Editing Theobromine

{{Short description|Bitter alkaloid of the cacao plant}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Distinguish|bromine}}

{{Infobox drug
| Watchedfields      = changed
| verifiedrevid      = 622941253
| IUPAC_name         = 3,7-dimethyl-1''H''-purine-2,6-dione
| image              = Theobromine.svg
| image_class        = skin-invert-image
| width              = 135
| image2             = Theobromine 3D ball.png

<!--Clinical data-->| legal_status       = In general: Unscheduled.
| dependency_liability = None
| addiction_liability = 
| routes_of_administration = [[Mouth|Oral]]

<!--Pharmacokinetic data-->| metabolism         = [[Liver|Hepatic]] [[demethylation]] and [[redox|oxidation]]
| elimination_half-life = 6–8 hours<ref name="halflife1">{{cite journal | vauthors = Drouillard DD, Vesell ES, Dvorchik BH | title = Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines | journal = Clinical Pharmacology and Therapeutics | volume = 23 | issue = 3 | pages = 296–302 | date = March 1978 | pmid = 627135 | doi = 10.1002/cpt1978233296 | s2cid = 10519385 }}</ref><ref name="halflife2">{{cite journal | vauthors = Lelo A, Birkett DJ, Robson RA, Miners JO | title = Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man | journal = British Journal of Clinical Pharmacology | volume = 22 | issue = 2 | pages = 177–182 | date = August 1986 | pmid = 3756065 | pmc = 1401099 | doi = 10.1111/j.1365-2125.1986.tb05246.x }}</ref>
| excretion          = [[Kidney|Renal]] (10% unchanged, rest as metabolites)

<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|CAS}}
| CAS_number         = 83-67-0
| ATC_prefix         = C03
| ATC_suffix         = BD01
| ATC_supplemental   = {{ATC|R03|DA07}}
| PubChem            = 5429
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB01412
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 5236
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = OBD445WZ5P
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = C07480
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 28946
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 1114

<!--Chemical data-->| C                  = 7
| H                  = 8
| N                  = 4
| O                  = 2
| chemical_formula_ref = 
| smiles             = Cn1cnc2c1c(=O)[nH]c(=O)n2C
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)9-7(13)11(5)2/h3H,1-2H3,(H,9,12,13)
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = YAPQBXQYLJRXSA-UHFFFAOYSA-N
| synonyms           = xantheose<br />diurobromine<br />3,7-dimethylxanthine<br />3,7-dihydro-3,7-dimethyl-1''H''-purine-2,6-dione
}}

{{Chembox
|container_only = yes
| ImageFile = 
| ImageSize = 
| ImageAlt = 
| IUPACName = 
| OtherNames = 
|Section1={{Chembox Identifiers
| CASNo = 
| PubChem = 
| SMILES = }}
|Section2={{Chembox Properties
| Formula = 
| MolarMass =
| Appearance = white solid
| Density = 1.524 g/cm<sup>3</sup><ref name=Acta/>
| MeltingPtC = 351
| BoilingPt = 
| Solubility = 330&nbsp;mg/L)}}
|Section3={{Chembox Hazards
| MainHazards = 
| FlashPt = 
| AutoignitionPt = }}
}}
'''Theobromine''', also known as '''xantheose''', is the principal [[alkaloid]] of ''[[Theobroma cacao]]'' (cacao plant).<ref name="pubchem">{{cite web |title=Theobromine |url=https://pubchem.ncbi.nlm.nih.gov/compound/5429 |publisher=PubChem, US National Library of Medicine |access-date=3 September 2022 |date=27 August 2022}}</ref> Theobromine is slightly water-[[solubility|soluble]] (330&nbsp;mg/L) with a bitter taste.<ref name=Hbk>{{cite book | vauthors = Smit HJ | chapter = Theobromine and the Pharmacology of Cocoa | title = Methylxanthines | series = Handbook of Experimental Pharmacology | volume = 200 | issue = <!-- none --> | pages = 201–234 | year = 2011 | pmid = 20859797 | doi = 10.1007/978-3-642-13443-2_7 | isbn = 978-3-642-13442-5 }}</ref> In industry, theobromine is used as an [[food additive|additive]] and precursor to some [[cosmetics]].<ref name=pubchem/> It is found in [[chocolate]], as well as in a number of other foods, including [[tea]] (''[[Camellia sinensis]]''), some American [[Holly|hollies]] ([[Ilex vomitoria|yaupon]] and [[Ilex guayusa|guayusa]]) and the [[kola nut]]. It is a white or colourless solid, but commercial samples can appear yellowish.<ref name=Hbk/>

