Tyramine

{{Short description|Chemical compound}} {{distinguish|Amphetamine{{!}}thyramine}} {{Use dmy dates|date=March 2014}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | verifiedrevid = | image = Tyramine structure.svg | image_class = skin-invert-image | width = 250px | caption = Skeletal formula of tyramine | image2 = Tyramine_3D_ball.png | image_class2 = bg-transparent | caption2 = Ball-and-stick model of the neutral (non-zwitterionic) form of tyramine found in the crystal structure<ref>{{ cite journal | title = Tautomeric and ionisation forms of dopamine and tyramine in the solid state | vauthors = Cruickshank L, Kennedy AR, Shankland N | journal = J. Mol. Struct. | volume = 1051 | pages = 132–136 | year = 2013 | doi = 10.1016/j.molstruc.2013.08.002 | bibcode = 2013JMoSt1051..132C }}</ref>

| pronounce = {{IPAc-en|ˈ|t|aɪ|r|ə|m|iː|n}} {{respell|TY|rə|meen}} | tradename = | Drugs.com = | MedlinePlus = | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_US =  | pregnancy_category = | routes_of_administration =  | legal_AU =  | legal_AU_comment = | legal_CA =  | legal_DE =  | legal_NZ =  | legal_UK =  | legal_US =  | legal_UN =  | legal_status =  | bioavailability = | protein_bound = | metabolism = CYP2D6, flavin-containing monooxygenase 3, monoamine oxidase A, monoamine oxidase B, phenylethanolamine ''N''-methyltransferase, dopamine β-hydroxylase, others | metabolites = 4-Hydroxyphenylacetaldehyde, dopamine, ''N''-methyltyramine, octopamine | onset = | elimination_half-life = | duration_of_action = | excretion =  | CAS_number = 51-67-2 | CAS_number_Ref = {{cascite|correct|CAS}} | ATC_prefix = none | ATC_suffix = | PubChem = 5610 | DrugBank = | IUPHAR_ligand = 2150 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5408 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = X8ZC7V0OX3 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C00483 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 11608 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 15760 | synonyms = Tyramin; 4-Hydroxyphenethylamine; ''para''-Tyramine; ''p''-Tyramine; 4-Tyramine; Mydrial; Uteramin

| IUPAC_name = 4-(2-aminoethyl)phenol | C = 8 | H = 11 | N = 1 | O = 1 | SMILES = Oc1ccc(cc1)CCN | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C8H11NO/c9-6-5-7-1-3-8(10)4-2-7/h1-4,10H,5-6,9H2 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = DZGWFCGJZKJUFP-UHFFFAOYSA-N

| density = 1.103 | density_notes = predicted<ref>SciFinder, Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2021 ACD/Labs)</ref> | boiling_point = 206 | boiling_notes = at 25 mmHg; 166 °C at 2 mmHg<ref name = Merck/> | melting_point = 164.5 | melting_notes = <ref name = Merck>The Merck Index, 10th Ed. (1983), p. 1405, Rahway: Merck & Co.</ref> }}

'''Tyramine''' ({{IPAc-en|ˈ|t|aɪ|r|ə|m|iː|n}} {{respell|TY|rə|meen}}) (also spelled '''tyramin'''), also known under several other names,{{#tag:ref|Synonyms and alternative names include: '''4-hydroxyphenethylamine''', '''para-tyramine''', '''mydrial''', and '''uteramin'''; the latter two names are not commonly used. The IUPAC name is {{nowrap|4-(2-aminoethyl)phenol}}.|group="note"}} is a naturally occurring trace amine derived from the amino acid tyrosine.<ref name="pubchem">{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/5610|title=tyramine {{!}} C8H11NO|website=PubChem|language=en|access-date=2017-04-08}}</ref> Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

