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Caffeine is a
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS)
stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
of the methylxanthine
class Class or The Class may refer to: Common uses not otherwise categorized * Class (biology), a taxonomic rank * Class (knowledge representation), a collection of individuals or objects * Class (philosophy), an analytical concept used differently ...
. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of
adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside building ...
to the adenosine A1 receptor, which enhances release of the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
. 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 Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...
levels through nonselective inhibition of phosphodiesterase. Caffeine is a bitter, white crystalline
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
, a methylxanthine
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...
, and is chemically related to the
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
and
guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is ...
bases of deoxyribonucleic acid (DNA) and
ribonucleic acid Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohyd ...
(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 A coffee bean is a seed of the '' Coffea'' plant and the source for coffee. It is the pip inside the red or purple fruit often referred to as a coffee cherry. Just like ordinary cherries, the coffee fruit is also a so-called stone fruit. Even th ...
, 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 Infusion is the process of extracting chemical compounds or flavors from plant material in a solvent such as water, oil or alcohol, by allowing the material to remain suspended in the solvent over time (a process often called steeping). An in ...
. Caffeine-containing drinks, such as
coffee Coffee is a drink prepared from roasted coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulating effect on humans, primarily due to its caffeine content. It is the most popular hot drink in the world. Seeds of ...
, 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 A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior. ...
. 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 Bronchopulmonary dysplasia (BPD; part of the spectrum of chronic lung disease of infancy) is a chronic lung disease in which premature infants, usually those who were treated with supplemental oxygen, require long-term oxygen. The alveoli that are ...
of prematurity and apnea of prematurity. Caffeine citrate is on the
WHO Model List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. It may confer a modest protective effect against some diseases, including
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
. 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 Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...
 – associated with
withdrawal symptoms Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs. In order for the symptoms of wit ...
such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake.
Tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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 (darker roasts have less caffeine), and how it is prepared (e.g.,
drip Drip or DRIP may refer to: * Mesomycetozoea, a class of eukaryotes also known as the DRIP clade * Drip gas, natural gas condensate * Drip irrigation, in agriculture and gardening * Dripping liquid * Drip email (campaign), the process of automa ...
, percolation, or
espresso Espresso (, ) is a coffee-brewing method of Italian origin, in which a small amount of nearly boiling water (about ) is forced under of pressure through finely-ground coffee beans. Espresso can be made with a wide variety of coffee beans a ...
). 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 A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
, can be lethal in tablespoon-sized amounts.


Use


Medical

Caffeine is used in: *
Bronchopulmonary dysplasia Bronchopulmonary dysplasia (BPD; part of the spectrum of chronic lung disease of infancy) is a chronic lung disease in which premature infants, usually those who were treated with supplemental oxygen, require long-term oxygen. The alveoli that are ...
in
premature Premature may refer to: * ''Premature'' (2014 film), an American comedy film * ''Premature'' (2019 film), an American romantic drama film * '' PREMature'', a 2015 British television drama miniseries See also * Premature aging, of an organism * ...
infants for both prevention and treatment. It may improve weight gain during therapy and reduce the incidence of
cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sens ...
as well as reduce language and cognitive delay. On the other hand, subtle long-term side effects are possible. * Apnea of prematurity as a primary treatment, but not prevention. *
Orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...
treatment. * Some people use caffeine-containing beverages such as coffee or tea to try to treat their
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
. 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 Spirometry (meaning ''the measuring of breath'') is the most common of the pulmonary function tests (PFTs). It measures lung function, specifically the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Spirometry is he ...
(FEV1) by 5% to 18%, with this effect lasting for up to four hours. *The addition of caffeine (100–130 mg) to commonly prescribed pain relievers such as
paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...
or
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus ar ...
modestly improves the proportion of people who achieve
pain relief Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professional ...
. * 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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
. It is considered less effective than
methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...
or
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
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.


Enhancing performance


Cognitive performance

Caffeine is a
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
stimulant that may reduce
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
and drowsiness. At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time,
wakefulness Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognitive and behavioral responses to the external world. Being awake is the opposite of being asleep, in which m ...
, concentration, and
motor coordination Motor coordination is the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. This coordination is achieved by adjusting kinematic and kinetic parameters associated with each body part involved in ...
. 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 Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...
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 A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...
and
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
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 Performance-enhancing substances, also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans. A well-known example of cheating in sports involves doping in sport, where bann ...
in humans. Caffeine improves athletic performance in aerobic (especially
endurance sports An endurance game is a game where the object is to last as long as possible under some sort of stress. The stress might be physical pain, fear, social embarrassment or any other negative sensation. The important distinguishing feature of endura ...
) and anaerobic conditions. Quote: 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 Central nervous system fatigue, or central fatigue, is a form of fatigue that is associated with changes in the synaptic concentration of neurotransmitters within the central nervous system (CNS; including the brain and spinal cord) which affec ...
), and cycling power output. Caffeine increases
basal metabolic rate Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O2/min or joule per hour per kg body mass J/(h·kg). P ...
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.


Specific populations


Adults

For the general population of healthy adults,
Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the department of the Government of Canada responsible for national health poli ...
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 6 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 The American Academy of Pediatrics (AAP) is an American professional association of pediatricians, headquartered in Itasca, Illinois. It maintains its Department of Federal Affairs office in Washington, D.C. Background The Academy was found ...
recommends that caffeine consumption 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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
, Sports Medicine & Fitness committee, National Federations of High School Associations). For children age 12 and under,
Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the department of the Government of Canada responsible for national health poli ...
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). Current 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 The Food Standards Agency is a non-ministerial government department of the Government of the United Kingdom. It is responsible for protecting public health in relation to food in England, Wales and Northern Ireland. It is led by a board ap ...
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 The American College of Obstetricians and Gynecologists (ACOG) is a professional association of physicians specializing in obstetrics and gynecology in the United States. Several Latin American countries are also represented within Districts o ...
(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 Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemica ...
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 Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an infant of or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal int ...
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.


