Caffeine is a central nervous system (CNS) stimulant of the methylxanthineclass and is the most commonly consumed psychoactive substance globally.[9][10] It is mainly used for its eugeroic (wakefulness promoter), ergogenic (physical performance enhancing), or nootropic (cognition improving) properties.[11][12]Caffeine can supposedly, after a person grows used to it, have a lesser effect on wakefulness.[citation needed] Caffeine acts by blocking binding of adenosine at a number of adenosine receptor types, inhibiting the centrally depressant effects of adenosine and enhancing the release of acetylcholine.[13] Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors.[14] Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase, increases calcium release from intracellular stores, and antagonises GABA receptors, although these mechanisms typically occur at concentrations beyond usual human consumption.[10][15]
Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guaninebases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, fruits, nuts, or leaves of a number of plants native to Africa, East Asia and South America[16] and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds,[17] as well as encouraging consumption by select animals such as honey bees.[18] The best-known source of caffeine is the coffee bean, the seed of the Coffea plant. People may drink beverages containing caffeine to relieve or prevent drowsiness and to improve cognitive 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 consumed globally in high volumes. In 2020, almost 10 million tonnes of coffee beans were consumed globally.[19] Caffeine is the world's most widely consumed psychoactive drug.[20][21] Unlike most other psychoactive substances, caffeine remains largely unregulated and legal in nearly all parts of the world. Caffeine is also an outlier as its use is seen as socially acceptable in most cultures with it even being encouraged.
Caffeine has 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.[22] It may confer a modest protective effect against some diseases,[23] including Parkinson's disease.[24] Some people experience sleep disruption or anxiety if they consume caffeine,[25] but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit caffeine to the equivalent of two cups of coffee per day or less.[26][27] 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.[28][29][2]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).[30]
Caffeine is classified by the U.S. Food and Drug Administration (FDA) as generally recognized as safe. Toxic doses, over 10 grams per day for an adult, are much higher than the typical dose of under 500 milligrams per day.[31] The European Food Safety Authority reported that up to 400 mg of caffeine per day (around 5.7 mg/kg of body mass per day) does not raise safety concerns for non-pregnant adults, while intakes up to 200 mg per day for pregnant and lactating women do not raise safety concerns for the fetus or the breast-fed infants.[32] A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used, how it is roasted, and how it is prepared (e.g., drip, percolation, or espresso).[33] Thus it requires roughly 50–100 ordinary cups of coffee to reach the toxic dose. However, pure powdered caffeine, which is available as a dietary supplement, can be lethal in tablespoon-sized amounts.
Caffeine is used for both prevention[34] and treatment[35] of bronchopulmonary dysplasia in premature infants. It may improve weight gain during therapy[36] and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay.[37][38] On the other hand, subtle long-term side effects are possible.[39]
Some people use caffeine-containing beverages such as coffee or tea to try to treat their asthma.[45] Evidence to support this practice is poor.[45] It appears that caffeine in low doses improves airway function in people with asthma, increasing forced expiratory volume (FEV1) by 5% to 18% for up to four hours.[46]
The addition of caffeine (100–130 mg) to commonly prescribed pain relievers such as paracetamol or ibuprofen modestly improves the proportion of people who achieve pain relief.[47]
Consumption of caffeine after abdominal surgery shortens the time to recovery of normal bowel function and shortens length of hospital stay.[48]
Caffeine was formerly used as a second-line treatment for ADHD. It is considered less effective than methylphenidate or amphetamine but more so than placebo for children with ADHD.[49][50] Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of self-medication.[50][51]
Enhancing performance
Cognitive performance
Caffeine is a central nervous system stimulant that may reduce fatigue and drowsiness.[9] At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination.[52][53] The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance.[52] 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.[4]
Caffeine can delay or prevent sleep and improves task performance during sleep deprivation.[54]Shift workers who use caffeine make fewer mistakes that could result from drowsiness.[55]
Caffeine in a dose dependent manner increases alertness in both fatigued and normal individuals.[56]
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;[57] these effects are most pronounced during the first hour post-dose.[57]
Physical performance
Caffeine is a proven ergogenic aid in humans.[58] Caffeine improves athletic performance in aerobic (especially endurance sports) and anaerobic conditions.[58] Moderate doses of caffeine (around 5 mg/kg[58]) can improve sprint performance,[59] cycling and running time trial performance,[58] endurance (i.e., it delays the onset of muscle fatigue and central fatigue),[58][60][61] and cycling power output.[58] Caffeine increases basal metabolic rate in adults.[62][63][64] Caffeine ingestion prior to aerobic exercise increases fat oxidation, particularly in persons with low physical fitness.[65]
