Caffeine

Template:Short description Template:About Template:Pp-move-indef Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

|preview=

}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = | _drugtype =

| _has_physiological_data= | _has_gene_therapy=

| vaccine_type= | mab_type= | _number_of_combo_chemicals={{#invoke:ParameterCount |main |component1 |component2 |component3 |component4|component5|component6 }} | _vaccine_data= | _mab_data= | _mab_vaccine_data= | _mab_other_data=81042CN1C=NC2=C1C(=O)N(C(=O)N2C)C1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3RYYVLZVUVIJVGH-UHFFFAOYSA-N1.23235238 | _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.comLow (9%)<ref name="pmid24761279" /> Template:FvPhysical: Low–moderate (9–30%)<ref>Template:Cite journal</ref>
Psychological: Low–moderate<ref name="pmid15448977" />Caffeine ACommon: By mouth Medical: Intravenous
Uncommon: Insufflation, rectal, transdermal, topicalStimulant;
Adenosinergic;
Eugeroic;
Nootropic;
Anxiogenic;
Analeptic;
PDE inhibitor;
DiureticN06BTemplate:ATC, Template:ATC | _legal_data=UnscheduledUnscheduledUnscheduledUnscheduledUnscheduledGSLUnscheduledUnscheduledCN: OTC In general Legal for all uses

| _other_data=1,3,7-Trimethyl-3,7-dihydro-1H-purine-2,6-dione

| _image_0_or_2 = Caffeine structure.svg | _image_LR = Caffeine molecule ball from xtal (1).pngCaffeine molecule spacefill from xtal (1).png

| _datapage = Caffeine (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=UnscheduledUnscheduledUnscheduledGSLUnscheduledUnscheduledCN: OTC In general Legal for all uses | _ATC_prefix_supplemental=N06BTemplate:ATC, Template:ATC | _has_EMA_link = | CAS_number=58-08-2 | PubChem=2519 | ChemSpiderID=2424 | ChEBI=27732 | ChEMBL=113 | DrugBank=DB00201 | KEGG=D00528 | _hasInChI_or_Key={{#if:1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3RYYVLZVUVIJVGH-UHFFFAOYSA-N |yes}} | UNII=3G6A5W338E | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields= |verifiedrevid=}}

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class and is the most commonly consumed psychoactive substance globally.<ref name="pmid1356551">Template:Cite journal</ref><ref name=":4">Template:Cite journal</ref> It is mainly used for its eugeroic (wakefulness promoting), ergogenic (physical performance-enhancing), or nootropic (cognitive-enhancing) properties; it is also used recreationally or in social settings.<ref name="caffeine & theanine">Template:Cite journal</ref><ref name="Continuum">Template:Cite journal</ref> Caffeine acts by blocking the binding of adenosine at a number of adenosine receptor types, inhibiting the centrally depressant effects of adenosine and enhancing the release of acetylcholine.<ref>Template:Cite journal</ref> Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors.<ref>Template:Cite book</ref> Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase, increases calcium release from intracellular stores, and antagonizes GABA receptors, although these mechanisms typically occur at concentrations beyond usual human consumption.<ref name=":4" /><ref>Template:Cite journal</ref>

Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, fruits, nuts, or leaves of a number of plants native to Africa, East Asia, and South America<ref name="Caballero Finglas Toldra 2015">Template:Cite book</ref> and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds,<ref name="Myers 2007">Template:Cite book</ref> as well as encouraging consumption by select animals such as honey bees.<ref name="pmid23471406">Template:Cite journal</ref> The most common sources of caffeine for human consumption are the tea leaves of the Camellia sinensis plant and the coffee bean, the seed of the Coffea plant. Some people drink beverages containing caffeine to relieve or prevent drowsiness and to improve cognitive performance. To make these drinks, caffeine is extracted by steeping the plant product in water, a process called infusion. Caffeine-containing drinks, such as tea, coffee, and cola, are consumed globally in high volumes. In 2020, almost 10 million tonnes of coffee beans were consumed globally.<ref>Template:Cite web</ref> Caffeine is the world's most widely consumed psychoactive drug.<ref name="abc.net" /><ref>Template:Cite journal</ref> Unlike most other psychoactive substances, caffeine remains largely unregulated and legal in nearly all parts of the world.Template:Cn Caffeine is also an outlier as its use is seen as socially acceptable in most cultures and is encouraged in some.Template:Vague

Caffeine has both positive and negative health effects. It can treat and prevent the premature infant breathing disorders bronchopulmonary dysplasia of prematurity and apnea of prematurity. Caffeine citrate is on the WHO Model List of Essential Medicines.<ref name="WHOMedList">Template:Cite book</ref> It may confer a modest protective effect against some diseases,<ref>Template:Cite journal</ref> including Parkinson's disease.<ref name="Qi 2014">Template:Cite journal</ref> Caffeine can acutely improve reaction time and accuracy for cognitive tasks.<ref>Template:Cite journal</ref> Some people experience sleep disruption or anxiety if they consume caffeine,<ref>Template:Cite journal</ref><ref name = "Zhang_2024">Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name=Jah2015>Template:Cite journal</ref><ref name="ACOG policy 462 caffeine">Template:Cite journal</ref> Caffeine can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake.<ref name="Nestler caffeine dependence-addiction">Template:Cite book</ref><ref name="DSM-5 definitions + addiction-dependence distinction + Caffeine use disorder">Template:Cite web</ref><ref name="pmid15448977">Template:Cite journal</ref> Tolerance to the autonomic effects of increased blood pressure, heart rate, and urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).<ref>Template:Cite journal</ref>

Caffeine is classified by the US Food and Drug Administration (FDA) as generally recognized as safe. Lethal doses, over 10 grams per day for an adult, greatly exceed the typical dose of under 500 milligrams per day.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> A 6 ounce cup of coffee typically contains 50–175 mg of caffeine, depending on what "bean" (seed) is used (and how much), how it is roasted, and how it is prepared (e.g., drip, percolation, or espresso).<ref>Template:Cite journal</ref> Thus roughly 50–100 ordinary cups of coffee would be required to reach a lethal dose. However, pure powdered caffeine, which is available as a dietary supplement, can be lethal in tablespoon-sized amounts. Template:TOC limit