Adverse effects


Physical

Caffeine in coffee and other
caffeinated drink A caffeinated drink, or caffeinated beverage, is a drink that contains caffeine, a stimulant that is legal practically all over the world. The most common naturally caffeinated beverages are coffee and tea, which in one form or another (usua ...
s can affect gastrointestinal motility and
gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...
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 Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pr ...
(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 In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
. However, chronic users of caffeine develop a
tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
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 Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
. According to a 2011 literature review, caffeine use may induce anxiety and panic disorders in people with
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
. 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 Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...
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 Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder. Consumption of caffeine has long been linked to anxiety. The effects of caffeine and the symptoms of anxiety both increase a ...
is a subclass of the
DSM-5 The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the '' Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiatri ...
diagnosis of substance/medication-induced anxiety disorder.


Reinforcement disorders


Addiction

Whether caffeine can result in an addictive disorder depends on how addiction is defined. Compulsive caffeine consumption under any circumstances has not been observed, and caffeine is therefore not generally considered addictive. However, some diagnostic models, such as the and
ICD-10 ICD-10 is the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD), a medical classification list by the World Health Organization (WHO). It contains codes for diseases, signs and symptoms ...
, 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 Nida or NIDA may refer to: People * Nida Allam (born 1993), American politician * Nida Fazli (1938–2016), Indian Hindi and Urdu poet and lyricist * Nida Eliz Üstündağ (born 1996), Turkish female swimmer * Eugene Nida (1914–2011), American l ...
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 The American Psychiatric Association (APA) is the main professional organization of psychiatrists and trainee psychiatrists in the United States, and the largest psychiatric organization in the world. It has more than 37,000 members are invo ...
's 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. Mild
physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certai ...
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 Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms—e.g. anxiety and anhedonia—upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent exp ...
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 Depression is a mental state of low mood and aversion to activity, which affects more than 280 million people of all ages (about 3.5% of the global population). Classified medically as a mental and behavioral disorder, the experience o ...
/
irritability Irritability (also called as crankiness) is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessi ...
, flu-like symptoms,
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
, and
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
. 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 Caffeine dependence is the condition of having a substance dependence on caffeine, a commonplace central nervous system stimulant drug which occurs naturally in coffee, tea, yerba mate, cocoa, and other plants. Caffeine is also one of the most ...
as a distinct diagnostic category, which closely mirrors the
DSM-5 The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the '' Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiatri ...
'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 In medicine and psychology, clinical significance is the practical importance of a treatment effect—whether it has a real genuine, palpable, noticeable effect on daily life. Types of significance Statistical significance Statistical 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 Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
to the effects of caffeine occurs for caffeine-induced elevations in
blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...
and the subjective feelings of nervousness.
Sensitization Sensitization is a non-associative learning process in which repeated administration of a stimulus results in the progressive amplification of a response. Sensitization often is characterized by an enhancement of response to a whole class of sti ...
, the process whereby effects become more prominent with use, occurs 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 cup of coffee or two to three 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 protective effect of caffeine against
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
and dementia is possible but the evidence is inconclusive. It may protect people from
liver cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
. Caffeine may lessen the severity of
acute mountain sickness Altitude sickness, the mildest form being acute mountain sickness (AMS), is the harmful effect of high altitude, caused by rapid exposure to low amounts of oxygen at high elevation. People can respond to high altitude in different ways. Sympt ...
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 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
. Regular caffeine consumption may reduce the risk of developing
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
and may slow the progression of Parkinson's disease. Caffeine increases
intraocular pressure Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated t ...
in those with
glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for aqueous humor, fluid withi ...
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".


Overdose

Consumption of per day is associated with a condition known as ''
caffeinism Caffeinism is a state of intoxication caused by excessive consumption of caffeine. This intoxication covers a variety of unpleasant physical and mental symptoms associated with the consumption of excessive amounts of caffeine. Caffeine is consid ...
.'' Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
, 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 Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pr ...
, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech,
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...
or cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adult ...
, periods of inexhaustibility, and
psychomotor agitation Psychomotor agitation is a symptom in various disorders and health conditions. It is characterized by unintentional and purposeless motions and restlessness, often but not always accompanied by emotional distress. Typical manifestations include ...
. 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 Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of ...
.


Energy drinks

High caffeine consumption in energy drinks (at least 1 liter or 320 mg of caffeine) was associated with short-term cardiovascular side effects including hypertension, prolonged
QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...
, 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

As of 2007 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 Peritoneal dialysis (PD) is a type of dialysis which uses the peritoneum in a person's abdomen as the membrane through which fluid and dissolved substances are exchanged with the blood. It is used to remove excess fluid, correct electrolyte pro ...
,
hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
, or
hemofiltration Hemofiltration, also haemofiltration, is a renal replacement therapy which is used in the intensive care setting. It is usually used to treat acute kidney injury (AKI), but may be of benefit in multiple organ dysfunction syndrome or sepsis. During ...
. 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 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 Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
who overdosed on caffeinated mints.


Interactions

Caffeine is a substrate for
CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...
, and interacts with many substances through this and other mechanisms.


Alcohol

According to DSST,
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
provides a reduction in performance and caffeine has a significant improvement in performance. When alcohol and caffeine are consumed jointly, the effects produced by caffeine are affected, but the alcohol effects remain the same. For example, when additional caffeine is added, the drug effect produced by alcohol is not reduced. However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed. Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control. The Dietary Guidelines for Americans recommend avoidance of concomitant consumption of alcohol and caffeine, as this may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.


Tobacco

Smoking tobacco Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believed ...
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 Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. Female Two types of female oral contraceptive pill, taken once per day, are widely available: * The combi ...
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 Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a resu ...
. Caffeine was determined to increase the potency of some over-the-counter
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
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 Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
and
aminophylline Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate. Aminophylline is less potent and shorter-acting tha ...
, which are prescribed to relieve symptoms of asthma or
COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
.


