Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

sympathomimetic Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in hea ...

effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...

s (MAOIs).

Occurrence

Tyramine occurs widely in plants and animals, and is metabolized by various enzymes, including

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...

s. In foods, it often is produced by the

decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...

of tyrosine during

fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...

or decay. Foods that are fermented, cured, pickled, aged, or spoiled have high amounts of tyramine. Tyramine levels go up when foods are at room temperature or go past their freshness date. Specific foods containing considerable amounts of tyramine include: * strong or aged cheeses: cheddar, Swiss, Parmesan; Stilton, Gorgonzola or blue cheeses; Camembert, feta, Muenster. * meats that are cured, smoked, or processed, such as salami, pepperoni, dry sausages, hot dogs, bologna, bacon, corned beef, pickled or smoked fish, caviar, aged chicken livers, soups or gravies made from meat extract. * pickled or fermented foods: sauerkraut, kimchi, tofu (especially stinky tofu), pickles, miso soup, bean curd, tempeh, sourdough breads * condiments: soy, shrimp, fish, miso, teriyaki, and bouillon-based sauces. * drinks: beer (especially tap or home-brewed), vermouth, red wine, sherry, liqueurs. * beans, vegetables, and fruits: fermented or pickled vegetables, overripe fruits. * chocolate Scientists more and more consider tyramine in food as an aspect of safety. They propose projects of regulations aimed to enact control of biogenic amines in food by various strategies, including usage of proper fermentation starters, or preventing their decarboxylase activity. Some authors wrote that this has already given positive results, and tyramine content in food is now lower than it has been in the past.

In plants

Mistletoe Mistletoe is the common name for obligate hemiparasitic plants in the order Santalales. They are attached to their host tree or shrub by a structure called the haustorium, through which they extract water and nutrients from the host plant. ...

(toxic and not used by humans as a food, but historically used as a medicine).

In animals

Tyramine also plays a role in animals including: In

behavior Behavior (American English) or behaviour (British English) is the range of actions and mannerisms made by individuals, organisms, systems or artificial entities in some environment. These systems can include other systems or organisms as wel ...

al and motor functions in ''

Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...

''; '' Locusta migratoria''

swarming behaviour Swarm behaviour, or swarming, is a collective behaviour exhibited by entities, particularly animals, of similar size which aggregate together, perhaps milling about the same spot or perhaps moving ''en masse'' or migrating in some direction. ...

; and various nervous roles in '' Rhipicephalus'', ''

Apis Apis or APIS may refer to: * Apis (deity), an ancient Egyptian god * Apis (Greek mythology), several different figures in Greek mythology * Apis (city), an ancient seaport town on the northern coast of Africa **Kom el-Hisn, a different Egyptian ci ...

'', '' Locusta'', '' Periplaneta'', '' Drosophila'', '' Phormia'', '' Papilio'', '' Bombyx'', '' Chilo'', '' Heliothis'', ''

Mamestra ''Mamestra'' is a genus of moths of the family Noctuidae described by Ochsenheimer in 1816. Perhaps the best known species is the cabbage moth, ''M. brassicae''. Species * ''Mamestra brassicae'' (Linnaeus, 1758) * ''Mamestra configurata'' Walker, ...

'', '' Agrotis'', and '' Anopheles''.

Physical effects and pharmacology

Evidence for the presence of tyramine in the human brain has been confirmed by postmortem analysis. Additionally, the possibility that tyramine acts directly as a neuromodulator was revealed by the discovery of a G protein-coupled receptor with high affinity for tyramine, called TAAR1. The TAAR1 receptor is found in the brain, as well as peripheral tissues, including the kidneys. Tyramine binds to TAAR1 as an agonist in humans. Tyramine is physiologically metabolized by

s (primarily MAO-A), FMO3,

PNMT Phenylethanolamine ''N''-methyltransferase (PNMT) is an enzyme found primarily in the adrenal medulla that converts norepinephrine (noradrenaline) to epinephrine (adrenaline). It is also expressed in small groups of neurons in the human brain and ...

, DBH, and CYP2D6.
Table 5: N-containing drugs and xenobiotics oxygenated by FMO
/ref> Human monoamine oxidase enzymes metabolize tyramine into

4-hydroxyphenylacetaldehyde 4-Hydroxyphenylacetaldehyde, also known as ''p''-hydroxyphenylacetaldehyde, is a natural product with the formula HOC6H4CH2CHO. It is a derivative of phenylacetaldehyde and occurs as a white solid at room temperature. Synthesis 4-Hydroxyphenyla ...

. If monoamine metabolism is compromised by the use of

s (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result, as tyramine also can displace stored monoamines, such as

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

, norepinephrine, and

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...

, from pre- synaptic vesicles. Tyramine is considered a "

false neurotransmitter A false neurotransmitter is a chemical compound which closely imitates the action of a neurotransmitter in the nervous system. Examples include 5-MeO-αMT (mimicking serotonin) and α-methyldopa. These chemicals can be accumulated by a neuron or s ...