Uses

Medical

Caffeine is used for both prevention<ref name="pmid21815280">Template:Cite journal</ref> and treatment<ref name="pmid16210843">Template:Cite journal</ref> of bronchopulmonary dysplasia in premature infants. It may improve weight gain during therapy<ref name="pmid16707748">Template:Cite journal</ref> and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay.<ref name="caffeine for AOP NEJM">Template:Cite journal</ref><ref name="caffeine for AOP JAMA 2012">Template:Cite journal</ref> On the other hand, subtle long-term side effects are possible.<ref name="Funk">Template:Cite journal</ref>

Caffeine is used as a primary treatment for apnea of prematurity,<ref name="pmid21127467">Template:Cite journal</ref> but not prevention.<ref>Template:Cite journal</ref><ref name="IUPHAR" /> It is also used for orthostatic hypotension treatment.<ref>Template:Cite journal</ref><ref name="IUPHAR">Template:Cite web</ref><ref>Template:Cite journal</ref>

Some people use caffeine-containing beverages such as coffee or tea to try to treat their asthma.<ref name=Alf2017>Template:Cite journal</ref> Evidence to support this practice is poor.<ref name=Alf2017/> It appears that caffeine in low doses improves airway function in people with asthma, increasing forced expiratory volume (FEV1) by 5% to 18% for up to four hours.<ref name="pmid20091514">Template:Cite journal</ref>

The addition of caffeine (100–130 mg) to commonly prescribed pain relievers such as paracetamol or ibuprofen modestly improves the proportion of people who achieve pain relief.<ref name="Derry">Template:Cite journal</ref>

Consumption of caffeine after abdominal surgery shortens the time to recovery of normal bowel function and shortens length of hospital stay.<ref>Template:Cite journal</ref>

Caffeine was formerly used as a second-line treatment for ADHD. It is considered less effective than methylphenidate or amphetamine but more so than placebo for children with ADHD.<ref>Template:Cite journal</ref><ref name=Downs>Template:Cite journal</ref> Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of self-medication.<ref name=Downs/><ref>Template:Cite journal</ref>

Enhancing performance

Cognitive performance

Caffeine is a central nervous system stimulant that may reduce fatigue and drowsiness.<ref name="pmid1356551"/> At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination.<ref name="effects">Template:Cite journal</ref><ref name=Cog10>Template:Cite journal</ref> The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance.<ref name="effects" /> 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.<ref name = "Poleszak 2015"/>

Caffeine can delay or prevent sleep and improves task performance during sleep deprivation.<ref name="pmid21531247">Template:Cite book</ref> Shift workers who use caffeine make fewer mistakes that could result from drowsiness.<ref name="pmid20464765">Template:Cite journal</ref>

Caffeine in a dose dependent manner increases alertness in both fatigued and normal individuals.<ref name="pmid27612937">Template:Cite journal</ref>

A systematic review and meta-analysis from 2014 found that concurrent caffeine and [[L-theanine|Template:Smallcaps all-theanine]] use has synergistic psychoactive effects that promote alertness, attention, and task switching;<ref name="caffeine and theanine" /> these effects are most pronounced during the first hour post-dose.<ref name="caffeine and theanine">Template:Cite journal</ref>

A 2025 systematic review and meta-analysis found that acute caffeine intake can improve reaction time and accuracy for cognitive tasks. Increased dosages can further improve reaction time but lead to decreases in accuracy after specific intake thresholds are reached.<ref>Template:Cite journal</ref>

Physical performance

Caffeine is a proven ergogenic aid in humans.<ref name="Peripheral and central ergogenic effects" /> Caffeine improves athletic performance in aerobic (especially endurance sports) and anaerobic conditions.<ref name="Peripheral and central ergogenic effects">Template:Cite journal Quote: Template:Blockquote</ref> Moderate doses of caffeine (around 5 mg/kg<ref name="Peripheral and central ergogenic effects" />) can improve sprint performance,<ref name="pmid21058748">Template:Cite journal</ref> cycling and running time trial performance,<ref name="Peripheral and central ergogenic effects" /> endurance (i.e., it delays the onset of muscle fatigue and central fatigue),<ref name="Peripheral and central ergogenic effects" /><ref name="pmid21411838">Template:Cite journal</ref><ref name="Ergogenics">Template:Cite journal</ref> and cycling power output.<ref name="Peripheral and central ergogenic effects" /> Caffeine increases basal metabolic rate in adults.<ref name="pmid7369170">Template:Cite journal</ref><ref name="pmid2912010">Template:Cite journal</ref><ref name="pmid7486839">Template:Cite journal</ref> Caffeine ingestion prior to aerobic exercise increases fat oxidation, particularly in persons with low physical fitness.<ref>Template:Cite journal</ref>

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

Specific populations

Adults

For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.<ref name="healthcanada"/> This limit was found to be safe by a 2017 systematic review on caffeine toxicology.<ref name="Wikoff2017">Template:Cite journal</ref>

Children

In healthy children, moderate caffeine intake under 400 mg produces effects that are "modest and typically innocuous".<ref name="Temple2019">Template:Cite journal</ref><ref>Template:Cite journal</ref> As early as six months old, infants can metabolize caffeine at the same rate as that of adults.<ref>Template:Cite journal</ref> Higher doses of caffeine (>400 mg) can cause physiological, psychological and behavioral harm, particularly for children with psychiatric or cardiac conditions.<ref name="Temple2019" /> There is no evidence that coffee stunts a child's growth.<ref>Template:Cite book</ref> The American Academy of Pediatrics recommends that caffeine consumption, particularly in the case of energy and sports drinks, is not appropriate for children and adolescents and should be avoided.<ref name="Committee on Nutrition and the Council on Sports Medicine and Fitness 1182–1189">Template:Cite journal</ref> This recommendation is based on a clinical report released by American Academy of Pediatrics in 2011 with a review of 45 publications from 1994 to 2011 and includes inputs from various stakeholders (Pediatricians, Committee on nutrition, Canadian Pediatric Society, Centers for Disease Control & Prevention, Food and Drug Administration, Sports Medicine & Fitness committee, National Federations of High School Associations).<ref name="Committee on Nutrition and the Council on Sports Medicine and Fitness 1182–1189"/> For children age 12 and under, Health Canada recommends a maximum daily caffeine intake of no more than 2.5 milligrams per kilogram of body weight. Based on average body weights of children, this translates to the following age-based intake limits:<ref name="healthcanada">Template:Cite web</ref>

