PsychoTropical Research - Monoamine oxidase inhibitors

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors and diet

Advice and information concerning 'Parnate' and 'Nardil' (MAOIs, monoamine oxidase inhibitors).

This advice is relevant for all persons taking 'Parnate' or 'Nardil' MAOIs. These drugs all belong to a group that are similar and are called Mono-Amine Oxidase Inhibitors ('MAOIs'). The enzyme 'MAO' has two sub-types, A and B.

This document covers diet (both food and drink) and also drug interactions for those on 'MAOIs'. It is intended to inform and assist both doctors 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 kept on the person (handbag or wallet), and also in the car (glove box) as well as at home.

Information such as that contained in here should be given to any person supplying treatment, or advising on any aspect of treatment, including 'herbalists', 'naturopaths' and any other similar therapists, as well as any dentist or any medical practitioner who is consulted.

Sticking to a simple diet is important, and necessary, whilst taking MAOIs. This is because a few foods contain a natural substance in them (an amino acid called tyramine) that can make the blood pressure (BP) go dangerously high. Remember, the seriousness of any BP reaction is in proportion to the amount of any of the ‘wrong’ food (or drink) that is consumed.

Deaths from MAOI induced hypertension are very rare. It is hard to find many reported in the last 50 years. This suggests that to regard MAOIs as dangerous is a significant over-reaction. A search of the whole Pubmed data base returns 67 hits for the keywords ‘fatal’ + ‘monoamine oxidase inhibitor’. Many of these relate to serotonin toxicity, older reports to hepatic toxicity, but not one single report of intra-cranial bleeding. It can, and does occur, but there are no reliable estimates of frequency. Another possible perspective is to note that fatal cerebral bleeds are documented as a result of the increase in arterial blood pressure secondary to weight lifting (1), which can elevate BP to 480 mm Hg.

The only foods that have enough tyramine in them to cause significant reactions, when eaten in moderation, are those that have been subjected to the action of micro-organisms. If that has happened then such foods may sometimes contain so much tyramine that they are dangerous.

The reaction can only occur if a relatively large amount of ‘tyramine’ is eaten or drunk (see list below). A reaction consists of a big increase in blood pressure (BP). The increase in BP is greater with larger quantities of the food; this is important to remember because there is no cause for worry if, as an example, a little grated cheese on a salad has been eaten (see the list below). The reaction could make the BP high enough to produce a severe pounding headache. This headache is unlike a usual headache because it comes on quickly and is very severe (i.e. painful). It usually starts soon after eating, maybe within 15 minutes, usually within one hour. Any headache starting more than two hours after eating is unlikely to be due to a high blood pressure reaction. 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’ would occur (as a result of the high BP).

Foods to be restricted or avoided because of 'tyramine'

(see below for details of tyramine levels in different foods, and references)