Caffeine improves muscular strength and power,[66] and may enhance muscular endurance.[67] Caffeine also enhances performance on anaerobic tests.[68] Caffeine consumption before constant load exercise is associated with reduced perceived exertion. While this effect is not present during exercise-to-exhaustion exercise, performance is significantly enhanced. This is congruent with caffeine reducing perceived exertion, because exercise-to-exhaustion should end at the same point of fatigue.[69] Caffeine also improves power output and reduces time to completion in aerobic time trials,[70] an effect positively (but not exclusively) associated with longer duration exercise.[71]
Specific populations
Adults
For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.[72] This limit was found to be safe by a 2017 systematic review on caffeine toxicology.[73]
Children
In healthy children, moderate caffeine intake under 400 mg produces effects that are "modest and typically innocuous".[74][75] As early as six months old, infants can metabolize caffeine at the same rate as that of adults.[76] Higher doses of caffeine (>400 mg) can cause physiological, psychological and behavioral harm, particularly for children with psychiatric or cardiac conditions.[74] There is no evidence that coffee stunts a child's growth.[77] The American Academy of Pediatrics recommends that caffeine consumption, particularly in the case of energy and sports drinks, is not appropriate for children and adolescents and should be avoided.[78] This recommendation is based on a clinical report released by American Academy of Pediatrics in 2011 with a review of 45 publications from 1994 to 2011 and includes inputs from various stakeholders (Pediatricians, Committee on nutrition, Canadian Pediatric Society, Centers for Disease Control & Prevention, Food and Drug Administration, Sports Medicine & Fitness committee, National Federations of High School Associations).[78] 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:[72]
Age range
Maximum recommended daily caffeine intake
4–6
45 mg (slightly more than in 355 ml (12 fl. oz) of a typical caffeinated 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 experiencing adverse effects.[72]
Pregnancy and breastfeeding
The metabolism of caffeine is reduced in pregnancy, especially in the third trimester, and the half-life of caffeine during pregnancy can be increased up to 15 hours (as compared to 2.5 to 4.5 hours in non-pregnant adults).[79] Evidence regarding the effects of caffeine on pregnancy and for breastfeeding are inconclusive.[26] There is limited primary and secondary advice for, or against, caffeine use during pregnancy and its effects on the fetus or newborn.[26]
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.[80] 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.[27] 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.[72] A 2017 systematic review on caffeine toxicology found evidence supporting that caffeine consumption up to 300 mg/day for pregnant women is generally not associated with adverse reproductive or developmental effect.[73]
There are conflicting reports in the scientific literature about caffeine use during pregnancy.[81] A 2011 review found that caffeine during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts.[82] Other reviews, however, concluded that 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,[83] and may be associated with a higher risk of pregnancy loss.[84] 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.[85]
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.[92] 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.[93] 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.[94][95][96]
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.[52][97] Caffeine can have negative effects on anxiety disorders.[98] According to a 2011 literature review, caffeine use may induce anxiety and panic disorders in people with Parkinson's disease.[99] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety.[100] For some people, discontinuing caffeine use can significantly reduce anxiety.[101]
In moderate doses, caffeine has been associated with reduced symptoms of depression and lower suicide risk.[102] Two reviews indicate that increased consumption of coffee and caffeine may reduce the risk of depression.[103][104]
Some textbooks state that caffeine is a mild euphoriant,[105][106][107] while others state that it is not a euphoriant.[108][109]
Whether caffeine can result in an addictive disorder depends on how addiction is defined. Compulsive caffeine consumption under any circumstances has not been observed, and caffeine is therefore not generally considered addictive.[111] However, some diagnostic models, such as the ICDM-9 and ICD-10, include a classification of caffeine addiction under a broader diagnostic model.[112] Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.[3][113]
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.[114] Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction.[28][115][116][117] Other research states it can affect the reward system.[118]
"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.[28][119][120] 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.[110][121]
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.[122] and most cases of caffeine withdrawal were 13% in the moderate sense. Moderately physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day, although these symptoms last no longer than a day.[28] Some symptoms associated with psychological dependence may also occur during withdrawal.[2] The diagnostic criteria for caffeine withdrawal require a previous prolonged daily use of caffeine.[123] Following 24 hours of a marked reduction in consumption, a minimum of 3 of these signs or symptoms is required to meet withdrawal criteria: difficulty concentrating, depressed mood/irritability, flu-like symptoms, headache, and fatigue.[123] Additionally, the signs and symptoms must disrupt important areas of functioning and are not associated with effects of another condition.[123]