==Occurrence== Tyramine occurs widely in plants<ref>T. A. Smith (1977) ''Phytochemistry'' '''16''' 9–18.</ref> and animals, and is metabolized by various enzymes, including monoamine oxidases. In foods, it often is produced by the decarboxylation of tyrosine during fermentation 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:<ref>{{cite web | vauthors = Hall-Flavin DK |title=Avoid the combination of high-tyramine foods and MAOIs |url=https://www.mayoclinic.org/diseases-conditions/depression/expert-answers/maois/faq-20058035 |website=Mayo Clinic |language=en |date=18 December 2018}}</ref><ref>{{cite web | vauthors = Robinson J |title=Tyramine-Rich Foods As A Migraine Trigger & Low Tyramine Diet |url=https://www.webmd.com/migraines-headaches/tyramine-and-migraines |website=WebMD |language=en |date=21 June 2020}}</ref>

* 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<ref>{{cite web |title=Tyramine |url=https://pubchem.ncbi.nlm.nih.gov/compound/Tyramine#section=Mechanism-of-Action |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref>

Scientists more and more consider tyramine in food as an aspect of safety.<ref>{{cite journal | vauthors = Martuscelli M, Esposito L, Mastrocola D | title = Biogenic Amines' Content in Safe and Quality Food | journal = Foods | volume = 10 | issue = 1 | page = 100 | date = January 2021 | pmid = 33418895 | pmc = 7825060 | doi = 10.3390/foods10010100 | doi-access = free }}</ref> 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.<ref>{{Cite journal |title=Scientific Opinion on risk based control of biogenic amine formation in fermented foods |journal=EFSA Journal |year=2011 |volume=9 |issue=10 |page=2393 |doi=10.2903/j.efsa.2011.2393 |doi-access=free }}</ref> 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.<ref>{{cite book |doi=10.1016/B978-0-12-386467-3.00009-1 |chapter=Selective inhibitors of monoamine oxidase type B and the "cheese effect" |title=Monoamine Oxidase and their Inhibitors |series=International Review of Neurobiology |year=2011 | vauthors = Finberg JP, Gillman K |volume=100 |pages=169–190 |pmid=21971008 |isbn=978-0-12-386467-3 }}</ref>

===In plants=== Mistletoe (toxic and not used by humans as a food, but historically used as a medicine).<ref>{{cite web |date=19 December 2005 |title=Tyramine |url=https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/tyramine.html |website=American Chemical Society |language=en}}</ref>

===In animals=== Tyramine also plays a role in animals including: In behavioral and motor functions in ''Caenorhabditis elegans'';<ref name="Alkema-Hunter-Ensor-Ringstad-Horvitz-2005" /> ''Locusta migratoria'' swarming behaviour;<ref name="Ma-et-al-2015" /> and various nervous roles in ''Rhipicephalus'', ''Apis'', ''Locusta'', ''Periplaneta'', ''Drosophila'', ''Phormia'', ''Papilio'', ''Bombyx'', ''Chilo'', ''Heliothis'', ''Mamestra'', ''Agrotis'', and ''Anopheles''.<ref name="Ohta-Ozoe-2014" />

