Tyramine ( 4-hydroxyphenethylamine; para-tyramine, mydrial or uteramin) is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a [1 ] catecholamine releasing agent. Notably, however, it is unable to cross the blood-brain barrier, resulting in only non psychoactive peripheral sympathomimetic effects. A hypertensive crisis can result from ingestion of tyramine-rich foods in conjunction with monoamine oxidase inhibitors (MAOIs). Occurrence [edit ]
Tyramine occurs widely in
plants and [5 ] animals, and is metabolized by the enzyme monoamine oxidase. In foods, it is often produced by the decarboxylation of tyrosine during fermentation or decay. Foods containing considerable amounts of tyramine include meats that are potentially spoiled or pickled, aged, smoked, fermented, or marinated (some fish, poultry, and beef); most pork (except cured ham); chocolate; alcoholic beverages; and fermented foods, such as most cheeses (except ricotta, cottage, cream and Neufchâtel cheeses), sour cream, yogurt, shrimp paste, soy sauce, soybean condiments, teriyaki sauce, tempeh, miso soup, sauerkraut, kimchi, broad (fava) beans, green bean pods, Italian flat (Romano) beans, snow peas, edamame, avocados, bananas, pineapple, eggplants, figs, red plums, raspberries, peanuts, Brazil nuts, coconuts, processed meat, yeast, and an array of cacti. Physical effects and pharmacology [edit ]
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 [6 ] neurotransmitter was revealed by the discovery of a G protein-coupled receptor with high affinity for tyramine, called TAAR1. [7 ] The TAAR1 receptor is found in the [8 ] brain, as well as peripheral tissues, including the kidneys. [9 ] Tyramine is physiologically metabolized by MAO A. In humans, 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 can also displace stored monoamines, such as dopamine, norepinephrine and epinephrine, from pre-synaptic vesicles. The first signs of this were discovered by a neurologist who noticed his wife, who at the time was on MAOI medication, had severe headaches when eating cheese. For this reason, the crisis is still called the "cheese effect" or "cheese crisis", though other foods can cause the same problem. [10 ] [11 ] :30–31 Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do. [12 ] [13 ]
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 displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur.
However, if one has had repeated exposure to tyramine, 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, and octopamine does not activate alpha or beta adrenergic receptors.
When using a MAO inhibitor (MAOI), the 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.
Research reveals a possible link between
migraine and elevated levels of tyramine. A 2007 review published in Neurological Sciences presented data showing migraine and cluster headaches are characterised by an increase of circulating neurotransmitters and [14 ] neuromodulators (including tyramine, octopamine and synephrine) in the hypothalamus, amygdala and dopaminergic system. Biosynthesis [edit ]
Biochemically, tyramine is produced by the
decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase. Tyramine can, in turn, be converted to methylated [15 ] alkaloid derivatives , N-methyltyramine (hordenine), and N, N-dimethyltyramine (candicine). N, N, N-trimethyltyramine N, N-Dimethyltyramine (hordenine) N, N, N-Trimethyltyramine (candicine)
In humans, tyramine is produced from tyrosine, as shown in the following diagram.
Human biosynthesis pathway for trace amines and catecholamines
[18 ] Chemistry [edit ]
In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine.