The ICD-11 includes caffeine dependence as a distinct diagnostic category, which closely mirrors the DSM-5's proposed set of criteria for "caffeine-use disorder".[121][124] Caffeine use disorder refers to dependence on caffeine characterized by failure to control caffeine consumption despite negative physiological consequences.[121][124] 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 the disorder is unclear.[125] Due to this inconclusive evidence on clinical significance, the DSM-5 classifies caffeine-use disorder as a "condition for further study".[121]
Tolerance to the effects of caffeine occurs for caffeine-induced elevations in blood pressure and the subjective feelings of nervousness. Sensitization, the process whereby effects become more prominent with use, may occur for positive effects such as feelings of alertness and wellbeing.[122] 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 (170 g) cup of coffee or two to three 12 oz (340 g) 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.[126] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.[127]
Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.[130] One meta analysis has found that caffeine consumption is associated with a reduced risk of type 2 diabetes.[131] Regular caffeine consumption may reduce the risk of developing Parkinson's disease and may slow the progression of Parkinson's disease.[132][133][24]
The DSM-5 also includes other caffeine-induced disorders consisting of caffeine-induced anxiety disorder, caffeine-induced sleep disorder and unspecified caffeine-related disorders. The first two disorders are classified under "Anxiety Disorder" and "Sleep-Wake Disorder" because they share similar characteristics. Other disorders that present with significant distress and impairment of daily functioning that warrant clinical attention but do not meet the criteria to be diagnosed under any specific disorders are listed under "Unspecified Caffeine-Related Disorders".[135]
Energy crash
Caffeine is reputed to cause a fall in energy several hours after drinking, but this is not well researched.[136][137][138][139]
Overdose
This section needs expansion with: practical management of overdose, see PMID30893206. You can help by adding to it. (November 2019)
Consumption of 1–1.5 grams (1,000–1,500 mg) per day is associated with a condition known as caffeinism.[141] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.[142]
Caffeine overdose can result in a state of central nervous system overstimulation known as caffeine intoxication, a clinically significant temporary condition that develops during, or shortly after, the consumption of caffeine.[143] 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). According to the DSM-5, caffeine intoxication may be diagnosed if five (or more) of the following symptoms develop after recent consumption of caffeine: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, periods of inexhaustibility, and psychomotor agitation.[144]
According to the International Classification of Diseases (ICD-11), cases of very high caffeine intake (e.g. > 5 g) may result in caffeine intoxication with symptoms including mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations or psychosis, and rhabdomyolysis.[143]
Energy drinks
High caffeine consumption in energy drinks (at least one liter or 320 mg of caffeine) was associated with short-term cardiovascular side effects including hypertension, prolonged QT interval, and heart palpitations. These cardiovascular side effects were not seen with smaller amounts of caffeine consumption in energy drinks (less than 200 mg).[79]
Severe intoxication
As of 2007[update] there is no known antidote or reversal agent for caffeine intoxication. Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration.[140][145][146]Intralipid infusion therapy is indicated in cases of imminent risk of cardiac arrest in order to scavenge the free serum caffeine.[146]
Lethal dose
Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications.[147] In 2016, 3702 caffeine-related exposures were reported to Poison Control Centers in the United States, of which 846 required treatment at a medical facility, and 16 had a major outcome; and several caffeine-related deaths are reported in case studies.[147] The LD50 of caffeine in rats is 192 milligrams per kilogram of body mass. The fatal dose in humans is estimated to be 150–200 milligrams per kilogram, which is 10.5–14 grams for a typical 70 kg (150 lb) adult, equivalent to about 75–100 cups of coffee.[148][149] There are cases where doses as low as 57 milligrams per kilogram have been fatal.[150] 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.[151] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease.[152] A death was reported in 2013 of a man with liver cirrhosis who overdosed on caffeinated mints.[153][154]
Interactions
Caffeine is a substrate for CYP1A2, and interacts with many substances through this and other mechanisms.[155]
According to DSST, alcohol causes a decrease in performance on their standardized tests, and caffeine causes a significant improvement.[156] When alcohol and caffeine are consumed jointly, the effects of the caffeine are changed, but the alcohol effects remain the same.[157] For example, consuming additional caffeine does not reduce the effect of alcohol.[157] However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed.[157] Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the effect of alcohol on the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.[158] The Dietary Guidelines for Americans recommend avoidance of concomitant consumption of alcohol and caffeine, as taking them together may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.