Pharmacology


Pharmacodynamics

In the absence of caffeine and when a person is awake and alert, little
adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside building ...
is present in CNS neurons. With a continued wakeful state, over time adenosine accumulates in the neuronal
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
, in turn binding to and activating
adenosine receptor The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
s 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 An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...
of adenosine A2A receptors, and
knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
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 The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain ...
(VLPO) reduces inhibitory GABA
neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
to the
tuberomammillary nucleus The tuberomammillary nucleus (TMN) is a histaminergic nucleus located within the posterior third of the hypothalamus. It consists of, largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, l ...
, a
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...
rgic 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 The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
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 center The respiratory center is located in the medulla oblongata and pons, in the brainstem. The respiratory center is made up of three major respiratory groups of neurons, two in the medulla and one in the pons. In the medulla they are the dorsal ...
s, which increases respiratory rate, reduces heart rate, and constricts blood vessels. Adenosine receptor antagonism also promotes
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...
release (e.g.,
monoamines Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines ar ...
and
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
), which endows caffeine with its stimulant effects;
adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside building ...
acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system.
Heart palpitation Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rap ...
s are caused by blockade of the A1 receptor. Because caffeine is both water- and lipid-soluble, it readily crosses the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...
that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...
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 A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
. In addition to its activity at adenosine receptors, caffeine is an inositol trisphosphate receptor 1 antagonist and a voltage-independent activator of the
ryanodine receptor Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...
s (
RYR1 Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle. In humans, it is encoded by ...
,
RYR2 Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the ''RYR2'' gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major med ...
, and
RYR3 Ryanodine receptor 3 is one of a class of ryanodine receptors and a protein that in humans is encoded by the ''RYR3'' gene. The protein encoded by this gene is both a calcium channel and a receptor for the plant alkaloid ryanodine. RYR3 and RY ...
). It is also a competitive antagonist of the ionotropic glycine receptor.


Effects on striatal dopamine

While caffeine does not directly bind to any
dopamine receptor Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
s, it influences the binding activity of
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...
at its receptors in the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives gluta ...
by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1D1 receptor
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
(this is a receptor complex with 1 adenosine A1 receptor and 1 dopamine D1 receptor) and the A2AD2 receptor
heterotetramer A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer c ...
(this is a receptor complex with 2 adenosine A2A receptors and 2 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 The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamat ...
and
nucleus accumbens core The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypo ...
(a substructure within the
ventral striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutam ...
), but not the
nucleus accumbens shell The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypo ...
, by antagonizing A1 receptors in the
axon terminal Axon terminals (also called synaptic boutons, terminal boutons, or end-feet) are distal terminations of the telodendria (branches) of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that cond ...
of dopamine neurons and A1A2A heterodimers (a receptor complex composed of 1 adenosine A1 receptor and 1 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 Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, furthe ...
.


Enzyme targets

Caffeine, like other
xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffein ...
s, also acts as a
phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and c ...
. As a competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular
cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...
, activates
protein kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
, inhibits TNF-alpha and
leukotriene Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. Leukotrienes ...
synthesis, and reduces inflammation and
innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
. Caffeine also affects the
cholinergic system Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...
where it is a moderate inhibitor of the enzyme
acetylcholinesterase Acetylcholinesterase ( HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalyzes the breakdown of ac ...
.


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 In chemistry, the rate law or rate equation for a reaction is an equation that links the initial or forward reaction rate with the concentrations or pressures of the reactants and constant parameters (normally rate coefficients and partial reactio ...
. Caffeine can also be absorbed rectally, evidenced by suppositories of
ergotamine Ergotamine, sold under the brand names Cafergot (with caffeine) and Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural sim ...
tartrate A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−. The main forms of tartrates used commercially are pure crystalline ta ...
and caffeine (for the relief of
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
) and of
chlorobutanol Chlorobutanol (trichloro-2-methyl-2-propanol) is a preservative, sedative, hypnotic and weak local anesthetic similar in nature to chloral hydrate. It has antibacterial and antifungal properties. Chlorobutanol is typically used at a concentration ...
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 Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
 – 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 Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin tim ...
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 Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. Female Two types of female oral contraceptive pill, taken once per day, are widely available: * The combi ...
, 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 Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...
(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 Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
in the
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
by the
cytochrome P450 oxidase Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
enzyme system, in particular, by the
CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...
isozyme, into three dimethyl
xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffein ...
s, each of which has its own effects on the body: * Paraxanthine (84%): Increases
lipolysis Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...
, leading to elevated
glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
and free
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
levels in
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...
. *
Theobromine Theobromine, also known as xantheose, is the principal alkaloid of '' Theobroma cacao'' (cacao plant). Theobromine is slightly water- soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
(12%): Dilates
blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide awa ...
s and increases
urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...
volume. Theobromine is also the principal
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...
in the
cocoa bean The cocoa bean (technically cocoa seed) or simply cocoa (), also called the cacao bean (technically cacao seed) or cacao (), is the dried and fully Fermentation, fermented seed of ''Theobroma cacao'', from which cocoa solids (a mixture of non ...
(
chocolate Chocolate is a food made from roasted and ground cacao seed kernels that is available as a liquid, solid, or paste, either on its own or as a flavoring agent in other foods. Cacao has been consumed in some form since at least the Olmec ci ...
). *
Theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
(4%): Relaxes
smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...
s of the
bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...
, and is used to treat
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
. The
therapeutic dose The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
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 Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...
, 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 In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
on both
chromosomes A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
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 A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achi ...
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 A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
= ~0.6) requiring strong acid to protonate it.This is the pKa for protonated caffeine, given as a range of values included in Caffeine does not contain any stereogenic centers and hence is classified as an
achiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...
molecule. The
xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffein ...
core of caffeine contains two fused rings, a
pyrimidinedione Pyrimidinediones are a class of chemical compounds characterized by a pyrimidine ring substituted with two carbonyl groups. Examples include naturally occurring metabolites: drugs: * Fluorouracil * Idoxuridine * Primidone * Trifluridine and p ...
and
imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
. The pyrimidinedione in turn contains two
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
functional groups that exist predominantly in a
zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups. : With amino acids, for example, in solution a chemical equilibrium wil ...
ic
resonance Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied periodic force (or a Fourier component of it) is equal or close to a natural frequency of the system on which it acts. When an oscil ...
the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2 hybridized and planar. Therefore, the fused 5,6 ring core of caffeine contains a total of ten
pi electrons In chemistry, pi bonds (π bonds) are covalent chemical bonds, in each of which two lobes of an orbital on one atom overlap with two lobes of an orbital on another atom, and in which this overlap occurs laterally. Each of these atomic orbital ...
and hence according to
Hückel's rule In organic chemistry, Hückel's rule predicts that a planar ring molecule will have aromatic properties if it has 4''n'' + 2 π electrons, where ''n'' is a non-negative integer. The quantum mechanical basis for its formulation was ...
is
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
.