[[Theobromine]], a metabolite of [[caffeine]], is processed in the [[liver]] into [[xanthine]] and methyluric acid, peaks in the blood 2–3 hours after ingestion due to its fat solubility, and primarily acts by inhibiting [[adenosine receptor]]s with minor [[phosphodiesterase inhibitor|phosphodiesterase]] inhibition. It is a mild [[heart]] stimulant and [[bronchodilator]] in [[humans]] with limited [[central nervous system]] effects. It can be toxic or fatal to [[animals]] like [[dogs]] and [[cats]] due to their slower [[metabolism]] of the compound.<!--Per WP:CITELEAD, references are not needed in the lead if it is sourced in the body of the article.-->

==Structure==
Theobromine is a flat molecule,<ref name=Acta>{{cite journal |doi=10.1107/S0108270198009469|title=Methylxanthines. II. Anhydrous Theobromine |year=1998 | vauthors = Ford KA, Ebisuzaki Y, Boyle PD |journal=Acta Crystallographica Section C Crystal Structure Communications |volume=54 |issue=12 |pages=1980–1983 |bibcode=1998AcCrC..54.1980F }}</ref> a derivative of [[purine]] and an isomer of theophylline.<ref>{{cite web |title=Theophylline |url=https://pubchem.ncbi.nlm.nih.gov/compound/2153 |publisher=PubChem, US National Library of Medicine |access-date=2 September 2023 |date=26 August 2023}}</ref>  It is also classified as a [[methyl|dimethyl]] [[xanthine]].<ref name=Hbk/><ref name="envbeh-p200">{{cite book | title=Environment and Behavior |  vauthors = Baer DM, Pinkston EM | year=1997 | publisher=Westview Press | page=[https://archive.org/details/environmentbehav0000unse/page/200 200] | isbn=978-0813331591 | url=https://archive.org/details/environmentbehav0000unse/page/200 }}</ref> Related compounds include [[theophylline]], [[caffeine]], [[paraxanthine]], and [[7-methylxanthine]], each of which differ in the number or placement of the methyl groups.<ref name=Hbk/>