Smoking
Smoking tobacco has been shown to increase caffeine clearance by 56% as a result of polycyclic aromatic hydrocarbons inducing the CYP1A2 enzyme.[159][10] The CYP1A2 enzyme that is induced by smoking is responsible for the metabolism of caffeine; increased enzyme activity leads to increased caffeine clearance, and is associated with greater coffee consumption for regular smokers.[160]
Birth control
Birth control pills can extend the half-life of caffeine by as much as 40%, requiring greater attention to caffeine consumption.[161][162]
Medications
Caffeine sometimes increases the effectiveness of some medications, such as those for headaches.[163] Caffeine was determined to increase the potency of some over-the-counter analgesic medications by 40%.[164]
The pharmacological effects of adenosine may be blunted in individuals taking large quantities of methylxanthines like caffeine.[165] Some other examples of methylxanthines include the medications theophylline and aminophylline, which are prescribed to relieve symptoms of asthma or COPD.[166]
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 adenosine 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.[5]
Antagonism of adenosine receptors by caffeine also stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heart rate, and constricts blood vessels.[5] Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;[5][169]adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the A1 receptor.[5]
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.[170]
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 A1–D1 receptor heterodimer (this is a receptor complex with one adenosine A1 receptor and one dopamine D1 receptor) and the A2A–D2 receptor heterotetramer (this is a receptor complex with two adenosine A2A receptors and two dopamine D2 receptors).[173][174][175][176] The A2A–D2 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.[174][175][176]
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 A1 receptors in the axon terminal of dopamine neurons and A1–A2A heterodimers (a receptor complex composed of one adenosine A1 receptor and one adenosine A2A receptor) in the axon terminal of glutamate neurons.[173][168] During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance.[173][168]
Caffeine is metabolized in the liver via a single demethylation, resulting in three primary metabolites, paraxanthine (84%), theobromine (12%), and theophylline (4%), depending on which methyl group is removed.Urinary metabolites of caffeine in humans at 48 hours post-dose[184]
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues.[185] Peak blood concentration is reached within 1–2 hours.[186] It is eliminated by first-order kinetics.[187] Caffeine can also be absorbed rectally, evidenced by suppositories of ergotaminetartrate and caffeine (for the relief of migraine)[188] and of chlorobutanol and caffeine (for the treatment of hyperemesis).[189] However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.[190]
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 and 7 hours.[5] The half-life is decreased by 30-50% in adult male smokers, approximately doubled in women taking oral contraceptives, and prolonged in the last trimester of pregnancy.[127] In newborns the half-life can be 80 hours or more, dropping rapidly with age, possibly to less than the adult value by age 6 months.[127] 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.[191]
1,3,7-Trimethyluric acid is a minor caffeine metabolite.[5]7-Methylxanthine is also a metabolite of caffeine.[193][194] Each of the above metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.[195]
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.[196] 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.[7][8] Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but quickly soluble in boiling water (66 g/100 mL).[197] It is also moderately soluble in ethanol (1.5 g/100 mL).[197] It is weakly basic (pKa of conjugate acid = ~0.6) requiring strong acid to protonate it.[198] Caffeine does not contain any stereogenic centers[199] and hence is classified as an achiral molecule.[200]
The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominantly in a zwitterionicresonance 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 sp2hybridized and planar. The imidazole ring also has a resonance. 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.[201]
Caffeine may be synthesized in the lab starting with dimethylurea and malonic acid.[clarification needed][204][205][209] Production of synthesized caffeine largely takes place in pharmaceutical plants in China. Synthetic and natural caffeine are chemically identical and nearly indistinguishable. The primary distinction is that synthetic caffeine is manufactured from urea and chloroacetic acid, while natural caffeine is extracted from plant sources, a process known as decaffeination.[210]
Despite the different production methods, the final product and its effects on the body are similar. Research on synthetic caffeine supports that it has the same stimulating effects on the body as natural caffeine.[211] And although many claim that natural caffeine is absorbed slower and therefore leads to a gentler caffeine crash, there is little scientific evidence supporting the notion.[210]
Germany, the birthplace of decaffeinated coffee, is home to several decaffeination plants, including the world's largest, Coffein Compagnie.[212] Over half of the decaf coffee sold in the U.S. first travels from the tropics to Germany for caffeine removal before making its way to American consumers.[citation needed]
Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using a number of solvents. Following are 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.[213]
Supercritical carbon dioxide extraction:Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high-pressure water to remove the caffeine. The caffeine can then be isolated by charcoaladsorption (as above) or by distillation, recrystallization, or reverse osmosis.[213]
