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===Analogs===
===Analogs===
Some analog substances have been created which mimic caffeine's properties with either function or structure or both, one of the latter is the drug [[DMPX]].<ref name=DMPX>[http://www.ncbi.nlm.nih.gov/pubmed/3193854 3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs.] Life Sci. 1988;43(21):1671–84. PMID 3193854</ref> Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.<ref>{{cite web|last1=Kennerly|first1=Jason|title=N Substituted Xanthines: A Caffeine Analog Information File|date=22 September 1995|url=https://www.erowid.org/chemicals/caffeine/caffeine_chemistry1.shtml|accessdate=6 November 2015}}</ref>{{rs|date=November 2015}} Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.<ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882893/ Xanthines as Adenosine Receptor Antagonists] Handb Exp Pharmacol. 2011; (200): 10.1007/978-3-642-13443-2_6. doi: 10.1007/978-3-642-13443-2_6</ref>
Some analog substances have been created which mimic caffeine's properties with either function or structure or both, one of the latter is the drug [[DMPX]].<ref name=DMPX>[http://www.ncbi.nlm.nih.gov/pubmed/3193854 3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs.] Life Sci. 1988;43(21):1671–84. PMID 3193854</ref> Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.<ref>{{cite web|last1=Kennerly|first1=Jason|title=N Substituted Xanthines: A Caffeine Analog Information File|date=22 September 1995|url=https://www.erowid.org/chemicals/caffeine/caffeine_chemistry1.shtml|accessdate=6 November 2015}}</ref>{{rs|date=November 2015}} Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.<ref>{{cite journal|last1=Müller|first1=Christa E.|last2=Jacobson|first2=Kenneth A.|editor1-last=Fredholm|editor1-first=Bertil B.|title=Xanthines as Adenosine Receptor Antagonists|date=19 August 2010|volume=200|pages=151-199|doi=10.1007/978-3-642-13443-2_6|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882893/|accessdate=9 November 2015|series=Handbook of Experimental Pharmacology|publisher=Springer Berlin Heidelberg|issn=0171-2004}}</ref>


==Natural occurrence==
==Natural occurrence==

Revision as of 01:13, 9 November 2015

This article is about the stimulant. For other uses, see Caffeine (disambiguation).

Caffeine (INN)
2D structure of caffeine
3D structure of caffeine
Clinical data
Pronunciation/kæˈfiːn, ˈkæfiːn/
Other namesGuaranine
Methyltheobromine
1,3,7-Trimethylxanthine
Theine
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: A
Dependence
liability		Physical: low–moderate[1][2][3][4]
Psychological: very low[3]
Addiction
liability		Low[4] / None[1][2][3]
Routes of
administration		oral, insufflation, enema, rectal, intravenous
ATC code
Legal status
Legal status
  • AU: Unscheduled
  • CA: Unscheduled
  • DE: Unscheduled
  • NZ: Unscheduled
  • UK: Unscheduled
  • US: Unscheduled
  • UN: Unscheduled
  • EU: Unscheduled
Pharmacokinetic data
Bioavailability99%[5]
Protein binding25–36%[6]
MetabolismPrimary: CYP1A2[6]
Minor: CYP2E1,[6] CYP3A4,[6] CYP2C8,[6] CYP2C9[6]
MetabolitesParaxanthine (84%)
Theobromine (12%)
Theophylline (4%)
Onset of action~1 hour[5]
Elimination half-lifeAdults: 3–7 hours[6]
Neonates: 65–130 hours[6]
Duration of action3-4 hours[5]
Excretionurine (100%)
Identifiers
  • 1,3,7-Trimethylpurine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.000.329 Edit this at Wikidata
Chemical and physical data
FormulaC8H10N4O2
Molar mass194.19 g/mol g·mol−1
3D model (JSmol)
Density1.23 g/cm3
Melting point235 to 238 °C (455 to 460 °F) (anhydrous)[7][8]
  • CN1C=NC2=C1C(=O)N(C(=O)N2C)C
  • 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 checkY
Data page
Caffeine (data page)