==History==
Theobromine was first discovered in 1841<ref>{{cite book| vauthors = von Bibra E, Ott J |title=Plant Intoxicants: A Classic Text on the Use of Mind-Altering Plants|url=https://books.google.com/books?id=EWqhC4djXSQC&pg=PA67|date=1995|publisher=Inner Traditions / Bear & Co|isbn=978-0-89281-498-5|pages=67–|access-date=2015-12-12|archive-date=2019-09-18|archive-url=https://web.archive.org/web/20190918203121/https://books.google.com/books?id=EWqhC4djXSQC&pg=PA67|url-status=live}}</ref> in cacao beans by the chemist [[Aleksandr Voskresensky|A. Woskresensky]].<ref>{{cite journal | vauthors = Woskresensky A | year = 1842 | title = Über das Theobromin | url = https://books.google.com/books?id=ZE09AAAAcAAJ&pg=PA125 | journal = Liebigs Annalen der Chemie und Pharmacie | volume = 41 | pages = 125–127 | doi = 10.1002/jlac.18420410117 | access-date = 2015-12-12 | archive-date = 2016-06-10 | archive-url = https://web.archive.org/web/20160610112332/https://books.google.com/books?id=ZE09AAAAcAAJ&pg=PA125 | url-status = live }}</ref> Synthesis of theobromine from [[xanthine]] was first reported in 1882 by [[Hermann Emil Fischer]].<ref name="historicalchemistry">{{cite book | title=Essays in Historical Chemistry | url=https://archive.org/details/b31350975_0002 | vauthors = Thorpe TE | year=1902 | publisher=The MacMillan Company }}</ref><ref>{{cite journal | vauthors = Fischer, Emil | year = 1882 | title = Umwandlung des Xanthin in Theobromin und Caffein | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 15 | issue = 1 | pages = 453–456 | doi = 10.1002/cber.18820150194 | url = https://zenodo.org/record/1425264 | access-date = 2019-09-09 | archive-date = 2019-05-05 | archive-url = https://web.archive.org/web/20190505192210/https://zenodo.org/record/1425264/files/article.pdf | url-status = live }}</ref><ref>{{ cite journal | vauthors = Fischer E |year=1882| title = Über Caffein, Theobromin, Xanthin und Guanin | url = https://zenodo.org/record/1427381| journal = Justus Liebigs Annalen der Chemie | volume = 215 | issue = 3| pages = 253–320 | doi = 10.1002/jlac.18822150302 }}</ref>

==Etymology==
''Theobromine'' is derived from ''[[Theobroma]]'', the name of the [[genus]] of the cacao tree, with the suffix ''-ine'' given to alkaloids and other [[base (chemistry)|basic]] nitrogen-containing compounds.<ref name="dict-ine">{{cite book | chapter = -ine | title = The American Heritage Dictionary of the English Language, Fourth Edition | publisher = [[Houghton Mifflin Company]] | year = 2004 | chapter-url = http://dictionary.reference.com/browse/-ine | isbn = 978-0-395-71146-0 | access-date = 2007-02-23 | archive-date = 2016-03-03 | archive-url = https://web.archive.org/web/20160303171459/http://dictionary.reference.com/browse/-ine | url-status = live }}</ref> That name in turn is made up of the [[Greek (language)|Greek]] roots ''theo'' ("[[god]]") and ''broma'' ("food"), meaning "food of the gods".<ref name="worldofcaffeine">{{cite book | vauthors = Bennett AW, Bealer BK | title = The World of Caffeine: The Science and Culture of the World's Most Popular Drug | publisher = [[Routledge]], New York | year = 2002 | isbn = 978-0-415-92723-9 | url = https://archive.org/details/worldofcaffeines00benn }} (note: the book incorrectly states that the name "theobroma" is derived from Latin)</ref>

Despite its name, the compound contains no [[bromine]], which is based on Greek ''bromos'' ("stench").

==Sources==
[[Image:Chocolate02.jpg|thumb|right|A chocolate bar and molten chocolate. Chocolate is made from the [[cocoa bean]], which is a natural source of theobromine.]]

Theobromine is the primary alkaloid found in [[Cocoa bean|cocoa]] and [[chocolate]]. [[Cocoa butter]] only contains trace amounts of theobromine. There are usually higher concentrations in dark than in milk chocolate.<ref name="AmerMed_cocoa">{{cite web |url= http://www.amermed.com/cocoa.htm |title= AmerMed cocoa extract with 10% theobromine |publisher= AmerMed |access-date= 2008-04-13 |archive-date= 2015-08-11 |archive-url= https://web.archive.org/web/20150811092221/http://amermed.com/cocoa.htm |url-status= dead }}</ref>