==Biological activity== {| class="wikitable floatright" style="font-size:small;" |+ {{Nowrap|Monoamine release of tyramine and related agents ({{Abbrlink|EC<sub>50</sub>|Half maximal effective concentration}}, nM)}} |- ! Compound !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! Ref |- | Phenethylamine || 10.9 || 39.5 || >10,000 || <ref name="ReithBLoughHong2015">{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug and Alcohol Dependence | volume = 147 | issue = | pages = 1–19 | date = February 2015 | pmid = 25548026 | pmc = 4297708 | doi = 10.1016/j.drugalcdep.2014.12.005 }}</ref><ref name="Forsyth2012">{{cite web | last=Forsyth | first=Andrea N | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}</ref><ref name="Blough2008">{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref> |- | Tyramine || 40.6 || 119 || 2,775 || <ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /> |- | Dopamine || 66.2 || 86.9 || >10,000 ({{Abbr|RI|Reuptake inhibitor}}) || <ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /> |- | Norepinephrine || 164 || 869 || >10,000 || <ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /> |- | Tryptamine || 716 || 164 || 32.6 || <ref name="BloughLandavazoDecker2014">{{cite journal | vauthors = Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB | title = Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes | journal = Psychopharmacology | volume = 231 | issue = 21 | pages = 4135–4144 | date = October 2014 | pmid = 24800892 | pmc = 4194234 | doi = 10.1007/s00213-014-3557-7 }}</ref><ref name="BloughLandavazoPartilla2014">{{cite journal | vauthors = Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB | title = Alpha-ethyltryptamines as dual dopamine-serotonin releasers | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 19 | pages = 4754–4758 | date = October 2014 | pmid = 25193229 | pmc = 4211607 | doi = 10.1016/j.bmcl.2014.07.062 }}</ref> |- | Dextroamphetamine || 6.6–7.2 || 5.8–24.8 || 698–1,765 || <ref name="RothmanBaumannDersch2001">{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | url = }}</ref><ref name="BaumannPartillaLehner2013">{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | year = 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref> |- | colspan="5" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. '''Refs:'''<ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = Eur J Pharmacol | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 | url = }}</ref><ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = https://zenodo.org/record/1235860 }}</ref> |}

Tyramine is a norepinephrine and dopamine releasing agent (NDRA) and indirectly acting sympathomimetic.<ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /> Evidence for the presence of tyramine in the human brain has been confirmed by postmortem analysis.<ref>{{cite journal | vauthors = Philips SR, Rozdilsky B, Boulton AA | title = Evidence for the presence of m-tyramine, p-tyramine, tryptamine, and phenylethylamine in the rat brain and several areas of the human brain | journal = Biological Psychiatry | volume = 13 | issue = 1 | pages = 51–7 | date = February 1978 | pmid = 623853 }}</ref> 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 the trace amine-associated receptor (TAAR1).<ref>{{cite journal | vauthors = Navarro HA, Gilmour BP, Lewin AH | title = A rapid functional assay for the human trace amine-associated receptor 1 based on the mobilization of internal calcium | journal = Journal of Biomolecular Screening | volume = 11 | issue = 6 | pages = 688–93 | date = September 2006 | pmid = 16831861 | doi = 10.1177/1087057106289891 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Liberles SD, Buck LB | title = A second class of chemosensory receptors in the olfactory epithelium | journal = Nature | volume = 442 | issue = 7103 | pages = 645–50 | date = August 2006 | pmid = 16878137 | doi = 10.1038/nature05066 | s2cid = 2864195 | bibcode = 2006Natur.442..645L }}</ref> The TAAR1 receptor is found in the brain, as well as peripheral tissues, including the kidneys.<ref>{{cite journal | vauthors = Xie Z, Westmoreland SV, Miller GM | title = Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 325 | issue = 2 | pages = 629–640 | date = May 2008 | pmid = 18310473 | doi = 10.1124/jpet.107.135079 | s2cid = 178180 }}</ref> Tyramine is a full agonist of the TAAR1 in rodents and humans.<ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref><ref name="Human trace amines and hTAARs October 2016 review">{{cite journal | vauthors = Khan MZ, Nawaz W | title = The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system | journal = Biomedicine & Pharmacotherapy | volume = 83 | pages = 439–449 | date = October 2016 | pmid = 27424325 | doi = 10.1016/j.biopha.2016.07.002 }}</ref>