Age range	Maximum recommended daily caffeine intake
4–6	45 mg (slightly more than in 355 ml (12 fl. oz) of a typical caffeinated soft drink)
7–9	62.5 mg
10–12	85 mg (about Template:Frac cup of coffee)

Adolescents

Health Canada has not developed advice for adolescents because of insufficient data. However, they suggest that daily caffeine intake for this age group be no more than 2.5 mg/kg body weight. This is because the maximum adult caffeine dose may not be appropriate for light-weight adolescents or for younger adolescents who are still growing. The daily dose of 2.5 mg/kg body weight would not cause adverse health effects in the majority of adolescent caffeine consumers. This is a conservative suggestion since older and heavier-weight adolescents may be able to consume adult doses of caffeine without experiencing adverse effects.<ref name="healthcanada"/>

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).<ref name="Van Dam" /> Evidence regarding the effects of caffeine on pregnancy and for breastfeeding are inconclusive.<ref name=Jah2015 /> There is limited primary and secondary advice for, or against, caffeine use during pregnancy and its effects on the fetus or newborn.<ref name=Jah2015 />

The UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee.<ref>Template:Cite web</ref> The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women.<ref name="ACOG policy 462 caffeine" /> 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) Template:Not a typo.<ref name="healthcanada" /> 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.<ref name="Wikoff2017" />

There are conflicting reports in the scientific literature about caffeine use during pregnancy.<ref name="pmid19238414">Template:Cite journal</ref> A 2011 review found that caffeine during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts.<ref name="pmid21370398">Template:Cite journal</ref> Other reviews concluded that there is some evidence that higher caffeine intake by pregnant women may be associated with a higher risk of giving birth to a low birth weight baby,<ref>Template:Cite journal</ref> and may be associated with a higher risk of pregnancy loss.<ref>Template:Cite journal</ref> A meta-analysis found a correlation between childhood obesity and maternal caffeine intake during pregnancy.<ref name="Jin_2021">Template:Cite journal</ref> A systematic review analyzed the results of observational studies, and found that women who consumed large amounts of caffeine (greater than 300 mg/day) prior to becoming pregnant may have had a higher risk of experiencing pregnancy loss.<ref>Template:Cite journal</ref>

Adverse effectsTemplate:Anchor

File:Effects of moderate caffeine consumption.svg

Main effects of moderate consumption of Caffeine

File:Main side effects of Caffeine.svg

Main side effects of Caffeine

Physiological

Caffeine in coffee and other caffeinated drinks can affect gastrointestinal motility and gastric acid secretion.<ref name="Boekema1999">Template:Cite journal</ref><ref name="Cohen1975">Template:Cite journal</ref><ref name="Sherwood2004">Template:Cite book</ref> In postmenopausal women, high caffeine consumption can accelerate bone loss.<ref name="mp">Template:Cite web</ref><ref name="Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes">Template:Cite journal</ref> Caffeine, alongside other factors such as stress and fatigue, can also increase the pressure in various muscles, including the eyelids.<ref>Template:Cite web</ref>

Acute ingestion of caffeine in large doses (at least 250–300 mg, equivalent to the amount found in 2–3 Template:Not a typo or 5–8 Template:Not a typo) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks.<ref name="diuretic">Template:Cite journal</ref> This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); it is mediated via proximal tubular adenosine receptor blockade.<ref>Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism Am. J. Physiol. Renal Physiol. 1 July 2008 295:F35-F36</ref> The acute increase in urinary output may increase the risk of dehydration. However, chronic users of caffeine develop a tolerance to this effect and experience no increase in urinary output.<ref name="really">Template:Cite news</ref><ref name="armstrong2007">Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="effects" /><ref name="pmid21346331">Template:Cite journal</ref> Caffeine can have negative effects on anxiety disorders.<ref name="Winston_2005">Template:Cite journal</ref> According to a 2011 literature review, caffeine use may induce anxiety and panic disorders in people with Parkinson's disease.<ref>Template:Cite journal</ref> At high doses, typically greater than 300 to 400 mg caffeine can both cause and worsen anxiety.<ref name="pmid12204388">Template:Cite journal</ref><ref name = "Zhang_2024" />For some people, discontinuing caffeine use can significantly reduce anxiety.<ref name="pmid2727208">Template:Cite journal</ref>

In moderate doses, caffeine has been associated with reduced symptoms of depression and lower suicide risk.<ref name=Psyc10>Template:Cite journal</ref> Two reviews indicate that increased consumption of coffee and caffeine may reduce the risk of depression.<ref name="Wang_2016">Template:Cite journal</ref><ref name="Grosso_2016">Template:Cite journal</ref>

Some textbooks state that caffeine is a mild euphoriant,<ref>Template:Cite book</ref><ref>Template:Cite book</ref><ref>Template:Cite book</ref> while others state that it is not a euphoriant.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.<ref name=Add2014/>

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.<ref>Template:Cite book</ref> Some diagnostic sources, such as the Template:Nowrap and ICD-10, include a classification of caffeine addiction under a broader diagnostic model.<ref>Template:Cite journal</ref> Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.<ref name="pmid24761279">Template:Cite journal</ref><ref>Template:Cite book</ref>

Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, with people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA research monograph.<ref>Template:Cite book</ref> Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction.<ref name="Nestler caffeine dependence-addiction" /><ref name="Cellular basis">Template:Cite journal</ref><ref name="Human-caffeine NAcc neuroimaging">Template:Cite book</ref><ref name="Paper cited by preceding book ref">Template:Cite journal</ref> Other research states it can affect the reward system.<ref>Template:Cite journal</ref>

"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.<ref name="Nestler caffeine dependence-addiction" /><ref name="Clinical addiction & dependence">Template:Cite book</ref><ref name="ICD-10 F15.2">Template:Cite web</ref> The American Psychiatric Association's Template:Nowrap does not include the diagnosis of a caffeine addiction but proposes criteria for the disorder for more study.<ref name="Add2014">Template:Cite journal</ref><ref name=":2">Template:Cite book</ref>

Dependence and withdrawal

Caffeine 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<ref name="pmid19428492">Template:Cite journal</ref> and most cases of caffeine withdrawal were 13% in the moderate sense. Moderately physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day, although these symptoms last no longer than a day.<ref name="Nestler caffeine dependence-addiction" /> Some symptoms associated with psychological dependence may also occur during withdrawal.<ref name="pmid15448977" /> The diagnostic criteria for caffeine withdrawal require a previous prolonged daily use of caffeine.<ref name=":02">Template:Cite book</ref> Following 24 hours of a marked reduction in consumption, a minimum of 3 of these signs or symptoms is required to meet withdrawal criteria: difficulty concentrating, depressed mood/irritability, flu-like symptoms, headache, and fatigue.<ref name=":02" /> Additionally, the signs and symptoms must disrupt important areas of functioning and are not associated with effects of another condition.<ref name=":02" />

