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Caffeine

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

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, and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds, as well as encouraging consumption by select animals such as honey bees. 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. Caffeine is the world's most widely consumed psychoactive drug. 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. It may confer a modest protective effect against some diseases, including Parkinson's disease. Some people experience sleep disruption or anxiety if they consume caffeine, 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. Caffeine can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake. Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).

Caffeine is classified by the US Food and Drug Administration as generally recognized as safe. Toxic doses, over 10 grams per day for an adult, are much higher than the typical dose of under 500 milligrams per day. 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. 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). 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.

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

Caffeine is used as a primary treatment for apnea of prematurity, but not prevention. It is also used for orthostatic hypotension treatment.

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

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.

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

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. Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of self-medication.

Cognitive performance
Caffeine is a central nervous system stimulant that may reduce fatigue and drowsiness. At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination. The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance. The desired effects arise approximately one hour after consumption, and the desired effects of a moderate dose usually subside after about three or four hours.

Caffeine can delay or prevent sleep and improves task performance during sleep deprivation. Shift workers who use caffeine make fewer mistakes that could result from drowsiness.

Caffeine in a dose dependent manner increases alertness in both fatigued and normal individuals.

A systematic review and meta-analysis from 2014 found that concurrent caffeine and -theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching; these effects are most pronounced during the first hour post-dose.

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

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

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

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

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.

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

The UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee. The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. For women who breastfeed, are pregnant, or may become pregnant, Health Canada recommends a maximum daily caffeine intake of no more than 300 mg, or a little over two 8 oz (237 mL) cups of coffee. 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.

There are conflicting reports in the scientific literature about caffeine use during pregnancy. 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. 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, and may be associated with a higher risk of pregnancy loss. A systematic review, analyzing the results of observational studies, suggests that women who consume large amounts of caffeine (greater than 300 mg/day) prior to becoming pregnant may have a higher risk of experiencing pregnancy loss.

Physiological
Caffeine in coffee and other caffeinated drinks can affect gastrointestinal motility and gastric acid secretion. In postmenopausal women, high caffeine consumption can accelerate bone loss.

Acute ingestion of caffeine in large doses (at least 250–300 mg, equivalent to the amount found in 2–3 cups of coffee or 5–8 cups of tea) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks. This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); it is mediated via proximal tubular adenosine receptor blockade. The acute increase in urinary output may increase the risk of dehydration. However, chronic users of caffeine develop a tolerance to this effect and experience no increase in urinary output.

Psychological
Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common and include mild anxiety, jitteriness, insomnia, increased sleep latency, and reduced coordination. Caffeine can have negative effects on anxiety disorders. According to a 2011 literature review, caffeine use may induce anxiety and panic disorders in people with Parkinson's disease. At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety. For some people, discontinuing caffeine use can significantly reduce anxiety.

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

Some textbooks state that caffeine is a mild euphoriant,  while others state that it is not a euphoriant.

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

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

Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, with people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA research monograph. Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction. Other research states it can affect the reward system.

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

Dependence and withdrawal
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. 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. Some symptoms associated with psychological dependence may also occur during withdrawal. The diagnostic criteria for caffeine withdrawal require a previous prolonged daily use of caffeine. 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. Additionally, the signs and symptoms must disrupt important areas of functioning and are not associated with effects of another condition.

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

Tolerance to the effects of caffeine occurs for caffeine-induced elevations in blood pressure and the subjective feelings of nervousness. Sensitization, the process whereby effects become more prominent with use, may occur for positive effects such as feelings of alertness and wellbeing. Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine (750 to 1200 mg/day spread throughout the day) have been shown to produce complete tolerance to some, but not all of the effects of caffeine. Doses as low as 100 mg/day, such as a 6 oz cup of coffee or two to three 12 oz servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption. Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.

Risk of other diseases
A neuroprotective effect of caffeine against Alzheimer's disease and dementia is possible but the evidence is inconclusive.

Regular consumption of caffeine may protect people from liver cirrhosis. 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.

Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude. One meta analysis has found that caffeine consumption is associated with a reduced risk of type 2 diabetes. Regular caffeine consumption may reduce the risk of developing Parkinson's disease and may slow the progression of Parkinson's disease.

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

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".

Energy crash
Caffeine is reputed to cause a fall in energy several hours after drinking, but this is not well researched.

Overdose

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

Caffeine overdose can result in a state of central nervous system overstimulation known as caffeine intoxication, a clinically significant temporary condition that develops during, or shortly after, the consumption of caffeine. 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.

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.

Energy drinks
High caffeine consumption in energy drinks (at least one liter or 320 mg of caffeine) was associated with short-term cardiovascular side effects including hypertension, prolonged QT interval, and heart palpitations. These cardiovascular side effects were not seen with smaller amounts of caffeine consumption in energy drinks (less than 200 mg).

Severe intoxication
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. Intralipid infusion therapy is indicated in cases of imminent risk of cardiac arrest in order to scavenge the free serum caffeine.

Lethal dose
Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications. 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. 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 adult). There are cases where doses as low as 57 milligrams per kilogram have been fatal. A number of fatalities have been caused by overdoses of readily available powdered caffeine supplements, for which the estimated lethal amount is less than a tablespoon. The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease. A death was reported in 2013 of a man with liver cirrhosis who overdosed on caffeinated mints.

Interactions
Caffeine is a substrate for CYP1A2, and interacts with many substances through this and other mechanisms.

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

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

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

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

Pharmacodynamics

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.

Receptor and ion channel targets
Caffeine is an antagonist of adenosine A2A receptors, and knockout mouse studies have specifically implicated antagonism of the A2A receptor as responsible for the wakefulness-promoting effects of caffeine. Antagonism of A2A receptors in the ventrolateral preoptic area (VLPO) reduces inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal. This disinhibition of the tuberomammillary nucleus is the downstream mechanism by which caffeine produces wakefulness-promoting effects. Caffeine is an antagonist of all four adenosine receptor subtypes (A1, A2A, A2B, and A3), although with varying potencies. The affinity (KD) values of caffeine for the human adenosine receptors are 12 μM at A1, 2.4 μM at A2A, 13 μM at A2B, and 80 μM at A3.

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. Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects; adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the A1 receptor.

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

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

Effects on striatal dopamine
While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1–D1 receptor heterodimer (this is a receptor complex with one adenosine A1 receptor and one dopamine D1 receptor) and the A2A–D2 receptor heterotetramer (this is a receptor complex with two adenosine A2A receptors and two dopamine D2 receptors). The A2A–D2 receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.

