA - 21 LY - 404,187 LY - 503,430 Nooglutyl Org 26576 PEPA S - 18986 Sunifiram Unifiram Arylcyclohexylamines Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine Benzazepines 6 - Br - APB SKF - 77434 SKF - 81297 SKF - 82958 Cholinergics A-84,543 A-366,833 ABT - 202 ABT - 418 AR - R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS - 21 Ispronicline Nicotine PHA - 543,613 PNU - 120,596 PNU - 282,987 Pozanicline Rivanicline Sazetidine A SIB - 1553A SSR - 180,711 TC - 1698 TC - 1827 TC - 2216 Tebanicline UB - 165 Varenicline WAY - 317,538 Convulsants Anatoxin - a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone Eugeroics Adrafinil Armodafinil CRL - 40,940 CRL - 40,941 Fluorenol JZ - IV - 10 Modafinil Oxazolines 4 - Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone Phenethylamines 1 - ( 4 - Methylphenyl ) - 2 - aminobutane 1 - Methylamino - 1 - ( 3, 4 - methylenedioxyphenyl ) propane 2 - Fuoroamphetamine 2 - Fuoromethamphetamine 2 - OH - PEA 2 - Phenyl - 3 - aminobutane 2, 3 - MDA 3 - Fuoroamphetamine 3 - Fluoroethamphetamine 3 - Fluoromethcathinone 3 - Methoxyamphetamine 3 - Methylamphetamine 3, 4 - DMMC 4 - BMC 4 - CMC 4 - Ethylamphetamine 4 - Fluoroamphetamine 4 - Fluoromethamphetamine 4 - MA 4 - Methylbuphedrone 4 - Methylcathinone 4 - MMA 4 - Methylpentedrone 4 - MTA 6 - FNE AL - 1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amfepramone Amidephrine 2 - Amino - 1, 2 - dihydronaphthalene 2 - Aminoindane 5 - ( 2 - Aminopropyl ) indole 2 - Aminotetralin Acridorex Amphetamine ( Dextroamphetamine, Levoamphetamine ) Amphetaminil Arbutamine β - Methylphenethylamine β - Phenylmethamphetamine Benfluorex Benzedrone Benzphetamine BDB BOH 3 - Benzhydrylmorpholine BPAP Buphedrone Bupropion Butylone Camfetamine Cathine Cathinone Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D - Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dimethylcathinone Dobutamine DOPA ( Dextrodopa, Levodopa ) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethcathinone Ethylnorepinephrine Ethylone Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine ( Dexfenfluramine, Levofenfluramine ) Fenproporex Feprosidnine Flephedrone Fludorex Formetorex Furfenorex Gepefrine Hexapradol Hexedrone HMMA Hordenine 4 - Hydroxyamphetamine 5 - Iodo - 2 - aminoindane Ibopamine IMP Indanylamphetamine Iofetamine Isoetarine Isoethcathinone Isoprenaline L - Deprenyl ( Selegiline ) Lefetamine Lisdexamfetamine Lophophine MBDB MDA ( tenamfetamine ) MDBU MDEA MDMA ( midomafetamine ) MDMPEA MDOH MDPR MDPEA Mefenorex Mephedrone Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine ( Dextromethamphetamine, Levomethamphetamine ) Methoxamine Methoxyphenamine MMA Methcathinone Methedrone Methoxyphenamine Methylenedioxycathinone Methylone Mexedrone MMDA MMDMA MMMA Morforex N, alpha - Diethylphenylethylamine N - Ethylbuphedrone N - Ethylhexedrone N, N - Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L - Norpseudoephedrine Octopamine ( drug ) Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Pentedrone Pentylone Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Phthalimidopropiophenone Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol ( Levosalbutamol ) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine Phenylmorpholines 3 - Fluorophenmetrazine Fenbutrazate Fenmetramide G - 130 Manifaxine