There are approximately {{Convert|60|mg|abbr = off|0}} of theobromine in {{Convert|1|oz|order = flip}} of milk chocolate,<ref name="USDA db milk chocolate entry">{{cite web |url=http://ndb.nal.usda.gov/ndb/foods/show/5924?qlookup=milk+chocolate&offset=&format=Full#id-1 |title=USDA Nutrient database, entries for milk chocolate |access-date=2012-12-29 |archive-date=2017-07-08 |archive-url=https://web.archive.org/web/20170708121554/https://ndb.nal.usda.gov/ndb/foods/show/5924?qlookup=milk+chocolate&offset=&format=Full#id-1 |url-status=dead }}</ref> while the same amount of dark chocolate contains about {{Convert|200|mg|abbr = off|0}}.<ref name="USDA db dark chocolate entry">{{cite web |url=https://fdc.nal.usda.gov |title=USDA Nutrient database, entries for dark chocolate |access-date=2012-11-07 }}</ref> Cocoa beans naturally contain approximately 1% theobromine.<ref>{{cite journal | vauthors = Kuribara H, Tadokoro S | title = Behavioral effects of cocoa and its main active compound theobromine: evaluation by ambulatory activity and discrete avoidance in mice | journal = Arukoru Kenkyu to Yakubutsu Izon = Japanese Journal of Alcohol Studies & Drug Dependence | volume = 27 | issue = 2 | pages = 168–179 | date = April 1992 | pmid = 1586288 }}</ref>

Plant species and components with substantial amounts of theobromine are:<ref name="arsgrin-theobromine">{{cite web| url=https://phytochem.nal.usda.gov/phytochem/chemicals/show/17073?et=| title=Theobromine content in plant sources| publisher=Dr. Duke's Phytochemical and Ethnobotanical Databases, [[United States Department of Agriculture]]| date=6 February 2019| access-date=9 March 2019| archive-date=8 May 2019| archive-url=https://web.archive.org/web/20190508200500/https://phytochem.nal.usda.gov/phytochem/chemicals/show/17073?et=| url-status=dead}}</ref><ref name=":4">{{cite journal |vauthors=Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T |date=August 2012 |title=Ritual Black Drink consumption at Cahokia |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=109 |issue=35 |pages=13944–9 |doi=10.1073/pnas.1208404109 |pmc=3435207 |pmid=22869743 |doi-access=free}}</ref>

* ''[[Theobroma cacao]]'' &ndash; seed and [[Seed#Seed coat|seed coat]]
* ''[[Theobroma bicolor]]'' &ndash; seed coat
* ''[[Ilex paraguariensis]]'' &ndash; leaf
* ''[[Ilex guayusa]]'' &ndash; leaf
* ''[[Ilex vomitoria]]'' &ndash; leaf
* ''[[Camellia sinensis]]'' &ndash; leaf

Theobromine can also be found in trace amounts in the [[kola nut]], the [[guarana]] berry, [[yerba mate]] (''[[Ilex paraguariensis]]''),<ref>{{cite journal | vauthors = Schuster J, Mitchell ES | title = More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 89 | pages = 263–274 | date = March 2019 | pmid = 30213684 | doi = 10.1016/j.pnpbp.2018.09.005 | s2cid = 52274913 | doi-access = free }}</ref> and the [[Camellia sinensis|tea plant]].<ref name="culthistplants">{{cite book | vauthors = Prance G, Nesbitt M | title=The Cultural History of Plants | publisher=Routledge | year=2004 | location=New York | pages=137, 175, 178–180 | isbn = 978-0-415-92746-8}}</ref>

The mean theobromine concentrations in cocoa and [[carob]] products are:<ref>{{cite web |title=FoodData Central |url=https://fdc.nal.usda.gov/fdc-app.html#/food-details/169593/nutrients |website=fdc.nal.usda.gov}}</ref><ref name=Craig1984>{{cite journal| vauthors = Craig WJ, Nguyen TT | year = 1984| title = Caffeine and theobromine levels in cocoa and carob products| journal = [[Journal of Food Science]]| volume = 49| issue = 1| pages = 302–303| doi = 10.1111/j.1365-2621.1984.tb13737.x| quote = Mean theobromine and caffeine levels respectively, were 0.695 mg/g and 0.071 mg/g in cocoa cereals; 1.47 mg/g and 0.152 mg/g in chocolate bakery products; 1.95 mg/g and 0.138 mg/g in chocolate toppings; 2.66 mg/g and 0.208 mg/g in cocoa beverages; 0.621 mg/g and 0.032 mg/g in chocolate ice creams; 0.226 mg/g and 0.011 mg/g in chocolate milks; 74.8 mg/serving and 6.5 mg/serving in chocolate puddings.... Theobromine and caffeine levels in carob products ranged from 0–0.504 mg/g and 0-0.067 mg/g, respectively.}}</ref>