Caffeine also causes the release of dopamine in the dorsal striatum and nucleus accumbens core (a substructure within the ventral striatum), but not the nucleus accumbens shell, by antagonizing A1 receptors in the axon terminal of dopamine neurons and A1–A2A heterodimers (a receptor complex composed of one adenosine A1 receptor and one adenosine A2A receptor) in the axon terminal of glutamate neurons. During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance.

Enzyme targets
Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. As a competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular cyclic AMP, activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity. Caffeine also affects the cholinergic system where it is a moderate inhibitor of the enzyme acetylcholinesterase.

Pharmacokinetics

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

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. 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. In newborns the half-life can be 80 hours or more, dropping very rapidly with age, possibly to less than the adult value by age 6 months. The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and increases its elimination half-life more than tenfold; from 4.9 hours to 56 hours.

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

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

1,3,7-Trimethyluric acid is a minor caffeine metabolite. 7-Methylxanthine is also a metabolite of caffeine. 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.

A 2011 review found that increased caffeine intake was associated with a variation in two genes that increase the rate of caffeine catabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more caffeine per day than others. This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation.

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

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist 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.

Synthesis

The biosynthesis of caffeine is an example of convergent evolution among different species.

Caffeine may be synthesized in the lab starting with dimethylurea and malonic acid.

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

Decaffeination

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.
 * 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: is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions,  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  is then sprayed with high-pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.
 * Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.

"Decaffeinated" coffees do in fact contain caffeine in many cases – some commercially available decaffeinated coffee products contain considerable levels. One study found that decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of caffeine per cup for regular coffee.

Detection in body fluids
Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.

Analogs
Some analog substances have been created which mimic caffeine's properties with either function or structure or both. Of the latter group are the xanthines DMPX and 8-chlorotheophylline, which is an ingredient in dramamine. Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine. Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.

Some other caffeine analogs:
 * Dipropylcyclopentylxanthine
 * 8-Cyclopentyl-1,3-dimethylxanthine
 * 8-Phenyltheophylline

Precipitation of tannins
Caffeine, as do other alkaloids such as cinchonine, quinine or strychnine, precipitates polyphenols and tannins. This property can be used in a quantitation method.

Natural occurrence
Around thirty plant species are known to contain caffeine. Common sources are the "beans" (seeds) of the two cultivated coffee plants, Coffea arabica and Coffea canephora (the quantity varies, but 1.3% is a typical value); 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. High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection. In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival. Caffeine is stored in tea leaves in two places. Firstly, in the cell vacuoles where it is complexed with polyphenols. This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles. Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honey bees.

The differing perceptions in the effects of ingesting beverages made from various plants containing caffeine could be explained by the fact that these beverages also contain varying mixtures of other methylxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.

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

Coffee
The world's primary source of caffeine is the coffee "bean" (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee. Arabica coffee typically contains half the caffeine of the robusta variety. In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount.

Tea
Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since 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.

Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.

Soft drinks and energy drinks
Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain 0 to 55 milligrams of caffeine per 12 ounce (12 USfloz) serving. By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.

Other beverages

 * Mate is a drink popular in many parts of South America. Its preparation consists of filling a gourd with the leaves of the South American holly yerba mate, pouring hot but not boiling water over the leaves, and drinking with a straw, the bombilla, which acts as a filter so as to draw only the liquid and not the yerba leaves.
 * Guaraná 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.
 * 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. 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.

Cacao solids
Cocoa solids (derived from cocoa bean) contain 230 mg caffeine per 100 g.

The caffeine content varies between cocoa bean strains. Caffeine content mg/g (sorted by lowest caffeine content):
 * Forastero (defatted): 1.3 mg/g
 * Nacional (defatted): 2.4 mg/g
 * Trinitario (defatted): 6.3/g
 * Criollo (defatted): 11.3 mg/g

Chocolate
Caffeine per 100 g:
 * Dark chocolate, 70-85% cacao solids: 80 mg
 * Dark chocolate, 60-69% cacao solids: 86 mg
 * Dark chocolate, 45- 59% cacao solids: 43 mg
 * Milk chocolate: 20 mg

The stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as 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. These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.

Other oral products
One U.S. company is marketing oral dissolvable caffeine strips. Another intake route is SpazzStick, a caffeinated lip balm. Alert Energy Caffeine Gum was introduced in the United States in 2013, but was voluntarily withdrawn after an announcement of an investigation by the FDA of the health effects of added caffeine in foods.

Inhalants
Similar to an e-cigarette, a caffeine inhaler may be used to deliver caffeine or a stimulant like guarana by vaping. 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.

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".
 * Ya ba contains a combination of methamphetamine and caffeine.
 * Painkillers such as propyphenazone/paracetamol/caffeine combine caffeine with an analgesic.

Discovery and spread of use

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. Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.

The earliest credible evidence of either coffee drinking or knowledge of the coffee plant appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemen in southern Arabia. From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.

Kola nut use appears to have ancient origins. It is chewed in many West African cultures, in both private and social settings, to restore vitality and ease hunger pangs.

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

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines.

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

Chemical identification, isolation, and synthesis
In 1819, the German chemist Friedlieb Ferdinand Runge isolated caffeine for the first time; he called it "Kaffebase" (i.e., a base that exists in coffee). According to Runge, he did this at the behest of Johann Wolfgang von Goethe. In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work. However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating: "However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris."

Pelletier's article on caffeine was the first to use the term in print (in the French form Caféine from the French word for coffee: café). It corroborates Berzelius's account:

"Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Messrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ..."

Robiquet was one of the first to isolate and describe the properties of pure caffeine, whereas Pelletier was the first to perform an elemental analysis.

In 1827, M. Oudry isolated "théine" from tea, but in 1838 it was proved by Mulder and by Carl Jobst 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. Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.
 * This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
 * This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
 * This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
 * This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
 * This was part of the work for which Fischer was awarded the Nobel Prize in 1902.

Historic regulations
Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca and in the Ottoman Empire made coffee illegal for some classes. Charles II of England tried to ban it in 1676, Frederick II of Prussia banned it in 1777, and coffee was banned in Sweden at various times between 1756 and 1823.

In 1911, caffeine became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health". Although the 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.

