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Created on Tuesday, 10 July 2012 07:08

Last Updated on Tuesday, 10 July 2012 07:29

Written by Dr Ken Gillman

Monoamine Oxidase Inhibitors, Dietary Tyramine and Drug Interactions

 

Key MAOI Diet Facts

 

·        This info summarises recent research about tyramine

 

·        For people who already follow healthy eating (and drinking) amounts a low tyramine diet involves very few, if any, changes

 

·        Only those foods that are prepared using maturation and ‘fermenting’ techniques, can sometimes have high tyramine, or those that have ‘gone off’

 

·        The possible increased blood pressure reaction that can sometimes result from excess tyramine ingestion is proportional to the amount of the tyramine-containing food eaten

 

·        There is almost no food or drink that is so strong (i.e. high in tyramine) that a small amount (i.e. 50 grams or ml [or less]) is likely to cause a serious or risky degree of hypertension

 

·        Modern cheese is safe (in healthy-sized portions), some mature aged cheeses can have higher tyramine concentrations, so care is needed

 

·        If a reaction ever did occur, and provided you attend hospital if and when you get symptoms, the chance of coming to harm is remote

 

·        The symptoms of a reaction are: a thumping forceful heartbeat (usually a slower than normal pulse rate), paleness (pallor), rapid onset severe headache, tightness in the chest. Pulse may drop as low as 40 beats per minute

 

·        The risk of harm from blood pressure reactions with foods and MAOIs has previously been exaggerated

 

·        Remind your doctors to check the compatibility of any medications they recommended you to take, also re-check this info yourself.

 

·        There are very few over-the-counter (‘OTC’, non-doctor script) drugs that are a problem, because the pseudo-ephedrine type drugs (with intrinsic sympathomimetic activity [ISA]) have been restricted or taken off the market (in many western countries).

 

·        The full version of this monograph (15,000 words, 170+ references) is available as a pdf, see website, an abbreviated version is appended below.

 

 

 

General Summary

 

Interactions between monoamine oxidase inhibitors (MAOIs) and other drugs are now understood much more clearly: I am an internationally recognised expert on one aspect of this, namely serotonin toxicity (ST) aka ‘serotonin syndrome’, see (1-7), and an expert on drug interactions generally.

 

There is now more data on tyramine levels in foods, and also on how much tyramine is likely to constitute a problem. Some previous opinions and advice have over-extrapolated from poor information. This is a summary of my long monograph which surveys more original data on tyramine than any paper previously published.

 

All concentrations are given as milligrams (mg) of tyramine per kilogram (kg) or litre (L). Most food labels are legally obliged to quote information as content per 100 grams (abbreviation 100 g). Other abbreviations like: G, gm, gms and grms, are used, but ‘ g’ is the technically correct form.

 

Although a small proportion of people may get a significant blood pressure increase with only 10 mg of tyramine the majority of people need to have 50 mg or more (in a meal) to get a serious blood pressure increase (i.e. systolic blood pressure [SBP] > 220 mm Hg). For a detailed analysis of the evidence relating to tyramine dose and blood pressure see (1).

 

It is easy to work out how much tyramine is in 10 or 100 g or ml of any of these foods. Learn what 10 g or 100 g looks like, and what sensible food portion sizes are: some people will benefit by consulting a dietician. Also see website information like http://www.win.niddk.nih.gov/publications/PDFs/justenough.pdf

 

For those who already follow healthy eating amounts and patterns the low tyramine diet involves almost no changes at all. A healthy portion of cheese is 25 grams. Few cheeses (even ‘mature’ cheeses) contain more than 25 mg of tyramine in 100 grams (i.e. 25 mg in 100 g = 250 mg/kg). So a 25 gram portion contains only 6 mg of tyramine and that is very unlikely to cause any significant blood pressure increase at all in anyone.

 

Matured cheeses contain 2–3.5 g of salt per 100 g (8), or 20-35 g/kg. The recommended daily salt intake has now been reduced to 1-2 g daily. So that shows how little cheese is necessary, as part of a healthy diet.