The ICD-11 includes caffeine dependence as a distinct diagnostic category, which closely mirrors the DSM-5's proposed set of criteria for "caffeine-use disorder".<ref name=":2" /><ref name=":1">Template:Cite web</ref>  Caffeine use disorder refers to dependence on caffeine characterized by failure to control caffeine consumption despite negative physiological consequences.<ref name=":2" /><ref name=":1" /> The APA, which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of the disorder is unclear.<ref>American Psychiatric Association (2013). "Substance-Related and Addictive Disorders". American Psychiatric Publishing. pp. 1–2. Retrieved 18 November 2019.</ref> Due to this inconclusive evidence on clinical significance, the DSM-5 classifies caffeine-use disorder as a "condition for further study".<ref name=":2" />

Tolerance to the effects of caffeine occurs for caffeine-induced elevations in blood pressure and the subjective feelings of nervousness though the effects are not drastic. Sensitization, the process whereby effects become more prominent with use, may occur for positive effects such as feelings of alertness and wellbeing.<ref name="pmid19428492"/> 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 Template:Cvt cup of coffee or two to three Template:Cvt 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.<ref name="Caffeinedependence JohnHopkins">Template:Cite web</ref> Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.<ref name="Fredholm">Template:Cite journal</ref>

Risk of other diseases

Template:See also A neuroprotective effect of caffeine against Alzheimer's disease and dementia is possible but the evidence is inconclusive.<ref name="pmid20182026">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.<ref name="pmid20367483">Template:Cite journal</ref> One meta analysis has found that caffeine consumption is associated with a reduced risk of type 2 diabetes.<ref>Template:Cite journal</ref> Regular caffeine consumption may reduce the risk of developing Parkinson's disease and may slow the progression of Parkinson's disease.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Qi 2014" />

Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.<ref name="pmid20706731">Template:Cite journal</ref>

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".<ref>Template:Cite book</ref>

Energy crash

Caffeine is reputed to cause a fall in energy several hours after drinking, but this is not well researched.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref><ref>Template:Cite news</ref><ref>Template:Cite web</ref>

Overdose

Torso of a young man with overlaid text of main side-effects of caffeine overdose.

Primary symptoms of caffeine intoxication<ref name="Medline">Template:Cite web</ref>

Consumption of Template:Convert per day is associated with a condition known as caffeinism.<ref>Template:Cite journal</ref> Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.<ref>Template:Cite book</ref>

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.<ref name=":3">Template:Cite web</ref> This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g., more than 400–500 mg at a time). According to the DSM-5, caffeine intoxication may be diagnosed if five (or more) of the following symptoms develop after recent consumption of caffeine: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, periods of inexhaustibility, and psychomotor agitation.<ref>Template:Cite book</ref>

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.<ref name=":3" />

Energy drinks

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

Severe intoxication

Template:As of there is no known antidote or reversal agent for caffeine intoxication. Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration.<ref name="Medline" /><ref>Template:Cite journal</ref><ref name=":03">Template:Cite journal</ref> Intralipid infusion therapy is indicated in cases of imminent risk of cardiac arrest in order to scavenge the free serum caffeine.<ref name=":03" />

Lethal dose

Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications.<ref name="Murray2019">Template:Cite journal</ref> 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.<ref name="Murray2019" /> The LD₅₀ of caffeine in rats is 192 milligrams per kilogram of body mass. The fatal dose in humans is estimated to be 150–200 milligrams per kilogram, which is 10.5–14 grams for a typical Template:Cvt adult, equivalent to about 75–100 Template:Not a typo.<ref>Template:Cite web</ref><ref name="ld50">Template:Cite journal</ref> There are cases where doses as low as 57 milligrams per kilogram have been fatal.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite news</ref> The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease.<ref name="liver-damage">Template:Cite journal</ref> A death was reported in 2013 of a man with liver cirrhosis who overdosed on caffeinated mints.<ref name="independent-2013-10-11">Template:Cite news</ref><ref name="telegraph-2013-10-13">Template:Cite news</ref>

Interactions

Caffeine is a substrate for CYP1A2, and interacts with many substances through this and other mechanisms.<ref name="UTD">Template:Cite web</ref>

Alcohol

Template:See also According to DSST, alcohol causes a decrease in performance on their standardized tests, and caffeine causes a significant improvement.<ref name="Mackay2002">Template:Cite journal</ref> When alcohol and caffeine are consumed jointly, the effects of the caffeine are changed, but the alcohol effects remain the same.<ref name="Liguori2001">Template:Cite journal</ref> For example, consuming additional caffeine does not reduce the effect of alcohol.<ref name="Liguori2001"/> However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed.<ref name="Liguori2001"/> Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the effect of alcohol on the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.<ref name="Marczinski2003">Template:Cite journal</ref> The Dietary Guidelines for Americans recommend avoidance of concomitant consumption of alcohol and caffeine, as taking them together may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.

Smoking

Smoking tobacco has been shown to increase caffeine clearance by 56% as a result of polycyclic aromatic hydrocarbons inducing the CYP1A2 enzyme.<ref>Template:Cite journal</ref><ref name=":4" /> The CYP1A2 enzyme that is induced by smoking is responsible for the metabolism of caffeine; increased enzyme activity leads to increased caffeine clearance, and is associated with greater coffee consumption for regular smokers.<ref name="Bjørngaard_2017">Template:Cite journal</ref>

Birth control

Birth control pills can extend the half-life of caffeine by as much as 40%, requiring greater attention to caffeine consumption.<ref name="Benowitz1990">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Medications

Caffeine sometimes increases the effectiveness of some medications, such as those for headaches.<ref name="pmid21302868">Template:Cite journal</ref> Caffeine was determined to increase the potency of some over-the-counter analgesic medications by 40%.<ref>Template:Cite book</ref>

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

Pharmacology

Pharmacodynamics

Two skeletal formulas: left – caffeine, right – adenosine.

Caffeine's primary mechanism of action is as an adenosine receptor antagonist in the brain.

