Caffeine

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

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class.^[9] It is mainly used as a eugeroic (wakefulness promoter) or as a mild cognitive enhancer to increase alertness and attentional performance.^[10][11] Caffeine acts by blocking binding of adenosine to the adenosine A₁ receptor, which enhances release of the neurotransmitter acetylcholine.^[12] Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors.^[13] Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase.^[14]

Caffeine

Clinical data
Pronunciation	/kæˈfiːn, ˈkæfiːn/
Other names	Guaranine Methyltheobromine 1,3,7-Trimethylxanthine 7-methyltheophylline^[1] Theine
AHFS/Drugs.com	Monograph
License data	US DailyMed: Caffeine
Pregnancy category	AU: A
Dependence liability	Physical: Moderate 13% and variable low–high 10-73%^[2] Psychological: Low–moderate^[2]
Addiction liability	Relatively low: 9%^[3]
Routes of administration	Common: By mouth Uncommon: insufflation, enema, rectal, intravenous, transdermal
Drug class	Stimulant Adenosinergic Eugeroic Nootropic Anxiogenic Analeptic Anorectic Parasympathomimetic Cholinesterase inhibitor Phosphodiesterase inhibitor Diuretic
ATC code	N06BC01 (WHO) D11AX26 (WHO), V04CG30 (WHO)
Legal status
Legal status	AU: Unscheduled DE: Unscheduled UK: General sales list (GSL, OTC)
Pharmacokinetic data
Bioavailability	99%^[4]
Protein binding	25–36%^[5]
Metabolism	Primary: CYP1A2^[5] Minor: CYP2E1,^[5] CYP3A4,^[5] CYP2C8,^[5] CYP2C9^[5]
Metabolites	Paraxanthine (84%) Theobromine (12%) Theophylline (4%)
Onset of action	45 minutes–1 hour^[4]^[6]
Elimination half-life	Adults: 3–7 hours^[5] Infants (full term): 8 hours^[5] Infants (premature): 100 hours^[5]
Duration of action	3–4 hours^[4]
Excretion	Urine (100%)
Identifiers
IUPAC name 1,3,7-Trimethyl-3,7-dihydro-1H-purine-2,6-dione
CAS Number	58-08-2
PubChem CID	2519
IUPHAR/BPS	407
DrugBank	DB00201
ChemSpider	2424
UNII	3G6A5W338E
KEGG	D00528
ChEBI	CHEBI:27732
ChEMBL	ChEMBL113
PDB ligand	CFF (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID0020232
ECHA InfoCard	100.000.329
Chemical and physical data
Formula	C8H10N4O2
Molar mass	194.194 g·mol^−1
3D model (JSmol)	Interactive image
Density	1.23 g/cm^3
Melting point	235 to 238 °C (455 to 460 °F) (anhydrous)^[7]^[8]
SMILES CN1C=NC2=C1C(=O)N(C(=O)N2C)C
InChI InChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3 Key:RYYVLZVUVIJVGH-UHFFFAOYSA-N
Data page
Caffeine (data page)

Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, fruits, nuts, or leaves of a number of plants native to Africa, East Asia and South America,^[15] and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds,^[16] as well as encouraging consumption by select animals such as honey bees.^[17] 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.^[18] Caffeine is the world's most widely consumed psychoactive drug.^[19][20] 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 and even encouraged in others.

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.^[21] It may confer a modest protective effect against some diseases,^[22] including Parkinson's disease.^[23] Some people experience sleep disruption or anxiety if they consume caffeine,^[24] 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.^[25][26] 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.^[27][28][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).^[29]

Caffeine is classified by the US Food and Drug Administration 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.^[30] 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.^[31] 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).^[32] 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.

Uses

Medical

Main article: Caffeine citrate

Caffeine is used for both prevention^[33] and treatment^[34] of bronchopulmonary dysplasia in premature infants. It may improve weight gain during therapy^[35] and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay.^[36][37] On the other hand, subtle long-term side effects are possible.^[38]

Caffeine is used as a primary treatment for apnea of prematurity,^[39] but not prevention.^[40][41] It is also used for orthostatic hypotension treatment.^[42][41][43]

Some people use caffeine-containing beverages such as coffee or tea to try to treat their asthma.^[44] Evidence to support this practice is poor.^[44] 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.^[45]

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.^[46]

Consumption of caffeine after abdominal surgery shortens the time to recovery of normal bowel function and shortens length of hospital stay.^[47]

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.^[48][49] Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of self-medication.^[49][50]

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.^[51][52] The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance.^[51] 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.^[53] Shift workers who use caffeine make fewer mistakes that could result from drowsiness.^[54]

Caffeine in a dose dependent manner increases alertness in both fatigued and normal individuals.^[55]

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;^[56] these effects are most pronounced during the first hour post-dose.^[56]

Physical performance

Caffeine is a proven ergogenic aid in humans.^[57] Caffeine improves athletic performance in aerobic (especially endurance sports) and anaerobic conditions.^[57] Moderate doses of caffeine (around 5 mg/kg^[57]) can improve sprint performance,^[58] cycling and running time trial performance,^[57] endurance (i.e., it delays the onset of muscle fatigue and central fatigue),^[57][59][60] and cycling power output.^[57] Caffeine increases basal metabolic rate in adults.^[61][62][63] Caffeine ingestion prior to aerobic exercise increases fat oxidation, particularly in persons with low physical fitness.^[64]

Caffeine improves muscular strength and power,^[65] and may enhance muscular endurance.^[66] Caffeine also enhances performance on anaerobic tests.^[67] 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.^[68] Caffeine also improves power output and reduces time to completion in aerobic time trials,^[69] an effect positively (but not exclusively) associated with longer duration exercise.^[70]

Specific populations

Adults

For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.^[71] This limit was found to be safe by a 2017 systematic review on caffeine toxicology.^[72]

Children

In healthy children, moderate caffeine intake under 400 mg produces effects that are "modest and typically innocuous".^[73][74] As early as six months old, infants can metabolize caffeine at the same rate as that of adults.^[75] Higher doses of caffeine (>400 mg) can cause physiological, psychological and behavioral harm, particularly for children with psychiatric or cardiac conditions.^[73] There is no evidence that coffee stunts a child's growth.^[76] The American Academy of Pediatrics recommends that caffeine consumption is not appropriate for children and adolescents and should be avoided.^[77] 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).^[77] 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:^[71]

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.^[71]

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).^[78] Evidence regarding the effects of caffeine on pregnancy and for breastfeeding are inconclusive.^[25] There is limited primary and secondary advice for, or against, caffeine use during pregnancy and its effects on the fetus or newborn.^[25]

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.^[79] 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.^[26] 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.^[71] 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.^[72]

There are conflicting reports in the scientific literature about caffeine use during pregnancy.^[80] 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.^[81] 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,^[82] and may be associated with a higher risk of pregnancy loss.^[83] 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.^[84]

Adverse effects

Physiological

Caffeine in coffee and other caffeinated drinks can affect gastrointestinal motility and gastric acid secretion.^[85][86][87] In postmenopausal women, high caffeine consumption can accelerate bone loss.^[88][89]

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.^[90] 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.^[91] 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.^[92][93][94]

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.^[51][95] Caffeine can have negative effects on anxiety disorders.^[96] According to a 2011 literature review, caffeine use may induce anxiety and panic disorders in people with Parkinson's disease.^[97] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety.^[98] For some people, discontinuing caffeine use can significantly reduce anxiety.^[99]

In moderate doses, caffeine has been associated with reduced symptoms of depression and lower suicide risk.^[100] Two reviews indicate that increased consumption of coffee and caffeine may reduce the risk of depression.^[101][102]

Some textbooks state that caffeine is a mild euphoriant,^{[103][104][105]} while others state that it is not a euphoriant.^[106][107]

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.^[108]

Reinforcement disorders

Addiction

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.^[109] However, some diagnostic models, such as the ICDM-9 and ICD-10, include a classification of caffeine addiction under a broader diagnostic model.^[110] Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.^[3][111]

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.^[112] Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction.^{[27][113][114][115]} Other research states it can affect the reward system.^[116]

"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.^{[27][117][118]} 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.^[108][119]

Dependence and withdrawal

Main article: Caffeine dependence

See also: Caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeinism

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.^[120] 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.^[27] 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.^[121] 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.^[121] Additionally, the signs and symptoms must disrupt important areas of functioning and are not associated with effects of another condition.^[121]

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".^[119][122]  Caffeine use disorder refers to dependence on caffeine characterized by failure to control caffeine consumption despite negative physiological consequences.^[119][122] 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.^[123] Due to this inconclusive evidence on clinical significance, the DSM-5 classifies caffeine-use disorder as a "condition for further study".^[119]