Morazone Morforex Oxaflozane PD - 128,907 Phendimetrazine Phenmetrazine 2 - Phenyl - 3, 6 - dimethylmorpholine Pseudophenmetrazine Radafaxine Piperazines 2C - B - BZP 3C - PEP BZP CM156 DBL - 583 GBR - 12783 GBR - 12935 GBR - 13069 GBR - 13098 GBR - 13119 MeOPP MBZP oMPP Vanoxerine Piperidines 1 - Benzyl - 4 - ( 2 - ( diphenylmethoxy ) ethyl ) piperidine 2 - Benzylpiperidine 2 - Methyl - 3 - phenylpiperidine 3, 4 - Dichloromethylphenidate 4 - Benzylpiperidine 4 - Fluoromethylphenidate 4 - Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate Methylphenidate ( Dexmethylphenidate ) Nocaine Phacetoperane Pipradrol Propylphenidate SCH - 5472 Pyrrolidines 2 - Diphenylmethylpyrrolidine 5 - DBFPV α - PPP α - PBP α - PHP α - PVP α - PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone Racetams Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide Tropanes 4 - fluorotropacocaine 4 ' - Fluorococaine Altropane ( IACFT ) Brasofensine CFT ( WIN 35,428 ) β - CIT ( RTI - 55 ) Cocaethylene Cocaine Dichloropane ( RTI - 111 ) Difluoropine FE - β - CPPIT FP - β - CPPIT Ioflupane ( I ) Norcocaine PIT PTT RTI - 31 RTI - 32 RTI - 51 RTI - 112 RTI - 113 RTI - 120 RTI - 121 ( IPCIT ) RTI - 126 RTI - 150 RTI - 177 RTI - 229 RTI - 336 RTI - 354 RTI - 371 RTI - 386 Salicylmethylecgonine Tesofensine Troparil ( β - CPT, WIN 35,065 - 2 ) Tropoxane WF - 23 WF - 33 Tryptamines 4 - HO - αMT 4 - Methyl - αET 4 - Methyl - αMT 5 - Chloro - αMT 5 - Fluoro - αMT 5 - MeO - αET 5 - MeO - αMT 5 - MeO - DIPT 6 - Fluoro - αMT 7 - Methyl - αET αET αMT Others 2 - MDP 3, 3 - Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D - 161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI - 52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ - 7925476 Lazabemide Leptacline Lomevactone LR - 5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O - 2172 Oxaprotiline PNU - 99,194 PRC200 - SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH - 232 Yohimbine ATC code : N06B Pharmacodynamics Acetylcholine metabolism and transport modulators Enzyme ( modulators ) ChAT Inhibitors : 1 - ( - Benzoylethyl ) pyridinium 2 - ( α - Naphthoyl ) ethyltrimethylammonium 3 - Chloro - 4 - stillbazole 4 - ( 1 - Naphthylvinyl ) pyridine Acetylseco hemicholinium - 3 Acryloylcholine AF64A B115 BETA CM - 54,903 N, N - Dimethylaminoethylacrylate N, N - Dimethylaminoethylchloroacetate AChE Inhibitors : Reversible : Carbamates : Aldicarb Aminocarb Bendiocarb Bufencarb Carbaryl Carbendazim Carbetamide Carbofuran Carbosulfan Chlorbufam Chloropropham Dimetilan Ethienocarb Ethiofencarb Fenobucarb Formetanate Formparanate Methiocarb Methomyl Metolcarb Miotine Oxamyl Phenmedipham Pinmicarb Pirimicarb Propamocarb Propham Propoxur Thiofanox ; Stigmines : Distigmine Eptastigmine Ganstigmine Neostigmine Phenserine Physostigmine Pyridostigmine Quilostigmine Rivastigmine Terestigmine ; Others : Acotiamide Ambenonium Caffeine Donepezil Edrophonium Galantamine Huperzine A Ipidacrine Itopride Ladostigil Minaprine Tacrine Zanapezil Irreversible : Organophosphates : Acephate Anatoxin - a ( S ) Azinphos - ethyl Azinphos - methyl BAY - 29952 Bensulide Cadusafos Carbophenothion Chlorethoxyfos Chlorfenvinphos Chlorpyrifos Chlorpyrifos - methyl Coumaphos Cyanophos Cyclosarin Demephion Demeton Demeton - S - methyl Dialifor Diazinon Dichlorvos Dicrotophos