{| class="wikitable"
|+
! Item
! Mean theobromine per 100 g
|-
| [[Cocoa powder]]
| 2060&nbsp;mg<!--To verify this claim, see Table 1 in the reference-->
|-
| [[Cocoa (beverage)|Cocoa beverages]]
| 266&nbsp;mg
|-
| Chocolate toppings
| 195&nbsp;mg
|-
| Chocolate bakery products
| 147&nbsp;mg
|-
| Cocoa cereals
| 69.5&nbsp;mg
|-
| [[Chocolate ice cream]]s
| 62.1&nbsp;mg
|-
| [[Chocolate milk]]s
| 22.6&nbsp;mg
|-
| [[Carob]] products
| 0.00–50.4&nbsp;mg
|}

===Biosynthesis===
Theobromine is a purine alkaloid derived from [[xanthosine]], a [[nucleoside]].  Cleavage of the ribose and N-methylation yields 7-methylxanthosine.  7-Methylxanthosine in turn is the precursor to theobromine, which in turn is the precursor to [[caffeine]].<ref>{{cite book | vauthors = Ashihara H, Yokota T, Crozier A | title = New Light on Alkaloid Biosynthesis and Future Prospects | year = 2013 | chapter = Biosynthesis and catabolism of purine alkaloids | journal = Advances in Botanical Research | volume = 68 | pages = 111–138 | doi = 10.1016/B978-0-12-408061-4.00004-3 |isbn=9780124080614 }}</ref>

==Pharmacology==
[[File:Caffeine metabolites.svg|class=skin-invert-image|thumb|250px|Caffeine is metabolized in the liver into three primary metabolites:
[[paraxanthine]] (84%), theobromine (12%), and [[theophylline]] (4%){{Citation needed|date=August 2019}}|alt=A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.]]
Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of [[caffeine]], which is [[metabolism|metabolised]] in the liver into 12% theobromine, 4% [[theophylline]], and 84% [[paraxanthine]].<ref name="pharmgkb">{{cite web | title = Caffeine | publisher = The Pharmacogenetics and Pharmacogenomics Knowledge Base | url = http://www.pharmgkb.org/do/serve?objId=PA448710&objCls=Drug#tabview=tab1 | access-date = 2011-01-08 | archive-date = 2010-11-24 | archive-url = https://web.archive.org/web/20101124155701/http://www.pharmgkb.org/do/serve?objId=PA448710&objCls=Drug#tabview=tab1 | url-status = dead }}</ref>

In the liver, theobromine is metabolized into [[xanthine]] and subsequently into [[methyluric acid]].<ref>{{cite journal | vauthors = Cornish HH, Christman AA | title = A study of the metabolism of theobromine, theophylline, and caffeine in man | journal = The Journal of Biological Chemistry | volume = 228 | issue = 1 | pages = 315–323 | date = September 1957 | doi = 10.1016/S0021-9258(18)70714-X | pmid = 13475320 | doi-access = free }}</ref> Important enzymes include [[CYP1A2]] and [[CYP2E1]].<ref>{{cite journal | vauthors = Gates S, Miners JO | title = Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism | journal = British Journal of Clinical Pharmacology | volume = 47 | issue = 3 | pages = 299–305 | date = March 1999 | pmid = 10215755 | pmc = 2014222 | doi = 10.1046/j.1365-2125.1999.00890.x }}</ref> The elimination half life of theobromine is between 6 and 8 hours.<ref name="halflife1" /><ref name="halflife2" />