United States
The US Food and Drug Administration (FDA) considers safe beverages containing less than 0.02% caffeine; but caffeine powder, which is sold as a dietary supplement, is unregulated. It is a regulatory requirement that the label of most prepackaged foods must declare a list of ingredients, including food additives such as caffeine, in descending order of proportion. However, there is no regulatory provision for mandatory quantitative labeling of caffeine, (e.g., milligrams caffeine per stated serving size). There are a number of food ingredients that naturally contain caffeine. These ingredients must appear in food ingredient lists. However, as is the case for "food additive caffeine", there is no requirement to identify the quantitative amount of caffeine in composite foods containing ingredients that are natural sources of caffeine. While coffee or chocolate are broadly recognized as caffeine sources, some ingredients (e.g., guarana, yerba maté) are likely less recognized as caffeine sources. For these natural sources of caffeine, there is no regulatory provision requiring that a food label identify the presence of caffeine nor state the amount of caffeine present in the food. The FDA guidance was updated in 2018.

Consumption
Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to an average of one serving of a caffeinated beverage for every person every day. The consumption of caffeine has remained stable between 1997 and 2015. 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.

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). Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: "... the Church revelation spelling out health practices (Doctrine and Covenants 89) does not mention the use of caffeine. The Church's health guidelines prohibit alcoholic drinks, smoking or chewing of tobacco, and 'hot drinks' – taught by Church leaders to refer specifically to tea and coffee."

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

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

Other organisms

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

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

Research
Caffeine has been used to double chromosomes in haploid wheat.

title: Caffeine


text:
Talk:Caffeine

Semi-protected edit request on 25 July 2023
Caffeine isn't a "mild cognitive nootropic" the wikipedia nootropic page classifieds it as a nootropic wrong information saying that it's a "mild one" James.Pater (talk) 22:43, 25 July 2023 (UTC)
 * Red question icon with gradient background.svg Not done: it's not clear what changes you want to be made. Please mention the specific changes in a "change X to Y" format and provide a reliable source if appropriate. HouseBlastertalk 01:30, 26 July 2023 (UTC)

Semi-protected edit request on 30 July 2023
Hello Wikipedia Community,

I am writing to propose an update to the "Caffeine" article. Specifically, the current citation number 243 ("Some Common Questions". Eagle Energy. Retrieved 22 May 2017), which is permanently dead and no longer provides valuable information to the article's readers, with my own recently published article titled "Caffeine Inhalers: An In-Depth Look at Use, Effects, and Regulation," which can be found at the following URL: https://thegoldenlamb.com/coffee-science/caffeine-inhalers/.

This report not only provides a high level of detail on caffeine inhalers but also has been structured and written to meet the standards of reliable sources as defined by Wikipedia's guidelines.

Therefore, I propose that this article can be a suitable replacement for the dead link, thus improving the quality of the information provided on the "Caffeine" Wikipedia page.

I kindly request that a member of the Wikipedia community who has the ability to edit the page reviews this proposal and, if found suitable, replaces the current citation number 243 with the following:

"Caffeine Inhalers: An In-Depth Look at Use, Effects, and Regulation". The Golden Lamb. Retrieved 29 July 2023.

Please feel free to contact me if there are any questions or further clarifications needed regarding this request. Thank you for your consideration.

Best regards,

Kelsey HappyFhantum (talk) 02:36, 30 July 2023 (UTC)

- your blog would not qualify as a WP:RS source; WP:PROMO violation and WP:NOTBLOG. Also, misuse of bold in your message. Zefr (talk) 04:44, 30 July 2023 (UTC)

Semi-protected edit request on 30 August 2023
Error in table under Products, last line 'Coffee-flavored milk drink': the value in the mg/L column reads 660-3290, should read 66-354 according to the cited source. Also, although the caffeine per serving values agree with the cited reference, the stated serving size of 250 ml does not match the citation. 80.216.216.86 (talk) 21:04, 30 August 2023 (UTC)
 * ❌ Cited material states The mean (±SD) caffeine concentration was 1930 ± 90 mg/L, the median was 1745 mg/L and values ranged from 660 to 3290 mg/L. -- Wiki Linuz  { talk } 21:13, 30 August 2023 (UTC)
 * The sentence above from the body of the cited material is likely a typo. Refer to Table 3 of the same publication, where the stated values range from 6.6 to 35.4 mg/100 ml, i.e. 66 to 354 mg/l. 213.65.212.191 (talk) 18:45, 3 September 2023 (UTC)
 * Red information icon with gradient background.svg Not done: Or the values in the table are a typo. Given the situation, I'd take the text from the article body as more convincing, without some other RS saying otherwise. -- Pinchme123 (talk) 03:09, 10 September 2023 (UTC)
 * I see several good reasons to believe that the values in Table 3 of the paper, rater than the Results, are more likely to be correct:
 * 1) the 'Caffeine per serving' values reported in the paper (and also in this Wikipedia article) are consistent with the values per 100 mL given in Table 3 of the paper, but not with those in the paper Results
 * 2) since the Results sumarise the information in Table 3, it is more likely that the text was composed after the table. It is unlikely that an error was first introduced in the table but then disappeared again in the Results
 * 3) the information in the table is more detailed; the liklihood of getting 20 numbers (or 40, including the consistent 'mg per serving' column) wrong is much smaller than getting just two numbers wrong
 * 4) the values in the Results are about an order of magnitude higher than for comparable beverages indicating an error
 * If this is not convincing I would suggest contacting the author for a clarification, or just delete this row from the table in the Caffeine page.
 * Regardless of the above, the serving size listed in the Wikipedia article table (250 ml) does not match the serving size of the paper (300-600 ml) from which the 'Caffeine per serving' of the Wikipedia article are derived. So either the serving size stated in the table should be changed, or the caffeine per serving in the same table recalculated. Joakim da Silva (talk) 11:20, 15 September 2023 (UTC)
 * ✅ - the values as they were are very obviously wrong. It appears the reason for the issue was likely that while converting from mg/100mL to mg/L, they multiplied by 100 instead of 10. Tollens (talk) 18:51, 15 September 2023 (UTC)

Semi-protected edit request on 21 September 2023
In the last paragraph of the introduction it says "A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used, how it is roasted (darker roasts have less caffeine), and how it is prepared (e.g., drip, percolation, or espresso)." and cites here .

The claim that darker roasts have less caffeine isn't supported by the article, which agrees that the numbers are not statistically significant.

I suggest that this should either be reworded to reflect this, use a different citation, or be removed altogether.