Synthesis

The
biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...
of caffeine is an example of
convergent evolution Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last com ...
among different species. Caffeine may be synthesized in the lab starting with dimethylurea and
malonic acid Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is 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 "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an inter ...
, 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 Supercritical carbon dioxide (s) is a fluid state of carbon dioxide where it is held at or above its critical temperature and critical pressure. Carbon dioxide usually behaves as a gas in air at standard temperature and pressure (STP), or as ...
is an excellent nonpolar
solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
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 State may refer to: Arts, entertainment, and media Literature * ''State Magazine'', a monthly magazine published by the U.S. Department of State * ''The State'' (newspaper), a daily newspaper in Columbia, South Carolina, United States * ''Our S ...
: 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 Charcoal is a lightweight black carbon residue produced by strongly heating wood (or other animal and plant materials) in minimal oxygen to remove all water and volatile constituents. In the traditional version of this pyrolysis process, ...
adsorption Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the ''adsorbate'' on the surface of the ''adsorbent''. This process differs from absorption, in which a ...
(as above) or by
distillation Distillation, or classical distillation, is the process of separating the components or substances from a liquid mixture by using selective boiling and condensation, usually inside an apparatus known as a still. Dry distillation is the he ...
, recrystallization, or
reverse osmosis Reverse osmosis (RO) is a water purification process that uses a partially permeable membrane to separate ions, unwanted molecules and larger particles from drinking water. In reverse osmosis, an applied pressure is used to overcome osmotic ...
. * Extraction by organic solvents: Certain organic solvents such as
ethyl acetate Ethyl acetate ( systematically ethyl ethanoate, commonly abbreviated EtOAc, ETAC or EA) is the organic compound with the formula , simplified to . This colorless liquid has a characteristic sweet smell (similar to pear drops) and is used in glues ...
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 An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
, 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
xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffein ...
s
DMPX DMPX (3,7-dimethyl-1-propargylxanthine) is a caffeine analog which displays affinity to A2 adenosine receptors, in contrast to the A1 subtype receptors. DMPX had 28× and 15× higher potency than caffeine in blocking peripheral and central NECA- ...
and 8-chlorotheophylline, which is an ingredient in
dramamine Dimenhydrinate, sold under the brand name Dramamine, among others, is an over-the-counter drug used to treat motion sickness and nausea. Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chloro ...
. 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-dipropylxanthine (DPCPX, PD-116,948) is a drug which acts as a potent and selective antagonist for the adenosine A1 receptor. It has high selectivity for A1 over other adenosine receptor subtypes, but as with other xanthine ...
*
8-Cyclopentyl-1,3-dimethylxanthine 8-Cyclopentyl-1,3-dimethylxanthine (8-Cyclopentyltheophylline, 8-CPT, CPX) is a drug which acts as a potent and selective antagonist for the adenosine receptors, with some selectivity for the A1 receptor subtype, as well as a non-selective p ...
*
8-Phenyltheophylline 8-Phenyltheophylline (8-phenyl-1,3-dimethylxanthine, 8-PT) is a drug derived from the xanthine family which acts as a potent and selective antagonist for the adenosine receptors A1 and A2A, but unlike other xanthine derivatives has virtually ...


Precipitation of tannins

Caffeine, as do other alkaloids such as cinchonine,
quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
or
strychnine Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the e ...
, precipitates polyphenols and
tannin Tannins (or tannoids) are a class of astringent, polyphenolic biomolecules that bind to and precipitate proteins and various other organic compounds including amino acids and alkaloids. The term ''tannin'' (from Anglo-Norman ''tanner'' ...
s. 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 ''Coffea arabica'' (), also known as the Arabic coffee, is a species of flowering plant in the coffee and madder family Rubiaceae. It is believed to be the first species of coffee to have been cultivated and is currently the dominant cultivar, ...
'' and ''
Coffea canephora ''Coffea canephora'' ( syn. ''Coffea robusta'', commonly known as ''robusta coffee'') is a species of coffee that has its origins in central and western sub-Saharan Africa. It is a species of flowering plant in the family Rubiaceae. Though wid ...
'' (the quantity varies, but 1.3% is a typical value); and of the cocoa plant, ''
Theobroma cacao ''Theobroma cacao'', also called the cacao tree and the cocoa tree, is a small ( tall) evergreen tree in the family Malvaceae. Its seeds, cocoa beans, are used to make chocolate liquor, cocoa solids, cocoa butter and chocolate. The largest pr ...
''; the leaves of the
tea plant ''Camellia sinensis'' is a species of evergreen shrub or small tree in the flowering plant family Theaceae. Its leaves and leaf buds are used to produce the popular beverage, tea. Common names include tea plant, tea shrub, and tea tree (not to ...
; and
kola nut The term kola nut usually refers to the seeds of certain species of plant of the genus ''Cola'', placed formerly in the cocoa family Sterculiaceae and now usually subsumed in the mallow family Malvaceae (as subfamily Sterculioideae). These col ...
s. Other sources include the leaves of
yaupon holly ''Ilex vomitoria'', commonly known as yaupon () or yaupon holly, is a species of holly that is native to southeastern North America. The word ''yaupon'' was derived from the Catawban ''yą́pą'', from ''yą-'' tree + ''pą'' leaf. Another commo ...
, South American holly
yerba mate Yerba mate or yerba-maté (''Ilex paraguariensis''; from Spanish ; pt, erva-mate, or ; gn, ka'a, ) is a plant species of the holly genus '' Ilex'' native to South America. It was named by the French botanist Augustin Saint-Hilaire. The lea ...
, and Amazonian holly guayusa; and seeds from Amazonian maple
guarana Guaraná ( from the Portuguese ''guaraná'' ), ''Paullinia cupana'', syns. ''P. crysan, P. sorbilis'') is a climbing plant in the family Sapindaceae, native to the Amazon basin and especially common in Brazil. Guaraná has large leaves and cl ...
berries. Temperate climates around the world have produced unrelated caffeine-containing plants. Caffeine in plants acts as a natural
pesticide Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and ...
: 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
vacuole A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic m ...
s where it is complexed with
polyphenol Polyphenols () are a large family of naturally occurring organic compounds characterized by multiples of phenol units. They are abundant in plants and structurally diverse. Polyphenols include flavonoids, tannic acid, and ellagitannin, some ...
s. 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 Pollen is a powdery substance produced by seed plants. It consists of pollen grains (highly reduced microgametophytes), which produce male gametes (sperm cells). Pollen grains have a hard coat made of sporopollenin that protects the gametop ...
producing plants by enhancing the reward memory of pollinators such as
honey bee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current cosm ...
s. 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
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...
s, including the
cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
stimulants
theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
and
theobromine Theobromine, also known as xantheose, is the principal alkaloid of '' Theobroma cacao'' (cacao plant). Theobromine is slightly water- soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
, and polyphenols that can form insoluble complexes with caffeine.


