I just started taking MAOIs for depression. Do I really need to follow a low-tyramine diet?
Tyramine, one of the toxicologically important biogenic amines (BA), is formed in foods by the action of tyrosine-decarboxylase produced by bacteria associated with the foods. The physiological effects of tyramine include peripheral vasoconstriction, increased cardiac output, increased respiration, elevated blood glucose, and release of norepinephrine. Tyramine is broken down in the mammalian organism (to corresponding ketone, NH 3, and H 2 O 2) in mitochondrion of neurons, hepatocytes and enterocytes (and other tissues) by the oxidative deamination catalyzed by monoamine oxidase (MAO). However, the detoxification mechanisms in man are insufficient in the following cases: too high intake in a diet; in the allergic individuals; in patients consuming drugs with an action of the MAO inhibitors (anti-Parkinsonian drugs and anti-depressants inhibiting MAO-B and MAO-A, respectively).
A definition of a clinically significant tyramine level relates to the severity of the blood pressure rise. The presence of 6 mg in one or two usual servings is thought to be sufficient to cause a mild adverse event while 10–25 mg will produce a severe adverse event in those using MAOI drugs. For unmedicated adults, 200–800 mg of dietary tyramine is needed to induce a mild rise (30 mm Hg) in blood pressure. A limit of 200–800 mg in one or two usual servings has been proposed for tyramine in foods. Tyramine is a vasopressor amine responsible for some food-induced migraines and hypertensive crisis in sensitive individuals.
Although the toxicity of individual biogenic amines in general is beyond all doubt, it is very difficult to determine the exact toxicity threshold of these compounds. The toxic dose is strongly dependent on the efficiency of detoxification, which may vary considerably between different individuals. However, concentrations above 100 mg kg−1 of food are supposed to be deleterious, especially in the above-mentioned risky groups of consumers.
Tyramine: structure and biosynthesis
Tyramine (IUPAC name: 4-(2-aminoethyl)phenol) is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Biochemically, tyramine is produced by the decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase. It is an indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. Notably, however, it is unable to cross the blood-brain barrier, resulting in only nonpsychoactive peripheral sympathomimetic effects. When tyramine-rich foods are ingested in conjunction with a monoamine oxidase inhibitor (MAOI), tyramine is responsible for the so-called "cheese reaction" sometimes seen with their use.
Tyramine and tyramine-producer bacteria in foods
Prerequisites for the formation of tyramine in foods are the availability of free tyrosine, the presence of tyrosine decarboxylase (TDC)-positive microorganisms, conditions that allow bacterial growth and conditions that favor decarboxylase activity. Free amino acids occur as such in foods, but may also be liberated from proteins as a result of proteolytic activity. Decarboxylase-positive bacteria may constitute part of the associated population of the food or may be introduced by contamination before, during, or after processing of the food. In the case of fermented foods and beverages, the applied starter cultures may also affect the production of tyramine.
Tyramine could be expected in virtually all foods that contain proteins or free tyrosine and that are subject to conditions enabling microbial activity. Most foods can be safely consumed if bought fresh, cooked fresh, and consumed fresh in modest quantities. In cheeses, the food industry has striven to develop new processes using different microbial strains to reduce the development of tyramine in cured or aged cheeses. The milk quality and the length of the ripening or storage appear to be dominant factors in the production of tyramine in cheeses. Starting with high quality fresh meat and using good manufacturing practices greatly reduces the risk of tyramine formation in processed meat products. Most case reports of tyramine in fresh meat have been from meats stored at or beyond the end of the recommendation storage time. Vegetables processed in brine from high-quality raw materials do not develop high levels of tyramine unless contaminated or abused by temperature and storage time. Alcoholic beverages, particularly wines, do not contain high levels of tyramine when consumed in modest quantities.
In tyramine-containing foods the majority of the tyramine is generated by decarboxylation of the amino acid tyramine through tyrosine decarboxylase (TDC) specific enzymes derived from the bacteria present in food. Tyramine often is the main amine found in fermented products, especially cheeses and fermented sausages. This amine is produced through tyrosine decarboxylation by a variety of lactic acid bacteria (including lactobacilli, enterococci, and carnobacteria), all of which are actively present during the manufacture of most fermented food products. The ability of bacteria to decarboxylate tyramine is highly variable. It depends not only on the species, but also on the strain and the environmental conditions. Tyramine and phenylethylamine biosynthesis by food bacteria. 2012
The factors with potential effect on tyramine content in Dutch-type semi-hard cheese are compared in Table 1. Quantitatively most important factors were time of ripening and part of the cheese, which accounted for 67% and 28% of explained variability, respectively. Effect of the starter culture was still significant (P<0.01), but this factor accounted for only 4% of explained variability. However, as it is also apparent from Table 1, all factors tested in the present experiment explained only 41% of total variability in tyramine content.
From comparison of tyramine content in particular cheeses at the end of ripening, only one clear tendency is apparent at first sight: there was a significantly higher (P<0.01) tyramine content in the edge part of the cheese in comparison with the core part in most samples.