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class of psychoactive drugs.[9] It is the world's most widely consumed psychoactive drug, but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. It is a bitter, white crystalline purine, a methylxanthine alkaloid, and thus closely related chemically to the adenine and guanine contained in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, nuts, or leaves of a number of plants native to South America and East Asia. The most well known source of caffeine is the seed (commonly incorrectly referred to as the "bean") of Coffea plants. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to increase one's energy level. Caffeine is extracted from the plant part containing it for making beverages by steeping it in water, a process called infusion. These beverages are very popular; in North America, 90% of adults consume caffeine daily.[10]

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

Caffeine can have both positive and negative health effects. It can be used to treat bronchopulmonary dysplasia of prematurity, and to prevent apnea of prematurity: caffeine citrate was placed on the WHO Model List of Essential Medicines in 2007.[11] It may confer a modest protective effect against some diseases,[12] including Parkinson's disease[13] and certain types of cancer. One meta-analysis concluded that cardiovascular disease such as coronary artery disease and stroke is less likely with 3–5 cups of non-decaffeinated coffee per day but more likely with over 5 cups per day.[14] 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.[15][16] Whether or not caffeine is an addictive drug depends on how an addiction is defined. It can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake.[1][3][17] Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).[citation needed]

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

Uses

Main article: Health effects of caffeine

Medical

Caffeine is used in:

Enhancing performance

Caffeine is a central nervous system and metabolic stimulant,[9] and is used to reduce physical fatigue and to prevent or treat drowsiness. It produces increased wakefulness, improved thought-processing, increased focus, and better general body coordination.[28] The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance.[28] Desired effects begin approximately one hour after consumption, and a moderate dose usually subsides in about three or four hours.[5]

Caffeine has the desired effect of delaying/preventing sleep, but does not affect all people in the same way. It also improves performance during sleep deprivation.[29] Shift workers have fewer mistakes caused by drowsiness.[30]

In athletes, moderate doses of caffeine can improve sprint,[31] stamina, endurance,[32] and team sports performance,[33] but the improvements are usually limited. Some evidence suggests that coffee does not produce the performance-enhancing effects observed in other caffeine sources.[34]

Caffeine is a mild cognition enhancer as it is related to the effect on wakefulness, concentration, and mood.[35] At normal doses, caffeine improves memory in learning and sleep deprived activities, but has both beneficial and harmful effects on the working memory depending on the nature of the task.[35] Concurrent caffeine and L-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching;[36] these effects are most pronounced during the first hour post-dose.[36]

Side effects

Side effects of caffeine

Physical

Caffeine can increase blood pressure and cause vasoconstriction.[37][38][39] Long term consumption at sufficiently high doses has been associated with chronic arterial stiffness.[39] Coffee and caffeine can affect gastrointestinal motility and gastric acid secretion.[40][41][42]

Caffeine increases basal metabolic rate in adults.[43][44][45] In postmenopausal women, high caffeine consumption can accelerate bone loss.[46][47]

Caffeine increases urine output acutely, but not chronically.[48] 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.[49] 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.[50][51]

Caffeine in low doses may cause weak bronchodilation for up to four hours in asthmatics.[52]

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.[28][53] Caffeine can have negative effects on anxiety disorders.[54] According to a 2011 literature review, caffeine use is positively associated with anxiety and panic disorders.[55] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety.[56] For some people, discontinuing caffeine use can significantly reduce anxiety.[57]

Low doses of caffeine cause increased alertness and decreased fatigue.[58] In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk.[59]

Risk during pregnancy

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.[60] However, as the data supporting this conclusion is of poor quality, some suggest limiting caffeine consumption during pregnancy.[61][62] 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.[63] 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.[16] Although the evidence that caffeine may be harmful during pregnancy is equivocal, there is some evidence that the hormonal changes during pregnancy slow the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting effects (as long as 15 hours in the third trimester).[64]