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, occurs for positive effects such as feelings of alertness and wellbeing.^[120] 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.^[124] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.^[125]

Risk of other diseases

See also: Coffee § Health effects

A neuroprotective effect of caffeine against Alzheimer's disease and dementia is possible but the evidence is inconclusive.^[126][127]

Regular consumption of caffeine may protect people from liver cirrhosis.^[128] It was also found to slow the progression of liver disease in people who already have the condition, reduce the risk of liver fibrosis, and offer a protective effect against liver cancer among moderate coffee drinkers. A study conducted in 2017 found that the effects of caffeine from coffee consumption on the liver were observed regardless of how the drink was prepared.^[129]

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][23]}

Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.^[134]

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]

Overdose

 

Primary symptoms of caffeine intoxication^[136]

Consumption of 1–1.5 grams (1,000–1,500 mg) per day is associated with a condition known as caffeinism.^[137] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.^[138]

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.^[139] 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.^[140]

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.^[139]

Energy drinks

High caffeine consumption in energy drinks (at least 1 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).^[78]

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.^{[136][141][142]} Intralipid infusion therapy is indicated in cases of imminent risk of cardiac arrest in order to scavenge the free serum caffeine.^[142]

Lethal dose

Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications.^[143] 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.^[143] The LD₅₀ of caffeine in rats is 192 milligrams per kilogram, the fatal dose in humans is estimated to be 150–200 milligrams per kilogram (2.2 lb) of body mass (75–100 cups of coffee for a 70 kg (150 lb) adult).^[144][145] There are cases where doses as low as 57 milligrams per kilogram have been fatal.^[146] 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.^[147] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease.^[148] A death was reported in 2013 of a man with liver cirrhosis who overdosed on caffeinated mints.^[149][150]

Interactions

Caffeine is a substrate for CYP1A2, and interacts with many substances through this and other mechanisms.^[151]

Alcohol

See also: Caffeinated alcoholic drink

According to DSST, alcohol causes a decrease in performance on their standardized tests, and caffeine causes a significant improvement.^[152] When alcohol and caffeine are consumed jointly, the effects of the caffeine are changed, but the alcohol effects remain the same.^[153] For example, consuming additional caffeine does not reduce the effect of alcohol.^[153] However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed.^[153] Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.^[154] 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.

Tobacco

Smoking tobacco increases caffeine clearance by 56%.^[155] Cigarette smoking induces the cytochrome P450 1A2 enzyme that breaks down caffeine, which may lead to increased caffeine tolerance and coffee consumption for regular smokers.^[156]

Birth control

Birth control pills can extend the half-life of caffeine, requiring greater attention to caffeine consumption.^[157]

Medications

Caffeine sometimes increases the effectiveness of some medications, such as those for headaches.^[158] Caffeine was determined to increase the potency of some over-the-counter analgesic medications by 40%.^[159]

The pharmacological effects of adenosine may be blunted in individuals taking large quantities of methylxanthines like caffeine.^[160] Some other examples of methylxanthines include the medications theophylline and aminophylline, which are prescribed to relieve symptoms of asthma or COPD.^[161]

Pharmacology

Pharmacodynamics

 

Postsynaptic
density

Voltage-
gated Ca⁺⁺
channel

Synaptic
vesicle

Neurotransmitter
transporter

Receptor

Neurotransmitter

Axon terminal

Synaptic cleft

Dendrite

Structure of a typical chemical synapse

 

Caffeine's primary mechanism of action is as an adenosine receptor antagonist 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 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]

Receptor and ion channel targets

Caffeine is an antagonist of adenosine A_2A receptors, and knockout mouse studies have specifically implicated antagonism of the A_2A receptor as responsible for the wakefulness-promoting effects of caffeine.^[162] Antagonism of A_2A receptors in the ventrolateral preoptic area (VLPO) reduces inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal.^[163] This disinhibition of the tuberomammillary nucleus is the downstream mechanism by which caffeine produces wakefulness-promoting effects.^[163] Caffeine is an antagonist of all four adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃), although with varying potencies.^[5][162] The affinity (K_D) values of caffeine for the human adenosine receptors are 12 μM at A₁, 2.4 μM at A_2A, 13 μM at A_2B, and 80 μM at A₃.^[162]

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][164] 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.^[165]

In addition to its activity at adenosine receptors, caffeine is an inositol trisphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3).^[166] It is also a competitive antagonist of the ionotropic glycine receptor.^[167]

Effects on striatal dopamine

While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A₁–D₁ receptor heterodimer (this is a receptor complex with 1 adenosine A₁ receptor and 1 dopamine D₁ receptor) and the A_2A–D₂ receptor heterotetramer (this is a receptor complex with 2 adenosine A_2A receptors and 2 dopamine D₂ receptors).^{[168][169][170][171]} The A_2A–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.^{[169][170][171]}

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–A_2A heterodimers (a receptor complex composed of 1 adenosine A₁ receptor and 1 adenosine A_2A receptor) in the axon terminal of glutamate neurons.^[168][163] During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance.^[168][163]

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.^[172] As a competitive nonselective phosphodiesterase inhibitor,^[173] caffeine raises intracellular cyclic AMP, activates protein kinase A, inhibits TNF-alpha^[174][175] and leukotriene^[176] synthesis, and reduces inflammation and innate immunity.^[176] Caffeine also affects the cholinergic system where it is a moderate inhibitor of the enzyme acetylcholinesterase.^[177][178]

Pharmacokinetics

 

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^[179]

Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues.^[180] Peak blood concentration is reached within 1–2 hours.^[181] It is eliminated by first-order kinetics.^[182] Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine)^[183] and of chlorobutanol and caffeine (for the treatment of hyperemesis).^[184] However, rectal absorption is less efficient than oral: the maximum concentration (C_max) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.^[185]

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.^[125] 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.^[125] 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.^[186]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,^[187] each of which has its own effects on the body:

• Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in blood plasma.
• Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean (chocolate).
• Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.^[45]

1,3,7-Trimethyluric acid is a minor caffeine metabolite.^[5] 7-Methylxanthine is also a metabolite of caffeine.^[188][189] 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.^[190]

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.^[191] 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 very soluble in boiling water (66 g/100 mL).^[192] It is also moderately soluble in ethanol (1.5 g/100 mL).^[192] It is weakly basic (pK_a of conjugate acid = ~0.6) requiring strong acid to protonate it.^[193] Caffeine does not contain any stereogenic centers^[194] and hence is classified as an achiral molecule.^[195]

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 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. 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.^[196]

Synthesis

 

One biosynthetic route of caffeine, as performed by Camellia and Coffea species^[197][198]

 

One laboratory synthesis of caffeine^[199][200]

The biosynthesis of caffeine is an example of convergent evolution among different species.^{[201][202][203]}

Caffeine may be synthesized in the lab starting with dimethylurea and malonic acid.^{[clarification needed][199][200][204]}

Commercial supplies of caffeine are not usually manufactured synthetically because the chemical is readily available as a byproduct of decaffeination.^[205]

Decaffeination

Main article: Decaffeination

 

Fibrous crystals of purified caffeine. Dark-field microscopy image, about 7 mm × 11 mm.

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.^[206]
• 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.^[206]
• 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.^[206]

"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.^[207]

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.^[208]

Analogs

Some analog substances have been created which mimic caffeine's properties with either function or structure or both. Of the latter group are the xanthines DMPX^[209] 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.^{[210][unreliable source?]} Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.^[211]

Some other caffeine analogs:

• Dipropylcyclopentylxanthine
• 8-Cyclopentyl-1,3-dimethylxanthine
• 8-Phenyltheophylline

Precipitation of tannins

Caffeine, as do other alkaloids such as cinchonine, quinine or strychnine, precipitates polyphenols and tannins. This property can be used in a quantitation method.^{[clarification needed][212]}

Natural occurrence

 

Roasted coffee beans

Around thirty plant species are known to contain caffeine.^[213] 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.^[214] High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.^[215] 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.^[216] 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.^[217] Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honey bees.^[17]

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.^[218]

Products

Caffeine content in select food and drugs^{[219][220][221][222][223]}

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 mL (6.0 US fl oz)	22–74^[222]^[223]	124–418
Guayakí yerba mate (loose leaf)	6 g (0.21 oz)	85^[224]	approx. 358
Coca-Cola	355 mL (12.0 US fl oz)	34	96
Mountain Dew	355 mL (12.0 US fl oz)	54	154
Pepsi Zero Sugar	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
Coffee-flavored milk drink	300–600 mL (10–20 US fl oz)	33–197^[225]	66–354^[225]

Products containing caffeine include coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,^[226] 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.^[78] Energy drinks are more commonly consumed as a source of caffeine in adolescents as compared to adults.^[78]

Beverages

Main article: Caffeinated drink

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;^[227] 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.^[228][229] Arabica coffee typically contains half the caffeine of the robusta variety.^[227] 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.^[228][229]

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.^[230]

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.^[230]

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.^[231] 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.^[232]

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.^[233]
• 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.^[234]
• 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.^[235] 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.^[225]

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.^[236] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount of caffeine as coffee: 80–160 mg per 100 g. Higher percentages of cocoa such as 90% amount to 200 mg per 100 g approximately and thus, a 100-gram 85% cocoa chocolate bar contains about 195 mg caffeine.^[220]

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.^[237] These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.^[238]

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.^[239] Another intake route is SpazzStick, a caffeinated lip balm.^[240] 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.^[241]

Inhalants

Similar to an e-cigarette, a caffeine inhaler may be used to deliver caffeine or a stimulant like guarana by vaping.^[242] 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.^[243][244]

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".^[245]
• Ya ba contains a combination of methamphetamine and caffeine.
• Painkillers such as propyphenazone/paracetamol/caffeine combine caffeine with an analgesic.