Additionally, and I know this isn't a source, but I was a barista and learned a lot about coffee, I know that this isn't true - the type of bean matters way more than the roast for caffeine content. Padrillium (talk) 14:56, 21 September 2023 (UTC)

 * in the article it cites, it says, "it showed a positive correlation between the caffeine levels with the degree of roasting till a certain point where the levels dropped in the dark roasted coffee." so maybe just removing the darker roast part but still keeping the rest of it; like, "...on what "bean" (seed) is used, how it is roasted, and how it is prepared...". Frost.xyz  | ( talk ) 16:39, 21 September 2023 (UTC)

 * Pictogram voting wait.svg Already done by . -- Pinchme123 (talk) 04:41, 5 October 2023 (UTC)

Lethal Dose Lower In Combination With Other Chemicals and Preexisting Conditions
@Zefr I am seeking other references about this death and I am thinking about a re-write of what I posted. I purposely avoided mentioning the origin of the drink and the law suit to avoid my post looking like news. Additionally, I argue my post does not fit squarely into any of the four categories listed in WP:NOTNEWS. While it might be difficult to find a case study on this event, my purpose was to draw attention to the additive effects of other chemicals and/or preexisting conditions that might lower the amount of caffeine necessary to cause heart damage or death, and therefore I used a reference that I could find. Using this specific event in this context does seem like a good example of additive effects. Lastly, I would like to communicate that point without casting a shadow on energy drinks in general. You might know there continues to be debate about the health effects of "energy" drinks. If you have any ideas or references I would be glad to follow up. I have searched PubMed and the CDC so far and found it will take more research to find a non-newsy reference. Perhaps a good re-write and the use of multiple references, including some from peer-reviewed research, might work better. Thanks — Preceding unsigned comment added by Jstengel (talk • contribs) 05:54, 24 October 2023 (UTC)

Picture of chemical structure
The first picture of the structure does not include the 3 “CH3” groups in the molecule 149.88.21.138 (talk) 12:02, 15 December 2023 (UTC)
 * I see dead-end lines, which are the standard skeletal structure representation for methyl groups. DMacks (talk) 15:24, 15 December 2023 (UTC)

physical Dependence
All sources mentioned physical dependence. It was not specified that physical caffeine dependence is classified as “low-moderate” in the DSM-5, specifically “Functional Consequences of Caffeine Withdrawal.” “Caffeine Withdrawal Disorder” was rated as Moderate 13% and I modified it and it was removed after a short period Frome page. Yungocdy (talk) 22:26, 19 January 2024 (UTC)

Problem in citations with regards to the claim of caffeine being the most consumed psychoactive drug
It's a locked article so I can't edit it myself, but one of the sources in the caffeine article is wrong, specifically citation 24. https://en.wikipedia.org/wiki/Caffeine "Caffeine is the world's most widely consumed psychoactive drug.[23][24]" It does not say anywhere in the paper that it's the most widely consumed psychoactive drug.

An alternative source that actually makes that claim can be eg. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680974/

Link to the faulty paper in question https://academic.oup.com/jsh/article-abstract/35/2/269/965314?redirectedFrom=fulltext&login=false (edited) 82.147.167.3 (talk) 23:29, 19 January 2024 (UTC) ✅ GrayStorm (talk) 01:43, 20 January 2024 (UTC)

Wiki Education assignment: Research Process and Methodology - SP24 - Sect 201 - Thu
— Assignment last updated by Kph7917 (talk) 22:17, 20 April 2024 (UTC)

L-Theanine reference needs better citation or should be removed.
"A systematic review and meta-analysis from 2014 found that concurrent caffeine and l-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching; these effects are most pronounced during the first hour post-dose." 1.This point's reference #56 is from a research article paid for by Glaxosmithkline using Glaxosmithkline employees. Glaxosmithkline produces products with L-theanine and caffeine Which is a conflict interest. 2.Does not establish how L-theanine adds any benefit when it lists things caffeine is already associated with by itself. You can see an example of one of Glaxo's products here with caffeine and L-theanine. https://www.amazon.com/Replenish-Excedrin-Electrolytes-L-Theanine-Caffeine/dp/B0BN71G5CD?ref_=ast_sto_dp&th=1&psc=1 2601:8C:4E80:7578:1DD5:595D:5CFB:52AB (talk) 10:08, 3 June 2024 (UTC)

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Talk:Caffeine


text:
Talk:Chiang Kai-shek

Birth country Qing Empire or Qing China?
What should we refer to the China that was led by the Qing dynasty: Qing Empire or Qing China? Also says birthplace as Qing Empire on the Sun Yat-sen article. Alexysun (talk) 06:29, 17 May 2024 (UTC)

 * Be wary of WP:OTHERCONTENT as an argument in itself. I frankly think it's clunky to list either in the context of an infobox. It's not relevant here since he was born in a different polity than he died in, but it's not that bizarre much of the time in the case of China to omit the dynasty in one or both parameters imo. If we have to list something, I think "Qing China" is bad, but "Qing Empire" is worse. "Qing dynasty" is likely the most correct on Wikipedia, as it's a pretty natural synecdoche when referring to the polity. I might prefer simply "Qing", but that wouldn't really work on Wikipedia. Remsense  诉  06:38, 17 May 2024 (UTC)
 * Ok. You said a lot of things without offering a definitive solution. His article on the Traditional Chinese Wikipedia states his birthplace as "大清浙江省宁波府奉化縣溪口鎮玉泰鹽鋪". 大清 directly translates to Big Qing or Great Qing. So I'd say Qing Empire or Qing China isn't bad. Alexysun (talk) 07:19, 17 May 2024 (UTC)
 * I did, though. I mentioned two options that I do not like, and an option I prefer.
 * If we don't make choices based solely on what other English Wikipedia articles say, then we surely do not based on what other language Wikipedias say. We're trying to choose terminology that's well-understood and natural for an English language audience. That's probably simply "Qing dynasty", which is also the article name. By comparison, "Qing China" and "Qing Empire" are not the terms preferred by most writers, and they look a bit clunky and unnatural. When in doubt, use the article name. Remsense  诉  07:24, 17 May 2024 (UTC)
 * @Remsense Ok I get what you're saying now. You're trying to use terms that are most commonly used/understood in English-speaking society. Alexysun (talk) 17:02, 19 May 2024 (UTC)
 * As is policy on the English Wikipedia, yes. Remsense  诉  14:21, 20 May 2024 (UTC)
 * Note that the corresponding article on Chinese Wikipedia currently actually states his birthplace as "清朝浙江省宁波府奉化县溪口镇玉泰盐铺", where "清朝" means Qing dynasty. Clearly it is the norm (EDIT: what I meant is that it is the norm even in the Chinese language). --Wengier (talk) 16:43, 30 June 2024 (UTC)
 * While I do think this gestures to evidence, there's certainly a lot of Chinese-language style norms we don't adapt across wikis into English, Remsense  诉  17:07, 30 June 2024 (UTC)
 * Of course, Chinese-language style norms and English-language style norms may be very different, such as in the case of Northern Yuan. But in this case, it is actually the norm even in the Chinese language. --Wengier (talk) 17:11, 30 June 2024 (UTC)