Tyramine is physiologically metabolized by monoamine oxidases (primarily MAO-A), FMO3, PNMT, DBH, and CYP2D6.<ref name="BRENDA FMO3 Homo sapiens">{{cite encyclopedia | title=Trimethylamine monooxygenase (Homo sapiens)| url=http://www.brenda-enzymes.info/enzyme.php?ecno=1.14.13.148&Suchword=&reference=&organism%5B%5D=Homo+sapiens&show_tm=0 | encyclopedia=BRENDA | publisher=Technische Universität Braunschweig | access-date=18 September 2016 | date=July 2016 }}</ref><ref name="FMO">{{cite journal | vauthors = Krueger SK, Williams DE | title = Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism | journal = Pharmacology & Therapeutics | volume = 106 | issue = 3 | pages = 357–87 | date = June 2005 | pmid = 15922018 | pmc = 1828602 | doi = 10.1016/j.pharmthera.2005.01.001 }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]</ref><ref name="Trace amine template 1" /><ref name="Trace amine template 2" /><ref name="CYP2D6 tyramine-dopamine metabolism" /> Human monoamine oxidase enzymes metabolize tyramine into 4-hydroxyphenylacetaldehyde.<ref name="HMDB 4-Hydroxyphenylacetaldehyde">{{cite web |title=4-Hydroxyphenylacetaldehyde |url=http://www.hmdb.ca/metabolites/HMDB0003767 |website=Human Metabolome Database – Version 4.0 |publisher=University of Alberta |access-date=8 August 2019 |date=2019-07-23}}</ref> If monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result, as tyramine also can displace stored monoamines, such as dopamine, norepinephrine, and epinephrine, from pre-synaptic vesicles. Tyramine is considered a "false neurotransmitter", 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.<ref>{{cite news |id={{ProQuest|1346292101}} | vauthors = Bynum W |title=REVIEW --- Books: What Sets Your Heart Pounding |newspaper=Wall Street Journal |date=27 April 2013 |page=C.6 }}</ref>

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.<ref>{{cite journal | vauthors = Sathyanarayana Rao TS, Yeragani VK | title = Hypertensive crisis and cheese | journal = Indian Journal of Psychiatry | volume = 51 | issue = 1 | pages = 65–6 | date = January 2009 | pmid = 19742203 | pmc = 2738414 | doi = 10.4103/0019-5545.44910 | doi-access = free }}</ref> For this reason, it is still called the "cheese reaction" or "cheese crisis", although other foods can cause the same problem.<ref>{{cite web |title=Drugs, The Straight Facts: Antidepressants |pages=30–31 | vauthors = Mitchell ES | veditors = Triggle DJ |publisher=Chelsea House Publishers |url=http://iftandcs.org/Addictions/Drugs%20The%20Straight%20Facts,%20Antidepressants.pdf |archive-url=https://web.archive.org/web/20170214224003/http://iftandcs.org/Addictions/Drugs%20The%20Straight%20Facts,%20Antidepressants.pdf |archive-date=2017-02-14 |date=2004 |access-date=2022-10-06}}</ref>

Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do.<ref>{{cite journal | vauthors = Stahl SM, Felker A | title = Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants | journal = CNS Spectrums | volume = 13 | issue = 10 | pages = 855–870 | date = October 2008 | pmid = 18955941 | doi = 10.1017/S1092852900016965 | s2cid = 6118722 }}</ref><ref>{{cite web | url = http://web.squ.edu.om/med-lib/med_cd/e_cds/Griffith%27s%20Instructions%20Patients/pdf/Pg570.pdf | title = Tyramine-restricted Diet | archive-url = https://web.archive.org/web/20140513145012/http://web.squ.edu.om/med-lib/med_cd/e_cds/Griffith%27s%20Instructions%20Patients/pdf/Pg570.pdf | archive-date = 13 May 2014 | date = 1998 | publisher = W.B. Saunders Company | access-date = 19 April 2013 | url-status = dead }}</ref>

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 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 can occur.{{Medical citation needed|date=April 2013}} Although the mechanism is unclear, tyramine ingestion also triggers migraine attacks in sensitive individuals and can even lead to stroke.<ref>{{Cite encyclopedia|title=Tyramine | encyclopedia = Biochemistry | publisher = Encyclopedia Britannica|url=https://www.britannica.com/science/tyramine|access-date=2021-11-12 |language=en}}</ref> 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.<ref>{{cite journal | vauthors = Ghose K, Coppen A, Carrol D | title = Intravenous tyramine response in migraine before and during treatment with indoramin | journal = British Medical Journal | volume = 1 | issue = 6070 | pages = 1191–3 | date = May 1977 | pmid = 324566 | pmc = 1606859 | doi = 10.1136/bmj.1.6070.1191 }}</ref>