 

Even if excessive tyramine is ingested and BP increase occurs, serious consequences are most unlikely providing appropriate action is taken. That will usually mean monitoring blood pressure for a 2-3 hours and possibly having medication to lower it (in hospital) if it goes over about 180 – 200 mm Hg and there is evidence of harmful consequences. Hasty and alarmist treatment of high BP by inexperienced doctors (when there is no evidence of harmful consequences) risks doing more harm than good. Treatment of high BP should generally only be undertaken in hospital (9).

 

I recommend monitoring your own blood pressure with one of the easily available electronic BP monitoring devices. Most people can borrow or buy one of these quite easily. Keep a record of blood pressure for a week before the beginning of treatment. The drop in blood pressure caused by these drugs when you stand up is a good indication of whether they are having a sufficient effect. There is a separate PDF on my website explaining blood pressure and MAOIs [link].

 

Storage of foods below 5°C is a crucial factor, and some domestic fridges fail the test. It is vital to check your fridge temperature.

 

Introduction

 

The drugs in this monograph belong to a group called Mono-Amine Oxidase Inhibitors (MAOIs). The enzyme Mono-Amine Oxidase (MAO) has two sub-types, A and B. This information is most relevant for irreversible MAO-AB inhibitors (the most common are tranylcypromine & phenelzine) and less important for various other types of MAOI.

 

This monograph covers diet (food and drink) and also drug interactions for those on MAOIs. It is intended to inform and assist both doctors, interested non-medical people and those taking MAOIs.

 

Persons on these drugs may be advised to keep some means of identifying the fact that they are on MAOIs readily available. Similar steps as may be taken with insulin dependent diabetes and those suffering epilepsy are appropriate; this is in case of accidents or emergencies. This may be: medical alert bracelet, and/or information in handbag or purse or wallet.

 

The Mechanism of Tyramine Formation

 

Amino Acids

 

Tyramine formation requires the availability of the amino acid precursors tyrosine or phenylalanine and the presence of micro-organisms with amino acid decarboxylase enzyme activity. If favourable conditions for their growth and decarboxylating activity exist then tyramine, and other biogenic amines (BA) like histamine, cadaverine and putrescine may accumulate in foods.

 

Tyramine’s precursors, but little or no actual tyramine, are present at up to 20 mg/kg in animal protein sources, but are generally lower in plants. That is why fresh properly stored foods are always safe. Animal protein can rapidly accumulate tyramine if allowed to go ‘off’. That means any meat not stored at proper fridge temperature of less than 4°C. Meats that have been minced are especially prone to bacterial contamination. Poorly handled mince that has been improperly refrigerated could accumulate significant tyramine quite quickly. That is why all commercial meat and fish processing must now take place at below 4°C by regulation in most countries. Few people in western society would now accept green rotten smelly meat, but eating meat like that was common practice in times gone by, and still is in some places. Smell is only a guide for what to avoid, tyramine can accumulate without things seeming smelly or ‘off’.

 

Older estimations of tyramine concentrations may sometimes be inaccurate.

 

What are the Symptoms of a Blood Pressure Reaction?

 

A reaction is a slow and progressive increase of BP and consists of a thumping heartbeat with an increase in BP. The heart rate (pulse) usually becomes slower. If blood pressure goes up to 180 mm Hg, or more, quite rapid onset of severe headache is usual (although headache is not a reliable indicator of high BP). Tightness in the chest, paleness (pallor) may occur.

 

Any increase in BP is proportional to the amount of tyramine ingested. Symptoms usually start within about 30 minutes. Any symptoms, including headache, starting more than two hours after eating are unlikely to be due to a high blood pressure reaction: the duration of  the reaction is around 1 – 2 hours.

 

If such a reaction occurs, and nothing is done about it, i.e. getting medical help, then there is a small chance that a ‘stroke’ (cerebral bleed or haemorrhage) would occur, which could be serious.

 

Tyramine in Foods and Beverages

 

Minimising or avoiding the few risky foods and beverages that do exist is easy and necessary whilst taking MAOIs. Only a few foods can build up the degree of excess tyramine that can make the blood pressure (BP) go dangerously high. The seriousness of any BP reaction is in proportion to the amount of tyramine that is consumed. It is a dose-related effect, that is why it is safe to ‘test’ small quantities of some foods e.g. your favourite local cheese.

 

Be aware of the total tyramine load that is contained in a meal, even though individual components may not be particularly high.