  1. Cheeses. Some mature cheeses have very high levels of tyramine, especially ‘mature’ cheese types like Stilton, matured Cheddar, Parmigiano, Mozzarella, Brie and Camembert; the 'smellier' it is the more tyramine it probably contains. A twenty gram serving of a strong cheese could possibly raise the BP to a measurable extent (but not to a dangerous extent). Larger quantities become progressively more risky. Most modern supermarket processed cheese has low (to the extent of being completely safe) levels of tyramine; however tyramine levels are unpredictable, so it is risky to experiment because the worst possible outcome, even if that is remote, is a ‘stroke’. We can say that 'ricotta' and 'cottage' cheese types are always safe to eat because they are not ‘matured’.
  2. Extracts such as ‘Vegemite’, ‘Promite’, 'Marmite', ‘Bovril’ must be avoided. Foods like soy sauce, 'tofu' and 'miso' are made in a similar way; i.e. by 'fermentation' of brews containing proteins, so only small amounts can be safely eaten. Because the BP goes up in proportion to the amount of tyramine that is consumed, it is OK to have small quantities (see below for what 'small' actually means).
  3. Meat products are safe, but if they are not fresh, i.e. if they have been subject to decomposition by micro-organisms, then they may be risky; eg liver pate (and similar meat or fish pastes) are perfectly safe if freshly made and properly refrigerated. But after a couple days left out at room temperature they could be risky. Similarly 'salami' and 'pepperoni' sausages, and dried meats, are usually OK but caution is warranted. Liver that is near its' 'use by' date when purchased, and is then kept in a domestic fridge that is not cold enough, may become risky.
  4. Wine and beer in true moderation (two drinks in any six hour period) are definitely safe. Modern hygienic production methods will make excessive tyramine levels rare. Badly made or stored drinks may be risky, so avoid ‘home made’ wines or beers. Bottled beer is almost certain to be safe; except avoid ‘live’ beers which may be available from 'boutique' producers. They can be distinguished by the sediment (of dead yeast) in the bottom and they are cloudy if shaken. Also ‘keg’ or 'tap' beers may sometimes have significant tyramine levels, but only because the pipes are not kept clean (pipe runs can be very long, and not chilled, so the residue is in a dirty state, and can be risky if you have the first stagnant sample).
  5. Sauerkraut can sometimes contain sufficient tyramine levels to warrant restriction (see below) and broad (fava) beans are OK but the bean pods should not be eaten.

Other non-serious interactions that are not dangerous

Many plant derived substances, eg 'herbs' and 'foods' like chocolate, coffee, and tea contain chemical compounds that act as 'drugs', eg stimulants like caffeine. These effect everyone but may have an exaggerated effect in those taking various sorts of antidepressant drugs, including MAOIs; they should be taken in moderation and avoided if they precipitate symptoms such as anxiety, jitteriness, agitation, poor sleep etc.

MAOIs Interactions with other drugs

Different kinds of 'psychotropic' drugs (i.e. those that effect the brain) should not be mixed without appropriate medical advice. This, of course, includes both alcohol and 'illicit' drugs, some of which may prove fatal if mixed with MAOIs, eg MDMA 'ecstasy'. Remember the term 'psychotropic' includes, among other drugs, narcotic analgesics, anti-histamines and anti-epileptic drugs as well as 'herbal' preparations like St John's Wort and ginseng.

Note especially:-- cough and cold remedies available 'over the counter' must be checked. The anti-histamines brompheniramine or chlorpheniramine are best avoided because they are SRIs (serotonin reuptake inhibitors), all other anti-histamines are safe (2).

Analgesics (pain killers) that are safe to take with MAOIs:-- Aspirin and Paracetamol and all the 'NSAIDs' (anti-inflammatory drugs used for arthritis) are safe, such as: ibuprofen, mefenamic acid, naproxen, indomethacin, phenylbutazone etc..

All anti-anxiety drugs (benzodiazepines) like diazepam, oxazepam and temazepam are safe.

Stronger analgesics (opioids like morphine) that are safe are:-- codeine, oxycodone, buprenorphine and morphine. Some other strong analgesics are dangerous (see below) because they can sometimes precipitate serotonin toxicity, often called the serotonin syndrome (3).

Risky analgesics

The risk with opioid analgesics (and 'SSRI' type antidepressant drugs) is that of serotonin toxicity (ST) or 'serotonin syndrome', this is quite different to the hypertensive reaction with tyramine (4). Do please note that many supposedly authoritative current texts ( e.g. Physicians Desk Reference, British National Formulary, Australian Medicines Handbook) still contain serious inaccuracies (3). The analgesics that are dangerous are dangerous because they posses serotonergic activity, probably as serotonin reuptake inhibitors. Pethidine (aka meperidine) and tramadol especially must not be given to anyone on MAOIs. Dextromethorphan, (dextro)propoxyphene and pentazocine are also to be avoided.