In the absence of caffeine and when a person is awake and alert, little adenosine is present in CNS neurons. With a continued wakeful state, over time adenosine accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes adenosine receptors; in other words, caffeine prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.<ref name="Drugbank-Caffeine" />

Receptor and ion channel targets

Caffeine is an antagonist of adenosine A_2A receptors, and knockout mouse studies have specifically implicated antagonism of the A_2A receptor as responsible for the wakefulness-promoting effects of caffeine.<ref name="pmid22886028" /> Antagonism of A_2A receptors in the ventrolateral preoptic area (VLPO) reduces inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal.<ref name="Ferre_2008" /> This disinhibition of the tuberomammillary nucleus is the downstream mechanism by which caffeine produces wakefulness-promoting effects.<ref name="Ferre_2008" /> Caffeine is an antagonist of all four adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃), although with varying potencies.<ref name="Drugbank-Caffeine" /><ref name="pmid22886028" /> The affinity (K_D) values of caffeine for the human adenosine receptors are 12 μM at A₁, 2.4 μM at A_2A, 13 μM at A_2B, and 80 μM at A₃.<ref name="pmid22886028">Template:Cite journal</ref>

Antagonism of adenosine receptors by caffeine also stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heart rate, and constricts blood vessels.<ref name="Drugbank-Caffeine" /> Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;<ref name="Drugbank-Caffeine" /><ref>Template:Cite web</ref> adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the A₁ receptor.<ref name="Drugbank-Caffeine" />

Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive antagonist.<ref name="pmid15095008">Template:Cite journal</ref>

In addition to its activity at adenosine receptors, caffeine is an inositol trisphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3).<ref name="IUPHAR caffeine">Template:Cite web</ref> It is also a competitive antagonist of the ionotropic glycine receptor.<ref name="pmid19564396">Template:Cite journal</ref>

Effects on striatal dopamine

While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A₁–D₁ receptor heterodimer (this is a receptor complex with one adenosine A₁ receptor and one dopamine D₁ receptor) and the A_2A–D₂ receptor heterotetramer (this is a receptor complex with two adenosine A_2A receptors and two dopamine D₂ receptors).<ref name="A1-DRD1 and A2a-DRD2 review">Template:Cite journal</ref><ref name="Caffeine heterotetramer review" /><ref name="Caffeine psychostimulant effects" /><ref name="Caffeine SUD interactions" /> The A_2A–D₂ receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.<ref name="Caffeine heterotetramer review">Template:Cite journal</ref><ref name="Caffeine psychostimulant effects">Template:Cite journal</ref><ref name="Caffeine SUD interactions">Template:Cite journal</ref>

Caffeine also causes the release of dopamine in the dorsal striatum and nucleus accumbens core (a substructure within the ventral striatum), but not the nucleus accumbens shell, by antagonizing A₁ receptors in the axon terminal of dopamine neurons and A₁–A_2A heterodimers (a receptor complex composed of one adenosine A₁ receptor and one adenosine A_2A receptor) in the axon terminal of glutamate neurons.<ref name="A1-DRD1 and A2a-DRD2 review" /><ref name="Ferre_2008" /> During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance.<ref name="A1-DRD1 and A2a-DRD2 review" /><ref name="Ferre_2008">Template:Cite journal</ref>

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.<ref name="pmid20164566">Template:Cite journal</ref> As a competitive nonselective phosphodiesterase inhibitor,<ref name="PDEs-Essayan">Template:Cite journal</ref> caffeine raises intracellular cyclic AMP, activates protein kinase A, inhibits TNF-alpha<ref name="PTX-Deree">Template:Cite journal</ref><ref name="pmid9927365">Template:Cite journal</ref> and leukotriene<ref name="LT-Peters-Golden">Template:Cite journal</ref> synthesis, and reduces inflammation and innate immunity.<ref name="LT-Peters-Golden"/> Caffeine also affects the cholinergic system where it is a moderate inhibitor of the enzyme acetylcholinesterase.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pharmacokinetics

A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.

Caffeine is metabolized in the liver via a single demethylation, resulting in three primary metabolites, paraxanthine (84%), theobromine (12%), and theophylline (4%), depending on which methyl group is removed.

File:Caffeine metabolism.png

Urinary metabolites of caffeine in humans at 48 hours post-dose<ref name="pmid20859793">Template:Cite book</ref>

Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues.<ref name="pmid9329065">Template:Cite journal</ref> Peak blood concentration is reached within 1–2 hours.<ref>Template:Cite journal</ref> It is eliminated by first-order kinetics.<ref name="pmid7333346">Template:Cite journal</ref> Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine)<ref name="pmid13165929">Template:Cite journal</ref> and of chlorobutanol and caffeine (for the treatment of hyperemesis).<ref name="pmid17553397">Template:Cite journal</ref> However, rectal absorption is less efficient than oral: the maximum concentration (C_max) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.<ref>Template:Cite journal</ref>

Caffeine's biological half-life – the time required for the body to eliminate one-half of a dose – varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for caffeine metabolism) and age. In healthy adults, caffeine's half-life is between 3 and 7 hours.<ref name="Drugbank-Caffeine" /> The half-life is decreased by 30–50% in adult male smokers, approximately doubled in women taking oral contraceptives, and prolonged in the last trimester of pregnancy.<ref name=Fredholm /> In newborns the half-life can be 80 hours or more, dropping rapidly with age, possibly to less than the adult value by age 6 months.<ref name=Fredholm /> The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and increases its elimination half-life more than tenfold, from 4.9 hours to 56 hours.<ref name="half-life">Template:Cite web</ref>

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

• Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in blood plasma.
• Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean (chocolate).
• Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.<ref name="pmid20091514" />

1,3,7-Trimethyluric acid is a minor caffeine metabolite.<ref name="Drugbank-Caffeine" /> 7-Methylxanthine is also a metabolite of caffeine.<ref name="InxightDrugs">Template:Cite web</ref><ref name="pmid35918918">Template:Cite journal</ref> Each of the above metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.<ref name="pmid18762933">Template:Cite journal</ref>

A 2011 review found that increased caffeine intake was associated with a variation in two genes that increase the rate of caffeine catabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more caffeine per day than others.<ref name="Gibson2011">Template:Cite journal</ref> This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation.