The uneven tyramine distribution in cheese (core×edge polarization) is confirmed by the data presented in the figure below; to generalize an effect of the part of the cheese on tyramine content during the ripening, all core and edge samples, respectively, regardless of producer, fat content and starter culture, were taken as two sets. The dependences were statistically different based on the linear regression equality test (F=21.6, P<0.05). The research group admitted he had not been able to present satisfactory explanations for their respective differences in tyramine distribution within the cheese, mentioning unspecified different external and internal microenvironmental conditions, possible different O 2 or water activity (aw) requirements of tyramine producers. Aw was measured, but with inconclusive results: aw in the edge part (0.955) was significantly (P<0.01) lower (therefore, this part of the cheese was less suitable for the growth of microorganisms from this viewpoint) in comparison with the core part (0.961). However, the absolute differences in the aw values were small; the more probable explanation of higher tyramine concentration in the E-parts of the cheese was higher counts of contaminant enterococci, some of which possessed tyrosine-decarboxylase activity.
At any rate, consumers from risky groups (patients consuming drugs with an effect of MAO-inhibitors) should avoid consumption of Dutch-type cheese ripening more than 5 months and are recommended to remove 3 cm outer part of the cheese (which contains higher tyramine concentration) before consumption.
Tyramine production in Dutch-type semi-hard cheese from two different producers. 2008
Monoamine oxidase (MAO, EC 18.104.22.168) is a flavin-dependent metabolic enzyme, responsible for the oxidative deamination of both endogenous, aminergic neurotransmitters and xenobiotic amines, which plays an important role in controlling mood and the regulation of emotional and other brain functions. There are two isoforms of this enzyme, MAO-A and MAO-B, which are distinguished by different but overlapping substrate specificities and varying tissue distributions (probably due to the different promoter organization of the corresponding genes). cDNA cloning has demonstrated unequivocally that both isoforms were coded by two genes located on the X chromosome (Xp11.23) presenting identical exon–intron organization, 70% amino acid sequence identity and anchorage to the outer membrane of mitochondria.
Monoamine oxidase A is the predominant isoform in the gastrointestinal tract, where it is crucial for the metabolism of tyramine in the intestine, and in catecholaminergic neurons. It preferentially metabolizes serotonin (5-HT) and norepinephrine, and is inhibited by clorgyline and moclobemide. MAO-A deficiency caused by spontaneous mutation in man or MAO-A knock-out mice was associated to impulsive aggressive behaviors and mild mental retardation. MAO-A inhibitors have been shown to be effective antidepressant agents, but the risk of hypertensive crisis (cheese reaction) and the interaction with serotonergic drugs (serotonin syndrome) reserved them as a prescription only for patients who have failed to respond to the first-line therapy (i.e. tricyclic antidepressants). Now the trend may be changing due to the discovery that they can be useful in major depressive disorders, especially those with atypical features and with tricyclic antidepressants-resistant treatment, and in Parkinson's disease (PD) for their ability to improve motor function.
In contrast, MAO-B accounts for > 80% of the total MAO activity in the brain (serotonergic and histaminergic neurons and glial cells) and liver, where it metabolizes dopamine and other amines (i.e. phenylethylamine, PEA). It is inhibited irreversibly by selegiline and rasagiline. Brain hMAO-B activity appears to increase with aging-related gliosis and is crucial in the brain of patients with Alzheimer's disease (AD), where it has been found to be highly expressed in astrocytes around senile plaques. Increased hMAO-B activity would be expected to reduce dopamine concentration and to release catalytic reaction products (H 2 O 2). It has been shown that MAO inhibitors, which selectively inhibit the B isoform, may have neuroprotective and/or neurorestorative properties, as demonstrated in vivo by rasagiline, and can stimulate the expression of neurotrophic factors (NGF, BDNF, GDNF). Dopamine has been also involved in R-synuclein aggregation implicated in the etiology of PD, whereas high levels of H 2 O 2 in the cell promote apoptotic signaling events in AD. Inhibition of hMAO-B can allow some neuroprotection against this bioactivation and can provide protection against oxidative neurodegeneration. Given the implication of hMAO in the neurological disorders mentioned above, there is considerable interest in obtaining potent and selective inhibitors that would permit control over this enzymatic activity."Patent-related survey on new monoamine oxidase inhibitors and their therapeutic potential. 2012":http://www.ncbi.nlm.nih.gov/pubmed/22702491
Monoamine oxidase inhibitors (MAOIs)
Although primary care clinicians have developed considerable expertise in managing patients with major depressive disorder, and a range of treatment strategies is currently available, some patients still fail to reach remission. Two strategies have fallen out of common use: treating patients with monoamine oxidase inhibitors (MAOIs) and subgrouping patients by diagnosis when selecting antidepressant treatment. Monoamine oxidase inhibitors became less popular because other treatments were perceived to be safer and easier to use. However, a newer transdermal formulation of an MAOI that limits the need for the dietary restrictions of oral MAOIs may make it worthwhile to consider using this class of medication in patients who have failed several treatment trials. Although adverse events due to patients' diets are less likely with the transdermal MAOI, clinicians should still be alert for drug interactions and observe recommended washout periods. Patients who may benefit from MAOI treatment include those with treatment-resistant depression, atypical depression, anxiety, or anergic bipolar depression and those who have experienced intolerable metabolic or sexual side effects with other medications. The use of monoamine oxidase inhibitors in primary care. 2012
Mechanism of action of MAOIs
Utilizing MAOIs has often been considered risky due to the potential of developing a hypertensive crisis after ingesting high amounts of tyramine from the diet. Tyramine is a potent releaser of NE and can thus elevate blood pressure. Normally, NE cannot accumulate to dangerous levels, due to the efficient destruction of NE by MAO-A. When foods high in tyramine content are ingested, MAO-A in the intestinal wall and liver safely destroys massive amounts of tyramine before it is absorbed. If any tyramine escapes into the systemic circulation and is delivered to the noradrenergic sympathetic neuron, the MAO-A there destroys any synaptic NE that tyramine releases. Thus, there is a large capacity to protect the sympathetic nervous system from ingested tyramine. The average person can handle ~400 mg of ingested tyramine before excessive stimulation of postsynaptic adrenergic receptors occurs, and thus results in elevated blood pressure. Since a “high tyramine meal” generally contains only about 40 mg of tyramine, a tyramine reaction usually does not occur in a normal unmedicated person eating a normal diet.