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.[65] Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.[66][67]

Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction.[1][68][69][70] Other research states it can affect the reward system.[71]

"Caffeine addiction" was added to the ICDM-9 and ICD-10; however, its addition was contested with claims that this diagnostic model of caffeine addiction is not supported by evidence.[1][2][72] The American Psychiatric Association's DSM-5 does not include the diagnosis of a caffeine addiction but propose criteria for the disorder for more study.[73][74]

Dependence and withdrawal

Mild physical dependence may occur with repeated daily intake;[1] the associated physical withdrawal symptoms such as fatigue, headache, irritability, inability to concentrate, sleepiness or drowsiness, stomach pain, and joint pain.[1][17] Withdrawal headaches are experienced by roughly half of those who stop consuming caffeine for two days following an average daily intake of 235 mg.[75]

The ICD-10 includes a diagnostic model for caffeine dependence, but the DSM-5 does not.[3][72] The APA, which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of this disorder is unclear.[3] The DSM-5 instead lists "caffeine use disorder" in the emerging models section of the manual.[3]

Tolerance

Tolerance to the desired effect of alertness does not occur following repeated use. Tolerance to some undesired effects, particularly to caffeine's autonomic effects, develops quickly, especially among heavy coffee and energy drink consumers.[76] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.[64]

Risk of other diseases

Coffee consumption is associated with a lower overall risk of cancer.[77] This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer.[78] There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer.[78] A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.[79][80][81] Moderate coffee consumption may decrease the risk of cardiovascular disease,[14] and it may somewhat reduce the risk of type 2 diabetes.[82] Drinking four or more cups of coffee per day does not affect the risk of hypertension compared to drinking little or no coffee. However those who drink 1–3 cups per day may be at a slightly increased risk.[83] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.[84] It may protect people from liver cirrhosis.[85] There is no evidence that coffee stunts a child's growth.[86] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.[87] Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.[88]

Overdose

Torso of a young man with overlaid text of main side-effects of caffeine overdose.
Primary symptoms of caffeine intoxication[89]

Consumption of 1,000–1,500 mg per day is associated with a condition known as caffeinism.[90] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.[91]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90).[92] 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.[89] 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.[93][94]

Massive overdose can result in death.[95][96] The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be 150 to 200 milligrams per kilogram of body mass (75–100 cups of coffee for a 70 kilogram adult).[97] 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.[98] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease[99] A death was reported in a man with liver cirrhosis who overdosed on caffeinated mints.[100][101][102]

Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration.[89]

Pharmacology

Pharmacodynamics

Structure of a typical chemical synapse
Two skeletal formulas: left – caffeine, right – adenosine.
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.[6]

Receptor and ion channel targets

Caffeine is a receptor antagonist at all adenosine receptor subtypes (A1, A2A, A2B, and A3 receptors).[6] Antagonism at these receptors stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heartrate, and constricts blood vessels.[6] Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;[6][103] adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the adenosine A1 receptor.[6]

Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.[104]

In addition to its activity at adenosine receptors, caffeine is an inositol triphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3).[105] It is also a competitive antagonist of the ionotropic glycine receptor.[106]

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.[107] As a competitive nonselective phosphodiesterase inhibitor,[108] caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha[109][110] and leukotriene[111] synthesis, and reduces inflammation and innate immunity.[111] Caffeine is also significantly implicated in cholinergic system where it e.g. inhibits enzyme acetylcholinesterase.[112]

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.[113] Disinhibition of the tuberomammillary nucleus is the chief mechanism by which caffeine produces wakefulness-promoting effects.[113]

Pharmacokinetics

A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.
Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)

Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues.[114] Peak blood concentration is reached within 1–2 hours.[citation needed] It is eliminated by first-order kinetics.[115] Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine)[116] and chlorobutanol and caffeine (for the treatment of hyperemesis).[117]

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.[6] Nicotine decreases the half-life by 30–50%,[64] while oral contraceptives can double it[64] and pregnancy can raise it to as much as 15 hours during the last trimester.[64] 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.[64] 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.[118]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,[119] each of which has its own effects on the body:

1,3,7-Trimethyluric acid is a minor caffeine metabolite.[6] 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.[120]

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.[121] This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene "forces" people to drink coffee.