History

Discovery and spread of use

 

Coffeehouse in Palestine, c. 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, inadvertently discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted.^[246] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.^[247]

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.^[248] 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.^[249]

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.^[250]

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.^[251]

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^[252] and the Philippines.^[253]

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".^[254] Archaeologists have found evidence of this use far into antiquity,^[255] possibly dating to Late Archaic times.^[254]

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).^[256] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.^[a][258] 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.^[259] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:^[260] "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).^[261] 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,^[262] whereas Pelletier was the first to perform an elemental analysis.^[263]

In 1827, M. Oudry isolated "théine" from tea,^[264] but in 1838 it was proved by Mulder^[265] and by Carl Jobst^[266] 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.^[267] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.^[268]

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.^{[269][270][271]} Charles II of England tried to ban it in 1676,^[272][273] Frederick II of Prussia banned it in 1777,^[274][275] 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".^[276] Although the Supreme Court later ruled in favor of Coca-Cola in United States v. Forty Barrels and Twenty Kegs 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.^[277]

Society and culture

Regulations

See also: Energy drink § Regulations

United States

The US Food and Drug Administration (FDA) considers safe beverages containing less than 0.02% caffeine;^[278] but caffeine powder, which is sold as a dietary supplement, is unregulated.^[279] 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.^[280] The FDA guidance was updated in 2018.^[281]

Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance.^[19] This amounts to an average of one serving of a caffeinated beverage for every person every day.^[19] The consumption of caffeine has remained stable between 1997 and 2015.^[282] Coffee, tea and soft drinks are the most important caffeine sources, with energy drinks contributing little to the total caffeine intake across all age groups.^[282]

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).^[283] 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."^[284]

Gaudiya Vaishnavas generally also abstain from caffeine, because they believe it clouds the mind and overstimulates the senses.^[285] To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.^[286]

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.^[287][288]

Other organisms

 

Caffeine effects on spider webs

See also: Effect of psychoactive drugs on animals

The bacteria Pseudomonas putida CBB5 can live on pure caffeine and can cleave caffeine into carbon dioxide and ammonia.^[289]

Caffeine is toxic to birds^[290] and to dogs and cats,^[291] and has a pronounced adverse effect on mollusks, various insects, and spiders.^[292] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.^[179] Caffeine has also been found to enhance the reward memory of honey bees.^[17]

Research

Caffeine has been used to double chromosomes in haploid wheat.^[293]

See also

• Theobromine
• Theophylline
• Methylliberine
• Adderall
• Amphetamine
• Cocaine
• Nootropic
• Wakefulness-promoting agent

References

Notes

1. 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.").^[257]