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.[213]
"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.[214]
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.[215]
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 xanthinesDMPX[216] 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.[217][unreliable source?] Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.[218]
Around thirty plant species are known to contain caffeine.[220] 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); and of the cocoa plant, Theobroma cacao; the leaves of the tea plant; and kola nuts. Other sources include the leaves of yaupon holly, South American holly yerba mate, and Amazonian holly guayusa; and seeds from Amazonian maple guarana berries. 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.[221] High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.[222] 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.[223] 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.[224] Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honey bees.[18]
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 methylxanthinealkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.[225]
Products containing caffeine include coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,[239] caffeine tablets, other oral products, and inhalation products. According to a 2020 study in the United States, coffee is the major source of caffeine intake in middle-aged adults, while soft drinks and tea are the major sources in adolescents.[79] Energy drinks are more commonly consumed as a source of caffeine in adolescents as compared to adults.[79]
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;[240] 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.[241][242]Arabica coffee typically contains half the caffeine of the robusta variety.[240]
In general, dark-roast coffee has slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount.[241][242]
Tea
Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since less of the product is used as compared to an equivalent serving of coffee. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, teas contain varying amounts of caffeine.[243]
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 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 minimal content.[243]
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 (350 mL) serving.[244] 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-releaseexcipient.[245]
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.[246]
Guaraná is a soft drink originating in Brazil made from the seeds of the Guaraná fruit.
The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea.[247]
The leaves of Ilex vomitoria, the yaupon holly tree, are placed in boiling water to make a yaupon tea.
Commercially prepared coffee-flavoured milk beverages are popular in Australia.[248] Examples include Oak's Ice Coffee and Farmers Union Iced Coffee. The amount of caffeine in these beverages can vary widely. Caffeine concentrations can differ significantly from the manufacturer's claims.[232]
The stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.[249]
Tablets
No-Doz 100 mg caffeine tablets
Tablets offer several advantages over coffee, tea, and other caffeinated beverages, including convenience, known dosage, and avoidance of concomitant intake of sugar, acids, and fluids. A use of caffeine in this form is said to improve mental alertness.[250] These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.[251]
Other oral products
One U.S. company is marketing oral dissolvable caffeine strips.[252] Another intake route is SpazzStick, a caffeinated lip balm.[253] 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.[254]
Inhalants
Similar to an e-cigarette, a caffeine inhaler may be used to deliver caffeine or a stimulant like guarana by vaping.[255] In 2012, the FDA sent a warning letter to one of the companies marketing an inhaler, expressing concerns for the lack of safety information available about inhaled caffeine.[256][257]
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, the United States Food and Drug Administration has classified caffeine added to malt liquor beverages as an "unsafe food additive".[258]
According to Chinese legend, the Chinese emperorShennong, reputed to have reigned in about 3000 BCE, inadvertently discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted.[259] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[260]
The earliest credible evidence of either coffee drinking or knowledge of the coffee plant appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemen in southern Arabia.[261] 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.[262]
Kola nut use appears to have ancient origins. It is chewed in many West African cultures, in both private and social settings, to restore vitality and ease hunger pangs.[263]
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-ColumbianMesoamerica, and cocoa beans were often used as currency.[264]
In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure[vague] caffeine for the first time; he called it "Kaffebase" (i.e., a base that exists in coffee).[269] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[a][271] 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.[272] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:[273] "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).[274] 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,[275] whereas Pelletier was the first to perform an elemental analysis.[276]
In 1827, M. Oudry isolated "théine" from tea,[277] but in 1838 it was proved by Mulder[278] and by Carl Jobst[279] that theine was actually the same as 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.[280] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.[281]
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.[282][283][284]Charles II of England tried to ban it in 1676,[285][286]Frederick II of Prussia banned it in 1777,[287][288] and coffee was banned in Sweden at various times between 1756 and 1823.