Antidepressant drugs

Any antidepressant drug that works as a serotonin reuptake inhibitor (SRI) is potentially dangerous (possibly even fatal) if combined with any MAOI, even the newer 'RIMAs' like moclobemide that are said to be 'selective' and 'reversible' (5). If people have been taking any serotonin reuptake inhibitor type drug including:-- sertraline, paroxetine, fluvoxamine, cipramil, clomipramine, or imipramine, milnacipran, venlafaxine, duloxetine or sibutramine within two or three weeks specialist advice may be needed before starting MAOIs (including 'Aurorix', and 'Eldepryl' and 'Selgene'). Washout intervals varying between one and five weeks may be required for these drugs.

Fluoxetine

If fluoxetine has been taken (Prozac and other names) at any time within the previous three months caution is required and specialist advice may be needed before starting various drugs, but particularly any MAOIs including moclobemide. This is because fluoxetine has a very long elimination half-life in some people (it takes a long time to get out of the system).

Ceasing treatment

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

Medical treatment of high BP

If the blood pressure is very high then drugs may be given to reduce it; eg oral nifedipine 10 mg, phentolamine 5-10 mg IV, or chlorpromazine 25-50 mg IMI or IV.

How much is safe?

Many people on MAOIs can ingest up to about 25 mg of tyramine (as part of a meal) without experiencing a medically dangerous level of hypertension. However, there is a lot of individual variation in sensitivity to tyramine. It seems reasonable to aim not to exceed an intake of 25 mg of tyramine. However it is possible that some individuals may get significant reactions with as little as 10 mg of tyramine. A quantity of 50 grams of high tyramine content cheese could contain as much as 25 mg of tyramine and would therefore be likely to be safe for most people on an MAOI. Similarly 25 ml of the ‘strongest’ soy sauce might contain as much as 25 mg of tyramine.

Tyramine in liquids taken on an empty stomach should be regarded as a separate issue. This is because they are likely to be absorbed much more rapidly (6). One small (330 ml) glass of some beers could possibly have up to 30 mg of tyramine; this might be sufficient to cause a serious reaction in some people if taken on an empty stomach.

The variability between people will mean that it is possible that a undetermined percentage of people may experience a severe reaction with less than 25 mg of tyramine.

The following list gives an indication of likely tyramine levels for relevant substances as indicated by currently available research. It may be used as a guide. It is all to do with ‘freshness’ for fish and meat, whether tyramine is present depends on the type of micro-organism causing the spoilage (e.g. see (7)).

  • Cheese Products
    • A selection of 43 soft and hard cheeses:-- up to 60 mg per 100 grams
    • Goats cheese (8) usually ~ 20 mg per Kg, max 70 mg per Kg.
    • See (9)
  • Soy Bean Products
    • Soy sauce:-- Maximum:-- 940 mg per litre (approx 1 mg per ml). Most samples measured have ranged between 10-200 mg per litre (10,11)
    • 'tofu':-- fresh, less than 1 mg per 100 grams
    • 'tofu':-- 7 days refrigerated, 16 mg per 100 grams
    • 'Soya bean curd':-- fresh, less than 1 mg per 100 grams
    • 'Soya bean curd':-- 7 days refrigerated, less than 1 mg per 100 grams
    • 'miso' soup etc. max ~ 100 mg per 100 ml
  • Dried sausages, saucisson etc (12-14)
    • Most have 100-200 mg per Kg, many samples have been measured and the maximum level in one sample was 740 mg per kg.
    • A typical 100 gram serving would therefore contain 10-20 mg of tyramine.
  • Fish products
    • Fresh:-- up to 16 mg per 100 grams
    • Usually more like 1 mg per Kg (15)
    • Dried salted Tuna roe 90 mg/kg (16)
    • Whole and filleted trout kept on ice for up to 18 days, max at 18 days was 7 mg/kg (7)
    • Raw fish up to 2.6 mg per 100 grams
  • Misc
    • Ripe banana peel:-- 6.5 mg per 100 grams
    • Protein extracts:-- three brands of meat extract contained 10, 20 and 30 mg per 100 grams
    • Sauerkraut:-- varies from 2 to 10 mg per 100 grams
  • Alcohol
    • (17)
    • White wine (12 samples) max 6.5 mg/L
    • Red wine (10 samples) max 3.8 mg/L
    • Chianti (12 samples) max 4.7 mg/L
  • Beer
    • 'Keg' or 'tap' beers:-- 25 to 100 mg per litre
    • Bottled beers:-- 10 mg per litre
    • Beer (9 samples, all same brewery) max 2.6 mg/L