Citations

1. "Caffeine". ChemSpider. from the original on 14 May 2019. Retrieved 16 November 2021.
2. Juliano LM, Griffiths RR (October 2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features". Psychopharmacology. 176 (1): 1–29. doi:10.1007/s00213-004-2000-x. PMID 15448977. S2CID 5572188. Results: Of 49 symptom categories identified, the following 10 fulfilled validity criteria: headache, fatigue, decreased energy/ activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy/not clearheaded. In addition, flu-like symptoms, nausea/vomiting, and muscle pain/stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%. Typically, onset of symptoms occurred 12–24 h after abstinence, with peak intensity at 20–51 h, and for a duration of 2–9 days.
3. Meredith SE, Juliano LM, Hughes JR, Griffiths RR (September 2013). "Caffeine Use Disorder: A Comprehensive Review and Research Agenda". Journal of Caffeine Research. 3 (3): 114–130. doi:10.1089/jcr.2013.0016. PMC 3777290. PMID 24761279.
4. Poleszak E, Szopa A, Wyska E, Kukuła-Koch W, Serefko A, Wośko S, et al. (February 2016). "Caffeine augments the antidepressant-like activity of mianserin and agomelatine in forced swim and tail suspension tests in mice". Pharmacological Reports. 68 (1): 56–61. doi:10.1016/j.pharep.2015.06.138. PMID 26721352. S2CID 19471083.
5. "Caffeine". DrugBank. University of Alberta. 16 September 2013. from the original on 4 May 2015. Retrieved 8 August 2014.
6. Institute of Medicine (US) Committee on Military Nutrition Research (2001). "2, Pharmacology of Caffeine". Pharmacology of Caffeine. National Academies Press (US). from the original on 28 September 2021. Retrieved 15 December 2022.
7. "Caffeine". Pubchem Compound. NCBI. Retrieved 16 October 2014.
   Boiling Point
   178 °C (sublimes)
   Melting Point
   238 DEG C (ANHYD)
8. "Caffeine". ChemSpider. Royal Society of Chemistry. from the original on 14 May 2019. Retrieved 16 October 2014. Experimental Melting Point:
   234–236 °C Alfa Aesar
   237 °C Oxford University Chemical Safety Data
   238 °C LKT Labs [C0221]
   237 °C Jean-Claude Bradley Open Melting Point Dataset 14937
   238 °C Jean-Claude Bradley Open Melting Point Dataset 17008, 17229, 22105, 27892, 27893, 27894, 27895
   235.25 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
   236 °C Jean-Claude Bradley Open Melting Point Dataset 27892, 27893, 27894, 27895
   235 °C Jean-Claude Bradley Open Melting Point Dataset 6603
   234–236 °C Alfa Aesar A10431, 39214
   Experimental Boiling Point:
   178 °C (Sublimes) Alfa Aesar
   178 °C (Sublimes) Alfa Aesar 39214
9. Nehlig A, Daval JL, Debry G (1992). "Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects". Brain Research. Brain Research Reviews. 17 (2): 139–170. doi:10.1016/0165-0173(92)90012-B. PMID 1356551. S2CID 14277779.
10. Camfield DA, Stough C, Farrimond J, Scholey AB (August 2014). "Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis". Nutrition Reviews. 72 (8): 507–522. doi:10.1111/nure.12120. PMID 24946991.
11. Wood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacological Reviews. 66 (1): 193–221. doi:10.1124/pr.112.007054. PMC 3880463. PMID 24344115.
12. Ribeiro JA, Sebastião AM (2010). "Caffeine and adenosine". Journal of Alzheimer's Disease. 20 (Suppl 1): S3-15. doi:10.3233/JAD-2010-1379. PMID 20164566.
13. Hillis DM, Sadava D, Hill RW, Price MV (2015). Principles of Life (2 ed.). Macmillan Learning. pp. 102–103. ISBN 978-1-4641-8652-3.
14. Faudone G, Arifi S, Merk D (June 2021). "The Medicinal Chemistry of Caffeine". Journal of Medicinal Chemistry. 64 (11): 7156–7178. doi:10.1021/acs.jmedchem.1c00261. PMID 34019396. S2CID 235094871.
15. Caballero B, Finglas P, Toldra F (2015). Encyclopedia of Food and Health. Elsevier Science. p. 561. ISBN 978-0-12-384953-3. Retrieved 17 June 2018.
16. Myers RL (2007). The 100 Most Important Chemical Compounds: A Reference Guide. Greenwood Press. p. 55. ISBN 978-0-313-33758-1. Retrieved 17 June 2018.
17. Wright GA, Baker DD, Palmer MJ, Stabler D, Mustard JA, Power EF, et al. (March 2013). "Caffeine in floral nectar enhances a pollinator's memory of reward". Science. 339 (6124): 1202–4. Bibcode:2013Sci...339.1202W. doi:10.1126/science.1228806. PMC 4521368. PMID 23471406.
18. "Global coffee consumption, 2020/21". Statista. from the original on 3 March 2021. Retrieved 10 March 2021.
19. Burchfield G (1997). Meredith H (ed.). . Australian Broadcasting Corporation. Archived from the original on 26 July 2009. Retrieved 15 January 2014.
20. Ferré S (June 2013). "Caffeine and Substance Use Disorders". Journal of Caffeine Research. 3 (2): 57–58. doi:10.1089/jcr.2013.0015. ISSN 2156-5783. PMC 3680974. PMID 24761274.
21. WHO Model List of Essential Medicines (PDF) (18th ed.). World Health Organization. October 2013 [April 2013]. p. 34 [p. 38 of pdf]. (PDF) from the original on 23 April 2014. Retrieved 23 December 2014.
22. Cano-Marquina A, Tarín JJ, Cano A (May 2013). "The impact of coffee on health". Maturitas. 75 (1): 7–21. doi:10.1016/j.maturitas.2013.02.002. PMID 23465359.
23. Qi H, Li S (April 2014). "Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease". Geriatrics & Gerontology International. 14 (2): 430–9. doi:10.1111/ggi.12123. PMID 23879665. S2CID 42527557.
24. O'Callaghan F, Muurlink O, Reid N (7 December 2018). "Effects of caffeine on sleep quality and daytime functioning". Risk Management and Healthcare Policy. 11: 263–271. doi:10.2147/RMHP.S156404. PMC 6292246. PMID 30573997.
25. Jahanfar S, Jaafar SH, et al. (Cochrane Pregnancy and Childbirth Group) (June 2015). "Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes". The Cochrane Database of Systematic Reviews. 2015 (6): CD006965. doi:10.1002/14651858.CD006965.pub4. PMC 10682844. PMID 26058966.
26. American College of Obstetricians and Gynecologists (August 2010). "ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstetrics and Gynecology. 116 (2 Pt 1): 467–8. doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.
27. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 375. ISBN 978-0-07-148127-4. Long-term caffeine use can lead to mild physical dependence. A withdrawal syndrome characterized by drowsiness, irritability, and headache typically lasts no longer than a day. True compulsive use of caffeine has not been documented.
28. American Psychiatric Association (2013). (PDF). American Psychiatric Publishing. pp. 1–2. Archived from the original (PDF) on 1 July 2014. Retrieved 10 July 2015. Substance use disorder in DSM-5 combines the DSM-IV categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe. ... Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with "addiction" when in fact dependence can be a normal body response to a substance. ... DSM-5 will not include caffeine use disorder, although research shows that as little as two to three cups of coffee can trigger a withdrawal effect marked by tiredness or sleepiness. There is sufficient evidence to support this as a condition, however it is not yet clear to what extent it is a clinically significant disorder.
29. Robertson D, Wade D, Workman R, Woosley RL, Oates JA (April 1981). "Tolerance to the humoral and hemodynamic effects of caffeine in man". The Journal of Clinical Investigation. 67 (4): 1111–7. doi:10.1172/JCI110124. PMC 370671. PMID 7009653.
30. Heckman MA, Weil J, Gonzalez de Mejia E (April 2010). "Caffeine (1, 3, 7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters". Journal of Food Science. 75 (3): R77–R87. doi:10.1111/j.1750-3841.2010.01561.x. PMID 20492310.
31. EFSA Panel on Dietetic Products, Nutrition and Allergies (2015). "Scientific Opinion on the safety of caffeine". EFSA Journal. 13 (5): 4102. doi:10.2903/j.efsa.2015.4102.
32. Awwad S, Issa R, Alnsour L, Albals D, Al-Momani I (December 2021). "Quantification of Caffeine and Chlorogenic Acid in Green and Roasted Coffee Samples Using HPLC-DAD and Evaluation of the Effect of Degree of Roasting on Their Levels". Molecules. 26 (24): 7502. doi:10.3390/molecules26247502. PMC 8705492. PMID 34946584.
33. Kugelman A, Durand M (December 2011). "A comprehensive approach to the prevention of bronchopulmonary dysplasia". Pediatric Pulmonology. 46 (12): 1153–65. doi:10.1002/ppul.21508. PMID 21815280. S2CID 28339831.
34. Schmidt B (2005). "Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial". Biology of the Neonate. 88 (3): 208–13. doi:10.1159/000087584. PMID 16210843. S2CID 30123372.
35. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. (May 2006). "Caffeine therapy for apnea of prematurity". The New England Journal of Medicine. 354 (20): 2112–21. doi:10.1056/NEJMoa054065. PMID 16707748. S2CID 22587234. from the original on 22 April 2020. Retrieved 19 September 2018.
36. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. (November 2007). "Long-term effects of caffeine therapy for apnea of prematurity". The New England Journal of Medicine. 357 (19): 1893–902. doi:10.1056/NEJMoa073679. PMID 17989382. S2CID 22983543.
37. Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, et al. (January 2012). "Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity". JAMA. 307 (3): 275–82. doi:10.1001/jama.2011.2024. PMID 22253394.
38. Funk GD (November 2009). "Losing sleep over the caffeination of prematurity". The Journal of Physiology. 587 (Pt 22): 5299–300. doi:10.1113/jphysiol.2009.182303. PMC 2793860. PMID 19915211.
39. Mathew OP (May 2011). "Apnea of prematurity: pathogenesis and management strategies". Journal of Perinatology. 31 (5): 302–10. doi:10.1038/jp.2010.126. PMID 21127467.
40. Henderson-Smart DJ, De Paoli AG (December 2010). "Prophylactic methylxanthine for prevention of apnoea in preterm infants". The Cochrane Database of Systematic Reviews. 2010 (12): CD000432. doi:10.1002/14651858.CD000432.pub2. PMC 7032541. PMID 21154344.
41. "Caffeine: Summary of Clinical Use". IUPHAR Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. from the original on 14 February 2015. Retrieved 13 February 2015.
42. Gibbons CH, Schmidt P, Biaggioni I, Frazier-Mills C, Freeman R, Isaacson S, et al. (August 2017). "The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension". J. Neurol. 264 (8): 1567–1582. doi:10.1007/s00415-016-8375-x. PMC 5533816. PMID 28050656.
43. Gupta V, Lipsitz LA (October 2007). "Orthostatic hypotension in the elderly: diagnosis and treatment". The American Journal of Medicine. 120 (10): 841–7. doi:10.1016/j.amjmed.2007.02.023. PMID 17904451.
44. Alfaro TM, Monteiro RA, Cunha RA, Cordeiro CR (March 2018). "Chronic coffee consumption and respiratory disease: A systematic review". The Clinical Respiratory Journal. 12 (3): 1283–1294. doi:10.1111/crj.12662. PMID 28671769. S2CID 4334842.
45. Welsh EJ, Bara A, Barley E, Cates CJ (January 2010). Welsh EJ (ed.). "Caffeine for asthma". The Cochrane Database of Systematic Reviews. 2010 (1): CD001112. doi:10.1002/14651858.CD001112.pub2. PMC 7053252. PMID 20091514.
46. Derry CJ, Derry S, Moore RA (December 2014). "Caffeine as an analgesic adjuvant for acute pain in adults". The Cochrane Database of Systematic Reviews. 2019 (12): CD009281. doi:10.1002/14651858.cd009281.pub3. PMC 6485702. PMID 25502052.
47. Yang TW, Wang CC, Sung WW, Ting WC, Lin CC, Tsai MC (March 2022). "The effect of coffee/caffeine on postoperative ileus following elective colorectal surgery: a meta-analysis of randomized controlled trials". International Journal of Colorectal Disease. 37 (3): 623–630. doi:10.1007/s00384-021-04086-3. PMC 8885519. PMID 34993568. S2CID 245773922.
48. Grimes LM, Kennedy AE, Labaton RS, Hine JF, Warzak WJ (2015). "Caffeine as an Independent Variable in Behavioral Research: Trends from the Literature Specific to ADHD". Journal of Caffeine Research. 5 (3): 95–104. doi:10.1089/jcr.2014.0032.
49. Downs J, Giust J, Dunn DW (September 2017). "Considerations for ADHD in the child with epilepsy and the child with migraine". Expert Review of Neurotherapeutics. 17 (9): 861–869. doi:10.1080/14737175.2017.1360136. PMID 28749241. S2CID 29659192.
50. Temple JL (January 2019). "Review: Trends, Safety, and Recommendations for Caffeine Use in Children and Adolescents". Journal of the American Academy of Child and Adolescent Psychiatry. 58 (1): 36–45. doi:10.1016/j.jaac.2018.06.030. PMID 30577937. S2CID 58539710.
51. Bolton S, Null G (1981). "Caffeine: Psychological Effects, Use and Abuse" (PDF). Orthomolecular Psychiatry. 10 (3): 202–211. (PDF) from the original on 6 October 2008.
52. Nehlig A (2010). (PDF). Journal of Alzheimer's Disease. 20 (Suppl 1): S85–94. doi:10.3233/JAD-2010-091315. PMID 20182035. S2CID 17392483. Archived from the original (PDF) on 31 January 2021. Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on this, and caffeine appears to improve memory performance under suboptimal alertness. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. ... Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties.
53. Snel J, Lorist MM (2011). "Effects of caffeine on sleep and cognition". Human Sleep and Cognition Part II - Clinical and Applied Research. Progress in Brain Research. Vol. 190. pp. 105–17. doi:10.1016/B978-0-444-53817-8.00006-2. ISBN 978-0-444-53817-8. PMID 21531247.
54. Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I (May 2010). Ker K (ed.). "Caffeine for the prevention of injuries and errors in shift workers". The Cochrane Database of Systematic Reviews. 2010 (5): CD008508. doi:10.1002/14651858.CD008508. PMC 4160007. PMID 20464765.
55. McLellan TM, Caldwell JA, Lieberman HR (December 2016). "A review of caffeine's effects on cognitive, physical and occupational performance". Neuroscience and Biobehavioral Reviews. 71: 294–312. doi:10.1016/j.neubiorev.2016.09.001. PMID 27612937.
56. Camfield DA, Stough C, Farrimond J, Scholey AB (August 2014). "Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis". Nutrition Reviews. 72 (8): 507–22. doi:10.1111/nure.12120. PMID 24946991. S2CID 42039737.
57. Pesta DH, Angadi SS, Burtscher M, Roberts CK (December 2013). "The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance". Nutrition & Metabolism. 10 (1): 71. doi:10.1186/1743-7075-10-71. PMC 3878772. PMID 24330705. Quote:

    Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see [26,30,31])...

58. Bishop D (December 2010). "Dietary supplements and team-sport performance". Sports Medicine. 40 (12): 995–1017. doi:10.2165/11536870-000000000-00000. PMID 21058748. S2CID 1884713.
59. Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (February 2011). (PDF). International Journal of Sport Nutrition and Exercise Metabolism. 21 (1): 71–84. doi:10.1123/ijsnem.21.1.71. PMID 21411838. S2CID 7109086. Archived from the original (PDF) on 14 November 2020.
60. Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
    Physiologic and performance effects
     • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     • Improved reaction time
     • Increased muscle strength and delayed muscle fatigue
     • Increased acceleration
     • Increased alertness and attention to task
61. Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K, Jéquier E (May 1980). (PDF). The American Journal of Clinical Nutrition. 33 (5): 989–97. doi:10.1093/ajcn/33.5.989. PMID 7369170. S2CID 4515711. Archived from the original (PDF) on 15 February 2020.
62. Dulloo AG, Geissler CA, Horton T, Collins A, Miller DS (January 1989). "Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers". The American Journal of Clinical Nutrition. 49 (1): 44–50. doi:10.1093/ajcn/49.1.44. PMID 2912010.
63. Koot P, Deurenberg P (1995). "Comparison of changes in energy expenditure and body temperatures after caffeine consumption". Annals of Nutrition & Metabolism. 39 (3): 135–42. doi:10.1159/000177854. PMID 7486839.
64. Collado-Mateo D, Lavín-Pérez AM, Merellano-Navarro E, Coso JD (November 2020). "Effect of Acute Caffeine Intake on the Fat Oxidation Rate during Exercise: A Systematic Review and Meta-Analysis". Nutrients. 12 (12): 3603. doi:10.3390/nu12123603. PMC 7760526. PMID 33255240.
65. Grgic J, Trexler ET, Lazinica B, Pedisic Z (2018). "Effects of caffeine intake on muscle strength and power: a systematic review and meta-analysis". Journal of the International Society of Sports Nutrition. 15: 11. doi:10.1186/s12970-018-0216-0. PMC 5839013. PMID 29527137.
66. Warren GL, Park ND, Maresca RD, McKibans KI, Millard-Stafford ML (July 2010). "Effect of caffeine ingestion on muscular strength and endurance: a meta-analysis". Medicine and Science in Sports and Exercise. 42 (7): 1375–87. doi:10.1249/MSS.0b013e3181cabbd8. PMID 20019636.
67. Grgic J (March 2018). "Caffeine ingestion enhances Wingate performance: a meta-analysis" (PDF). European Journal of Sport Science. 18 (2): 219–225. doi:10.1080/17461391.2017.1394371. PMID 29087785. S2CID 3548657. (PDF) from the original on 5 March 2020. Retrieved 2 December 2019.
68. Doherty M, Smith PM (April 2005). "Effects of caffeine ingestion on rating of perceived exertion during and after exercise: a meta-analysis". Scandinavian Journal of Medicine & Science in Sports. 15 (2): 69–78. doi:10.1111/j.1600-0838.2005.00445.x. PMID 15773860. S2CID 19331370.
69. Southward K, Rutherfurd-Markwick KJ, Ali A (August 2018). "The Effect of Acute Caffeine Ingestion on Endurance Performance: A Systematic Review and Meta-Analysis". Sports Medicine. 48 (8): 1913–1928. doi:10.1007/s40279-018-0939-8. PMID 29876876. S2CID 46959658.
70. Shen JG, Brooks MB, Cincotta J, Manjourides JD (February 2019). "Establishing a relationship between the effect of caffeine and duration of endurance athletic time trial events: A systematic review and meta-analysis". Journal of Science and Medicine in Sport. 22 (2): 232–238. doi:10.1016/j.jsams.2018.07.022. PMID 30170953.
71. "Caffeine in Food". Health Canada. 6 February 2012. from the original on 10 August 2020. Retrieved 24 August 2020.
72. Wikoff D, Welsh BT, Henderson R, Brorby GP, Britt J, Myers E, et al. (November 2017). "Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children". Food and Chemical Toxicology (Systematic review). 109 (Pt 1): 585–648. doi:10.1016/j.fct.2017.04.002. PMID 28438661.
73. Temple JL (January 2019). "Review: Trends, Safety, and Recommendations for Caffeine Use in Children and Adolescents". Journal of the American Academy of Child and Adolescent Psychiatry (Review). 58 (1): 36–45. doi:10.1016/j.jaac.2018.06.030. PMID 30577937.
74. Castellanos FX, Rapoport JL (September 2002). "Effects of caffeine on development and behavior in infancy and childhood: a review of the published literature". Food and Chemical Toxicology. 40 (9): 1235–1242. doi:10.1016/S0278-6915(02)00097-2. PMID 12204387. from the original on 27 July 2020. Retrieved 2 December 2019.
75. Temple JL, Bernard C, Lipshultz SE, Czachor JD, Westphal JA, Mestre MA (26 May 2017). "The Safety of Ingested Caffeine: A Comprehensive Review". Frontiers in Psychiatry. 8 (80): 80. doi:10.3389/fpsyt.2017.00080. PMC 5445139. PMID 28603504.
76. Levounis P, Herron AJ (2014). The Addiction Casebook. American Psychiatric Pub. p. 49. ISBN 978-1-58562-458-4.
77. Schneider MB, Benjamin HJ, et al. (Committee on Nutrition and the Council on Sports Medicine and Fitness) (June 2011). "Sports drinks and energy drinks for children and adolescents: are they appropriate?". Pediatrics. 127 (6): 1182–1189. doi:10.1542/peds.2011-0965. PMID 21624882.
78. van Dam RM, Hu FB, Willett WC (July 2020). "Coffee, Caffeine, and Health". The New England Journal of Medicine. 383 (4): 369–378. doi:10.1056/NEJMra1816604. PMID 32706535. S2CID 220731550.
79. . Archived from the original on 17 October 2010. Retrieved 3 August 2009.
80. Kuczkowski KM (November 2009). "Caffeine in pregnancy". Archives of Gynecology and Obstetrics. 280 (5): 695–8. doi:10.1007/s00404-009-0991-6. PMID 19238414. S2CID 6475015.
81. Brent RL, Christian MS, Diener RM (April 2011). "Evaluation of the reproductive and developmental risks of caffeine". Birth Defects Research Part B: Developmental and Reproductive Toxicology. 92 (2): 152–87. doi:10.1002/bdrb.20288. PMC 3121964. PMID 21370398.
82. Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM (September 2014). "Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis". BMC Medicine. 12 (1): 174. doi:10.1186/s12916-014-0174-6. PMC 4198801. PMID 25238871.
83. Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM (May 2016). "Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose-response meta-analysis of prospective studies". Public Health Nutrition. 19 (7): 1233–44. doi:10.1017/S1368980015002463. PMC 10271029. PMID 26329421.
84. Lassi ZS, Imam AM, Dean SV, Bhutta ZA (September 2014). "Preconception care: caffeine, smoking, alcohol, drugs and other environmental chemical/radiation exposure". Reproductive Health. 11 (Suppl 3): S6. doi:10.1186/1742-4755-11-S3-S6. PMC 4196566. PMID 25415846.
85. Boekema PJ, Samsom M, van Berge Henegouwen GP, Smout AJ (1999). "Coffee and gastrointestinal function: facts and fiction. A review". Scandinavian Journal of Gastroenterology. Supplement. 34 (230): 35–9. doi:10.1080/003655299750025525. PMID 10499460.
86. Cohen S, Booth GH (October 1975). "Gastric acid secretion and lower-esophageal-sphincter pressure in response to coffee and caffeine". The New England Journal of Medicine. 293 (18): 897–9. doi:10.1056/NEJM197510302931803. PMID 1177987.
87. Sherwood L, Kell R (2009). Human Physiology: From Cells to Systems (1st Canadian ed.). Nelsen. pp. 613–9. ISBN 978-0-17-644107-4.
88. "Caffeine in the diet". MedlinePlus, US National Library of Medicine. 30 April 2013. from the original on 5 January 2015. Retrieved 2 January 2015.
89. Rapuri PB, Gallagher JC, Kinyamu HK, Ryschon KL (November 2001). "Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes". The American Journal of Clinical Nutrition. 74 (5): 694–700. doi:10.1093/ajcn/74.5.694. PMID 11684540.
90. Maughan RJ, Griffin J (December 2003). (PDF). Journal of Human Nutrition and Dietetics. 16 (6): 411–20. doi:10.1046/j.1365-277X.2003.00477.x. PMID 19774754. S2CID 41617469. Archived from the original (PDF) on 8 March 2019.
91. Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism Am. J. Physiol. Renal Physiol. 1 July 2008 295:F35-F36
92. O'Connor A (4 March 2008). "Really? The claim: caffeine causes dehydration". New York Times. from the original on 3 September 2011. Retrieved 3 August 2009.
93. Armstrong LE, Casa DJ, Maresh CM, Ganio MS (July 2007). "Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance". Exercise and Sport Sciences Reviews. 35 (3): 135–40. doi:10.1097/jes.0b013e3180a02cc1. PMID 17620932. S2CID 46352603.
94. Maughan RJ, Watson P, Cordery PA, Walsh NP, Oliver SJ, Dolci A, et al. (March 2016). "A randomized trial to assess the potential of different beverages to affect hydration status: development of a beverage hydration index". The American Journal of Clinical Nutrition. 103 (3): 717–23. doi:10.3945/ajcn.115.114769. PMID 26702122. S2CID 378245.
95. Tarnopolsky MA (2010). "Caffeine and creatine use in sport". Annals of Nutrition & Metabolism. 57 (Suppl 2): 1–8. doi:10.1159/000322696. PMID 21346331.
96. Winston AP (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment. 11 (6): 432–439. doi:10.1192/apt.11.6.432.
97. Vilarim MM, Rocha Araujo DM, Nardi AE (August 2011). "Caffeine challenge test and panic disorder: a systematic literature review". Expert Review of Neurotherapeutics. 11 (8): 1185–95. doi:10.1586/ern.11.83. PMID 21797659. S2CID 5364016.
98. Smith A (September 2002). "Effects of caffeine on human behavior". Food and Chemical Toxicology. 40 (9): 1243–55. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
99. Bruce MS, Lader M (February 1989). "Caffeine abstention in the management of anxiety disorders". Psychological Medicine. 19 (1): 211–4. doi:10.1017/S003329170001117X. PMID 2727208. S2CID 45368729.
100. Lara DR (2010). "Caffeine, mental health, and psychiatric disorders". Journal of Alzheimer's Disease. 20 (Suppl 1): S239–48. doi:10.3233/JAD-2010-1378. PMID 20164571.
101. Wang L, Shen X, Wu Y, Zhang D (March 2016). "Coffee and caffeine consumption and depression: A meta-analysis of observational studies". The Australian and New Zealand Journal of Psychiatry. 50 (3): 228–42. doi:10.1177/0004867415603131. PMID 26339067. S2CID 23377304.
102. Grosso G, Micek A, Castellano S, Pajak A, Galvano F (January 2016). "Coffee, tea, caffeine and risk of depression: A systematic review and dose-response meta-analysis of observational studies". Molecular Nutrition & Food Research. 60 (1): 223–34. doi:10.1002/mnfr.201500620. PMID 26518745.
103. Kohn R, Keller M (2015). "Chapter 34 Emotions". In Tasman A, Kay J, Lieberman JA, First MB, Riba M (eds.). Psychiatry. Vol. 1. New York: John Wiley & Sons. pp. 557–558. ISBN 978-1-118-84547-9. Table 34-12... Caffeine Intoxication – Euphoria
104. 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. ISBN 9788024633787. At a high dose, caffeine shows a euphoric effect.
105. Schulteis G (2010). "Brain stimulation and addiction". In Koob GF, Le Moal M, Thompson RF (eds.). Encyclopedia of Behavioral Neuroscience. Elsevier. p. 214. ISBN 978-0-08-091455-8. Therefore, caffeine and other adenosine antagonists, while weakly euphoria-like on their own, may potentiate the positive hedonic efficacy of acute drug intoxication and reduce the negative hedonic consequences of drug withdrawal.
106. Salerno BB, Knights EK (2010). Pharmacology for health professionals (3rd ed.). Chatswood, N.S.W.: Elsevier Australia. p. 433. ISBN 978-0-7295-3929-6. In contrast to the amphetamines, caffeine does not cause euphoria, stereotyped behaviors or psychoses.
107. Ebenezer I (2015). Neuropsychopharmacology and Therapeutics. John Wiley & Sons. p. 18. ISBN 978-1-118-38578-4. However, in contrast to other psychoactive stimulants, such as amphetamine and cocaine, caffeine and the other methylxanthines do not produce euphoria, stereotyped behaviors or psychotic like symptoms in large doses.
108. Addicott MA (September 2014). "Caffeine Use Disorder: A Review of the Evidence and Future Implications". Current Addiction Reports. 1 (3): 186–192. doi:10.1007/s40429-014-0024-9. PMC 4115451. PMID 25089257.
109. Nestler EJ, Hymen SE, Holtzmann DM, Malenka RC. "16". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). McGraw-Hill Education. True compulsive use of caffeine has not been documented, and, consequently, these drugs are not considered addictive.
110. Budney AJ, Emond JA (November 2014). "Caffeine addiction? Caffeine for youth? Time to act!". Addiction. 109 (11): 1771–2. doi:10.1111/add.12594. PMID 24984891. Academics and clinicians, however, have not yet reached consensus about the potential clinical importance of caffeine addiction (or 'use disorder')
111. Riba A, Tasman J, Kay JS, Lieberman MB, First MB (2014). Psychiatry (Fourth ed.). John Wiley & Sons. p. 1446. ISBN 978-1-118-75336-1.
112. Fishchman N, Mello N. (PDF). Rockville, MD: U.S. Department of Health and Human Services Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse. p. 179. Archived from the original (PDF) on 22 December 2016.
113. 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. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement
114. Miller PM (2013). "Chapter III: Types of Addiction". Principles of addiction comprehensive addictive behaviors and disorders (1st ed.). Elsevier Academic Press. p. 784. ISBN 978-0-12-398361-9. Retrieved 11 July 2015. Astrid Nehlig and colleagues present evidence that in animals caffeine does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. A single photon emission computed tomography (SPECT) assessment of brain activation in humans showed that caffeine activates regions involved in the control of vigilance, anxiety, and cardiovascular regulation but did not affect areas involved in reinforcement and reward.
115. 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. PMC 3181952. PMID 20623930. Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. ... these earlier data plus the present data reflect that caffeine at doses representing about two cups of coffee in one sitting does not activate the circuit of dependence and reward and especially not the main target area, the nucleus accumbens. ... Therefore, caffeine appears to be different from drugs of dependence like cocaine, amphetamine, morphine, and nicotine, and does not fulfil the common criteria or the scientific definitions to be considered an addictive substance.⁴²
116. Temple JL (June 2009). "Caffeine use in children: what we know, what we have left to learn, and why we should worry". Neuroscience and Biobehavioral Reviews. 33 (6): 793–806. doi:10.1016/j.neubiorev.2009.01.001. PMC 2699625. PMID 19428492. Through these interactions, caffeine is able to directly potentiate dopamine neurotransmission, thereby modulating the rewarding and addicting properties of nervous system stimuli.
117. Karch SB (2009). Karch's pathology of drug abuse (4th ed.). Boca Raton: CRC Press. pp. 229–230. ISBN 978-0-8493-7881-2. The suggestion has also been made that a caffeine dependence syndrome exists ... In one controlled study, dependence was diagnosed in 16 of 99 individuals who were evaluated. The median daily caffeine consumption of this group was only 357 mg per day (Strain et al., 1994).
     Since this observation was first published, caffeine addiction has been added as an official diagnosis in ICDM 9. This decision is disputed by many and is not supported by any convincing body of experimental evidence. ... All of these observations strongly suggest that caffeine does not act on the dopaminergic structures related to addiction, nor does it improve performance by alleviating any symptoms of withdrawal
118. "ICD-10 Version:2015". World Health Organization. 2015. 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