Research reveals a possible link between migraines and elevated levels of tyramine. A 2007 review published in Neurological Sciences<ref>{{cite journal | vauthors = D'Andrea G, Nordera GP, Perini F, Allais G, Granella F | title = Biochemistry of neuromodulation in primary headaches: focus on anomalies of tyrosine metabolism | journal = Neurological Sciences | volume = 28 | issue = S2 | pages = S94-6 | date = May 2007 | pmid = 17508188 | doi = 10.1007/s10072-007-0758-4 | s2cid = 1548732 }}</ref> 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.<ref>{{Cite news|url=http://www.headaches.org/headache-sufferers-diet/|title=Headache Sufferer's Diet {{!}} National Headache Foundation|work=National Headache Foundation|access-date=2017-04-08|language=en-US|archive-url=https://web.archive.org/web/20170702160059/http://www.headaches.org/headache-sufferers-diet|archive-date=2 July 2017}}</ref>

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).{{Citation needed|date=May 2014}} 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, and octopamine does not activate alpha or beta adrenergic receptors.{{Medical citation needed|date=April 2013}}

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.<ref>{{cite journal | vauthors = McCabe BJ | title = Dietary tyramine and other pressor amines in MAOI regimens: a review | journal = Journal of the American Dietetic Association | volume = 86 | issue = 8 | pages = 1059–64 | date = August 1986 | doi = 10.1016/S0002-8223(21)04074-8 | pmid = 3525654 | s2cid = 902921 }}</ref>

Tyramine, like phenethylamine, is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its catecholamine-releasing activity.<ref name="ShimazuMiklya2004">{{cite journal | vauthors = Shimazu S, Miklya I | title = Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 28 | issue = 3 | pages = 421–427 | date = May 2004 | pmid = 15093948 | doi = 10.1016/j.pnpbp.2003.11.016 | s2cid = 37564231 }}</ref><ref name="Knoll2003">{{cite journal | vauthors = Knoll J | title = Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives | journal = Neurochem Res | volume = 28 | issue = 8 | pages = 1275–1297 | date = August 2003 | pmid = 12834268 | doi = 10.1023/a:1024224311289 | url = }}</ref><ref name="KnollMiklyaKnoll1996">{{cite journal | vauthors = Knoll J, Miklya I, Knoll B, Markó R, Rácz D | title = Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain | journal = Life Sci | volume = 58 | issue = 23 | pages = 2101–2114 | date = 1996 | pmid = 8649195 | doi = 10.1016/0024-3205(96)00204-4 | url = }}</ref> That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /><ref name="KnollMiklyaKnoll1996" /> The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /><ref name="KnollMiklyaKnoll1996" /> The MAE actions of tyramine and other MAEs may be mediated by TAAR1 agonism.<ref name="HarsingKnollMiklya2022">{{cite journal | vauthors = Harsing LG, Knoll J, Miklya I | title = Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum | journal = Int J Mol Sci | volume = 23 | issue = 15 | date = August 2022 | page = 8543 | pmid = 35955676 | pmc = 9369307 | doi = 10.3390/ijms23158543 | doi-access = free | url = }}</ref><ref name="HarsingTimarMiklya2023">{{cite journal | vauthors = Harsing LG, Timar J, Miklya I | title = Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline | journal = Int J Mol Sci | volume = 24 | issue = 17 | date = August 2023 | article-number = 13334 | pmid = 37686140 | pmc = 10487936 | doi = 10.3390/ijms241713334 | doi-access = free | url = }}</ref>