Unlike caffeine, which is highly water-soluble, theobromine is only slightly water-soluble and is more fat soluble, and thus peaks more slowly in the blood. While caffeine peaks after only 30 minutes, theobromine requires 2–3 hours to peak.<ref>{{cite journal | vauthors = Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR | title = Absorption rate of methylxanthines following capsules, cola and chocolate | journal = European Journal of Clinical Pharmacology | volume = 51 | issue = 3–4 | pages = 319–325 | date = 1 December 1996 | pmid = 9010706 | doi = 10.1007/s002280050205 | s2cid = 8405909 }}</ref>

The primary mechanism of action for theobromine inside the body is inhibition of [[adenosine]] receptors.<ref name=Hbk/>  Its effect as a [[phosphodiesterase inhibitor]]<ref name="PDEs-Essayan">{{cite journal | vauthors = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = The Journal of Allergy and Clinical Immunology | volume = 108 | issue = 5 | pages = 671–680 | date = November 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 | doi-access = free }}</ref> is thought to be small.<ref name=Hbk/>

==Effects==
{{see also|Theobromine poisoning}}

===Humans===
Theobromine is a heart stimulator and [[diuretic]] but has no significant stimulant effect on the human central nervous system.<ref name=pubchem/> It is a [[bronchodilator]] and causes relaxation of [[vascular smooth muscle]].<ref name=pubchem/> It is available as a [[prescription drug]] in South Korea.<ref>{{cite web|url=https://www.health.kr/searchDrug/result_drug.asp?drug_cd=A11AKP08G4675|title=Anycough Cap 300mg|publisher=Korea Pharmaceutical Information Center|access-date=8 January 2025|archive-date=8 August 2024|archive-url=https://web.archive.org/web/20240808134400/https://www.health.kr/searchDrug/result_drug.asp?drug_cd=A11AKP08G4675|url-status=live}}</ref> The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans.

Compared with caffeine, theobromine is weaker in both its inhibition of [[cyclic nucleotide]] [[phosphodiesterases]] and its [[Receptor antagonist|antagonism]] of [[adenosine receptors]].<ref name=pubchem/><ref name="therapeutics">{{cite book | veditors = Hardman J, Limbird L | title=Goodman & Gilman's the pharmacological basis of therapeutics, 10th ed. | publisher=McGraw-Hill | location=New York | year=2001 | page=745 | isbn=978-0-07-135469-1}}</ref> The potential [[phosphodiesterase inhibitor]]y effect of theobromine is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate.<ref>{{cite web|url=https://www.drugbank.ca/drugs/DB01412|title=Theobromine|publisher=DrugBank.ca|access-date=3 November 2018|archive-date=13 November 2018|archive-url=https://web.archive.org/web/20181113075732/https://www.drugbank.ca/drugs/DB01412|url-status=dead}}</ref>

====Toxicity====
At doses of 0.8–1.5 g/day (50–100 g cocoa), sweating, trembling and severe headaches were noted, with limited mood effects found at 250&nbsp;mg/day.<ref>{{cite web|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb%3A%40term+%40DOCNO+7332#permalink|title=3,7-Dimethylxanthine (Theobromine)|publisher=Toxnet, US National Library of Medicine|date=1 December 2017|access-date=13 November 2018|archive-date=7 October 2018|archive-url=https://web.archive.org/web/20181007145619/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+7332#permalink|url-status=live}}</ref>

Also, chocolate may be a factor for [[heartburn]] in some people because theobromine may affect the [[Lower esophageal sphincter|esophageal sphincter]] muscle in a way that permits stomach acids to enter the [[esophagus]].<ref name="Latif">{{cite journal | vauthors = Latif R | title = Chocolate/cocoa and human health: a review | journal = The Netherlands Journal of Medicine | volume = 71 | issue = 2 | pages = 63–68 | date = March 2013 | pmid = 23462053 | url = http://www.njmonline.nl/getpdf.php?id=1269 }}</ref>