119. Association American Psychiatry (2013). Diagnostic and statistical manual of mental disorders : DSM-5 (5th ed.). Washington [etc.]: American Psychiatric Publishing. pp. 792–795. ISBN 978-0-89042-555-8.
120. Temple JL (June 2009). "Caffeine use in children: what we know, what we have left to learn, and why we should worry". Neuroscience and Biobehavioral Reviews. 33 (6): 793–806. doi:10.1016/j.neubiorev.2009.01.001. PMC 2699625. PMID 19428492.
121. Desk reference to the diagnostic criteria from DSM-5. Arlington, VA: American Psychiatric Association. 2013. pp. 238–239. ISBN 978-0-89042-556-5.
122. "ICD-11 – Mortality and Morbidity Statistics". icd.who.int. Archived from the original on 1 August 2018. Retrieved 18 November 2019.
123. American Psychiatric Association (2013). "Substance-Related and Addictive Disorders". American Psychiatric Publishing. pp. 1–2. Retrieved 18 November 2019.
124. . Caffeinedependence.org. Johns Hopkins Medicine. 9 July 2003. Archived from the original on 23 May 2012. Retrieved 25 May 2012.
125. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (March 1999). "Actions of caffeine in the brain with special reference to factors that contribute to its widespread use". Pharmacological Reviews. 51 (1): 83–133. PMID 10049999.
126. Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N (2010). "Caffeine intake and dementia: systematic review and meta-analysis". Journal of Alzheimer's Disease. 20 (Suppl 1): S187-204. doi:10.3233/JAD-2010-091387. PMID 20182026.
127. Panza F, Solfrizzi V, Barulli MR, Bonfiglio C, Guerra V, Osella A, et al. (March 2015). "Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review". The Journal of Nutrition, Health & Aging. 19 (3): 313–28. doi:10.1007/s12603-014-0563-8. hdl:11586/145493. PMID 25732217. S2CID 8376733.
128. Muriel P, Arauz J (July 2010). "Coffee and liver diseases". Fitoterapia. 81 (5): 297–305. doi:10.1016/j.fitote.2009.10.003. PMID 19825397.
129. "Coffee and the Liver". British Liver Trust. from the original on 12 May 2023. Retrieved 12 May 2023.
130. Hackett PH (2010). "Caffeine at high altitude: java at base cAMP". High Altitude Medicine & Biology. 11 (1): 13–7. doi:10.1089/ham.2009.1077. PMID 20367483. S2CID 8820874.
131. Jiang X, Zhang D, Jiang W (February 2014). "Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies". European Journal of Nutrition. 53 (1): 25–38. doi:10.1007/s00394-013-0603-x. PMID 24150256. S2CID 5566177. Dose-response analysis suggested that incidence of T2DM decreased ...14% [0.86 (0.82-0.91)] for every 200 mg/day increment in caffeine intake.
132. Hong CT, Chan L, Bai CH (June 2020). "The Effect of Caffeine on the Risk and Progression of Parkinson's Disease: A Meta-Analysis". Nutrients. 12 (6): 1860. doi:10.3390/nu12061860. PMC 7353179. PMID 32580456.
133. Liu R, Guo X, Park Y, Huang X, Sinha R, Freedman ND, et al. (June 2012). "Caffeine intake, smoking, and risk of Parkinson disease in men and women". American Journal of Epidemiology. 175 (11): 1200–7. doi:10.1093/aje/kwr451. PMC 3370885. PMID 22505763.
134. Li M, Wang M, Guo W, Wang J, Sun X (March 2011). "The effect of caffeine on intraocular pressure: a systematic review and meta-analysis". Graefe's Archive for Clinical and Experimental Ophthalmology. 249 (3): 435–42. doi:10.1007/s00417-010-1455-1. PMID 20706731. S2CID 668498.
135. American Psychiatric Association (2013). Desk reference to the diagnostic criteria from DSM-5. Washington, DC: American Psychiatric Publishing. ISBN 978-0-89042-556-5. OCLC 825047464.
136. . MedlinePlus. 25 May 2000. Archived from the original on 23 February 2007. Retrieved 3 August 2009.
137. Winston AP, Hardwick E, Jaberi N (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment. 11 (6): 432–439. doi:10.1192/apt.11.6.432.
138. Iancu I, Olmer A, Strous RD (2007). "Caffeinism: History, clinical features, diagnosis, and treatment". In Smith BD, Gupta U, Gupta BS (eds.). Caffeine and Activation Theory: Effects on Health and Behavior. CRC Press. pp. 331–344. ISBN 978-0-8493-7102-8. Retrieved 15 January 2014.
139. "ICD-11 – Mortality and Morbidity Statistics". icd.who.int. Archived from the original on 1 August 2018. Retrieved 25 November 2019.
140. American Psychiatric Association (22 May 2013). Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.). American Psychiatric Association. CiteSeerX 10.1.1.988.5627. doi:10.1176/appi.books.9780890425596. hdl:2027.42/138395. ISBN 978-0-89042-555-8.
141. Carreon CC, Parsh B (April 2019). "How to recognize caffeine overdose". Nursing (Clinical tutorial). 49 (4): 52–55. doi:10.1097/01.NURSE.0000553278.11096.86. PMID 30893206. S2CID 84842436.
142. Fintel 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. PMID 6520875.
143. Murray A, Traylor J (January 2019). "Caffeine Toxicity". StatPearls [Internet] (Mini-review). PMID 30422505.
144. "Caffeine | C8H10N4O2". pubchem.ncbi.nlm.nih.gov. National Center for Biotechnology Information. from the original on 2 March 2022. Retrieved 1 March 2022.
145. Peters JM (1967). . The Journal of Clinical Pharmacology and the Journal of New Drugs. 7 (3): 131–141. doi:10.1002/j.1552-4604.1967.tb00034.x. Archived from the original on 12 January 2012.
146. Evans J, Richards JR, Battisti AS (January 2019). "Caffeine". StatPearls [Internet] (Mini-review). PMID 30137774.
147. Carpenter M (18 May 2015). "Caffeine powder poses deadly risks". New York Times. from the original on 25 January 2022. Retrieved 18 May 2015.
148. Rodopoulos N, Wisén O, Norman A (May 1995). "Caffeine metabolism in patients with chronic liver disease". Scandinavian Journal of Clinical and Laboratory Investigation. 55 (3): 229–42. doi:10.3109/00365519509089618. PMID 7638557.
149. Cheston P, Smith L (11 October 2013). "Man died after overdosing on caffeine mints". The Independent. from the original on 12 October 2013. Retrieved 13 October 2013.
150. Prynne M (11 October 2013). . The Telegraph. Archived from the original on 11 October 2013. Retrieved 13 October 2013.
151. "Caffeine Drug Monographs". UpToDate. from the original on 25 April 2013. Retrieved 28 November 2018.
152. Mackay M, Tiplady B, Scholey AB (April 2002). "Interactions between alcohol and caffeine in relation to psychomotor speed and accuracy". Human Psychopharmacology. 17 (3): 151–6. doi:10.1002/hup.371. PMID 12404692. S2CID 21764730.
153. Liguori A, Robinson JH (July 2001). "Caffeine antagonism of alcohol-induced driving impairment". Drug and Alcohol Dependence. 63 (2): 123–9. doi:10.1016/s0376-8716(00)00196-4. PMID 11376916.
154. Marczinski CA, Fillmore MT (August 2003). "Dissociative antagonistic effects of caffeine on alcohol-induced impairment of behavioral control". Experimental and Clinical Psychopharmacology. 11 (3): 228–36. doi:10.1037/1064-1297.11.3.228. PMID 12940502.
155. Zevin S, Benowitz NL (June 1999). "Drug interactions with tobacco smoking. An update". Clinical Pharmacokinetics. 36 (6): 425–438. doi:10.2165/00003088-199936060-00004. PMID 10427467. S2CID 19827114.
156. Bjørngaard JH, Nordestgaard AT, Taylor AE, Treur JL, Gabrielsen ME, Munafò MR, et al. (December 2017). "Heavier smoking increases coffee consumption: findings from a Mendelian randomization analysis". International Journal of Epidemiology. 46 (6): 1958–1967. doi:10.1093/ije/dyx147. PMC 5837196. PMID 29025033.
157. Benowitz NL (1990). "Clinical pharmacology of caffeine". Annual Review of Medicine. 41: 277–88. doi:10.1146/annurev.me.41.020190.001425. PMID 2184730.
158. Gilmore B, Michael M (February 2011). "Treatment of acute migraine headache". American Family Physician. 83 (3): 271–80. PMID 21302868.
159. Benzon H (12 September 2013). Practical management of pain (Fifth ed.). Elsevier Health Sciences. pp. 508–529. ISBN 978-0-323-08340-9.
160. . R&S Pharmchem. April 2011. Archived from the original on 15 July 2011.
161. Gottwalt B, Prasanna T (29 September 2021). "Methylxanthines". StatPearls. PMID 32644591. from the original on 20 March 2022. Retrieved 15 November 2021.
