Theobromine, also known as xantheose, is the principal

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

of ''

Theobroma cacao ''Theobroma cacao'', also called the cacao tree and the cocoa tree, is a small ( tall) evergreen tree in the family Malvaceae. Its seeds, cocoa beans, are used to make chocolate liquor, cocoa solids, cocoa butter and chocolate. The largest pro ...

'' (cacao plant). Theobromine is slightly water-

soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubil ...

(330 mg/L) with a bitter taste. In industry, theobromine is used as an

additive Additive may refer to: Mathematics * Additive function, a function in number theory * Additive map, a function that preserves the addition operation * Additive set-functionn see Sigma additivity * Additive category, a preadditive category with f ...

and precursor to some

cosmetics Cosmetics are constituted mixtures of chemical compounds derived from either natural sources, or synthetically created ones. Cosmetics have various purposes. Those designed for personal care and skin care can be used to cleanse or protect ...

. It is found in

chocolate Chocolate is a food made from roasted and ground cacao seed kernels that is available as a liquid, solid, or paste, either on its own or as a flavoring agent in other foods. Cacao has been consumed in some form since at least the Olmec civ ...

, as well as in a number of other foods, including the leaves of the

tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of '' Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of southwestern China and northe ...

plant, and the

kola nut The term kola nut usually refers to the seeds of certain species of plant of the genus ''Cola'', placed formerly in the cocoa family Sterculiaceae and now usually subsumed in the mallow family Malvaceae (as subfamily Sterculioideae). These cola ...

. It is a white or colourless solid, but commercial samples can appear yellowish.

Structure

Theobromine is a flat molecule, a derivative of

purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...

. It is also classified as a di

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base (genetics), base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, incl ...

. Related compounds include

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...

paraxanthine Paraxanthine, or 1,7-dimethylxanthine, is a dimethyl derivative of xanthine, structurally related to caffeine. Production and metabolism Paraxanthine is not known to be produced by plants but is observed in nature as a metabolite of caffeine in a ...

, and 7-methylxanthine, each of which differ in the number or placement of the methyl groups.

History

Theobromine was first discovered in 1841 in cacao beans by Russian chemist

Aleksandr Voskresensky Aleksandr Abramovich Voskresensky (Russian: Александр Абрамович Воскресенский; 25 November 1808 – 21 January 1880) was a Russian chemist who served as rector of Saint Petersburg Imperial University in 1861–1863 ...

. Synthesis of theobromine from

was first reported in 1882 by

Hermann Emil Fischer Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of dra ...

Etymology

''Theobromine'' is derived from ''

Theobroma ''Theobroma'' is a genus of flowering plants in the mallow family, Malvaceae, that is sometimes classified as a member of Sterculiaceae. It contains roughly 20 species of small understory trees native to the tropical forests of Central and So ...

'', the name of the

genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...

of the cacao tree, with the suffix ''-ine'' given to alkaloids and other

basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...

nitrogen-containing compounds. That name in turn is made up of the

Greek Greek may refer to: Greece Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group. *Greek language, a branch of the Indo-European language family. **Proto-Greek language, the assumed last common ancestor ...

roots ''theo'' ("

god In monotheism, monotheistic thought, God is usually viewed as the supreme being, creator deity, creator, and principal object of Faith#Religious views, faith.Richard Swinburne, Swinburne, R.G. "God" in Ted Honderich, Honderich, Ted. (ed)''The Ox ...

") and ''broma'' ("food"), meaning "food of the gods". (note: the book incorrectly states that the name "theobroma" is derived from Latin) Despite its name, the compound contains no

bromine Bromine is a chemical element with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table (halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simila ...

Sources

Theobromine is the primary alkaloid found in

cocoa Cocoa may refer to: Chocolate * Chocolate * ''Theobroma cacao'', the cocoa tree * Cocoa bean, seed of ''Theobroma cacao'' * Chocolate liquor, or cocoa liquor, pure, liquid chocolate extracted from the cocoa bean, including both cocoa butter and ...

and

. Cocoa butter only contains trace amounts of theobromine. There are usually higher concentrations in dark than in milk chocolate. There are approximately of theobromine in of milk chocolate, while the same amount of dark chocolate contains about . Cocoa beans naturally contain approximately 1% theobromine. Plant species and components with substantial amounts of theobromine are: * ''

'' – seed and

seed coat A seed is an embryonic plant enclosed in a protective outer covering, along with a food reserve. The formation of the seed is a part of the process of reproduction in seed plants, the spermatophytes, including the gymnosperm and angiosperm p ...

* ''

Theobroma bicolor ''Theobroma bicolor'', known commonly as the mocambo tree, jaguar tree, balamte, or pataxte, among various other common names, is a tree in the genus ''Theobroma'' (family Malvaceae), which also contains the better-known ''Theobroma cacao'' (coco ...