Diisopropyl fluorophosphate Diisopropylphosphate Dimefox Dimethoate Dimethyl 4 - ( methylthio ) phenyl phosphate Dioxathion Disulfoton EA - 3148 Echothiophate Endothion Ethion Ethoprop Fenamiphos Fenitrothion Fenthion Fonofos Formothion Fosthiazate GV Hexaethyl tetraphosphate Isofluorophate Isoxathion Leptophos Malaoxon Malathion Methamidophos Methidathion Methyl phenkapton Metrifonate Mevinphos Monocrotophos Naled Novichok agent Omethoate Oxydemeton - methyl Paraoxon Parathion Parathion - methyl Phorate Phosalone Phosfolan Phosmet Phosphamidon Phoxim Pirimiphos - methyl Profenofos Prothoate Sarin Soman Tabun Tebupirimfos Temefos Terbufos Tetrachlorvinphos Triazofos Tribufos Trichlorfon Trichloronate VE VG VM VR VX ; Others : Demecarium Fasciculins ( green mamba toxins ) ( 1, 2, 3, 4 ) Onchidal ( Onchidella binneyi ) Unsorted : α - Pinene α - Viniferin Affinine Affinisine Arisugacin A Bulbocapnine Conodurine Coronaridine Corydaline Corynoline Crimidine Cyclanoline Cymserine Harmaline Kobophenol A Lactucopicrin Phosacetim Rosmarinic acid Stercuronium iodide Taspine Tetrahydrocannabinol Ungeremine Ungiminorine Reactivators : Asoxime chloride Methoxime Obidoxime Pralidoxime Trimedoxime bromide BChE Inhibitors : Affinine Affinisine Conodurine Cymserine Ladostigil Profenamine ( ethopropazine ) Rivastigmine Tacrine ZINC - 12613047 Many of the other AChE inhibitors listed above Transporter ( modulators ) CHT Inhibitors : Hemicholinium - 3 ( hemicholine ) Triethylcholine Enhancers : Coluracetam VAChT Inhibitors : Vesamicol Release ( modulators ) Inhibitors SNAP - 25 inactivators : Botulinum toxin ( A, C, E ) VAMP inactivators : Botulinum toxin ( B, D, F, G ) Others : Bungarotoxins ( β - bungarotoxin, γ - bungarotoxin ) Enhancers LPHN agonists : α - Latrotoxin Others : Atracotoxin ( e.g., robustoxin, versutoxin ) Crotoxin See also : Receptor / signaling modulators Muscarinic acetylcholine receptor modulators Nicotinic acetylcholine receptor modulators Glycine receptor modulators Receptor ( ligands ) GlyR Agonists : β - Alanine β - ABA ( BABA ) β - AIBA Caesium D - Alanine D - Serine GABA Glycine Hypotaurine Ivermectin L - Alanine L - Proline L - Serine L - Threonine MDL - 27531 Milacemide Picolinic acid Propofol Quisqualamine Sarcosine Taurine Positive modulators : Alcohols ( e.g., brometone, chlorobutanol ( chloretone ), ethanol ( alcohol ), tert - butanol ( 2M2P ), tribromoethanol, trichloroethanol, trifluoroethanol ) Alkylbenzene sulfonate Anandamide Barbiturates ( e.g., pentobarbital, sodium thiopental ) Chlormethiazole D12 - 116 Dihydropyridines ( e.g., nicardipine ) Etomidate Ginseng constituents ( e.g., ginsenosides ( e.g., ginsenoside - Rf ) ) Glutamic acid ( glutamate ) Ivermectin Ketamine Neuroactive steroids ( e.g., alfaxolone, pregnenolone ( eltanolone ), pregnenolone acetate, minaxolone, ORG - 20599 ) Nitrous oxide Penicillin G Propofol Tamoxifen Tetrahydrocannabinol Triclofos Tropeines ( e.g., atropine, bemesetron, cocaine, LY - 278584, tropisetron, zatosetron ) Volatiles / gases ( e.g., chloral hydrate, chloroform, desflurane, diethyl ether ( ether ), enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, toluene, trichloroethane ( methyl chloroform ), trichloroethylene ) Xenon Zinc Antagonists : 2 - Aminostrychnine 2 - Nitrostrychnine 4 - Phenyl - 4 - formyl - N - methylpiperidine αEMBTL Bicuculline Brucine Cacotheline Caffeine Colchicine Colubrine Cyanotriphenylborate Dendrobine Diaboline Endocannabinoids ( e.g., 2 - AG, anandamide ( AEA ) ) Gaboxadol ( THIP ) Gelsemine iso - THAZ Isobutyric acid Isonipecotic acid Isostrychnine Laudanosine N - Methylbicuculline N - Methylstrychnine N, N - Dimethylmuscimol Nipecotic acid Pitrazepin Pseudostrychnine Quinolines ( e.g., 4 - hydroxyquinoline, 4 - hydroxyquinoline - 3 - carboxylic acid, 5, 7 - CIQA, 7 - CIQ, 7 - TFQ, 7 - TFQA ) RU - 5135 Sinomenine Strychnine Thiocolchicoside Tutin Negative modulators : Amiloride Benzodiazepines ( e.g., bromazepam, clonazepam, diazepam, flunitrazepam, flurazepam ) Corymine Cyanotriphenylborate Daidzein Dihydropyridines ( e.g., nicardipine, nifedipine, nitrendipine ) Furosemide Genistein Ginkgo constituents ( e.g., bilobalide, ginkgolides ( e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M ) ) Imipramine NBQX Neuroactive steroids ( e.g., 3α - androsterone sulfate, 3β - androsterone sulfate, deoxycorticosterone, DHEA sulfate, pregnenolone sulfate, progesterone ) Opioids ( e.g., codeine, dextromethorphan, dextrorphan, levomethadone, levorphanol, morphine, oripavine, pethidine, thebaine ) Picrotoxin ( i.e., picrotin and picrotoxinin ) PMBA Riluzole Tropeines ( e.g., bemesetron, LY - 278584, tropisetron, zatosetron ) Verapamil Zinc NMDAR See here instead. Transporter ( blockers ) GlyT1 ACPPB ALX - 1393 ALX - 5407 ( NFPS ) AMG - 747 ASP2535 Bitopertin ( RG1678 / RO4917838 ) CP - 802079 Ethanol ( alcohol ) Glycyldodecylamide GSK1018921 LY - 2365109 ORG - 24598 ORG - 25935 ( SCH - 900435 ) PF - 02545920 PF - 03463275 PF - 04958242 Sarcosine SSR - 103,800 SSR - 504,734 GlyT2 Amoxapine Ethanol ( alcohol ) NAGly Opiranserin ( VVZ - 149 ) ORG - 25543 VVZ - 368 See also Receptor / signaling modulators GABA receptor modulators GABA receptor positive modulators Ionotropic glutamate receptor modulators Phosphodiesterase inhibitors PDE1 MMPX SCH - 51866 Vinpocetine PDE2 BAY 60 - 7550 Carbazeran EHNA Oxindole PDP PDE3 Adibendan Amrinone ( inamrinone ) Anagrelide Benafentrine Bucladesine Carbazeran Cilostamide Cilostazol Enoximone Imazodan KMUP - 1 Meribendan Milrinone Olprinone Parogrelil Pimobendan Pumafentrine Quazinone RPL - 554 Siguazodan Trequinsin Vesnarinone Zardaverine PDE4 Apremilast Arofylline Atizoram Benafentrine Catramilast CC - 1088 CDP - 840 CGH - 2466 Cilomilast Cipamfylline Crisaborole Denbutylline Drotaverine Etazolate Filaminast Glaucine HT - 0712 ICI - 63197 Indimilast Irsogladine Lavamilast Lirimilast Luteolin Mesembrenone Mesembrine Mesopram Oglemilast Piclamilast Pumafentrine Revamilast Ro 20 - 1724 Roflumilast Rolipram Ronomilast RPL - 554 RS - 25344 Tetomilast Tofimilast YM - 976 Zardaverine PDE5 Acetildenafil Aildenafil Avanafil Beminafil Benzamidenafil Dasantafil Icariin Gisadenafil Homosildenafil Lodenafil Mirodenafil MY - 5445 Nitrosoprodenafil Norcarbodenafil SCH - 51866 Sildenafil Sulfoaildenafil T - 0156 Tadalafil Udenafil Vardenafil PDE7 BRL - 50481 PDE9 BAY 73 - 6691 PF - 04447943 PDE10 Balipodect Mardepodect Papaverine TC - E 5005 Tofisopam PDE11 BC11 - 38 Non-selective Aminophylline Caffeine Choline theophyllinate CPX Dipyridamole Doxofylline Enprofylline Ibudilast IBMX Luteolin Paraxanthine Pentoxifylline Propentofylline