Chemistry

Pure anhydrous caffeine is a bitter-tasting, white, odorless powder with a melting point of 235–238 °C.<ref name="Pubchem properties" /><ref name="ChemSpider" /> Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but quickly soluble in boiling water (66 g/100 mL).<ref name="solu"/> It is also moderately soluble in ethanol (1.5 g/100 mL).<ref name="solu">Template:Cite book</ref> It is weakly basic (pK_a of conjugate acid = ~0.6) requiring strong acid to protonate it.<ref name="pKa">This is the pK_a for protonated caffeine, given as a range of values included in Template:Cite book</ref> Caffeine does not contain any stereogenic centers<ref name="isbn0-7614-2242-0">Template:Cite book</ref> and hence is classified as an achiral molecule.<ref name="isbn1-58409-016-2">Template:Cite book</ref>

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominantly in a zwitterionic resonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp² hybridized and planar. The imidazole ring also has a resonance. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.<ref name="urlquantum.esu.edu">Template:Cite web</ref>

Synthesis

File:Caffeine biosynthesis.tif

One biosynthetic route of caffeine, as performed by Camellia and Coffea species<ref name="urlcaffeine biosynthesis">Template:Cite web</ref><ref>Template:Cite web</ref>

File:Caffeine synthesis-en.svg

One laboratory synthesis of caffeine<ref name="isbn1-58829-173-1"/><ref name = "US2785162"/>

The biosynthesis of caffeine is an example of convergent evolution among different species.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite magazine</ref>

Caffeine may be synthesized in the lab starting with 1,3-dimethylurea and malonic acid.Template:Clarify<ref name="isbn1-58829-173-1">Template:Cite book</ref><ref name = "US2785162">Template:Cite patent</ref><ref name="Zajac_2003">Template:Cite journal</ref>

Industrially, caffeine is synthesized from urea and chloroacetic acid.<ref name="Hu_2018">Template:Cite web</ref> A range of alternative processes are also possible. Most processes for synthesizing caffeine are old, having been patented between the 1940s and the 1960s. The synthesis of caffeine is inexpensive.<ref name="Mazzafera_2012">Template:Cite journal</ref>

Decaffeination

File:CaffeineCrystals Fibrous 10xDarkField.jpg

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

Germany, the birthplace of decaffeinated coffee, is home to several decaffeination plants, including the world's largest, Coffein Compagnie.<ref>Template:Cite web</ref> Over half of the decaf coffee sold in the US first travels from the tropics to Germany for caffeine removal before making its way to American consumers.Template:Cn Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.<ref name=Decaffeination/>

Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using various solvents. Following are main methods:

• Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor.<ref name="Decaffeination">Template:Cite web</ref>
• Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: Template:CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, Template:CO2 is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden Template:CO2 is then sprayed with high-pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.<ref name="Decaffeination" />
• Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.<ref name=Decaffeination/>

Decaffination does not happen completely; some caffeine remains in the coffee beans. 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.<ref name="pmid17132260">Template:Cite journal</ref>

Detection in body fluids

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

Analogs

Some analog substances have been created which mimic caffeine's properties with either function or structure or both. Of the latter group are the xanthines DMPX<ref name=DMPX>Template:Cite journal</ref> and 8-chlorotheophylline, which is an ingredient in dramamine. Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.<ref>Template:Cite web</ref>Template:Unreliable source? Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.<ref>Template:Cite book</ref>

Some other caffeine analogs:

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

Precipitation of tannins

Caffeine, as do other alkaloids such as cinchonine, quinine or strychnine, precipitates polyphenols and tannins. This property can be used in a quantitation method.Template:Clarify<ref>Plant Polyphenols: Synthesis, Properties, Significance. Richard W. Hemingway, Peter E. Laks, Susan J. Branham (page 263)</ref>

Commercial sources

The world's supply of pure (mostly anhydrous) caffeine for adding to drinks, pharmaceuticals, and other products comes from two sources: industrial synthesis and decaffeination of natural sources. Despite the different production methods, the final products are chemically identical and so are their effects on the body. Research on synthetic caffeine supports that it has the same stimulating effects on the body as natural caffeine.<ref name="Hu18">Template:Cite web</ref> And although many claim that natural caffeine is absorbed slower and therefore leads to a gentler caffeine crash, there is little scientific evidence supporting the notion.<ref name="Hu18" /> Nevertheless, a demand for natural caffeine to satisfy consumer perception has grown so large that the decaffinated product may be now considered a byproduct for the production of caffeine.<ref name=Mazzafera12>Template:Cite journal</ref>

The global market exchanged 128,127 tons of anhydrous caffeine in 2022.<ref name=PMR22>Template:Cite press release</ref> Most of the world's synthetic caffeine is produced by Chinese pharmaceutical companies, but an exact breakdown of supply between synthetic and natural does not seem to be available.<ref name=Mazzafera12/>

It is possible to distinguish between natural and synthetic caffeine using carbon-13-to-carbon-12 isotope ratios, as most of the carbon from synthetic caffeine comes from petroleum sources with a more "ancient" carbon isotope signature.<ref>Template:Cite web</ref>

Natural occurrence

File:Coffee beans2.jpg

Roasted coffee beans

Around thirty plant species are known to contain caffeine.<ref>Template:Cite web</ref> Common sources are the "beans" (seeds) of the two cultivated coffee plants, Coffea arabica and Coffea canephora (the quantity varies, but 1.3% is a typical value); and of the cocoa plant, Theobroma cacao; the leaves of the tea plant; and kola nuts. Other sources include the leaves of yaupon holly, South American holly yerba mate, and Amazonian holly guayusa; and seeds from Amazonian maple guarana berries. Temperate climates around the world have produced unrelated caffeine-containing plants.

Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant.<ref name="insecticide">Template:Cite journal</ref> High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Caffeine is stored in tea leaves in two places. Firstly, in the cell vacuoles where it is complexed with polyphenols. This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles.<ref>Template:Cite journal</ref> Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honey bees.<ref name="pmid23471406"/>

The differing perceptions in the effects of ingesting beverages made from various plants containing caffeine could be explained by the fact that these beverages also contain varying mixtures of other methylxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.<ref name="Ref-1">Template:Cite book</ref>

Products

Caffeine content in select food and drugs<ref name="Content">Template:Cite web</ref><ref name="Erowid">Template:Cite web</ref><ref>Template:Cite web</ref><ref name="JAT" /><ref name="Richardson" />

Product	Serving size	Caffeine per serving (mg)	Caffeine (mg/L)
Caffeine tablet (regular-strength)	1 tablet	Template:Nts	—
Caffeine tablet (extra-strength)	1 tablet	Template:Nts	—
Excedrin tablet	1 tablet	Template:Nts	—
Percolated coffee	Template:Nowrap	Template:Nts–135	Template:Nts–652
Drip coffee	Template:Nowrap	Template:Nts–175	Template:Nts–845
Template:Nowrap	Template:Nowrap	Template:Nts–15	Template:Nts–72
Coffee, espresso	Template:Nowrap	Template:Nts	Template:Nts–2,254
Tea – black, green, and other types, – steeped for 3 min.	Template:Nowrap	Template:Nts–74<ref name="JAT">Template:Cite journal</ref><ref name="Richardson">Template:Cite web</ref>	Template:Nts–418
Guayakí yerba mate (loose leaf)	Template:Nowrap	Template:Nts<ref name="Guayakí">Template:Cite web</ref>	Template:Nts
Coca-Cola	Template:Nowrap	Template:Nts	Template:Nts
Diet Coke	Template:Nowrap	46<ref>Template:Cite journal</ref>	130
Mountain Dew	Template:Nowrap	Template:Nts	Template:Nts
Pepsi Zero Sugar	Template:Nowrap	Template:Nts	Template:Nts
Guaraná Antarctica	Template:Nowrap	Template:Nts	Template:Nts
Jolt Cola	Template:Nowrap	Template:Nts	Template:Nts
Red Bull	Template:Nowrap	Template:Nts	Template:Nts
Coffee-flavored milk drink	Template:Nowrap	Template:Nts–197<ref name="Desbrow" />	Template:Nts–354<ref name="Desbrow" />
Cocoa, dry powder, unsweetened [unspecified strain]	100 g	230<ref name="USDA Food Central item 169593">Template:Cite web</ref>	—
Cocoa solids, defatted, Criollo strain	100 g	1130<ref name="caffeine content in cocoa solids by strain" />	—
Cocoa solids, defatted, Forastero strain	100 g	130<ref name="caffeine content in cocoa solids by strain">Template:Cite book</ref>	—
Cocoa solids, defatted, Nacional strain	100 g	240<ref name="caffeine content in cocoa solids by strain" />	—
Cocoa solids, defatted, Trinitario strain	100 g	630<ref name="caffeine content in cocoa solids by strain" />	—
Chocolate, dark, 70–85% cacao solids	100 g	80<ref name="USDA Food Central item 170273">Template:Cite web</ref>	—
Chocolate, dark, 60–69% cacao solids	100 g	86<ref name="USDA Food Central item 170272">Template:Cite web</ref>	—
Chocolate, dark, 45–59% cacao solids	100 g	43<ref name="USDA Food Central item 170271">Template:Cite web</ref>	—
Candies, milk chocolate	100 g	20<ref name="USDA Food Central item 167587">Template:Cite web</ref>	—
Hershey's Special Dark (45% cacao content)	Template:Nowrap	Template:Nts	—
Hershey's Milk Chocolate (11% cacao content)	Template:Nowrap	Template:Nts	—

Products containing caffeine include coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,<ref name="Matissek R 1997 175–84">Template:Cite journal</ref> 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.<ref name="Van Dam">Template:Cite journal</ref> Energy drinks are more commonly consumed as a source of caffeine in adolescents as compared to adults.<ref name="Van Dam" />

Beverages

Coffee

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

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.<ref name="FRI">Template:Cite journal</ref>

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

Soft drinks and energy drinks

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

Other beverages

• Maté is a drink popular in many parts of South America. Its preparation consists of filling a gourd with the leaves of the South American holly yerba mate, pouring hot but not boiling water over the leaves, and drinking with a straw, the bombilla, which acts as a filter so as to draw only the liquid and not the yerba leaves.<ref>Template:Cite web</ref>
• Guaraná is a soft drink originating in Brazil made from the seeds of the Guaraná fruit.
• The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea.<ref>Template:Cite book</ref>
• The leaves of Ilex vomitoria, the yaupon holly tree, are placed in boiling water to make a yaupon tea.
• Commercially prepared coffee-flavoured milk beverages are popular in Australia.<ref>Template:Cite news</ref> 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.<ref name="Desbrow">Template:Cite journal</ref>

Cacao solids

Cocoa solids (derived from cocoa bean) contain 230 mg caffeine per 100 g.<ref name="USDA Food Central item 169593" />

The caffeine content varies between cocoa bean strains. Caffeine content mg/g (sorted by lowest caffeine content):<ref name="caffeine content in cocoa solids by strain" />

• Forastero (defatted): 1.3 mg/g
• Nacional (defatted): 2.4 mg/g
• Trinitario (defatted): 6.3/g
• Criollo (defatted): 11.3 mg/g

Chocolate

Caffeine per 100 g:

• Dark chocolate, 70–85% cacao solids: 80 mg<ref name="USDA Food Central item 170273" />
• Dark chocolate, 60–69% cacao solids: 86 mg<ref name="USDA Food Central item 170272" />
• Dark chocolate, 45–59% cacao solids: 43 mg<ref name="USDA Food Central item 170271" />
• Milk chocolate: 20 mg<ref name="USDA Food Central item 167587" />

The stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.<ref name="pmid15549276">Template:Cite journal</ref>

Tablets

File:No-Doz.jpg

No-Doz 100 mg caffeine tablets

Tablets offer several advantages over coffee, tea, and other caffeinated beverages, including convenience, known dosage, and avoidance of concomitant intake of sugar or acids. The use of caffeine in this form may increase alertness.<ref>Template:Cite web</ref> These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.<ref>Template:Cite book</ref>

Other oral products

One US company is marketing oral dissolvable caffeine strips.<ref>Template:Cite news</ref> Another intake route is SpazzStick, a caffeinated lip balm.<ref>Template:Cite news</ref> 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.<ref name=NYT5813>Template:Cite newsTemplate:Cbignore</ref>

There is weak evidence that the use of caffeine mouth washes might help cognitive performance.<ref>Template:Cite journal</ref>

Inhalants

Similar to an e-cigarette, a caffeine inhaler may be used to deliver caffeine or a stimulant like guarana by vaping.<ref>Template:Cite news</ref> In 2012, the FDA sent a warning letter to one of the companies marketing an inhaler, expressing concerns for the lack of safety information available about inhaled caffeine.<ref>Template:Cite web</ref><ref>Template:Cite news</ref>

Combinations with other drugs

• Some beverages combine alcohol with caffeine to create a caffeinated alcoholic drink. The stimulant effects of caffeine may mask the depressant effects of alcohol, potentially reducing the user's awareness of their level of intoxication. Such beverages have been the subject of bans due to safety concerns. In particular, the United States Food and Drug Administration has classified caffeine added to malt liquor beverages as an "unsafe food additive".<ref>Template:Cite web</ref>
• Ya ba contains a combination of methamphetamine and caffeine.
• Painkillers such as propyphenazone/paracetamol/caffeine combine caffeine with an analgesic.