Physical and chemical properties

Pure anhydrous caffeine is a white odorless powder with a melting point of 235–238 °C.[7][8] Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL).[122] It is also moderately soluble in ethanol (1.5 g/100 mL).[122] It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.[123] Caffeine does not contain any stereogenic centers[124] and hence is classified as an achiral molecule.[125]

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2 hybridized and planar. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.[126]

Biosynthesis

Caffeine may be synthesized from dimethylurea and malonic acid,[127][128][129] but is rarely obtained from synthesis since it is readily available as a byproduct of decaffeination.[130]

Synthesis diagram
Caffeine biosynthesis[131]
Synthesis diagram
Caffeine laboratory synthesis[127][128]

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.[132]

Analogs

Some analog substances have been created which mimic caffeine's properties with either function or structure or both, one of the latter is the drug DMPX.[133] Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.[134][unreliable source?] Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.[135]

Natural occurrence

Around sixty plant species are known to contain caffeine.[136] Common sources are the "bean" (seed) of the coffee plant (the quantity varies, but 1.3% is a typical value[137]); 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:[138] high caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.[139] 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.[140]

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.[141][clarification needed]

Products

See also: Caffeinated drink
Caffeine content in select food and drugs[142][143][144][145][146]
Product Serving size Caffeine per serving (mg) Caffeine (mg/L)
Caffeine tablet (regular-strength) 1 tablet 100 —
Caffeine tablet (extra-strength) 1 tablet 200 —
Excedrin tablet 1 tablet 65 —
Hershey's Special Dark (45% cacao content) 1 bar (43 g or 1.5 oz) 31 —
Hershey's Milk Chocolate (11% cacao content) 1 bar (43 g or 1.5 oz) 10 —
Percolated coffee 207 mL (7.0 US fl oz)* 80–135 386–652
Drip coffee 207 mL (7.0 US fl oz) 115–175 555–845
Coffee, decaffeinated 207 mL (7.0 US fl oz) 5–15 24–72
Coffee, espresso 44–60 mL (1.5–2.0 US fl oz) 100 1,691–2,254
Tea – black, green, and other types, – steeped for 3 min. 177 millilitres (6.0 US fl oz) 22–74[145][146] 124–418
Guayakí yerba mate (loose leaf) 6 g (0.21 oz) 85[147] approx. 358
Coca-Cola Classic 355 mL (12.0 US fl oz) 34 96
Mountain Dew 355 mL (12.0 US fl oz) 54 154
Pepsi Max 355 mL (12.0 US fl oz) 69 194
Guaraná Antarctica 350 mL (12 US fl oz) 30 100
Jolt Cola 695 mL (23.5 US fl oz) 280 403
Red Bull 250 mL (8.5 US fl oz) 80 320

Products containing caffeine are coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,[148] 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;[149] 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.[150][151] Arabica coffee typically contains half the caffeine of the robusta variety.[149] 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.[150][151]

Tea

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed more weakly than coffee. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, certain types of tea may contain somewhat more caffeine than other teas.[152]

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.[152]

Soft drinks and energy drinks

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain 10 to 69 milligrams of caffeine per 12 ounce serving.[citation needed] By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.[153]

Other beverages

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

Chocolate

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.[154] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount caffeine as coffee: 80–160 mg per 100 g.[143]