 

MAOIs lower blood pressure. One of the commonest incorrect statements you will see is that MAOIs raise blood pressure. That is wrong: it is the interaction between tyramine & MAOIs that raises blood pressure, i.e. produces hypertension.

 

A serious BP reaction can only occur if a relatively large amount of  tyramine is eaten or drunk (see list below), i.e. for most people at least 25 mg of tyramine.

 

Only very rarely encountered foods have really high tyramine concentrations (1,000 mg/kg, is exceptionally high) that would require the consumption of at least 25 grams of such a food to get a measureable, but not dangerous, elevation of BP.

 

Milk Products

 

Mature cheeses

 

Matured ‘artisanal’ cheeses can develop high concentrations of tyramine (~ 1,000 mg/kg), e.g. Stilton, Cheddar, Parmigiano, Manchego, Compté. ‘Matured’ means aged for more than 3 months. A twenty-five gram serving of such a strong cheese would have 25 mg of tyramine (i.e. around 1,000 mg/kg), and could possibly raise the BP to a measurable, but not to a dangerous, extent. Most commercial ‘supermarket’ cheeses are low in tyramine (<100 mg/kg) because budget prices do not pay for long warehouse ageing.

 

E.g papers found– Portuguese traditional cheese, Terrincho (10), 29 cheeses from five batches, dairy farms located throughout the region: all < 100 mg/kg. Blue cheese, Czech (11, 12), the mean being 380 mg/kg and different cheeses (vats) varied widely, from 10 mg/kg, to 875 mg/kg. Dutch-type semi-hard cheeses mostly < 50 mg/kg, max 250 (13, 14).

 

Brie and Camembert styles (normally matured for 4 weeks before release): there seem to be no recent assays, all the author has found is older papers; Horwitz (15, 16) found ~ 100 mg/kg. A little more recently: Camembert, 15 samples 100 – 1800 mg/kg, Brie 260 mg/kg (17, 18). One suspects tyramine concentrations are less now because of starter cultures and better storage.

 

Non-matured cheeses

 

Fresh non-matured, i.e. unripened/unaged, cheese styles, and yoghurt, are always safe because milk itself has no tyramine, e.g. curd styles, fromage frais, mascarpone, cream, ricotta, cottage cheeses, bocconcini.

 

Unripened cheeses: 10 samples (19) < 0.5 mg/kg.

 

Goats cheese (20) ‘frais’ styles, usually ~ 20 mg/kg, but aged goats cheeses will be higher, max 70 mg/kg (20).

 

Milk and yoghurt

 

Yoghurt has no tyramine. Novella-Rodriguez, 5 samples no tyramine (19).

 

Fermented Sauces – Vegetable

 

Marmite

 

It has relatively high amounts of biogenic amines ~ 320 mg/kg of tyramine (21). One would need to take 30 ml to get 10 mg tyramine, A teaspoon would have only 5/1000 x 300 mg of tyramine, i.e. only a couple of milligrams.

 

Soy sauce, miso and sufu etc

 

Soy sauce is made from steamed soybeans fermented for as much as 2 years after which it is filtered and pasteurised. Tyramine is produced slowly during the fermentation, typical concentrations ~150 mg per kilo (litre). Miso is similar.

 

Miso, 5 samples tyramine ~ 20 mg/kg (23).

 

Japanese soy sauce: Maximum 940 mg/L (i.e. approx 1 mg/ml). Most samples measured have ranged between only 10-200 mg/L (24).

 

Most supermarket Soy sauces actually have only around 100 mg/L. Yongmeia (25), 40 samples of Chinese soy, mostly less than 200 mg litre (20 of the 40 were < 100 mg/kg). Stute (26), 23 samples soy, < 200 mg/L.

 

Fermented Sauces: Animal

 

Fish sauces

 

They are ubiquitous now, but deeply rooted in Far Eastern cuisine. see Wikipedia, and for a recent reviews refs (23, 26, 27).

 

They will, like everything, vary a bit with producer and hygiene quality, but seem usually to be OK, 200 – 500 mg/kg (bearing in mind its is, like soy sauce, a condiment, so if used in modest amounts (no more than ~ 20 grams) will be safe (28).

 

Korean fermented fish products < 50 mg/kg (23),

 

Stute (26), 45 commercial fish sauces from the Far East, most < 200 mg/kg.