When MAO-A is inhibited, the capacity to handle dietary tyramine is significantly reduced. A high-tyramine meal is sufficient to increase blood pressure when a substantial amount of MAO-A is irreversibly inhibited.
It may take only 8–10 mg of dietary tyramine to increase blood pressure when MAO-A is “knocked out” by high doses of an MAOI. Such blood pressure elevations can potentially be sudden and dramatic, creating a hypertensive crisis, which can (rarely) cause intracerebral hemorrhage or even death. This risk is generally alleviated by restricting the diet so foods high in tyramine are eliminated. Until recently, dietary restrictions and the risk of a hypertensive crisis were the price most patients had to pay in order to receive the therapeutic benefits of the MAOIs in the treatment of depression.
Due to this potential danger of a hypertensive crisis from a tyramine reaction in patients taking an irreversible MAOI various myths have arisen surrounding the amount of tyramine in certain foods and which dietary restrictions are necessary. The “cheese reaction” has led to the myth that all cheese must be restricted. This is not the case, as only aged cheeses (eg, English Stilton) are high in tyramine, whereas most processed cheeses or those utilized on commercial chain pizzas do not contain high levels of tyramine.
Reversible Inhibitors of Monamine (RIMAs)
Reversible inhibitors of monoamine (RIMAs) are an ingenious development because they have the potential of providing MAO-A inhibition with decreased risk of a tyramine reaction. For example, if someone taking a RIMA eats aged cheese high in tyramine, as the tyramine is absorbed it will release NE; however, this released NE will chase the reversible inhibitor off the MAO-A enzyme, reactivating MAO-A in the intestine, liver, and sympathomimetic neurons and allowing destruction of the dangerous amines.
Moclobemide is the best known RIMA and has demonstrated efficacy similar to amitriptyline, clomipramine, fluvoxamine, and imipramine. Numerous studies have indicated that moclobemide can maintain its antidepressant effects for 6–12 months. There is still a warning posted regarding tyramine reactions with moclobemide, as some degree of dietary caution is still recommended. Nevertheless, when adequately dosed, there is much less likelihood of a dangerous reaction when tyramine is ingested in conjunction with a reversible MAOI. Although the risk for a hypertensive reaction from dietary tyramine may be reduced by RIMAs, the risk for serotonin syndrome with drugs that block 5-HT reuptake may not be similarly reduced, as the mechanism of 5-HT toxicity is different.
Transdermal delivery of a selective MAO-B inhibitor
While RIMAs may be as efficacious as irreversible MAOIs and may theoretically require less dietary tyramine restriction, transdermal delivery of an MAOI can allow the patient to have a diet without any dietary tyramine restrictions. Selective MAO-B inhibitors given orally at low doses do not inhibit a significant amount of MAO-A, and thus there is little risk of hypertension from dietary amines. However, at low oral doses, MAO-B inhibitors are also not effective antidepressants due to the lack of significant elevations in brain 5-HT or NE. An antidepressant effect, however, can be achieved when the MAO-B inhibitor selegiline is given orally in doses that cause it to lose its selectivity and inhibit MAO-A as well. However, this type of dose would also cause a tyramine reaction. In order to prevent this problem, selegiline is administered transdermally, thus delivering the drug directly into the systemic circulation, hitting the brain in high doses and avoiding a first pass through the liver. Once the drug recirculates to the intestine and liver, the levels have decreased and mostly MAO-B is inhibited. This action is sufficiently robust and selective that for low doses of transdermal selegiline, no dietary tyramine restrictions are necessary. At high doses of transdermal selegiline, there is likely some MAO-A inhibition in the gut, and thus some dietary tyramine restrictions may be prudent. In some studies of depressed patients receiving transdermal selegiline,46 dietary restrictions were not followed, yet tyramine reactions were not reported. Therefore, at high doses of transdermal selegiline, some dietary caution may be warranted, but it appears that at low doses, dietary restrictions may not be necessary.
Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants. 2008