When given via intracerebroventricular injection in rodents pre-treated with monoamine oxidase inhibitors (MAOIs), tyramine has been found to induce the head-twitch response in rodents.<ref name="Sakurada1975">{{cite journal | vauthors = Sakurada S | title = [Effects of beta-phenylethylamine derivatives on the central nervous system. (5) The effect of intracerebral administration of tyramine on head twitching in mice pre-treated with isocarboxazid] | language = Japanese | journal = Nihon Yakurigaku Zasshi | volume = 71 | issue = 8 | pages = 779–787 | date = November 1975 | pmid = 130286 | doi = | url = }}</ref><ref name="OrikasaSakuradaKisara1980">{{cite journal | vauthors = Orikasa S, Sakurada S, Kisara K | title = Head-twitch response induced by tyramine | journal = Psychopharmacology (Berl) | volume = 67 | issue = 1 | pages = 53–59 | date = January 1980 | pmid = 6245422 | doi = 10.1007/BF00427595 | url = }}</ref><ref name="OrikasaKisara1981">{{cite journal | vauthors = Orikasa S, Kisara K | title = [Effects of parasympathetic drugs on head-twitch response induced by tyramine (author's transl)] | language = Japanese | journal = Nihon Yakurigaku Zasshi | volume = 77 | issue = 5 | pages = 477–482 | date = May 1981 | pmid = 7197657 | doi = | url = }}</ref><ref name="OrikasaKisara1982">{{cite journal | vauthors = Orikasa S, Kisara K | title = A possible mechanism of the tyramine-induced head-twitch response | journal = Eur J Pharmacol | volume = 80 | issue = 2-3 | pages = 163–169 | date = May 1982 | pmid = 6213417 | doi = 10.1016/0014-2999(82)90050-4 | url = }}</ref> This effect appears to be mediated by induction of serotonin release.<ref name="Sakurada1975" /><ref name="OrikasaKisara1982" />

==Biosynthesis== Biochemically, tyramine is produced by the decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase.<ref>{{cite encyclopedia | url = http://www.genome.jp/kegg/pathway/map/map00350.html | title = Tyrosine metabolism - Reference pathway | encyclopedia = Kyoto Encyclopedia of Genes and Genomes (KEGG) | access-date = 3 October 2011 | archive-date = 26 July 2019 | archive-url = https://web.archive.org/web/20190726082244/http://www.genome.jp/kegg/pathway/map/map00350.html }}</ref> Tyramine can, in turn, be converted to methylated alkaloid derivatives ''N''-methyltyramine, ''N'',''N''-dimethyltyramine (hordenine), and ''N'',''N'',''N''-trimethyltyramine (candicine).

<gallery class="center skin-invert-image"> File:Tyramine.svg|Tyramine File:Methyltyramine.svg|''N''-Methyltyramine File:Dimethyltyramine.svg|''N'',''N''-Dimethyltyramine (hordenine) File:Candicine.svg|''N'',''N'',''N''-Trimethyltyramine (candicine) </gallery>

In humans, tyramine is produced from tyrosine, as shown in the following diagram.{{Phenylalanine biosynthesis|align=center}}{{clear}}

==Chemistry== In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine.<ref>{{cite journal | vauthors = Barger G | journal = J. Chem. Soc. | volume = 95 | pages = 1123–1128 | year = 1909 | doi = 10.1039/ct9099501123 | title=CXXVII.?Isolation and synthesis of p-hydroxyphenylethylamine, an active principle of ergot soluble in water| url = https://zenodo.org/record/1429723 }}</ref><ref>{{Cite journal | doi = 10.1002/hlca.192500801106 | title = Untersuchungen in der Phenylalanin-Reihe VI. Decarboxylierung des Tyrosins und des Leucins | year = 1925 | vauthors = Waser E | journal = Helvetica Chimica Acta | volume = 8 | pages = 758–773 | bibcode = 1925HChAc...8..758W }}</ref><ref>{{Cite journal | doi = 10.1021/ja01335a058 | year = 1933 | vauthors = Buck JS | journal = Journal of the American Chemical Society | volume = 55 | issue = 8 | pages = 3388–3390 | title=Reduction of Hydroxymandelonitriles. A New Synthesis of Tyramine | bibcode = 1933JAChS..55.3388B }}</ref> class=skin-invert-image|500px|center|thumb|Tyrosine decarboxylation