Change in infobox image
I propose a change in the infobox image for the subject. The proposed image is an official portrait of Chiang from 1955, which is the one used on Chinese Wikipedia. Personally I believe the new image looks better, and more in the style of historic politician portaits (e.g. Mao or Zhou Enlai). Fellow KMT commanders such as He Yingqin and Chen Cheng all have official photos of them in suits taken from around the same era, instead of them in military uniforms. I'm pinging some notable editors (who are still active) of this page, sorry if this bothers:,, ,, Zinderboff(talk) 09:03, 23 June 2024 (UTC)

 * I'm fine with this for the reasons stated. Remsense  诉  10:06, 23 June 2024 (UTC)
 * Your rationale makes good sense to me as well. JArthur1984 (talk) 13:29, 23 June 2024 (UTC)
 * I agree -- it's fine to have an "official" but not military photo at the head of the article, esp. since we have a range of styles in the images down the page.ch (talk) 18:43, 23 June 2024 (UTC)

Order of Brilliant Jade
If anyone can find a source for him receiving the Order of Brilliant Jade, adding it to the article for the award as well would be appreciated. Thanks. Damien Linnane (talk) 00:50, 14 July 2024 (UTC)

title: Talk:Chiang Kai-shek


text:
Cyc

Cyc (pronounced ) is a long-term artificial intelligence project that aims to assemble a comprehensive ontology and knowledge base that spans the basic concepts and rules about how the world works.

Hoping to capture common sense knowledge, Cyc focuses on implicit knowledge that other AI platforms may take for granted.

This is contrasted with facts one might find somewhere on the internet or retrieve via a search engine or Wikipedia.

Cyc enables semantic reasoners to perform human-like reasoning and be less "brittle" when confronted with novel situations.

Douglas Lenat began the project in July 1984 at MCC, where he was Principal Scientist 1984–1994, and then, since January 1995, has been under active development by the Cycorp company, where he was the CEO.

Overview
The need for a large-scale symbolic artificial intelligence project emerged in the early 1980s. AI researchers had observed over the preceding 25 years that AI programs often produced promising initial results but struggled to "scale up"—failing to extend beyond their initial training sets to a wider range of cases. This issue was highlighted by Douglas Lenat and Alan Kay, who organized a meeting at Stanford University in 1983 to discuss the problem.

The back-of-the-envelope calculations by Lenat, Kay, and their colleagues (including Marvin Minsky, Allen Newell, Edward Feigenbaum, and John McCarthy) indicated that that effort would require between 1,000 and 3,000 person-years of effort. Events within a year of that meeting enabled an effort of that scale to get underway.

The project began in July 1984 as the flagship project of the 400-person Microelectronics and Computer Technology Corporation (MCC), a research consortium started by two dozen large United States-based corporations "to counter a then ominous Japanese effort in AI, the so-called "fifth-generation" project." The US Government reacted to the Fifth Generation threat by passing the National Cooperative Research Act of 1984, which for the first time allowed US companies to "collude" on long-term high-risk high-payoff research, and MCC and Sematech sprang up to take advantage of that ten-year opportunity. MCC's first President and CEO was Bobby Ray Inman, former NSA Director and Central Intelligence Agency deputy director.

The objective of the Cyc project was to codify, in machine-usable form, the millions of pieces of knowledge that compose human common sense. This entailed, along the way, (1) developing an adequately expressive representation language, CycL, (2) developing an ontology spanning all human concepts down to some appropriate level of detail, (3) developing a knowledge base on that ontological framework, comprising all human knowledge about those concepts down to some appropriate level of detail, and (4) developing an inference engine exponentially faster than those used in then-conventional expert systems, to be able to infer the same types and depth of conclusions that humans are capable of, given their knowledge of the world.

In slightly more detail:
 * The CycL representation language started as an extension of RLL (the so-called Representation Language Language, developed in 1979–1980 by Lenat and his graduate student Russell Greiner while at Stanford University), but within a few years of the launch of the Cyc project it became clear that even representing a typical news story or novel or advertisement would require more than the expressive power of full first-order logic, namely second-order predicate calculus ("What is the relationship between rain and water?") and then even higher-level orders of logic including modal logic, reflection (enabling the system to reason about its progress so far, on a problem on which it is working), and context logic (enabling the system to reason explicitly about the contexts in which its various premises and conclusions might hold), non-monotonic logic, and circumscription. By 1989, CycL had expanded in expressive power to higher-order logic (HOL).
 * Triplestore representations (which are akin to the Frame -and-slot representation languages of the 1970s from which RLL sprang) are widespread today in AI. It may be useful to cite a few examples that stress or break that type of representation, typical of the examples that forced the Cyc project to move from a triplestore representation to a much more expressive one during the period 1984–1989: English sentences including negations ("Fred does not own a dog"), nested quantifiers ("Every American has a mother" means for-all x there-exists y... but "Every American has a President" means there-exists y such that for-all x...), nested modals such as "The United States believes that Germany wants NATO to avoid pursuing..." and it is even awkward to represent, in a Triplestore, relationships of arity higher than 2, such as "Los Angeles is between San Diego and San Francisco along US101."
 * Cyc's ontology grew to about 100,000 terms during the first decade of the project, to 1994, and as of 2017 contained about 1,500,000 terms. This ontology included:
 * 416,000 collections (types, sorts, natural kinds, which includes both types of things such as Fish and types of actions such as Fishing)
 * a little over a million individuals representing
 * 42,500 predicates (relations, attributes, fields, properties, functions),
 * about a million generally well-known entities such as TheUnitedStatesOfAmerica, BarackObama, TheSigningOfTheUSDeclarationOfIndependence, etc.
 * An arbitrarily large number of additional terms are also implicitly present in the Cyc ontology, in the sense that there are term-denoting functions such as CalendarYearFn (when given the argument 2016, it denotes the calendar year 2016), GovernmentFn (when given the argument France it denotes the government of France), Meter (when given the argument 2016, it denotes a distance of 2.016 kilometers), and nestings and compositions of such function-denoting terms.
 * The Cyc knowledge base of general common-sense rules and assertions involving those ontological terms was largely created by hand axiom-writing; it grew to about 1 million in 1994, and as of 2017 is about 24.5 million and has taken well over 1,000 person-years of effort to construct.
 * It is important to understand that the Cyc ontological engineers strive to keep those numbers as small as possible, not inflate them, so long as the deductive closure of the knowledge base is not reduced. Suppose Cyc is told about one billion individual people, animals, etc. Then it could be told 1018 facts of the form "Mickey Mouse is not the same individual as ". But instead of that, one could tell Cyc 10,000 Linnaean taxonomy rules followed by just 108 rules of the form "No mouse is a moose". And even more compactly, Cyc could instead just be given those 10,000 Linnaean taxonomy rules followed by just one rule of the form "For any two Linnaean taxons, if neither is explicitly known to be a supertaxon of the other, then they are disjoint". Those 10,001 assertions have the same deductive closure as the earlier-mentioned 1018 facts.
 * The Cyc inference engine design separates the epistemological problem (what content should be in the Cyc KB) from the heuristic problem (how Cyc could efficiently infer arguments hundreds of steps deep, in a sea of tens of millions of axioms). To do the former, the CycL language and well-understood logical inference might suffice. For the latter, Cyc used a community-of-agents architecture, where specialized reasoning modules, each with its own data structure and algorithm, "raised their hand" if they could efficiently make progress on any of the currently open sub-problems. By 1994 there were 20 such heuristic level (HL) modules; as of 2017 there are over 1,050 HL modules.
 * Some of these HL modules are very general, such as a module that caches the Kleene Star (transitive closure) of all the commonly-used transitive relations in Cyc's ontology.
 * Some are domain-specific, such as a chemical equation-balancer. These can be and often are an "escape" to (pointer to) some externally available program, web-service or online database, such as a module to quickly "compute" the current population of a city by knowing where/how to look that up.