 

Meat and Fish Products

 

Fresh meats

 

Meat products are safe, but if they are not fresh, i.e. if they have been subject to decomposition by micro-organisms, then they could be risky. Fresh liver has no tyramine (29), but if stored badly or past its 'use by' date when purchased, and then kept in a domestic fridge that is not cold enough, may become risky. Similarly, liver pate (and similar meat or fish pastes) are safe if freshly made and properly refrigerated (i.e. below 4°C).

 

Dry cured ham

 

As with all dry cured meat products only low concentrations of tyramine are expected, Lorenzo found < 5 mg/kg (30), which agrees with (31). So ‘Parma ham’, prosciutto, copa etc will all be safe.

 

Fermented sausages

 

Concentrations of tyramine depend, as would be predicted, on the hygienic quality of the meat used and the strains of bacteria involved. Those produced with frozen meat (low temperature processing) usually have maximum concentrations of about 100 mg/kg. The improved starter cultures, now widely used, show a lack of, or much diminished, amino acid decarboxylase activity which results in lower concentrations of BAs (32-35). Latorre-Moratalla et al is a good recent review: it found average of 150 mg/kg, max < 200 mg/kg. The study received financial support from the European community project: Assessment and improvement of safety of traditional dry sausages from producers to consumers (QLK1 CT-2002-02240, Website: www.clermont.inra.fr/tradisausage/). It is a good example of the efforts being made to monitor and improve hygiene standards.

 

In Spanish fermented sausages tyramine was detected at up to 600 mg/kg in some sausages, with mean values of about 200 mg/kg (36). French sausages, both artisanal and industrial, had tyramine maxima of 270 mg/kg (37, 38).

 

Preparations of stock cubes, powders, bouillon, etc.

 

These are not prepared by fermentation but are flavoured extracts and reductions. Populin tested broths, soups, bouillon cubes, pastes and granulated powders etc (21) and found none exceeded 10 mg/kg.

 

Fish

 

Fresh fish

 

Fresh fish is fine, but with fish histamine can be greatly elevated without significant elevation of tyramine. Many regulations limit histamine to between 50 (USA) and 200 mg/kg (EU). Histamine itself causes Scombroidosis (39).

 

Cured fish

 

Various types of fish (especially salmon) are ‘cooked’ using food acids (see also ‘pickling’) e.g. Gravlax, gravad lax is completely safe.

 

Dried fish

 

Dried salted Tuna roe was 90 mg/kg (40).

 

Canned fish

 

Some canned samples reach 10 mg/kg, but that seems rare (41). Max 70 mg/kg (42). Histamine (some were > FDA limit of 50 mg/kg), one was 1,000 mg/kg of histamine! see (43, 44).

 

Pickled fish

 

Pickled herring does not involve a fermentation process and such products are safe providing they are hygienically prepared from fresh fish. Product, like the Strömming (herring) in Baltic countries, which is fermented, will probably contain high concentrations of tyramine.

 

Pizza

 

It depends what you put on it! It should be clear from the data in this monograph that almost all commercial pizzas are highly likely to be safe, as found by Shulman (45).

 

Vegetables

 

Normal servings of vegetables, fruits etc. are unlikely to have any serious adverse effects via histamine, tyramine or l-DOPA.

 

Fava beans

 

Fava beans (Vicia Faba, aka broad beans) have tyramine at about 10 mg/kg (46), & L-DOPA, but not sufficient to have a problematic effect in normal portions.

 

Sauerkraut

 

Sauerkraut is made by lacto-fermentation, as are kimchi & traditional  pickled cucumbers. More than 100 samples from 7 countries, almost all tyramine < 200 mg/kg, (47), < 12 mg/kg (46) and more recently tyramine none at all (48). Korean ‘kimchi’ cabbage average 50 mg/kg, max 120 mg/kg (23).

 

Chocolate

 

Chocolate is completely safe in usual quantities. Pastore (49) found 1 mg/kg for tyramine.

 

Wine and Beer

 

Wine and beer in moderation (two drinks in 2 hours) are safe because they do not contain tyramine unless contaminated. Tyramine in liquids taken on an empty stomach is absorbed more rapidly. One small (330 ml) glass of some ‘live’ beers could, in rare instances, have about 10 mg of tyramine; this might be sufficient to cause a reaction in a minority of people.