Products

Products containing caffeine include coffee, tea,
soft drink A soft drink (see § Terminology for other names) is a drink A drink or beverage is a liquid intended for human consumption. In addition to their basic function of satisfying thirst, drinks play important roles in human culture. Common t ...
s ("colas"), energy drinks, other beverages,
chocolate Chocolate is a food made from roasted and ground cacao seed kernels that is available as a liquid, solid, or paste, either on its own or as a flavoring agent in other foods. Cacao has been consumed in some form since at least the Olmec ci ...
, 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.


Beverages


Coffee

The world's primary source of caffeine is the coffee "bean" (the seed of the
coffee plant ''Coffea'' is a genus of flowering plants in the family Rubiaceae. ''Coffea'' species are shrubs or small trees native to tropical and southern Africa and tropical Asia. The seeds of some species, called coffee beans, are used to flavor variou ...
), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of
coffee bean A coffee bean is a seed of the '' Coffea'' plant and the source for coffee. It is the pip inside the red or purple fruit often referred to as a coffee cherry. Just like ordinary cherries, the coffee fruit is also a so-called stone fruit. Even th ...
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 Espresso (, ) is a coffee-brewing method of Italian origin, in which a small amount of nearly boiling water (about ) is forced under of pressure through finely-ground coffee beans. Espresso can be made with a wide variety of coffee beans a ...
, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee. '' Arabica'' coffee typically contains half the caffeine of the ''
robusta ROBUSTA (Radiation on Bipolar for University Satellite Test Application) is a nano-satellite scientific experiment developed by the University of Montpellier students as part of a Centre National d'Études Spatiales (CNES) call for student project ...
'' 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 Theobromine, also known as xantheose, is the principal alkaloid of '' Theobroma cacao'' (cacao plant). Theobromine is slightly water- soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
and slightly higher levels of
theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
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 Green tea is a type of tea that is made from '' Camellia sinensis'' leaves and buds that have not undergone the same withering and oxidation process which is used to make oolong teas and black teas. Green tea originated in China, and since th ...
, '' 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 drink A soft drink (see § Terminology for other names) is a drink A drink or beverage is a liquid intended for human consumption. In addition to their basic function of satisfying thirst, drinks play important roles in human culture. Common t ...
s, such as cola, originally prepared from
kola nut The term kola nut usually refers to the seeds of certain species of plant of the genus ''Cola'', placed formerly in the cocoa family Sterculiaceae and now usually subsumed in the mallow family Malvaceae (as subfamily Sterculioideae). These col ...
s. Soft drinks typically contain 0 to 55 milligrams of caffeine per 12 ounce serving. By contrast, energy drinks, such as
Red Bull Red Bull is a brand of energy drinks of Austrian company Red Bull GmbH. With 38% market share, it is the most popular energy drink brand as of 2019. Since its launch in 1987, more than 100 billion cans of Red Bull have been sold worldwide, inclu ...
, 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 Decaffeination is the removal of caffeine from coffee beans, cocoa, tea leaves, and other caffeine-containing materials. Decaffeinated drinks contain typically 1–2% of the original caffeine content, and sometimes as much as 20%. Decaffeinate ...
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 An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
.


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 Yerba mate or yerba-maté (''Ilex paraguariensis''; from Spanish ; pt, erva-mate, or ; gn, ka'a, ) is a plant species of the holly genus '' Ilex'' native to South America. It was named by the French botanist Augustin Saint-Hilaire. The lea ...
, 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 Guaraná ( from the Portuguese ''guaraná'' ), ''Paullinia cupana'', syns. ''P. crysan, P. sorbilis'') is a climbing plant in the family Sapindaceae, native to the Amazon basin and especially common in Brazil. Guaraná has large leaves and cl ...
is a soft drink originating in Brazil made from the seeds of the
Guaraná Guaraná ( from the Portuguese ''guaraná'' ), ''Paullinia cupana'', syns. ''P. crysan, P. sorbilis'') is a climbing plant in the family Sapindaceae, native to the Amazon basin and especially common in Brazil. Guaraná has large leaves and cl ...
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 ''Ilex vomitoria'', commonly known as yaupon () or yaupon holly, is a species of holly that is native to southeastern North America. The word ''yaupon'' was derived from the Catawban ''yą́pą'', from ''yą-'' tree + ''pą'' leaf. Another comm ...
'', the yaupon holly tree, are placed in boiling water to make a yaupon tea. * Commercially prepared coffee-
flavoured milk Flavored milk is a sweetened dairy drink made with milk, sugar, flavorings, and sometimes food colorings. It may be sold as a pasteurized, refrigerated product, or as an ultra-high-temperature (UHT) treated product not requiring refrigeration ...
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.