The US Food and Drug Administration (FDA) considers safe beverages containing less than 0.02% caffeine;[291] but caffeine powder, which is sold as a dietary supplement, is unregulated.[292] 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.[293] The FDA guidance was updated in 2018.[294]
Consumption
Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance.[20] The consumption of caffeine has remained stable between 1997 and 2015.[295] Coffee, tea and soft drinks are the most common caffeine sources, with energy drinks contributing little to the total caffeine intake across all age groups.[295]
Religions
The Seventh-day Adventist Church asked for its members to "abstain from caffeinated drinks", but has removed this from baptismal vows (while still recommending abstention as policy).[296] 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."[297]
Gaudiya Vaishnavas generally also abstain from caffeine, because they believe it clouds the mind and overstimulates the senses.[298] To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.[299]
Caffeinated beverages are widely consumed by Muslims. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.[300][301]
The bacteria Pseudomonas putida CBB5 can live on pure caffeine and can cleave caffeine into carbon dioxide and ammonia.[302]
Caffeine is toxic to birds[303] and to dogs and cats,[304] and has a pronounced adverse effect on mollusks, various insects, and spiders.[305] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.[184] Caffeine has also been found to enhance the reward memory of honey bees.[18]
^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.").[270]
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^Hrnčiarove J, Barteček R (2017). "8. Substance Dependence". In Hosák L, Hrdlička M, et al. (eds.). Psychiatry and Pedopsychiatry. Prague: Karolinum Press. pp. 153–154. ISBN9788024633787. At a high dose, caffeine shows a euphoric effect.
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^Salerno BB, Knights EK (2010). Pharmacology for health professionals (3rd ed.). Chatswood, N.S.W.: Elsevier Australia. p. 433. ISBN978-0-7295-3929-6. In contrast to the amphetamines, caffeine does not cause euphoria, stereotyped behaviors or psychoses.
^Ebenezer I (2015). Neuropsychopharmacology and Therapeutics. John Wiley & Sons. p. 18. ISBN978-1-118-38578-4. 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.
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^Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–43. doi:10.31887/DCNS.2013.15.4/enestler. PMC3898681. PMID24459410. 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
^Miller PM (2013). "Chapter III: Types of Addiction". Principles of addiction comprehensive addictive behaviors and disorders (1st ed.). Elsevier Academic Press. p. 784. ISBN978-0-12-398361-9. 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.
^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. doi:10.31887/DCNS.2010.12.2/anehlig. PMC3181952. PMID20623930. 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.42
^Karch SB (2009). Karch's pathology of drug abuse (4th ed.). Boca Raton: CRC Press. pp. 229–230. ISBN978-0-8493-7881-2. 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
^"ICD-10 Version:2015". World Health Organization. 2015. Archived from the original on 2 November 2015. Retrieved 10 July 2015. F15 Mental and behavioural disorders due to use of other stimulants, including caffeine ...
.2 Dependence syndrome A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state. The dependence syndrome may be present for a specific psychoactive substance (e.g., tobacco, alcohol, or diazepam), for a class of substances (e.g., opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:] Chronic alcoholism Dipsomania Drug addiction
^American Psychiatric Association (2013). "Substance-Related and Addictive Disorders". American Psychiatric Publishing. pp. 1–2. Retrieved 18 November 2019.
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^ abFintel M, Langer GA, Duenas C (November 1984). "Effects of low sodium perfusion on cardiac caffeine sensitivity and calcium uptake". Journal of Molecular and Cellular Cardiology. 16 (11): 1037–1045. doi:10.1016/s0022-2828(84)80016-4. PMID6520875.
^"Caffeine | C8H10N4O2". pubchem.ncbi.nlm.nih.gov. National Center for Biotechnology Information. Archived from the original on 2 March 2022. Retrieved 1 March 2022.
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^Gottwalt B, Prasanna T (29 September 2021). "Methylxanthines". StatPearls. PMID32644591. Archived from the original on 20 March 2022. Retrieved 15 November 2021.
^ abcFerré 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. PMC9361505. PMID20182056. 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.
^Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–511. doi:10.1164/ajrccm.159.2.9804085. PMID9927365.