Theobromine Theophylline Zaprinast Unsorted Diazepam Diprophylline DPCPX Furafylline Lisofylline MDL - 12330A Moxaverine Oxagrelate Pentifylline Proxyphylline Quercetin Satigrel Tolafentrine Trapidil See also : Receptor / signaling modulators Purine receptor modulators Receptor ( ligands ) P0 ( adenine ) Agonists : 8 - Aminoadenine Adenine P1 ( adenosine ) Agonists : 2 - ( 1 - Hexynyl ) - N - methyladenosine 2 - Cl - IB - MECA 2 ' - MeCCPA 4 ' - O - β - D - Glucosyl - 9 - O - ( 6 ' ' - deoxysaccharosyl ) olivil 5 ' - N - ethylcarboxamidoadenosine Adenosine ADP AMP Apadenoson ATL - 146e ATP BAY 60 -- 6583 Binodenoson Capadenoson CCPA CGS - 21680 CP - 532,903 Evodenoson GR 79236 LUF - 5835 LUF - 5845 N - Cyclopentyladenosine Namodenoson Neladenoson dalanate Piclidenoson Regadenoson SDZ WAG 994 Selodenoson Sonedenoson Tecadenoson UK - 432,097 Antagonists : 8 - Chlorotheophylline 8 - Phenyl - 1, 3 - dipropylxanthine 8 - Phenyltheophylline Acefylline Aminophylline ATL - 444 Bamifylline Cafedrine Caffeine Caffeine citrate Cartazolate CGH - 2466 CGS - 15943 Choline theophyllinate CPX CVT - 6883 Dimethazan DMPX DPCPX Dyphylline Enprofylline Etazolate Fenethylline IBMX Isovaleric acid Istradefylline KF - 26777 MRE3008F20 MRS - 1220 MRS - 1334 MRS - 1706 MRS - 1754 MRS - 3777 Paraxanthine Pentoxifylline Preladenant Propentofylline Proxyphylline PSB - 10 PSB - 11 PSB - 36 PSB - 603 PSB - 788 PSB - 1115 Reversine Rolofylline SCH - 442,416 SCH - 58261 Theacrine Theobromine Theodrenaline Theophylline Tozadenant Tracazolate VUF - 5574 ZM - 241,385 P2 ( nucleotide ) P2X ( ATP ) Agonists : 2 - Me - SATP α, β - Me - ATP Adenosine ADP AMP Ap4A Ap5A ATP ATPγS BzATP Cibacron blue CTP D - β, γ - Me - ATP GTP HT - AMP Ivermectin L - β, γ - Me - ATP MRS - 2219 PAPET - ATP UTP Zinc Antagonists : 5 - BDBD A-317491 A-438079 A-740003 A-804598 A-839977 AF - 353 AZ - 10606120 AZ - 11645373 BBG Calcium Calmidazolium Chelerythrine Copper Emodin ( Rheum officinale ) Evans Blue GW - 791343 HMA Ip5I isoPPADS JNJ - 47965567 KN - 04 KN - 62 Magnesium MRS - 2159 NF - 023 NF - 110 NF - 157 NF - 279 NF - 449 Opiranserin ( VVZ - 149 ) Oxidized - ATP Phenol Red Phenolphthalein PPADS PPNDS PSB - 12062 Puerarin ( Radix puerariae ) Purotoxin 1 RB - 2 Ro 0437626 Ro 51 RO - 3 Sodium ferulate ( Angelica sinensis, Ligusticum wallichii ) Suramin TC - P 262 Tetramethylpyrazine ( ligustrazine ) ( Ligusticum wallichii ) TNP - ATP Zinc P2Y Agonists : 2 - Me - SADP 2 - Me - SATP 2 - Thio - UTP 5 - Br - UDP 5 - OMe - UDP α, β - Me - ATP Adenosine ADP ADPβS Ap3A AR - C 67085MX ATP ATPγS CTP dATP Denufosol Diquafosol IDP ITP INS - 365 INS - 37217 MRS - 2365 MRS - 2690 MRS - 2693 MRS - 2768 MRS - 2957 MRS - 4062 NF - 546 PAPET - ATP PSB - 0474 PSB - 1114 UDP UDPβS UDP - galactose UDP - glucose UDP - N - acetylglucosamine Up3U UTP UTPγS Antagonists : 2 - Me - SAMP A3P5PS AMPαS Ap4A AR - C 66096 AR - C 67085MX AR - C 69931MX AR - C 118925XX ATP BzATP C1330 - 7 Cangrelor Clopidogrel Elinogrel Ip5I MRS - 2179 MRS - 2211 MRS - 2279 MRS - 2395 MRS - 2500 MRS - 2578 NF - 157 NF - 340 PIT PPADS Prasugrel PSB - 0739 RB - 2 Regrelor Suramin Ticagrelor Ticlopidine UDP Transporter ( blockers ) CNTs 6 - Hydroxy - 7 - methoxyflavone Adenosine dMeThPmR Estradiol KGO - 2142 KGO - 2173 MeThPmR Phloridzin Progesterone ENTs Barbiturates Benzodiazepines