Chocolate

Chocolate Chocolate is a food made from roasted and ground cacao seed kernels that is available as a liquid, solid, or paste, either on its own or as a flavoring agent in other foods. Cacao has been consumed in some form since at least the Olmec ci ...
derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine. A typical 28-gram serving of a milk
chocolate bar A chocolate bar (Commonwealth English) or candy bar (some dialects of American English) is a confection containing chocolate, which may also contain layerings or mixtures that include nuts, fruit, caramel, nougat, and wafers. A flat, easily brea ...
has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount of caffeine as coffee: 80–160 mg per 100 g. Higher percentages of cocoa such as 90% amount to 200 mg per 100 g approximately and thus, a 100-gram 85% cocoa chocolate bar contains about 195 mg caffeine.


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 Lip balm or lip salve is a wax-like substance applied topically to the lips to moisturize and relieve chapped or dry lips, angular cheilitis, stomatitis, or cold sores. Lip balm often contains beeswax or carnauba wax, camphor, cetyl alcoho ...
. Alert Energy Caffeine Gum was introduced in the United States in 2013, but was voluntarily withdrawn after an announcement of an investigation by the FDA of the health effects of added caffeine in foods.


Inhalants

There are several products being marketed that offer inhalers that deliver proprietary blends of supplements, with caffeine being a key ingredient. In 2012, the FDA sent a warning letter to one of the companies marketing these inhalers, expressing concerns for the lack of safety information available about inhaled caffeine.


Combinations with other drugs

* Some beverages combine
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
with caffeine to create a
caffeinated alcoholic drink A caffeinated alcoholic drink is a drink that contains both alcohol (also known formally as ethanol) and a significant amount of caffeine. Caffeine, a stimulant, masks some of the depressant effects of alcohol. However, in 2010 and 2011, this ty ...
. The stimulant effects of caffeine may mask the
depressant A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the ...
effects of alcohol, potentially reducing the user's awareness of their level of
intoxication Intoxication — or poisoning, especially by an alcoholic or narcotic substance — may refer to: * Substance intoxication: ** Alcohol intoxication ** LSD intoxication ** Toxidrome ** Tobacco intoxication ** Cannabis intoxication ** Cocaine in ...
. Such beverages have been the subject of bans due to safety concerns. In particular, the
United States Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
has classified caffeine added to malt liquor beverages as an "unsafe food additive". * Ya ba contains a combination of
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
and caffeine. * Painkillers such as
propyphenazone/paracetamol/caffeine Propyphenazone/paracetamol/caffeine (trade name Saridon) is an analgesic combination indicated for the management of headache. It contains the analgesics propyphenazone and paracetamol and the stimulant caffeine. Saridon was first launched by ...
combine caffeine with an
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
.