Quotes Horwitz '6-10 mg provokes hypertensive response'. However, note that a response probably means a measurable elevation, like 30 millimetres of mercury, and that does not equate with any significant degree of medical risk.

References

1. Haykowsky, MJ, Findlay, JM, and Ignaszewski, AP, Aneurysmal subarachnoid hemorrhage associated with weight training: three case reports. Clin J Sport Med, 1996. 6(1): p. 52-5.

2. Gillman, PK, Serotonin syndrome: history and risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491.

3. Gillman, PK, Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 2005. 95: p. 434-441.

4. Gillman, PK and Whyte, IM, Serotonin syndrome, in Adverse Syndromes and Psychiatric Drugs, P. Haddad, S. Dursun, and B. Deakin, Editors. 2004, Oxford University Press: Oxford. p. 37-49.

5. Gillman, PK, Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). Central Nervous System Drug Reviews, 2004. 10: p. 83-85.

6. VanDenBerg, CM, et al., Tyramine pharmacokinetics and reduced bioavailability with food. J Clin Pharmacol, 2003. 43(6): p. 604-9.

7. Chytiri, S, et al., Relation of biogenic amines with microbial and sensory changes of whole and filleted freshwater rainbow trout (Onchorynchus mykiss) stored on ice. J Food Prot, 2004. 67(5): p. 960-5.

8. Novella-Rodriguez, S, et al., Influence of starter and nonstarter on the formation of biogenic amine in goat cheese during ripening. J Dairy Sci, 2002. 85(10): p. 2471-8.

9. Innocente, N and D'Agostin, P, Formation of biogenic amines in a typical semihard Italian cheese. J Food Prot, 2002. 65(9): p. 1498-501.

10. Ibe, A, et al., [Production of tyramine in "moromi" mash during soy sauce fermentation]. Shokuhin Eiseigaku Zasshi, 2003. 44(5): p. 220-6.

11. Shulman, KI and Walker, SE, Refining the MAOI diet: tyramine content of pizzas and soy products. J Clin Psychiatry, 1999. 60(3): p. 191-3.

12. Suzzi, G and Gardini, F, Biogenic amines in dry fermented sausages: a review. Int J Food Microbiol, 2003. 88(1): p. 41-54.

13. Parente, E, et al., Evolution of microbial populations and biogenic amine production in dry sausages produced in Southern Italy. J Appl Microbiol, 2001. 90(6): p. 882-91.

14. Bover-Cid, S, et al., Amino acid-decarboxylase activity of bacteria isolated from fermented pork sausages. Int J Food Microbiol, 2001. 66(3): p. 185-9.

15. Ruiz-Capillas, C and Moral, A, Formation of biogenic amines in bulk-stored chilled hake (Merluccius merluccius L.) packed under atmospheres. J Food Prot, 2001. 64(7): p. 1045-50.

16. Periago, MJ, et al., Monitoring volatile and nonvolatile amines in dried and salted roes of tuna (Thunnus thynnus L.) during manufacture and storage. J Food Prot, 2003. 66(2): p. 335-40.

17. Hannah, P, Glover, V, and Sandler, M, Tyramine in wine and beer. Lancet, 1988. 1(1): p. 879.