CycL has a publicly released specification and dozens of HL modules were described in Lenat and Guha's textbook, but the actual Cyc inference engine code, and the full list of 1000+ HL modules, is Cycorp-proprietary.

The name "Cyc" (from "encyclopedia", pronounced, like "syke") is a registered trademark owned by Cycorp. Access to Cyc is through paid licenses, but bona fide AI research groups are given research-only no-cost licenses (cf. ResearchCyc); as of 2017, over 600 such groups worldwide have these licenses.

Typical pieces of knowledge represented in the Cyc knowledge base are "Every tree is a plant" and "Plants die eventually". When asked whether trees die, the inference engine can draw the obvious conclusion and answer the question correctly.

Most of Cyc's knowledge, outside maths, is only true by default. For example, Cyc knows that as a default parents love their children, people smile when happy, a child's first step is a big accomplishment, people are happy when a loved one has a big accomplishment, and only adults have children. When asked whether a picture captioned "Someone watching his daughter take her first step" contains a smiling adult person, Cyc can logically infer that the answer is Yes, and "show its work" by presenting the step-by-step logical argument using those five pieces of knowledge from its knowledge base. These are formulated in the language CycL, which is based on predicate calculus and has a syntax similar to that of the Lisp programming language.

In 2008, Cyc resources were mapped to many Wikipedia articles. Cyc is presently connected to Wikidata. Future plans may connect Cyc to both DBpedia and Freebase.

Much of the current work Cyc continues to be knowledge engineering, representing facts about the world by hand, and implementing efficient inference mechanisms on that knowledge. Increasingly, however, work at Cycorp involves giving the Cyc system the ability to communicate with end users in natural language, and to assist with the ongoing knowledge formation process via machine learning and natural-language understanding. Another large effort at Cycorp is building a suite of Cyc-powered ontological engineering tools to lower the bar to entry for individuals to contribute to, edit, browse, and query Cyc.

Like many companies, Cycorp has ambitions to use Cyc's natural-language processing to parse the entire internet to extract structured data; unlike all others, it is able to call on the Cyc system itself to act as an inductive bias and as an adjudicator of ambiguity, metaphor, and ellipsis. There are few, if any, systematic benchmark studies of Cyc's performance.

Knowledge base
The concept names in Cyc are CycL terms or constants. Constants start with an optional  and are case-sensitive. There are constants for:
 * Individual items known as individuals, such as  or.
 * Collections, such as  (containing all trees) or   (containing all equivalence relations). A member of a collection is called an instance of that collection.
 * Functions, which produce new terms from given ones. For example,, when provided with an argument describing a type (or collection) of plants, will return the collection of its fruits. By convention, function constants start with an upper-case letter and end with the string.
 * Truth functions, which can apply to one or more other concepts and return either true or false. For example,  is the sibling relationship, true if the two arguments are siblings. By convention, truth function constants start with a lowercase letter. Truth functions may be broken down into logical connectives (such as ,  ,  ,  ), quantifiers ( ,  , etc.) and predicates.

Two important binary predicates are  and. The first one describes that one item is an instance of some collection, the second one that one collection is a subcollection of another one. Facts about concepts are asserted using certain CycL sentences. Predicates are written before their arguments, in parentheses: (#$isa #$BillClinton #$UnitedStatesPresident) "Bill Clinton belongs to the collection of U.S. presidents." (#$genls #$Tree-ThePlant #$Plant) "All trees are plants." (#$capitalCity #$France #$Paris) "Paris is the capital of France."

Sentences can also contain variables, strings starting with. These sentences are called "rules". One important rule asserted about the  predicate reads: (#$implies   (#$and (#$isa ?OBJ ?SUBSET) (#$genls ?SUBSET ?SUPERSET))   (#$isa ?OBJ ?SUPERSET)) "If  is an instance of the collection   and   is a subcollection of , then   is an instance of the collection  ". Another typical example is (#$relationAllExists #$biologicalMother #$ChordataPhylum #$FemaleAnimal) which means that for every instance of the collection  (i.e. for every chordate), there exists a female animal (instance of  ), which is its mother (described by the predicate  ).

The knowledge base is divided into microtheories (Mt), collections of concepts and facts typically pertaining to one particular realm of knowledge. Unlike the knowledge base as a whole, each microtheory must be free from monotonic contradictions. Each microtheory is a first-class object in the Cyc ontology; it has a name that is a regular constant; microtheory constants contain the string  by convention. An example is, the microtheory containing mathematical knowledge. The microtheories can inherit from each other and are organized in a hierarchy: one specialization of  is , the microtheory about geometry.