History


Discovery and spread of use

According to Chinese legend, the
Chinese emperor ''Huangdi'' (), translated into English as Emperor, was the superlative title held by monarchs of China who ruled various imperial regimes in Chinese history. In traditional Chinese political theory, the emperor was considered the Son of Heave ...
Shennong Shennong (), variously translated as "Divine Farmer" or "Divine Husbandman", born Jiang Shinian (), was a mythological Chinese ruler known as the first Yan Emperor who has become a deity in Chinese and Vietnamese folk religion. He is vene ...
, 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 Sufism ( ar, ''aṣ-ṣūfiyya''), also known as Tasawwuf ( ''at-taṣawwuf''), is a mystic body of religious practice, found mainly within Sunni Islam but also within Shia Islam, which is characterized by a focus on Islamic spirituality, r ...
monasteries of the
Yemen Yemen (; ar, ٱلْيَمَن, al-Yaman), officially the Republic of Yemen,, ) is a country in Western Asia. It is situated on the southern end of the Arabian Peninsula, and borders Saudi Arabia to the north and Oman to the northeast and ...
in southern Arabia. From Mocha, coffee spread to
Egypt Egypt ( ar, مصر , ), officially the Arab Republic of Egypt, is a List of transcontinental countries, transcontinental country spanning the North Africa, northeast corner of Africa and Western Asia, southwest corner of Asia via a land bridg ...
and North Africa, and by the 16th century, it had reached the rest of the Middle East,
Persia Iran, officially the Islamic Republic of Iran, and also called Persia, is a country located in Western Asia. It is bordered by Iraq and Turkey to the west, by Azerbaijan and Armenia to the northwest, by the Caspian Sea and Turkmeni ...
and
Turkey Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a transcontinental country located mainly on the Anatolian Peninsula in Western Asia, with a small portion on the Balkan Peninsula ...
. 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 The East Indies (or simply the Indies), is a term used in historical narratives of the Age of Discovery. The Indies refers to various lands in the East or the Eastern hemisphere, particularly the islands and mainlands found in and around ...
and to the Americas.
Kola nut The term kola nut usually refers to the seeds of certain species of plant of the genus ''Cola'', placed formerly in the cocoa family Sterculiaceae and now usually subsumed in the mallow family Malvaceae (as subfamily Sterculioideae). These col ...
use appears to have ancient origins. It is chewed in many
West Africa West Africa or Western Africa is the westernmost region of Africa. The United Nations defines Western Africa as the 16 countries of Benin, Burkina Faso, Cape Verde, The Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali ...
n cultures, in both private and social settings, to restore vitality and ease hunger pangs. The earliest evidence of
cocoa bean The cocoa bean (technically cocoa seed) or simply cocoa (), also called the cacao bean (technically cacao seed) or cacao (), is the dried and fully Fermentation, fermented seed of ''Theobroma cacao'', from which cocoa solids (a mixture of non ...
use comes from residue found in an ancient Mayan pot dated to 600 BCE. Also,
chocolate Chocolate is a food made from roasted and ground cacao seed kernels that is available as a liquid, solid, or paste, either on its own or as a flavoring agent in other foods. Cacao has been consumed in some form since at least the Olmec ci ...
was consumed in a bitter and spicy drink called ''xocolatl'', often seasoned with
vanilla Vanilla is a spice derived from orchids of the genus '' Vanilla'', primarily obtained from pods of the Mexican species, flat-leaved vanilla ('' V. planifolia''). Pollination is required to make the plants produce the fruit from whic ...
,
chile pepper Chili peppers (also chile, chile pepper, chilli pepper, or chilli), from Nahuatl '' chīlli'' (), are varieties of the berry-fruit of plants from the genus ''Capsicum'', which are members of the nightshade family Solanaceae, cultivated for t ...
, 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 In the history of the Americas, the pre-Columbian era spans from the original settlement of North and South America in the Upper Paleolithic period through European colonization, which began with Christopher Columbus's voyage of 1492. Usually, ...
Mesoamerica Mesoamerica is a historical region and cultural area in southern North America and most of Central America. It extends from approximately central Mexico through Belize, Guatemala, El Salvador, Honduras, Nicaragua, and northern Costa Rica. Wit ...
, and cocoa beans were often used as currency. ''Xocolatl'' was introduced to
Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
by the
Spaniards Spaniards, or Spanish people, are a Romance ethnic group native to Spain. Within Spain, there are a number of national and regional ethnic identities that reflect the country's complex history, including a number of different languages, both ...
, and became a popular beverage by 1700. The Spaniards also introduced the
cacao tree ''Theobroma cacao'', also called the cacao tree and the cocoa tree, is a small ( tall) evergreen tree in the family Malvaceae. Its seeds, cocoa beans, are used to make chocolate liquor, cocoa solids, cocoa butter and chocolate. The largest p ...
into the
West Indies The West Indies is a subregion of North America, surrounded by the North Atlantic Ocean and the Caribbean Sea that includes 13 independent island countries and 18 dependencies and other territories in three major archipelagos: the Greate ...
and the
Philippines The Philippines (; fil, Pilipinas, links=no), officially the Republic of the Philippines ( fil, Republika ng Pilipinas, links=no), * bik, Republika kan Filipinas * ceb, Republika sa Pilipinas * cbk, República de Filipinas * hil, Republ ...
. The leaves and stems of the yaupon holly (''
Ilex vomitoria ''Ilex vomitoria'', commonly known as yaupon () or yaupon holly, is a species of holly that is native to southeastern North America. The word ''yaupon'' was derived from the Catawban ''yą́pą'', from ''yą-'' tree + ''pą'' leaf. Another comm ...
'') were used by Native Americans to brew a tea called ''asi'' or the "
black drink Black drink is a name for several kinds of ritual beverages brewed by Native Americans in the Southeastern United States. Traditional ceremonial people of the Yuchi, Caddo, Chickasaw, Cherokee, Choctaw, Muscogee and some other Indigenous pe ...
". 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 Friedlieb Ferdinand Runge (8 February 1794 – 25 March 1867) was a German analytical chemist. Runge identified the mydriatic (pupil dilating) effects of belladonna (deadly nightshade) extract, identified caffeine, and discovered the first c ...
isolated relatively pure caffeine for the first time; he called it ''"Kaffebase"'' (i.e., a base that exists in coffee). According to Runge, he did this at the behest of
Johann Wolfgang von Goethe Johann Wolfgang von Goethe (28 August 1749 – 22 March 1832) was a German poet, playwright, novelist, scientist, statesman, theatre director, and critic. His works include plays, poetry, literature, and aesthetic criticism, as well as t ...
. In 1821, caffeine was isolated both by the French chemist
Pierre Jean Robiquet Pierre Jean Robiquet (13 January 1780 – 29 April 1840) was a French chemist. He laid founding work in identifying amino acids, the fundamental building blocks of proteins. He did this through recognizing the first of them, asparagine, in 1806 ...
and by another pair of French chemists,
Pierre-Joseph Pelletier Pierre-Joseph Pelletier (, , ; 22 March 1788 – 19 July 1842) was a French chemist and pharmacist who did notable research on vegetable alkaloids Alkaloids are a class of basic, naturally occurring organic compounds that contain at leas ...
and Joseph Bienaimé Caventou, according to Swedish chemist
Jöns Jacob Berzelius Baron Jöns Jacob Berzelius (; by himself and his contemporaries named only Jacob Berzelius, 20 August 1779 – 7 August 1848) was a Swedish chemist. Berzelius is considered, along with Robert Boyle, John Dalton, and Antoine Lavoisier, to be o ...
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: 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 Elemental analysis is a process where a sample of some material (e.g., soil, waste or drinking water, bodily fluids, minerals, chemical compounds) is analyzed for its elemental and sometimes isotopic composition. Elemental analysis can be qualit ...
. In 1827, M. Oudry isolated "théine" from tea, but in 1838 it was proved by
Mulder Mulder is a surname of two possible origins: Dutch and German. It may be Dutch language occupational surname. It is an archaic Dutch word for "miller" (modern Dutch: ''molenaar''). With 38,207 people in the Netherlands named Mulder, it was the 12t ...
and by Carl Jobst that theine was actually the same as caffeine. In 1895, German chemist
Hermann Emil Fischer Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of draw ...
(1852–1919) first synthesized caffeine from its chemical components (i.e. a "
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...
"), and two years later, he also derived the structural formula of the compound. This was part of the work for which Fischer was awarded the
Nobel Prize The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
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 Mecca (; officially Makkah al-Mukarramah, commonly shortened to Makkah ()) is a city and administrative center of the Mecca Province of Saudi Arabia, and the holiest city in Islam. It is inland from Jeddah on the Red Sea, in a narrow v ...
and in the
Ottoman Empire The Ottoman Empire, * ; is an archaic version. The definite article forms and were synonymous * and el, Оθωμανική Αυτοκρατορία, Othōmanikē Avtokratoria, label=none * info page on book at Martin Luther University ...
made coffee illegal for some classes.
Charles II of England Charles II (29 May 1630 – 6 February 1685) was King of Scotland from 1649 until 1651, and King of England, Scotland and Ireland from the 1660 Restoration of the monarchy until his death in 1685. Charles II was the eldest surviving child o ...
tried to ban it in 1676,
Frederick II of Prussia Frederick II (german: Friedrich II.; 24 January 171217 August 1786) was King in Prussia from 1740 until 1772, and King of Prussia from 1772 until his death in 1786. His most significant accomplishments include his military successes in the S ...
banned it in 1777, and coffee was banned in
Sweden Sweden, formally the Kingdom of Sweden,The United Nations Group of Experts on Geographical Names states that the country's formal name is the Kingdom of SwedenUNGEGN World Geographical Names, Sweden./ref> is a Nordic countries, Nordic c ...
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 Coca-Cola, or Coke, is a carbonated soft drink manufactured by the Coca-Cola Company. Originally marketed as a temperance bar, temperance drink and intended as a patent medicine, it was invented in the late 19th century by John Stith Pembe ...
syrup in
Chattanooga, Tennessee Chattanooga ( ) is a city in and the county seat of Hamilton County, Tennessee, United States. Located along the Tennessee River bordering Georgia, it also extends into Marion County on its western end. With a population of 181,099 in 2020 ...
, alleging the caffeine in its drink was "injurious to health". Although the
Supreme Court A supreme court is the highest court within the hierarchy of courts in most legal jurisdictions. Other descriptions for such courts include court of last resort, apex court, and high (or final) court of appeal. Broadly speaking, the decisions of ...
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 The Pure Food and Drug Act of 1906, also known as Dr. Wiley's Law, was the first of a series of significant consumer protection laws which was enacted by Congress in the 20th century and led to the creation of the Food and Drug Administratio ...
, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.