==Society and culture== ===Legal status=== ====United States==== 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 says tyramine is illegal in "any material, compound, mixture, or preparation that contains any quantity of [tyramine] or that contains any of [its] 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."<ref name="Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL">{{Cite web|url=http://leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/0893.html|title=Statutes & Constitution :View Statutes: Online Sunshine|website=leg.state.fl.us|access-date=2019-04-03}}</ref>

This ban is likely the product of lawmakers overly eager to ban substituted phenethylamines, which tyramine is, in the mistaken assumption that ring-substituted phenethylamines are hallucinogenic drugs like the 2C series of psychedelic substituted phenethylamines. The further banning of tyramine's optical isomers, positional isomers, or geometric isomers, and salts of isomers where they exist, means that meta-tyramine and phenylethanolamine, a substance found in every living human body, and other common, non-hallucinogenic substances are also illegal to buy, sell, or possess in Florida.<ref name="Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL"/> 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.<ref>{{cite journal | vauthors = Suzzi G, Torriani S | title = Editorial: Biogenic amines in foods | journal = Frontiers in Microbiology | volume = 6 | page = 472 | date = 2015-05-18 | pmid = 26042107 | pmc = 4435245 | doi = 10.3389/fmicb.2015.00472 | doi-access = free }}</ref>

==Notes== {{Reflist|group=note}}

==References== {{Reflist|refs=

<ref name="Alkema-Hunter-Ensor-Ringstad-Horvitz-2005">{{cite journal | vauthors = Alkema MJ, Hunter-Ensor M, Ringstad N, Horvitz HR | title = Tyramine Functions Independently of Octopamine in the ''Caenorhabditis elegans'' Nervous System | journal = Neuron | volume = 46 | issue = 2 | pages = 247–60 | date = April 2005 | pmid = 15848803 | doi = 10.1016/j.neuron.2005.02.024 | publisher = Cell Press (Elsevier BV) | s2cid = 14914393 | doi-access = free }}</ref>

<ref name="Ohta-Ozoe-2014">{{cite book | vauthors = Ohta H, Ozoe Y | title=Advances in Insect Physiology | chapter=Molecular Signalling, Pharmacology, and Physiology of Octopamine and Tyramine Receptors as Potential Insect Pest Control Targets | publisher=Elsevier | year=2014 | volume=46 | isbn=978-0-12-417010-0 | doi=10.1016/b978-0-12-417010-0.00002-1 | pages=73–166 | s2cid=80723865}}</ref>

<ref name="Ma-et-al-2015">{{cite journal | vauthors = Ma Z, Guo X, Lei H, Li T, Hao S, Kang L | title = Octopamine and tyramine respectively regulate attractive and repulsive behavior in locust phase changes | journal = Scientific Reports | volume = 5 | issue = 1 | article-number = 8036 | date = January 2015 | pmid = 25623394 | pmc = 5389030 | doi = 10.1038/srep08036 | publisher = Nature/Springer | bibcode = 2015NatSR...5.8036M | s2cid = 2056338 }}</ref>

}}

{{Neurotransmitters}} {{Monoamine releasing agents}} {{Monoaminergic activity enhancers}} {{TAAR ligands}} {{Phenethylamines}} {{Chocolate}}

Category:Antihypotensive agents Category:Migraine Category:Monoamine oxidase inhibitors Category:Monoaminergic activity enhancers Category:Norepinephrine-dopamine releasing agents Category:Peripherally selective drugs Category:Phenethylamine alkaloids Category:Phenethylamines Category:TAAR1 agonists Category:Trace amines Category:4-Hydroxyphenyl compounds Category:Aminoethyl compounds