'' – seed coat * ''

Ilex paraguariensis ''Ilex'' (), or holly, is a genus of over 570 species of flowering plants in the family Aquifoliaceae, and the only living genus in that family. ''Ilex'' has the most species of any woody dioecious angiosperm genus. The species are evergreen o ...

'' – leaf * ''

Camellia sinensis ''Camellia sinensis'' is a species of evergreen shrub or small tree in the flowering plant family Theaceae. Its leaves and leaf buds are used to produce the popular beverage, tea. Common names include tea plant, tea shrub, and tea tree (not to ...

'' – leaf Theobromine can also be found in trace amounts in the

, the

guarana Guaraná ( from the Portuguese ''guaraná'' ), ''Paullinia cupana'', syns. ''P. crysan, P. sorbilis'') is a climbing plant in the family Sapindaceae, native to the Amazon basin and especially common in Brazil. Guaraná has large leaves and cl ...

berry,

yerba mate Yerba mate or yerba-maté (''Ilex paraguariensis''; from Spanish ; pt, erva-mate, or ; gn, ka'a, ) is a plant species of the holly genus ''Ilex'' native to South America. It was named by the French botanist Augustin Saint-Hilaire. The leave ...

( ''Ilex paraguariensis''), ''

Ilex vomitoria ''Ilex vomitoria'', commonly known as yaupon () or yaupon holly, is a species of holly that is native to southeastern North America. The word ''yaupon'' was derived from the Catawban ''yą́pą'', from ''yą-'' tree + ''pą'' leaf. Another comm ...

'', ''

Ilex guayusa ''Ilex guayusa'' ( or ) is a species of tree of the holly genus, native to the Amazon Rainforest. One of four known caffeinated holly trees, the leaves of the guayusa tree are harvested fresh and brewed like a tea for their stimulative effects. ...

'', and the tea plant. The mean theobromine concentrations in cocoa and

carob The carob ( ; ''Ceratonia siliqua'') is a flowering evergreen tree or shrub in the Caesalpinioideae sub-family of the legume family, Fabaceae. It is widely cultivated for its edible fruit pods, and as an ornamental tree in gardens and landscap ...

products are:

Biosynthesis

Theobromine is a purine alkaloid derived from

xanthosine Xanthosine is a nucleoside derived from xanthine and ribose. It is the biosynthetic precursor to 7-methylxanthosine by the action of 7-methylxanthosine synthase. 7-Methylxanthosine in turn is the precursor to theobromine (active alkaloid in cho ...

, a

nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...

. 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

Pharmacology

Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of

, which is metabolised in the liver into 12% theobromine, 4%

, and 84%

. In the liver, theobromine is metabolized into

and subsequently into methyluric acid. Important enzymes include

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

and

CYP2E1 Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, includ ...

. The elimination half life of theobromine is between 6 to 8 hours. 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. "The main mechanism of action for methylxanthines has long been established as an inhibition of adenosine receptors". Its effect as a

phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cycli ...

is thought to be small.

Effects

Humans

Theobromine has no significant stimulant effect on the human central nervous system. It is a

bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lun ...

and causes relaxation of

vascular smooth muscle Vascular smooth muscle is the type of smooth muscle that makes up most of the walls of blood vessels. Structure Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood ...

. It is not currently used as a

prescription drug A prescription drug (also prescription medication or prescription medicine) is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription. The rea ...

. The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. Theobromine and

are similar in that they are related alkaloids. Theobromine is weaker in both its inhibition of

cyclic nucleotide A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, a ...

phosphodiesterases A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...

and its antagonism of

adenosine receptors The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a ...

. The potential

y effect of theobromine is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate.

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 mg/day. Also, chocolate may be a factor for

heartburn Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the m ...

in some people because theobromine may affect the esophageal sphincter muscle in a way that permits stomach acids to enter the

esophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...

Animals

Theobromine is the reason chocolate is poisonous to dogs. Dogs and other animals that

metabolize Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

theobromine (found in chocolate) more slowly can succumb to theobromine poisoning from as little as of

milk chocolate Milk chocolate is a solid chocolate confectionery containing cocoa, sugar and milk. Chocolate was originally sold and consumed as a beverage in pre-Columbian times, and upon its introduction to Western Europe. Major milk chocolate producers incl ...

for a smaller dog and , or around nine small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (approximately ) is up to 10 times that of milk chocolate () – meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate. The same risk is reported for cats as well, although cats are less likely to ingest sweet food, with most cats having no sweet taste receptors. Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include

epileptic Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

-like

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s and death. If caught early on, theobromine poisoning is treatable. Although not common, the effects of theobromine poisoning can be fatal.

References

{{Phosphodiesterase inhibitors Adenosine receptor antagonists Bitter compounds Components of chocolate IARC Group 3 carcinogens Phosphodiesterase inhibitors Xanthines