Society and culture


Regulations


United States

The Food and Drug Administration (FDA) in the United States currently allows only beverages containing less than 0.02% caffeine; but caffeine powder, which is sold as a dietary supplement, is unregulated. It is a regulatory requirement that the label of most prepackaged foods must declare a list of ingredients, including food additives such as caffeine, in descending order of proportion. However, there is no regulatory provision for mandatory quantitative labeling of caffeine, (e.g., milligrams caffeine per stated serving size). There are a number of food ingredients that naturally contain caffeine. These ingredients must appear in food ingredient lists. However, as is the case for "food additive caffeine", there is no requirement to identify the quantitative amount of caffeine in composite foods containing ingredients that are natural sources of caffeine. While coffee or chocolate are broadly recognized as caffeine sources, some ingredients (e.g.,
guarana Guaraná ( from the Portuguese ''guaraná'' ), ''Paullinia cupana'', syns. ''P. crysan, P. sorbilis'') is a climbing plant in the family Sapindaceae, native to the Amazon basin and especially common in Brazil. Guaraná has large leaves and cl ...
, yerba maté) are likely less recognized as caffeine sources. For these natural sources of caffeine, there is no regulatory provision requiring that a food label identify the presence of caffeine nor state the amount of caffeine present in the food.


Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to 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

Until recently, the
Seventh-day Adventist Church The Seventh-day Adventist Church is an Adventist Protestant Christian denomination which is distinguished by its observance of Saturday, the seventh day of the week in the Christian (Gregorian) and the Hebrew calendar, as the Sabbath, and ...
asked for its members to "abstain from caffeinated drinks", but has removed this from
baptismal vows Baptismal vows are the renunciations required of an adult candidate for baptism just before the sacrament is conferred. In the case of an infant baptism they are given by the godparents (sponsors) or parents themselves. In many Christian denomin ...
(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 The Church of Jesus Christ of Latter-day Saints, informally known as the LDS Church or Mormon Church, is a Nontrinitarianism, nontrinitarian Christianity, Christian church that considers itself to be the Restorationism, restoration of the ...
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 Muslims ( ar, المسلمون, , ) are people who adhere to Islam, a monotheistic religion belonging to the Abrahamic tradition. They consider the Quran, the foundational religious text of Islam, to be the verbatim word of the God of Abrah ...
today. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under
Islamic dietary laws Islamic dietary laws are dietary laws that Muslims follow. Islamic jurisprudence specifies which foods are '' '' (, "lawful") and which are '' '' (, "unlawful"). The dietary laws are found in the Quran, the holy book of Islam, as well as in col ...
.


Other organisms

Recently discovered bacteria ''
Pseudomonas putida ''Pseudomonas putida'' is a Gram-negative, rod-shaped, saprotrophic soil bacterium. Based on 16S rRNA analysis, ''P. putida'' was taxonomically confirmed to be a ''Pseudomonas'' species (''sensu stricto'') and placed, along with several other ...
'' 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
mollusk Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000  extant species of molluscs are recognized. The number of fossil species is e ...
s, various insects, and
spider Spiders (order Araneae) are air-breathing arthropods that have eight legs, chelicerae with fangs generally able to inject venom, and spinnerets that extrude silk. They are the largest order of arachnids and rank seventh in total species ...
s. 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 bee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current cosm ...
s.


Research

Caffeine has been used to double chromosomes in
haploid Ploidy () is the number of complete sets of chromosomes in a cell, and hence the number of possible alleles for autosomal and pseudoautosomal genes. Sets of chromosomes refer to the number of maternal and paternal chromosome copies, respective ...
wheat Wheat is a grass widely cultivated for its seed, a cereal grain that is a worldwide staple food. The many species of wheat together make up the genus ''Triticum'' ; the most widely grown is common wheat (''T. aestivum''). The archaeologi ...
.


See also

*
Theobromine Theobromine, also known as xantheose, is the principal alkaloid of '' Theobroma cacao'' (cacao plant). Theobromine is slightly water- soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
*
Theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
*
Methylliberine Methylliberine is an isolate of coffee beans, tea, cola nuts, guarana, cocoa, and yerba mate Yerba mate or yerba-maté (''Ilex paraguariensis''; from Spanish ; pt, erva-mate, or ; gn, ka'a, ) is a plant species of the holly genus ''Ilex ...
*
Adderall Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio ...
*
Amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
*
Cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
*
Nootropic Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic dietary supplement, supplements or drugs and other substances that are claimed to improve cognitive function ...
* Wakefulness-promoting agent


References

;Notes ;Citations


Bibliography

* * * *


External links


GMD MS Spectrum




at ''
The Periodic Table of Videos ''Periodic Videos'' (also known as ''The Periodic Table of Videos'') is a video project and YouTube channel on chemistry. It consists of a series of videos about chemical elements and the periodic table, with additional videos on other topics i ...
'' (University of Nottingham) {{Authority control Acetylcholinesterase inhibitors Adenosine receptor antagonists Anxiogenics Bitter compounds Glycine receptor antagonists IARC Group 3 carcinogens Mutagens Phosphodiesterase inhibitors Plant toxin insecticides Vasoconstrictors Xanthines Alkaloids found in plants Ergogenic aids Stimulants X Components of chocolate