Tablets

No-Doz 100 mg caffeine tablets

Tablets offer the advantages over coffee and tea of convenience, known dosage, and avoiding concomitant fluid intake. Manufacturers of caffeine tablets claim that using caffeine of pharmaceutical quality improves mental alertness.[citation needed] These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.[155]

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.[156] Another intake route is SpazzStick, a caffeinated lip balm.[157] 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.[158]

Inhalants

Taking caffeine by inhalation was under scrutiny by some U.S. lawmakers in 2011.[159]

Combinations with other drugs

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.[161]
  • Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.[161]
  • 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.[161]

"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.[162]

History

Discovery and spread of use

An old photo of a dozen old and middle-aged men sitting on the ground around a mat. A man in front sits next to a mortar and holds a bat, ready for grinding. A man opposite to him holds a long spoon.
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.[163] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[164]

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.[165] 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.[166]

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

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

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as "black bean".[citation needed]

The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink".[167] Archaeologists have found evidence of this use far into antiquity,[168] possibly dating to Late Archaic times.[167]

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).[169] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[170][171] 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.[172] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:[173] "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).[174] 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,[175] whereas Pelletier was the first to perform an elemental analysis.[176]

In 1827, M. Oudry isolated "théine" from tea,[177] but it was later proved by Mulder[178] and by Carl Jobst[179] that theine was actually caffeine.[171]

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.[180] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.[181]

Society and culture

Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.[182]

Governments

Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca and in the Ottoman Empire made coffee illegal for some classes.[183][184][185] Charles II of England tried to ban it in 1676,[186][187] Frederick II of Prussia banned it in 1777,[188][189] 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".[190] 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.[191][unreliable source?] The Food and Drug Administration (FDA) in the United States currently allows only beverages containing less than 0.02% caffeine;[161] but caffeine powder, which is sold as a dietary supplement, is unregulated.[162]

Religions

Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine.[citation needed] Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: "With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided."[192]

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

Caffeinated beverages are widely consumed by Muslims today. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.[193][194]

Other organisms

Caffeine effects on spider webs.
Caffeine effects on spider webs
See also: Effect of psychoactive drugs on animals

Pseudomonas putida CBB5 can live on pure caffeine, and can cleave caffeine into carbon dioxide and ammonia.[195]

Caffeine is toxic to birds[196] and to dogs and cats,[197] and has a pronounced adverse effect on mollusks, various insects, and spiders.[198] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.[199] Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the pollen producing plants.[200]

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    .2 Dependence syndrome
    A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.
    The dependence syndrome may be present for a specific psychoactive substance (e.g. tobacco, alcohol, or diazepam), for a class of substances (e.g. opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:]
    Chronic alcoholism
    Dipsomania
    Drug addiction
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  170. ^ 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.
  171. ^ a b Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. ISBN 978-0-415-92723-9.[page needed]
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  173. ^ Berzelius JJ (1828). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius (in German). Vol. 7. p. 270. {{cite book}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help) 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.)
  174. ^ Pelletier, Pierre Joseph (1822). "Cafeine". Dictionnaire de Médecine (in French). Vol. 4. Paris: Béchet Jeune. pp. 35–36. Retrieved 3 March 2011.
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  179. ^ Jobst, Carl (1838). "Thein identisch mit Caffein". Liebig's Annalen der Chemie und Pharmacie. 25: 63–66. doi:10.1002/jlac.18380250106. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  180. ^ Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.
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  195. ^ "Newly Discovered Bacteria Lives on Caffeine". Blogs.scientificamerican.com. 24 May 2011. Retrieved 19 December 2013.
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Bibliography

  • Bersten, Ian (1999). Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria. Sydney: Helian Books. ISBN 0-9577581-0-3.{{cite book}}: CS1 maint: ref duplicates default (link)
  • Pendergrast, Mark (2001) [1999]. Uncommon Grounds: The History of Coffee and How It Transformed Our World. London: Texere. ISBN 1-58799-088-1.{{cite book}}: CS1 maint: ref duplicates default (link)

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