[19 ] [20 ] [21 ] Legal Status [edit ] United States [edit ]
Tyramine is not scheduled at the federal level in the
United States and is therefore legal to buy, sell, or possess. [22 ] US State of Florida [edit ]
Tyramine is a Schedule I
controlled substance in the state of Florida making it illegal to buy, sell, or possess. [23 ] See also [edit ] References [edit ] ^ a b PubChem ^ A. M. Andersen (1977). "The crystal and molecular structure of tyramine hydrochloride." Acta Chem. Scandinavica B 31 162-166. ^ a b c The Merck Index, 10th Ed. (1983), p.1405, Rahway: Merck & Co. ^ Kappe, T. (1965). Journal of Medicinal Chemistry 8: 368–374. doi: 10.1021/jm00327a018 ^ T. A. Smith (1977) Phytochem. 16 9-18. ^ Philips, Rozdilsky, Boulton (Feb 1978). "Evidence for the presence of m-tyramine, p-tyramine, tryptamine, and phenylethylamine in the rat brain and several areas of the human brain.". Biological Psychiatry,. 13(1) (1): 51–57. PMID 623853. ^ Navarro, Gilmour, Lewin (July 10, 2006). "A Rapid Functional Assay for the Human Trace Amine-Associated Receptor 1 Based on the Mobilization of Internal Calcium". J Biomol Screen 11: 668–693. doi: 10.1177/1087057106289891. PMID 16831861. ^ Liberles, Buck (August 10, 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature 441 (7103): 645–650. doi: 10.1038/nature05066. PMID 16878137. ^ Xie, Westmoreland, Miller (May 2008). "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.". J. Pharm. 441: 629–640. doi: 10.1124/jpet.107.135079. PMID 18310473. ^ Sathyanarayana Rao TS and Vikram K. Yeragani VK (2009) Hypertensive crisis and cheese Indian J Psychiatry. 51(1): 65–66. ^ E. Siobhan Mitchell Antidepressants, chapter in Drugs, the Straight Facts, edited by David J. Triggle. 2004, Chelsea House Publishers ^ Stahl SM, Felker A (2008). "Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants". Cns Spectrums 13 (10): 855–870. PMID 18955941. ^ Tyramine-restricted Diet 1998, W.B. Saunders Company. ^ D'Andrea, G; Nordera, GP; Perini, F; Allais, G; Granella, F (May 2007). "Biochemistry of neuromodulation in primary headaches: focus on anomalies of tyrosine metabolism". Neurological Sciences. 28, Supplement 2: S94–S96. doi: 10.1007/s10072-007-0758-4. PMID 17508188 ^ Tyrosine metabolism - Reference pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG) ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi: 10.1016/j.pharmthera.2009.11.005. PMID 19948186. ^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi: 10.1016/j.tips.2005.03.007. PMID 15860375. ^ [16 ] [17 ] ^ G. Barger (1909). J. Chem. Soc. 95: 1123. ^ Waser, Ernst (1925). "Untersuchungen in der Phenylalanin-Reihe VI. Decarboxylierung des Tyrosins und des Leucins". Helvetica Chimica Acta 8: 758. doi: 10.1002/hlca.192500801106. ^ Buck, Johannes S. (1933). Journal of the American Chemical Society 55 (8): 3388. doi: 10.1021/ja01335a058. ^ §1308.11 Schedule I. ^ Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL
Antagonists: Abanoquil Adimolol Ajmalicine Alfuzosin Amosulalol Arotinolol Atiprosin Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, risperidone) Benoxathian Buflomedil Bunazosin Carvedilol CI-926 Corynanthine Dapiprazole DL-017 Domesticine Doxazosin Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride) Etoperidone Eugenodilol Fenspiride GYKI-12,743 GYKI-16,084 Hydroxyzine Indoramin Ketanserin L-765,314 Labetalol mCPP Mephendioxan Mepiprazole Metazosin Monatepil Moxisylyte Naftopidil Nantenine Nefazodone Neldazosin Niaprazine Nicergoline Niguldipine Pardoprunox Pelanserin Phendioxan Phenoxybenzamine