Inference engine
An inference engine is a computer program that tries to derive answers from a knowledge base. The Cyc inference engine performs general logical deduction (including modus ponens, modus tollens, universal quantification and existential quantification). It also performs inductive reasoning, statistical machine learning and symbolic machine learning, and abductive reasoning (but of course sparingly and using the existing knowledge base as a filter and guide).

OpenCyc
The first version of OpenCyc was released in spring 2002 and contained only 6,000 concepts and 60,000 facts. The knowledge base was released under the Apache License. Cycorp stated its intention to release OpenCyc under parallel, unrestricted licences to meet the needs of its users. The CycL and SubL interpreter (the program that allows users to browse and edit the database as well as to draw inferences) was released free of charge, but only as a binary, without source code. It was made available for Linux and Microsoft Windows. The open source Texai project released the RDF-compatible content extracted from OpenCyc. A version of OpenCyc, 4.0, was released in June 2012. OpenCyc 4.0 included much of the Cyc ontology at that time, containing hundreds of thousands of terms, along with millions of assertions relating the terms to each other; however, these are mainly taxonomic assertions, not the complex rules available in Cyc. The OpenCyc 4.0 knowledge base contained 239,000 concepts and 2,093,000 facts.

The main point of releasing OpenCyc was to help AI researchers understand what was missing from what they now call ontologies and knowledge graphs. It is useful and important to have properly taxonomized concepts like person, night, sleep, lying down, waking, happy, etc., but what is missing from the OpenCyc content about those terms, but present in the Cyc KB content, are the various rules of thumb that most of us share about those terms: that (as a default, in the ModernWesternHumanCultureMt) each person sleeps at night, sleeps lying down, can be woken up, is not happy about being woken up, and so on. That point does not require continually-updated releases of OpenCyc, so, as of 2017, OpenCyc is no longer available.

ResearchCyc
In July 2006, Cycorp released the executable of ResearchCyc 1.0, a version of Cyc aimed at the research community, at no charge. (ResearchCyc was in beta stage of development during all of 2004; a beta version was released in February 2005.) In addition to the taxonomic information contained in OpenCyc, ResearchCyc includes significantly more semantic knowledge (i.e., additional facts and rules of thumb) involving the concepts in its knowledge base; it also includes a large lexicon, English parsing and generation tools, and Java-based interfaces for knowledge editing and querying. In addition it contains a system for ontology-based data integration. As of 2017, regular releases of ResearchCyc continued to appear, with 600 research groups utilizing licenses around the world at no cost for noncommercial research purposes. As of December 2019, ResearchCyc is no longer supported. Cycorp expects to improve and overhaul tools for external developers over the coming years.

Applications
There have been over a hundred successful applications of Cyc; listed here are a few mutually dissimilar instances:

Pharmaceutical Term Thesaurus Manager/Integrator
For over a decade, Glaxo has used Cyc to semi-automatically integrate all the large (hundreds of thousands of terms) thesauri of pharmaceutical-industry terms that reflect differing usage across companies, countries, years, and sub-industries. This ontology integration task requires domain knowledge, shallow semantic knowledge, but also arbitrarily deep common sense knowledge and reasoning. Pharma vocabulary varies across countries, (sub-) industries, companies, departments, and decades of time. E.g., what is a gel pak? What is the "street name" for ranitidine hydrochloride? Each of these n controlled vocabularies is an ontology with approximately 300k terms. Glaxo researchers need to issue a query in their current vocabulary, have it translated into a neutral “true meaning”, and then have that transformed in the opposite direction to find potential matches against documents each of which was written to comply with a particular known vocabulary.

They had been using a large staff to do that manually. Cyc is used as the universal interlingua capable of representing the union of all the terms' "true meanings", and capable of representing the 300k transformations between each of those controlled vocabularies and Cyc, thereby converting an n² problem into a linear one without introducing the usual sort of "telephone game" attenuation of meaning. Furthermore, creating each of those 300k mappings for each thesaurus is done in a largely automated fashion, by Cyc.

Terrorism Knowledge Base
The comprehensive Terrorism Knowledge Base was an application of Cyc in development that tried to ultimately contain all relevant knowledge about "terrorist" groups, their members, leaders, ideology, founders, sponsors, affiliations, facilities, locations, finances, capabilities, intentions, behaviors, tactics, and full descriptions of specific terrorist events. The knowledge is stored as statements in mathematical logic, suitable for computer understanding and reasoning.

Cleveland Clinic Foundation
The Cleveland Clinic has used Cyc to develop a natural-language query interface of biomedical information, spanning decades of information on cardiothoracic surgeries. A query is parsed into a set of CycL (higher-order logic) fragments with open variables (e.g., "this question is talking about a person who developed an endocarditis infection", "this question is talking about a subset of Cleveland Clinic patients who underwent surgery there in 2009", etc.); then various constraints are applied (medical domain knowledge, common sense, discourse pragmatics, syntax) to see how those fragments could possibly fit together into one semantically meaningful formal query; significantly, in most cases, there is exactly one and only one such way of incorporating and integrating those fragments. Integrating the fragments involves (i) deciding which open variables in which fragments actually represent the same variable, and (ii) for all the final variables, decide what order and scope of quantification that variable should have, and what type (universal or existential). That logical (CycL) query is then converted into a SPARQL query that is passed to the CCF SemanticDB that is its data lake.

MathCraft
One Cyc application aims to help students doing math at a 6th grade level, helping them much more deeply understand that subject matter. It is based on the experience that we often have thought we understood something, but only really understood it after we had to explain or teach it to someone else. Unlike almost all other educational software, where the computer plays the role of the teacher, this application of Cyc, called MathCraft, has Cyc play the role of a fellow student who is always slightly more confused than you, the user, are about the subject. The user's role is to observe the Cyc avatar and give it advice, correct its errors, mentor it, get it to see what it's doing wrong, etc. As the user gives good advice, Cyc allows the avatar to make fewer mistakes of that type, hence, from the user's point of view, it seems as though the user has just successfully taught it something. This is a variation of learning by teaching.

Criticisms
The Cyc project has been described as "one of the most controversial endeavors of the artificial intelligence history". Catherine Havasi, CEO of Luminoso, says that Cyc is the predecessor project to IBM's Watson. Machine-learning scientist Pedro Domingos refers to the project as a "catastrophic failure" for several reasons, including the unending amount of data required to produce any viable results and the inability for Cyc to evolve on its own.