", as it enters noradrenergic nerve terminals and displaces large amounts of norepinephrine, which enters the blood stream and causes vasoconstriction. Additionally, cocaine has been found to block blood pressure rise that is originally attributed to tyramine, which is explained by the blocking of adrenaline by cocaine from reabsorption to the brain. The first signs of this effect were discovered by a British pharmacist who noticed that his wife, who at the time was on MAOI medication, had severe headaches when eating cheese. For this reason, it is still called the "cheese effect" or "cheese crisis," although other foods can cause the same problem. Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do. A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30

mmHg A millimetre of mercury is a manometric unit of pressure, formerly defined as the extra pressure generated by a column of mercury one millimetre high, and currently defined as exactly pascals. It is denoted mmHg or mm Hg. Although not an SI ...

or more. The increased release of norepinephrine (noradrenaline) from neuronal cytosol or storage vesicles is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases,

adrenergic crisis An adrenergic storm is a sudden and dramatic increase in serum (blood), serum levels of the catecholamines adrenaline and noradrenaline (also known as epinephrine and norepinephrine respectively), with a less significant increase in dopamine trans ...

can occur. Although the mechanism is unclear, tyramine ingestion also triggers migraine attacks in sensitive individuals and can even lead to stroke. Vasodilation, dopamine, and circulatory factors are all implicated in the migraines. Double-blind trials suggest that the effects of tyramine on migraine may be adrenergic. Research reveals a possible link between

migraines Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

and elevated levels of tyramine. A 2007 review published in Neurological Sciences presented data showing migraine and cluster diseases are characterized by an increase of circulating neurotransmitters and neuromodulators (including tyramine, octopamine, and synephrine) in the hypothalamus, amygdala, and dopaminergic system. People with migraine are over-represented among those with inadequate natural monoamine oxidase, resulting in similar problems to individuals taking MAO inhibitors. Many migraine attack triggers are high in tyramine. If one has had repeated exposure to tyramine, however, there is a decreased pressor response; tyramine is degraded to octopamine, which is subsequently packaged in synaptic vesicles with norepinephrine (noradrenaline). Therefore, after repeated tyramine exposure, these vesicles contain an increased amount of octopamine and a relatively reduced amount of norepinephrine. When these vesicles are secreted upon tyramine ingestion, there is a decreased pressor response, as less norepinephrine is secreted into the

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

, and octopamine does not activate alpha or beta adrenergic receptors. When using a MAO inhibitor (MAOI), an intake of approximately 10 to 25 mg of tyramine is required for a severe reaction, compared to 6 to 10 mg for a mild reaction. The body can reduce tyramine formation by trypsin and chymotrypsin, digestive enzymes in the pancreas.

Biosynthesis

Biochemically, tyramine is produced by the

of tyrosine via the action of the enzyme

tyrosine decarboxylase The enzyme tyrosine decarboxylase () catalyzes the chemical reaction :L-tyrosine \rightleftharpoons tyramine + CO2 Hence, this enzyme has one substrate, L-tyrosine, and two products, tyramine and carbon dioxide. This enzyme belongs to the fam ...

. Tyramine can, in turn, be converted to methylated alkaloid derivatives ''N''-methyltyramine, ''N'',''N''-dimethyltyramine (hordenine), and ''N'',''N'',''N''-trimethyltyramine (candicine). File:Tyramine.svg, Tyramine File:Methyltyramine.svg, ''N''-Methyltyramine File:Dimethyltyramine.svg, ''N'',''N''-Dimethyltyramine (hordenine) File:Candicine.svg, ''N'',''N'',''N''-Trimethyltyramine (candicine) In humans, tyramine is produced from tyrosine, as shown in the following diagram.

Chemistry

In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine. Tyramine synthesis

Legal status

United States

Tyramine is not scheduled at the federal level in the United States and is therefore legal to buy, sell, or possess.§1308.11 Schedule I
/ref>

Status in Florida

Tyramine is a Schedule I controlled substance, categorized as a hallucinogen, making it illegal to buy, sell, or possess in the state of Florida without a license at any purity level or any form whatsoever. The language in the Florida

statute A statute is a formal written enactment of a legislative authority that governs the legal entities of a city, state, or country by way of consent. Typically, statutes command or prohibit something, or declare policy. Statutes are rules made by le ...

says tyramine is illegal in "any material, compound, mixture, or preparation that contains any quantity of yramineor that contains any of ts salts, isomers, including optical, positional, or geometric isomers, and salts of isomers, if the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation." This ban is likely the product of lawmakers overly eager to ban substituted phenethylamines, which tyramine is, in the mistaken belief that ring-substituted phenethylamines are hallucinogenic drugs like the 2C series of

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science of ...

substituted phenethylamines. The further banning of tyramine's

optical isomers In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are d ...

, positional isomers, or geometric isomers, and salts of isomers where they exist, means that meta-tyramine and

phenylethanolamine Phenylethanolamine (sometimes abbreviated PEOH), or β-hydroxyphenethylamine, is a trace amine with a structure similar to those of other trace phenethylamines as well as the catecholamine neurotransmitters dopamine, norepinephrine, and epinep ...

, a substance found in every living human body, and other common, non-hallucinogenic substances are also illegal to buy, sell, or possess in Florida. Given that tyramine occurs naturally in many foods and drinks (most commonly as a by-product of bacterial fermentation), e.g. wine, cheese, and chocolate, Florida's total ban on the substance may prove difficult to enforce.

Notes

References

{{Phenethylamines Migraine Monoamine oxidase inhibitors Norepinephrine-dopamine releasing agents Peripherally selective drugs Phenethylamine alkaloids Phenethylamines TAAR1 agonists Trace amines