Phentolamine Piperoxan Prazosin Quinazosin Ritanserin RS-97,078 SGB-1,534 Silodosin SL-89.0591 Spiperone Talipexole Tamsulosin Terazosin Tibalosin Tiodazosin Tipentosin Tolazoline Trazodone Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin) Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine) Trimazosin Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Upidosin Urapidil WB-4101 Zolertine Antagonists: 1-PP A-80426 Adimolol Aptazapine Atipamezole Atypical antipsychotics (e.g., asenapine, clozapine, lurasidone, paliperidone, quetiapine, risperidone, zotepine) Azapirones (e.g., buspirone, tandospirone) BRL-44408 Buflomedil Cirazoline Efaroxan Esmirtazapine Fenmetozole Fluparoxan GYKI-12,743 GYKI-16,084 Idazoxan mCPP Mianserin Mirtazapine MK-912 NAN-190 Olanzapine Pardoprunox Phentolamine Phenoxybenzamine Piperoxan Piribedil Rauwolscine Rotigotine SB-269,970 Setiptiline Spiroxatrine Sunepitron Tolazoline Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Yohimbine
Selective norepinephrine reuptake inhibitors: Amedalin Atomoxetine (tomoxetine) Ciclazindol Daledalin Edivoxetine Esreboxetine Lortalamine Mazindol Nisoxetine Reboxetine Talopram Talsupram Tandamine Viloxazine; Norepinephrine-dopamine reuptake inhibitors: Amineptine Bupropion Fencamine Fencamfamine Hydroxybupropion Lefetamine Levophacetoperane LR-5182 Manifaxine Methylphenidate Nomifensine O-2172 Radafaxine; Serotonin-norepinephrine reuptake inhibitors: Bicifadine Desvenlafaxine Duloxetine Eclanamine Levomilnacipran McN-5652 Milnacipran N-Methyl-PPPA PPPA SEP-227162 Sibutramine Venlafaxine WY-45233; Serotonin-norepinephrine-dopamine reuptake inhibitors: (S)-Duloxetine Brasofensine Dasotraline Desmethylsertraline Diclofensine DOV-102,677 DOV-21,947 DOV-216,303 JNJ-7925476 JZ-IV-10 Liafensine Methylnaphthidate Naphyrone NS-2359 Perafensine PRC200-SS SEP-228431 SEP-228432 Tesofensine; Tricyclic antidepressants: Amitriptyline Butriptyline Cianopramine Clomipramine Desipramine Dosulepin Doxepin Imipramine Lofepramine Melitracen Nortriptyline Protriptyline Trimipramine; Tetracyclic antidepressants: Amoxapine Maprotiline Mianserin Oxaprotiline Setiptiline; Others: Antihistamines (e.g., brompheniramine, chlorphenamine, pheniramine, tripelennamine) Arylcyclohexylamines (e.g., ketamine, phencyclidine) CP-39,332 Ethanol EXP-561 Fezolamine Ginkgo biloba Indeloxazine Loxapine Nefazodone Nefopam Opioids (e.g., methadone, pethidine (meperidine), tapentadol, tramadol) Pridefrine Tedatioxetine Teniloxazine Tofenacin Tropanes (e.g., cocaine) Ziprasidone
Agonists: Adamantanes: Amantadine Memantine Rimantadine; Aminotetralins: 7-OH-DPAT 8-OH-PBZI Rotigotine UH-232; Benzazepines: 6-Br-APB Fenoldopam SKF-38,393 SKF-77,434 SKF-81,297 SKF-82,958 SKF-83,959; Ergolines: Bromocriptine Cabergoline Dihydroergocryptine Epicriptine Lisuride LSD Pergolide; Dihydrexidine derivatives: 2-OH-NPA A-86,929 Ciladopa Dihydrexidine Dinapsoline Dinoxyline Doxanthrine; Others: A-68,930 A-77636 A-412,997 ABT-670 ABT-724 Aplindore Apomorphine Aripiprazole Bifeprunox BP-897 Captodiame CY-208,243 Dizocilpine Etilevodopa Flibanserin Ketamine Melevodopa Modafinil Pardoprunox Phencyclidine PD-128,907 PD-168,077 PF-219,061 Piribedil Pramipexole Propylnorapomorphine Pukateine Quinagolide Quinelorane Quinpirole RDS-127 Ro10-5824 Ropinirole Rotigotine Roxindole Salvinorin A SKF-89,145 Sumanirole Terguride Umespirone WAY-100,635
TAAR1 TAAR2 TAAR5 ‡
References for synthetic TAAR1 agonists can be found at
or in the associated compound articles. For TAAR2 and TAAR5 agonists, see