===Animals===
Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that [[metabolize]] theobromine (found in chocolate) more slowly<ref>{{cite web|url=http://www.merckmanuals.com/vet/toxicology/food_hazards/chocolate.html|title=Chocolate – Toxicology – Merck Veterinary Manual|access-date=23 December 2017|archive-date=12 July 2014|archive-url=https://web.archive.org/web/20140712005049/http://www.merckmanuals.com/vet/toxicology/food_hazards/chocolate.html|url-status=live}}</ref> can succumb to theobromine poisoning from as little as {{cvt|50|g|oz}} of [[milk chocolate]] for a smaller dog and {{cvt|400|g|oz}}, or around nine {{convert|1.55|oz|order=flip|adj=on}} small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (about {{cvt|10|g/kg}}) is up to 10 times that of milk chocolate ({{cvt|1|to|5|g/kg}}), meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate.{{Cn|date=May 2024}}

The [[median lethal dose]] of theobromine for dogs is {{cvt|100|–|200|mg/kg|}}; therefore, a {{cvt|10|kg|}} dog would need to consume a minimum of {{cvt|200|g|}} of the most theobromine-rich ({{cvt|5|g/kg|}}) dark chocolate, or a maximum of {{cvt|1|kg|}} (of theobromine-rich milk chocolate), to have a 50% chance of receiving a lethal dose. However, even {{cvt|40|g|}} of milk chocolate may induce vomiting and diarrhea.<ref>{{cite web |last1=Gwaltney-Brant |first1=Sharon |title=Chocolate Toxicosis in Animals |url=https://www.merckvetmanual.com/toxicology/food-hazards/chocolate-toxicosis-in-animals |website=Merck Veterinary Manual |publisher=Merck & Co., Inc. |access-date=24 December 2023}}</ref>

The same risk is reported for cats as well,<ref>{{cite web |url=http://aspcapro.org/sites/pro/files/m-toxbrief_0201_0.pdf |title=Chocolate intoxication |vauthors=Gwaltney-Brant S |publisher=[[American Society for the Prevention of Cruelty to Animals|ASPCA]] |website=aspcapro.org |access-date=23 December 2017 |archive-date=8 February 2017 |archive-url=https://web.archive.org/web/20170208145634/http://aspcapro.org/sites/pro/files/m-toxbrief_0201_0.pdf |url-status=dead}}</ref> although cats are less likely to ingest sweet food, as cats lack [[Sweetness#The sweetness receptor|sweet taste receptors]].<ref name=wired>{{cite magazine |url=https://wired.com/2013/02/the-poisonous-nature-of-chocolate |title=The Poisonous Chemistry of Chocolate |date=14 February 2013 |magazine=[[Wired (magazine)|Wired]] |access-date=12 March 2017 |archive-date=8 February 2017 |archive-url=https://web.archive.org/web/20170208145832/https://www.wired.com/2013/02/the-poisonous-nature-of-chocolate/ |url-status=live}}</ref> Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include [[epilepsy|epileptic]]-like [[seizure]]s and death. If caught early on, theobromine poisoning is treatable.<ref name="healthwatchcanines">{{cite news | title=HEALTH WATCH: How to Avoid a Canine Chocolate Catastrophe! | newspaper=The News Letter | location=Belfast, Northern Ireland | date=2005-03-01}}</ref> Although not common, the effects of theobromine poisoning can be fatal.<ref name="wired" />

== See also ==
* [[History of chocolate]]
* [[Theodrenaline]]

== References ==
{{Reflist}}

{{Commons category|Theobromine}}
{{Chocolate}}
{{Diuretics}}
{{Asthma and copd rx}}
{{Adenosinergics}}
{{Phosphodiesterase inhibitors}}

[[Category:Adenosine receptor antagonists]]
[[Category:Bitter compounds]]
[[Category:Components of chocolate]]
[[Category:IARC Group 3 carcinogens]]
[[Category:Phosphodiesterase inhibitors]]
[[Category:Xanthines]]
[[Category:Human drug metabolites]]