Robin Hanson, a professor of economics at George Mason University, gives a more balanced analysis:

"Of course the CYC project is open to criticism on its many particular choices. People have complained about its logic-like and language-like representations, about its selection of prototypical cases to build from (e.g., encyclopedia articles), about its focus on answering over acting, about how often it rebuilds vs. maintaining legacy systems, and about being private vs. publishing everything. But any large project like this would produce such disputes, and it is not obvious any of its choices have been seriously wrong.  They had to start somewhere, and in my opinion they have now collected a knowledge base with a truly spectacular size, scope, and integration. Other architectures may well work better, but if knowing lots is anywhere near as important as Lenat thinks, I’d expect serious AI attempts to import CYC’s knowledge, translating it into a new representation.  No other source has anywhere near CYC’s size, scope, and integration."

A similar sentiment was expressed by Marvin Minsky: "Unfortunately, the strategies most popular among AI researchers in the 1980s have come to a dead end," said Minsky. So-called "expert systems", which emulated human expertise within tightly defined subject areas like law and medicine, could match users' queries to relevant diagnoses, papers and abstracts, yet they could not learn concepts that most children know by the time they are 3 years old. "For each different kind of problem," said Minsky, "the construction of expert systems had to start all over again, because they didn't accumulate common-sense knowledge." Only one researcher has committed himself to the colossal task of building a comprehensive common-sense reasoning system, according to Minsky. Douglas Lenat, through his Cyc project, has directed the line-by-line entry of more than 1 million rules into a commonsense knowledge base.

Gary Marcus, a professor of psychology and neural science at New York University and the cofounder of an AI company called Geometric Intelligence, says "it represents an approach that is very different from all the deep-learning stuff that has been in the news.” This is consistent with Doug Lenat's position that "Sometimes the veneer of intelligence is not enough".

Stephen Wolfram writes:

"In the early days of the field of artificial intelligence, there were plenty of discussions of “knowledge representation”, with approaches based variously on the grammar of natural language, the structure of predicate logic or the formalism of databases. Very few large-scale projects were attempted (Doug Lenat’s Cyc being a notable counterexample)."

Marcus writes: "The field might well benefit if CYC were systematically described and evaluated. If CYC has solved some significant fraction of commonsense reasoning, then it is critical to know that, both as a useful tool, and as a starting point for further research. If CYC has run into difficulties, it would be useful to learn from the mistakes that were made. If CYC is entirely useless, then researchers can at least stop worrying about whether they are reinventing the wheel."

Every few years since it began publishing (1993), there is a new Wired Magazine article about Cyc, some positive and some negative (including one issue which contained one of each).

Notable employees
This is a list of some of the notable people who work or have worked on Cyc either while it was a project at MCC (where Cyc was first started) or Cycorp.

 * Douglas Lenat
 * Michael Witbrock
 * Pat Hayes
 * Ramanathan V. Guha
 * Stuart J. Russell
 * Srinija Srinivasan
 * Jared Friedman
 * John McCarthy

title: Cyc


text:
CE

CE, Ce, ce, or variants may refer to:

Business

 * CE marking (stylized Conformité Européenne (logo).svg), a mandatory administrative marking asserting conformity with relevant standards, applied certain products offered for sale within the European Economic Area;
 * Customer equity, the total combined customer lifetime values of all of the company's customers
 * Combustion Engineering, a former American manufacturer of power systems
 * Nationwide Airlines (South Africa) (IATA airline designator CE)

Calendar

 * Common Era (abbreviated CE), an alternative term to Anno Domini (AD)
 * "Christian Era", also known as Anno Domini

Education

 * College English, an official publication of the American National Council of Teachers of English
 * Common Entrance Examination, tests used by independent schools in the UK
 * Conductive education, an educational system developed for people with motor disorders
 * Continuing education, a broad spectrum of post-secondary learning activities and programs
 * Chartered engineer (UK), a professional engineer licensed by a professional body (modern abbreviation CEng)
 * Hong Kong Certificate of Education Examination, a standardized examination from 1974 to 2011

Entertainment

 * cê, a 2006 music album by Caetano Veloso
 * Chaotic Evil, an alignment in the tabletop game Dungeons and Dragons
 * Collector's edition, describing some special editions of software, movies, and books
 * Cash Explosion, Ohio Lottery's scratch off game and weekly game show
 * Halo: Combat Evolved, sometimes abbreviated as Halo: CE

Job titles

 * Chief Executive, administrative head of some regions
 * County executive, the head of the executive branch of county government, common in the U.S.
 * Construction Electrician (US Navy), a Seabee occupational rating in the U.S. Navy

Languages

 * Canadian English
 * Chechen language (ISO 639-1 language code: ce)
 * Commonwealth English

Organizations

 * Church of England, the state church of the U.K. and mother church of the Anglican Communion, also referred to as the C of E
 * Command element (United States Marine Corps), headquarters component of U.S. Marine Corps Marine Air-Ground Task Force (MAGTF)
 * European Community, (Communauté Européenne, Comunità Europea, Comunidade Europeia, Comunitatea Europeană, Comunidad Europea)

Places

 * Cé (Pictish territory), an early medieval Pictish territory in modern-day Scotland
 * Province of Caserta (ISO 3166-2:IT code CE), a province of Italy
 * County Clare, Ireland (vehicle registration plate code CE)
 * Ceará (ISO 3166-2:BR code CE), a state in Brazil
 * Ceper railway station, a railway station in Indonesia (station code)
 * Lough Key, known in Irish as Loch Cé
 * Sri Lanka (FIPS Pub 10-4 and obsolete NATO country code CE)

Computing

 * Central European, an alternate name for Windows-1250
 * Cheat Engine, a system debugger and cheating tool
 * Clear Entry, a button on a standard electronic calculator that clears the last number entered
 * c.e., a common abbreviation for Computably enumerable, a property of some sets in computability theory
 * Congestion Experienced, a protocol element of the Explicit Congestion Notification data networking protocol
 * Customer edge router, a router at the customer premises that is connected to a Multi-protocol Label Switching network
 * Windows CE, "Consumer Edition", a version of the Windows operating system designed for mobile devices

Other uses in science and technology

 * Capillary electrophoresis, a technique used to separate ionic species by their charge and frictional forces
 * CE phase, the phase between carrier and envelope of an electromagnetic wave
 * Cerium, symbol Ce, a chemical element
 * Cholesteryl ester
 * Civil engineering
 * Common envelope, gas containing a binary system.
 * Conjugated estrogen
 * Consumer electronics
 * Customer engineer

Other uses

 * Copy editing, improving the formatting, style, and accuracy of text

title: CE