History

Discovery and spread of use

An old photo of a dozen old and middle-aged men sitting on the ground around a mat. A man in front sits next to a mortar and holds a bat, ready for grinding. A man opposite to him holds a long spoon.

Coffeehouse in Palestine, Template:Circa

According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, inadvertently discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted.<ref>Template:Cite book</ref> Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.<ref>Template:Cite bookTemplate:Page needed</ref>

The earliest credible evidence of either coffee drinking or knowledge of the coffee plant appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemen in southern Arabia.<ref name=Bennett>Template:Cite book</ref> From Mokha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.<ref name = Meyers>Template:Cite web</ref>

Kola nut use appears to have ancient origins. It is chewed in many West African cultures, in both private and social settings, to restore vitality and ease hunger pangs.<ref>Template:Cite journal</ref>

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

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies<ref>Template:Cite web</ref> and the Philippines.<ref name=":5">Template:Cite report</ref>

The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink".<ref name=Fairbanks>Template:Cite book</ref> Archaeologists have found evidence of this use far into antiquity,<ref>Template:Cite journal</ref> possibly dating to Late Archaic times.<ref name=Fairbanks/>

Chemical identification, isolation, and synthesis

File:Friedlieb Ferdinand Runge.jpeg

Friedlieb Ferdinand Runge, discoverer of caffeine

In 1819, the German chemist Friedlieb Ferdinand Runge isolated Template:Vague caffeine for the first time; he called it "Kaffebase" (i.e., a base that exists in coffee).<ref>Template:Cite book</ref><ref name="weinberg">Template:Cite book</ref> In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work.<ref>Template:Cite book</ref> However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:<ref>Template:Cite book</ref> "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 Template:Lang from the French word for coffee: Template:Lang).<ref>Template:Cite encyclopedia</ref> It corroborates Berzelius's account:

Robiquet was one of the first to isolate and describe the properties of pure caffeine,<ref>Template:Cite encyclopedia</ref> whereas Pelletier was the first to perform an elemental analysis.<ref>Template:Cite journal</ref>

In 1827, M. Oudry isolated "théine" from tea,<ref>Template:Cite journal</ref> but in 1838 it was proved by Mulder<ref>Template:Cite journal</ref> and by Carl Jobst<ref>Template:Cite journal</ref> that theine was actually the same as caffeine.

In 1895, German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from its chemical components (i.e. a "total synthesis"), and two years later, he also derived the structural formula of the compound.<ref>Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.

• Template:Cite journal
• Template:Cite journal
• Template:Cite journal
• Template:Cite journal
• Template:Cite journal</ref> This was part of the work for which Fischer was awarded the Nobel Prize in 1902.<ref>Template:Cite web</ref>

Historic regulations

Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca and in the Ottoman Empire made coffee illegal for some classes.<ref>Template:Cite book</ref><ref name="agostonmasters2009">Template:Cite book</ref><ref name="hopkins2006">Template:Cite web</ref> Charles II of England tried to ban it in 1676,<ref>Template:Cite web</ref><ref name="Pendergrast13">Template:Harvnb</ref> Frederick II of Prussia banned it in 1777,<ref name="Pendergrast11">Template:Harvnb</ref><ref>Template:Harvnb</ref> and coffee was banned in Sweden at various times between 1756 and 1823.

In 1911, caffeine became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".<ref name="pmid2010614">Template:Cite journal</ref> Although the Supreme Court later ruled in favor of Coca-Cola in United States v. Forty Barrels and Twenty Kegs of Coca-Cola, two bills were introduced to the US House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.<ref>Template:Cite web</ref>

Society and culture

Regulations

United States

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

Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance.<ref name="abc.net">Template:Cite news</ref> The consumption of caffeine has remained stable between 1997 and 2015.<ref name="Verster2018">Template:Cite journal</ref> Coffee, tea and soft drinks are the most common caffeine sources, with energy drinks contributing little to the total caffeine intake across all age groups.<ref name="Verster2018" />

Religions

The Seventh-day Adventist Church asked for its members to "abstain from caffeinated drinks", but has removed this from baptismal vows (while still recommending abstention as policy).<ref>Template:Cite book</ref> Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: "... the Church revelation spelling out health practices (Doctrine and Covenants 89) does not mention the use of caffeine. The Church's health guidelines prohibit alcoholic drinks, smoking or chewing of tobacco, and 'hot drinks' – taught by Church leaders to refer specifically to tea and coffee."<ref>Template:Cite news</ref>

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

Caffeinated beverages are widely consumed by Muslims. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.<ref name="Campo2009">Template:Cite book</ref><ref name="Brown2011">Template:Cite book</ref>

Other organisms

Caffeine effects on spider webs

Caffeine effects on spider webs

The bacteria Pseudomonas putida CBB5 can live on pure caffeine and can cleave caffeine into carbon dioxide and ammonia.<ref>Template:Cite web</ref>

Caffeine is toxic to birds<ref>Template:Cite web</ref> and to dogs and cats,<ref>Template:Cite web</ref> and has a pronounced adverse effect on mollusks, various insects, and spiders.<ref>Template:Cite journal</ref> This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.<ref name="pmid20859793"/> Caffeine has also been found to enhance the reward memory of honey bees.<ref name="pmid23471406"/>

Research

Caffeine has been used to double chromosomes in haploid wheat.<ref name="pmid18464846">Template:Cite journal</ref>

See also

• Adderall
• Amphetamine
• Cocaine
• Health effects of coffee
• Health effects of tea
• List of chemical compounds in coffee
• Low caffeine coffee
• Methylliberine
• Nootropic
• Theobromine
• Theophylline
• Wakefulness-promoting agent

Bibliography

• Template:Cite book
• Template:Cite book
• Template:Cite book
• Template:Cite book

External links

• GMD MS Spectrum
• Caffeine: ChemSub Online
• Caffeine at The Periodic Table of Videos (University of Nottingham)