162. Froestl W, Muhs A, Pfeifer A (2012). (PDF). Journal of Alzheimer's Disease. 32 (4): 793–887. doi:10.3233/JAD-2012-121186. PMID 22886028. S2CID 10511507. Archived from the original (PDF) on 15 November 2020.
163. Ferré S (2008). "An update on the mechanisms of the psychostimulant effects of caffeine". J. Neurochem. 105 (4): 1067–1079. doi:10.1111/j.1471-4159.2007.05196.x. PMID 18088379. S2CID 33159096. On the other hand, our 'ventral shell of the nucleus accumbens' very much overlaps with the striatal compartment...
164. . World of Caffeine. 15 June 2013. Archived from the original on 10 December 2013. Retrieved 19 December 2013.
165. Fisone G, Borgkvist A, Usiello A (April 2004). "Caffeine as a psychomotor stimulant: mechanism of action". Cellular and Molecular Life Sciences. 61 (7–8): 857–72. doi:10.1007/s00018-003-3269-3. PMID 15095008. S2CID 7578473.
166. "Caffeine". IUPHAR. International Union of Basic and Clinical Pharmacology. from the original on 2 November 2014. Retrieved 2 November 2014.
167. Duan L, Yang J, Slaughter MM (August 2009). "Caffeine inhibition of ionotropic glycine receptors". The Journal of Physiology. 587 (Pt 16): 4063–75. doi:10.1113/jphysiol.2009.174797. PMC 2756438. PMID 19564396.
168. Ferré S (2010). "Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine". Journal of Alzheimer's Disease. 20 (Suppl 1): S35–49. doi:10.3233/JAD-2010-1400. PMC 9361505. PMID 20182056. By targeting A1-A2A receptor heteromers in striatal glutamatergic terminals and A1 receptors in striatal dopaminergic terminals (presynaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A-D2 and A1-D1 receptor heteromers.
169. Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, et al. (May 2016). "Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer". Neuropharmacology. 104: 154–60. doi:10.1016/j.neuropharm.2015.05.028. PMC 5754196. PMID 26051403.
170. Bonaventura J, Navarro G, Casadó-Anguera V, Azdad K, Rea W, Moreno E, et al. (July 2015). "Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer". Proceedings of the National Academy of Sciences of the United States of America. 112 (27): E3609–18. Bibcode:2015PNAS..112E3609B. doi:10.1073/pnas.1507704112. PMC 4500251. PMID 26100888. Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R.
171. Ferré S (May 2016). "Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders". Psychopharmacology. 233 (10): 1963–79. doi:10.1007/s00213-016-4212-2. PMC 4846529. PMID 26786412. The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants.
172. Ribeiro JA, Sebastião AM (2010). "Caffeine and adenosine". Journal of Alzheimer's Disease. 20 (Suppl 1): S3-15. doi:10.3233/JAD-2010-1379. hdl:10451/6361. PMID 20164566.
173. Essayan DM (November 2001). (PDF). The Journal of Allergy and Clinical Immunology. 108 (5): 671–680. doi:10.1067/mai.2001.119555. PMID 11692087. S2CID 21528985. Archived from the original (PDF) on 25 February 2020.
174. Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics. 63 (3): 321–328. doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.
175. 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. PMID 9927365.
176. Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–594. doi:10.4049/jimmunol.174.2.589. PMID 15634873.
177. Karadsheh N, Kussie P, Linthicum DS (March 1991). "Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives". Toxicology Letters. 55 (3): 335–342. doi:10.1016/0378-4274(91)90015-X. PMID 2003276.
178. Pohanka M, Dobes P (May 2013). "Caffeine inhibits acetylcholinesterase, but not butyrylcholinesterase". International Journal of Molecular Sciences. 14 (5): 9873–9882. doi:10.3390/ijms14059873. PMC 3676818. PMID 23698772.
179. Arnaud MJ (19 August 2010). "Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man". Methylxanthines. Handbook of Experimental Pharmacology. Vol. 200. pp. 33–91. doi:10.1007/978-3-642-13443-2_3. ISBN 978-3-642-13442-5. PMID 20859793.
180. Liguori A, Hughes JR, Grass JA (November 1997). "Absorption and subjective effects of caffeine from coffee, cola and capsules". Pharmacology, Biochemistry, and Behavior. 58 (3): 721–6. doi:10.1016/S0091-3057(97)00003-8. PMID 9329065. S2CID 24067050.
181. 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. PMID 6832208. S2CID 10502739.
182. Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID (1981). "Plasma and salivary pharmacokinetics of caffeine in man". European Journal of Clinical Pharmacology. 21 (1): 45–52. doi:10.1007/BF00609587. PMID 7333346. S2CID 12291731.
183. 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. PMID 13165929.
184. Brødbaek HB, Damkier P (May 2007). "[The treatment of hyperemesis gravidarum with chlorobutanol-caffeine rectal suppositories in Denmark: practice and evidence]". Ugeskrift for Laeger (in Danish). 169 (22): 2122–3. PMID 17553397.
185. Teekachunhatean S, Tosri N, Rojanasthien N, Srichairatanakool S, Sangdee C (8 January 2013). "Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects". ISRN Pharmacology. 2013 (147238): 147238. doi:10.1155/2013/147238. PMC 3603218. PMID 23533801.
186. "Drug Interaction: Caffeine Oral and Fluvoxamine Oral". Medscape Multi-Drug Interaction Checker.
187. . The Pharmacogenetics and Pharmacogenomics Knowledge Base. Archived from the original on 17 July 2011. Retrieved 25 October 2010.
188. "7-Methylxanthine". Inxight Drugs. from the original on 24 August 2022. Retrieved 24 August 2022.
189. Singh H, Singh H, Latief U, Tung GK, Shahtaghi NR, Sahajpal NS, et al. (August 2022). "Myopia, its prevalence, current therapeutic strategy and recent developments: A Review". Indian J Ophthalmol. 70 (8): 2788–2799. doi:10.4103/ijo.IJO_2415_21. PMC 9672758. PMID 35918918. S2CID 251281523.
190. Verbeeck RK (December 2008). "Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction". European Journal of Clinical Pharmacology. 64 (12): 1147–61. doi:10.1007/s00228-008-0553-z. PMID 18762933. S2CID 27888650.
191. Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, et al. (April 2011). Gibson G (ed.). "Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption". PLOS Genetics. 7 (4): e1002033. doi:10.1371/journal.pgen.1002033. PMC 3071630. PMID 21490707.
192. Susan Budavari, ed. (1996). The Merck Index (12th ed.). Whitehouse Station, NJ: Merck & Co., Inc. p. 268.
193. This is the pK_a for protonated caffeine, given as a range of values included in Prankerd RJ (2007). Brittain HG (ed.). "Critical Compilation of pK(a) Values for Pharmaceutical Substances". Profiles of Drug Substances, Excipients, and Related Methodology. Academic Press. 33: 1–33 (15). doi:10.1016/S0099-5428(07)33001-3. ISBN 978-0-12-260833-9. PMID 22469138.
194. Klosterman L (2006). The Facts About Caffeine (Drugs). Benchmark Books (NY). p. 43. ISBN 978-0-7614-2242-6.
195. Vallombroso T (2001). Organic Chemistry Pearls of Wisdom. Boston Medical Publishing Corp. p. 43. ISBN 978-1-58409-016-8.
196. Keskineva N. (PDF). Chemistry Department, East Stroudsburg University. Archived from the original (PDF) on 2 January 2014. Retrieved 2 January 2014.
197. "Caffeine biosynthesis". The Enzyme Database. Trinity College Dublin. from the original on 22 March 2012. Retrieved 24 September 2011.
198. "MetaCyc Pathway: caffeine biosynthesis I". MetaCyc database. SRI International. from the original on 29 May 2018. Retrieved 12 July 2017.
199. Temple NJ, Wilson T (2003). Beverages in Nutrition and Health. Totowa, NJ: Humana Press. p. 172. ISBN 978-1-58829-173-8.
200. US 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. 
201. Denoeud F, Carretero-Paulet L, Dereeper A, Droc G, Guyot R, Pietrella M, et al. (September 2014). "The coffee genome provides insight into the convergent evolution of caffeine biosynthesis". Science. 345 (6201): 1181–4. Bibcode:2014Sci...345.1181D. doi:10.1126/science.1255274. PMID 25190796.

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