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^Blanchard J, Sawers SJ (1983). "The absolute bioavailability of caffeine in man". European Journal of Clinical Pharmacology. 24 (1): 93–8. doi:10.1007/bf00613933. PMID6832208. S2CID10502739.
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^Graham JR (June 1954). "Rectal use of ergotamine tartrate and caffeine alkaloid for the relief of migraine". The New England Journal of Medicine. 250 (22): 936–8. doi:10.1056/NEJM195406032502203. PMID13165929.
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^Vallombroso T (2001). Organic Chemistry Pearls of Wisdom. Boston Medical Publishing Corp. p. 43. ISBN978-1-58409-016-8.
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^"Caffeine biosynthesis". The Enzyme Database. Trinity College Dublin. Archived from the original on 22 March 2012. Retrieved 24 September 2011.
^ abTemple NJ, Wilson T (2003). Beverages in Nutrition and Health. Totowa, NJ: Humana Press. p. 172. ISBN978-1-58829-173-8.
^ abUS patent 2785162, Swidinsky J, Baizer MM, "Process for the formylation of a 5-nitrouracil", published 12 March 1957, assigned to New York Quinine and Chemical Works, Inc.
^ abcSenese F (20 September 2005). "How is coffee decaffeinated?". General Chemistry Online. Archived from the original on 18 January 2012. Retrieved 3 August 2009.
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^Frischknecht PM, Ulmer-Dufek J, Baumann TW (1986). "Purine alkaloid formation in buds and developing leaflets of Coffea arabica: Expression of an optimal defence strategy?". Phytochemistry. 25 (3): 613–6. Bibcode:1986PChem..25..613F. doi:10.1016/0031-9422(86)88009-8.
^Baumann TW (1984). "Metabolism and excretion of caffeine during germination of Coffea arabica L". Plant and Cell Physiology. 25 (8): 1431–6. doi:10.1093/oxfordjournals.pcp.a076854.
^Balentine DA, Harbowy ME, Graham HN (1998). "Tea: the Plant and its Manufacture; Chemistry and Consumption of the Beverage". In Spiller GA (ed.). Caffeine Consumption. CRC Press. ISBN978-0-429-12678-9.
^ abcDesbrow B (2012). "An examination of consumer exposure to caffeine from commercial coffee and coffee-flavoured milk". Journal of Food Composition and Analysis. 28 (2): 114. doi:10.1016/j.jfca.2012.09.001. hdl:10072/49194.
^Matissek R (1997). "Evaluation of xanthine derivatives in chocolate: nutritional and chemical aspects". European Food Research and Technology. 205 (3): 175–84. doi:10.1007/s002170050148. S2CID83555251. INIST2861730.
^ ab"Caffeine". International Coffee Organization. Archived from the original on 27 March 2009. Retrieved 1 August 2009.
^ abHicks MB, Hsieh YH, Bell LN (1996). "Tea preparation and its influence on methylxanthine concentration". Food Research International. 29 (3–4): 325–330. doi:10.1016/0963-9969(96)00038-5.
^Ried K (21 June 2012). "Dark Chocolate and (Pre-)Hypertension". In Watson RR, Preedy VR, Zibadi S (eds.). Chocolate in Health and Nutrition. Humana Press. pp. 313–325. doi:10.1007/978-1-61779-803-0_23. ISBN978-1-61779-802-3.
^ abFairbanks CH (2004). "The function of black drink among the Creeks". In Hudson MC (ed.). Black Drink. University of Georgia Press. p. 123. ISBN978-0-8203-2696-2.
^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
^Berzelius JJ (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). Vol. 4. p. 180: Caféin ist eine Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und Pelletier und Caventou entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt machte. [Caffeine is a material in coffee, which was discovered at the same time, 1821, by Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known about it in the press.]
^Berzelius JJ (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual Report on the Progress of the Physical Sciences by Jacob Berzelius] (in German). Vol. 7. p. 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.
^Pelletier PJ (1822). "Cafeine". Dictionnaire de Médecine (in French). Vol. 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 3 March 2011.
^Robiquet PJ (1823). "Café". Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers (in French). Vol. 4. Paris: Thomine et Fortic. pp. 50–61. Retrieved 3 March 2011.
^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. Archived from the original on 15 October 2015. Retrieved 17 June 2013.
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. Archived from the original on 15 October 2015. Retrieved 17 June 2013.
^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. PMID18464846.
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