 

Wine

 

Wine never contains significant concentrations of tyramine unless contaminated. Recent major reviews covering many hundreds of different wines of all types show tyramine all < 5 mg/L.

 

Beers

 

It is likely that all standard commercial and modern beers all over the world will be safe. Some low volume ‘artisan’ and ‘boutique’ ones are risky on occasion. Some Belgian beers do have high tyramine. Loret et al (50), considered a large number of these Belgian beers and found 21/220 had a mean tyramine of 28 mg/L.

 

MAOIs: Interactions with Other Drugs

 

Believe it or not, but SSRIs interact with other drugs more than do the MAOIs. Tranylcypromine (Parnate) & phenelzine (Nardil) have no clinically significant pharmaco-kinetic interactions (1)

 

The potentially risky interactions are pharmaco-dynamic ones:

 

1.       Serotonin syndrome, caused by SRIs + MAOIs

 

2.       Blood pressure elevation, caused by tyramine in food, or by the other ‘indirectly acting sympathomimetic amines (ISAs)’ (releasers) like pseudoephedrine and phenylephrine.

 

MAOI interactions are clearly understood and are straightforward to avoid. Avoid all drugs that have ‘SRI’ actions: i.e. all SSRIs, SNRIs, the anti-histamines brompheniramine and chlorpheniramine have weak, but possibly significant, SRI potency. All other anti-histamines are safe (51).

 

Analgesics

 

The risk with opioid (narcotic) analgesics is that of serotonin toxicity  (ST) or 'serotonin syndrome' because some are serotonin reuptake inhibitors (SRIs) see (52, 53),

 

Avoid: Pethidine (aka meperidine) and tramadol, Dextromethorphan, (dextro)propoxyphene and pentazocine.

 

Stronger analgesics (narcotics or opioids, like morphine) that are safe: codeine, oxycodone, buprenorphine and morphine.

 

Anti-Depressant Drugs

 

Any drug that works as a serotonin reuptake inhibitor (SRI) is potentially dangerous (possibly even fatal) if combined with an MAOI,:-- sertraline, fluoxetine, paroxetine, fluvoxamine, citalopram, escitalopram, clomipramine or imipramine, or SNRIs like milnacipran, venlafaxine, desvenlafaxine, duloxetine or sibutramine.

 

Of the TCAs only clomipramine and imipramine are sufficiently potent as serotonin reuptake inhibitors to precipitate ST; all other TCAs are quite safe (as are selective NRIs like reboxetine and atomoxetine).

 

On ceasing other antidepressants to start MAOIs, washout intervals varying between one and five weeks may be required (the rule of thumb is allow 5 half-lives to elapse, which is about one week for many of these drugs). No washout is required for TCAs (other than clomipramine and imipramine), or mirtazapine, mianserin, trazodone or reboxetine, because they are safe taken together with MAOIs.

 

Triptans

 

There is no evidence of any significant risk of serotonin toxicity with triptans, despite the FDA warning.

 

Ceasing  Treatment

 

This advice on diet and possible interacting drugs should be followed for a minimum of two weeks (six weeks in some situations) after ceasing MAOIs (between one and three days in the case of moclobemide).

 

Medical Treatment of High BP Resulting from Tyramine Ingestion

 

If excessive tyramine is ingested in cheese etc. blood pressure starts to increase from about half an hour after ingestion, and remains elevated for 1 – 2 hours. Current evidence indicates that elevated BP without signs or symptoms of ‘end organ’ damage does not require treatment, because rapid BP reduction may do more harm than the short term BP elevation (usually less than 2 hours) caused by tyramine (9, 54).

 

It is generally inadvisable for treatment to be initiated by psychiatrists: on the rare occasions where treatment is required it is best initiated after admission to a critical care setting.

 

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References

 

 

 

1.                  Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol, 2011. 31(1): p. 66-74.

 

2.                  Gillman, PK, Combining antidepressants: Understanding Drug Interactions is the Sine Qua Non. Adv Psychiatr Treat, 2010. 16: p. 76-78.

 

3.                  Gillman, PK, CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol (Oxf), 2011. 25(3): p. 429-3.

 

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