Introduction

Tyramine is a trace monoamine with sympathomimetic properties. It is naturally found in foods, plants, and animals. By definition, all monoamines have an amine group separated from an aromatic ring by a two-carbon chain. Dopamine, norepinephrine, and serotonin are monoamines. Trace monoamines were named for their relatively low frequency in mammalian tissues compared to their more abundant and discussed monoamine neurotransmitter counterparts; epinephrine, norepinephrine, dopamine, and serotonin.[1]

Other trace amines include octopamine, phenethylamine, N-methylphenethylamine, and N-methyltyramine. Tyramine is degraded by several enzymes, most notably monoamine oxidase. Tyramine is often found in fermented, aged, cured, and spoiled foods where microbes with decarboxylase enzymes convert the amino acid tyrosine into tyramine.[2] Ingestion of high tyrosine containing foods in patients taking monoamine oxidase inhibitors produces headaches, blurry vision, chest pain, and palpitations associated with hypertension, intracranial hemorrhages, and myocardial injury.[3]

Tyramine has long been shown to cause cardiovascular effects when consumed in large, pathologic amounts.[4]  New evidence suggests endogenous tyramine and other trace amines in lower, physiologic levels may have additional roles, including modulating the immune system.[5]

Fundamentals

Tyramine is a trace monoamine with indirect catecholamine releasing properties.[1] Ingested tyramine produces mostly peripheral cardiovascular effects. Ingestion of large amounts of tyramine, especially combined with monoamine oxidase inhibitors (MAOIs), can precipitate a hypertensive crisis.[2] A hypertensive crisis becomes escalated from hypertensive urgency to a hypertensive emergency once there is evidence of end-organ damage such as retinal hemorrhages, papilledema, intracranial bleeds, pulmonary edema, or acute renal failure.[6] An adrenergic crisis induced by taking MAOI and consuming a high amount of tyramine can have a rapid onset, occurring in minutes.

Issues of Concern

Hypertensive crisis after tyramine ingestion, also referred to as the “cheese effect,” has become increasingly rare. Most documented cases occur in individuals receiving monoamine oxidase inhibitors, which have largely been replaced for newer classes of antidepressants with more selectivity and fewer side effects.[7] Monoamine oxidase inhibitors are also used to treat Parkinson disease to slow the breakdown of levodopa and dopamine.[8] Improvements in food production and storage have led to a decrease in tyramine containing foods.[9]

Tyramine and other biogenic amines (e.g., histamine) formed from decarboxylation of amino acids have been minimized in food production by the advent of culture starters with reduced carboxylase producing organisms.[10][11] Modern improvements in food storage (e.g., temperature and pH, packaging) decrease tyrosine decarboxylase activity, further reducing tyramine levels in modern foods. Biogenic amines are a marker for food safety.[12] Nonetheless, physicians should counsel patients taking monoamine oxidase inhibitors to avoid fermented or cured foods high in tyramine. This includes

• Fermented vegetables, including kimchi and sauerkraut,
• Select fresh produce including grapes, avocado, and beetroot
• Wine and beer,
• Cheese, especially cheddar and feta
• Cured or salt dried meats
• Chocolate
• Coffee
• Soy sauce, Worcestershire sauce
• Pickled or salt-dried fish or shrimp[13]

Ingestion of 10 to 25mg of tyramine in patients taking MAOIs will produce a severe adrenergic response, including hypertension, headaches, and possible intracranial hemorrhage.[14]

Although not completely understood, tyramine containing foods are known triggers for patients with migraines.[15] The adrenergic effects of tyramine may be responsible for the migraine phenomena.[16] Diets low in tyramine can be recommended when aiming to identify migraine triggers. 

Cellular Level

Tyramine exerts its vasopressor response as it is an indirectly acting sympathomimetic agent. Taken up by the NET- Norepinephrine reuptake transporter and precipitating the release of large quantities of norepinephrine into circulation[17]. Tyramine acts on the adipose tissues and has a dose-dependent antilipolytic effect. The antilipolytic effect is due to the inhibition of protein tyrosine phosphatases (PTPases), which is absent in the presence of ascorbic acid, a natural antioxidant.[18]

Mechanism

The administration of tyramine displaces norepinephrine, epinephrine, and dopamine from pre-synaptic storage vesicles.[19] The release of these neurotransmitters, particularly norepinephrine, is responsible for vasoconstriction, increased heart rate, and a rise in blood pressure. Therefore, tyramine functions as an indirect sympathomimetic by causing the release of presynaptic endogenous neurotransmitters. Tyramine acts as a substrate for monoamine oxidase, further limiting the breakdown of monoamine neurotransmitters.[20]

When not ingested, tyramine is made endogenously from the decarboxylation of the amino acid tyrosine by the enzyme aromatic L-amino acid decarboxylase (AADC).[1] This is the same enzyme that converts L-DOPA to dopamine. Monoamine oxidase converts tyramine to the inactive metabolite hydroxyphenyl acetic acid.[21] Tyramine can be converted to active secondary amines octopamine by the enzyme dopamine b-hydroxylase or N-methyltyramine by the enzyme phenylethanolamine N-methyltransferase. Octopamine can then be converted to synephrine by phenylethanolamine N-methyltransferase as well.[21]

Pathophysiology

New evidence has also revealed a G-protein coupled receptors that tyramine and other biogenic amines bind to directly, called Trace amine-associated receptors (TAARs).[1] Tyramine has a high affinity for binding TAAR1 and TAAR2. These receptors are found in the central nervous system and periphery. These receptors are the focus of recent research on endogenous trace amines.  The function of this class of receptors is still being elucidated and is hypothesized to include olfaction, modulation of other neurotransmitters, regulation of body weight, and immunologic functions.[1][22] In the central nervous system, TAAR1 signal transduction may modulate the reward circuits, the limbic system, and mood.[23]

TAAR1 has been found in large amounts in the stomach and small intestine and may play a role in the brain-gut-microbiome axis.[24] TAAR1 is the only subtype not represented in the olfactory epithelium; however, the utility of TAAR subtypes in olfaction is still being studied.[24] One study found an association between single-nucleotide polymorphism (SNPs) in the TAAR1 gene and fibromyalgia.[25] The peripheral vascular effects and resulting hypertension with tyramine ingestion, long attributed to norepinephrine displacement, may partly be the result of TAAR1 binding mechanisms as well.[26]

Clinical Significance

Counseling patients to avoid tyramine containing foods when taking MAOIs remains standard of care. Patients on MAOI should be instructed to keep a record of their blood pressures. Maintaining a high index of suspicion and inquiring about tyramine consumption containing foods in hypertensive patients on MAOIs can aid in diagnosis. The physiologic effects of irreversible MAOIs such as tranylcypromine, phenelzine, and selegiline can persist for up to 3 weeks, and tyramine avoidance should continue during that time. Dietary counseling for patients taking MAOIs should begin before therapy, continue during follow-up to monitor compliance, and include

• Education on a low tyramine diet with consumption of only fresh foods
• Identification and avoidance of high tyramine foods
• Instructions to begin the diet before MAOI therapy and continue for four weeks after stopping MAOIs[14]

Tyramine has been implicated as a potential migraine trigger.[16] The role of trace amine-associated receptors and their biogenic amine ligands in physiologic concentrations, such as tyramine, will require additional study.