Cilostazol Dilazep Dipyridamole Estradiol Ethanol Hexobendine NBMPR Pentoxifylline Progesterone Propentofylline PMAT Decynium - 22 Enzyme ( inhibitors ) XO Allopurinol Amflutizole Benzbromarone Caffeic acid Cinnamaldehyde Cinnamomum osmophloeum Febuxostat Myo - inositol Kaempferol Myricetin Niraxostat Oxipurinol Phytic acid Pistacia integerrima Propolis Quercetin Tisopurine Topiroxostat Others Aminopterin Azathioprine Methotrexate Mycophenolic acid Pemetrexed Pralatrexate Many others Others Precursors : Adenine Adenosine AMP ADP ATP Cytosine Cytidine CMP CDP CTP Guanine Guanosine GMP GDP GTP Hypoxanthine Inosine IMP IDP ITP Ribose Uracil Uridine UMP UDP UTP Others : Chrysophanol ( rhubarb ) See also : Receptor / signaling modulators Pharmacy and Pharmacology portal Chemistry portal Coffee portal GND : 4010359 - 6 NDL : 00564463 Retrieved from `` https://en.wikipedia.org/w/index.php?title=Caffeine&oldid=814422952 '' Categories : Caffeine Acetylcholinesterase inhibitors Adenosine receptor antagonists Anxiogenics Bitter compounds Glycine receptor antagonists IARC Group 3 carcinogens Mutagens Phosphodiesterase inhibitors Plant toxin insecticides Vasoconstrictors Xanthines Alkaloids found in plants Ergogenic aids Hidden categories : CS1 Danish - language sources ( da ) Wikipedia articles needing clarification from January 2014 Wikipedia articles needing page number citations from January 2014 CS1 German - language sources ( de ) CS1 French - language sources ( fr ) Wikipedia indefinitely semi-protected pages Wikipedia indefinitely move - protected pages Use dmy dates from September 2016 Template : drugs.com link with non-standard subpage Drugs with non-standard legal status ECHA InfoCard ID from Wikidata Chemical articles having a data page Articles containing unverified chemical infoboxes All articles with unsourced statements Articles with unsourced statements from March 2015 Wikipedia articles needing clarification from March 2017 All articles lacking reliable references Articles lacking reliable references from November 2015 Articles with unsourced statements from January 2015 Articles with unsourced statements from December 2014 Articles with unsourced statements from October 2011 Articles with unsourced statements from December 2011 Articles with unsourced statements from September 2011 Wikipedia articles with GND identifiers Talk View source Contents About Wikipedia Afrikaans Azərbaycanca বাংলা Беларуская Беларуская ( тарашкевіца ) ‎ Български Bosanski Català Čeština Cymraeg Dansk Deutsch Eesti Ελληνικά Español Esperanto Euskara فارسی Français Gaeilge Galego 한국어 Հայերեն हिन्दी Hrvatski Ido Bahasa Indonesia Interlingua Íslenska Italiano עברית Basa Jawa ಕನ್ನಡ ქართული Kiswahili Latviešu Lietuvių Ligure Magyar Македонски Bahasa Melayu မြန်မာဘာသာ Nederlands नेपाल भाषा 日本 語 Nordfriisk Norsk Norsk nynorsk Occitan Oʻzbekcha / ўзбекча پنجابی پښتو ភាសា ខ្មែរ Polski Português Română Русский Scots Shqip Simple English Slovenčina Slovenščina Српски / srpski Srpskohrvatski / српскохрватски Basa Sunda Suomi Svenska தமிழ் ไทย Türkçe Türkmençe Українська اردو Tiếng Việt Winaray ייִדיש 粵語 中文 Edit links This page was last edited on 8 December 2017, at 19 : 08. 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Question: where does caffeine come from in energy drinks
Answer: ingredients used