MAO inhibitors and tryptamines

Monoamine oxidase (MAO) is the primary inactivation pathway of most tryptamines. Because of this, inhibitors of the MAO enzyme (MAOIs) can be used to potentiate the effects of tryptamines and to make DMT and 5-MeO-DMT orally active.

MAO inhibitors fall into two classes: Irreversible and reversible MAOIs. In addition they can inhibit either or both of the two types of the MAO enzyme, MAO-A and MAO-B which are associated with serotonergic and dopaminergic neurons respectively. Irreversible MAOIs (e.g. the hydrazides iproniazid and phenelzine) bind permanently to the enzyme and cause MAO inhibition lasting 1-2 weeks after ingestion. They are used clinically to treat depression. Reversible MAOIs, such as moclobemide, which is used as an antidepressant, and the beta-carbolines harmine and harmaline, are effective for much shorter time, maybe up to 24 hours. Recreational drug users around the world are using mainly harmine and harmaline despite the lack of scientific studies on their effects on humans.

Natives of Amazon have traditionally combined Banisteriopsis caapi vine, which contains harmine, harmaline and related beta-carbolines, with DMT-containing plants to make the orally active brew ayahuasca. Other plants containing harmine and/or harmaline can be substituted for B. caapi. The usual 'North American ayahuasca' consists of Peganum harmala seeds and Desmanthus illinoensis roots, and in Australia 'acaciahuasca' leaves of Acacia complanata are combined with material from DMT-containing acacias (the effectivity of this mixture hasn't been confirmed). MAOIs have also been used to potentiate the effects of mushrooms containing psilocybin. Terence McKenna has mentioned chocolate being a weak MAOI, which could be a reason for the popular habit of ingesting mushrooms with cocoa.

Peganum harmala (Syrian rue) seeds are the most concentrated natural source of harmine and harmaline - about 3% of their weight consists of these alkaloids. Banisteriopsis caapi has been found to contain from 0.18% to 1.36% beta-carbolines, with the concentration of harmine being from 0.057% to 0.635% (McKenna et al [1984]). According to anecdotal reports one gram of P. harmala seeds ingested inhibits MAO enough to make DMT orally active.

Harmine and harmaline are hallucinogenic on their own with doses starting from around 300 mg (Naranjo [1967]), but often cause physical side-effects such as nausea and tremors in this dose range. They have little emotional or 'psychedelic' effects, but produce strong visual hallucinations. Because of this the natives of Amazon often add larger amounts (75-100 cm of stem per dose) of B. caapi to ayahuasca brew than is needed for MAO inhibition (Luna [1984]).

There are significant dangers in using MAO inhibitors. Most MAOIs potentiate the cardiovascular effects of tyramine and other monoamines found in foods. Ingestion of aged cheese, beer, wine, pickled herring, chicken liver, yeast, large amounts of coffee, citrus fruits, canned figs, broad beans, chocolate or cream while MAO is inhibited can cause a hypertensive crisis including a dangerous rise in blood pressure. Effects of amphetamines, general anaesthetics, sedatives, anti-histamines, alcohol, potent analgesics and anticholinergic and antidepressant agents are prolonged and intensified. Overdosage of MAOIs by themselves is also possible with effects including hyperreflexia and convulsions.


Foods to avoid on MAOIs

Micromedex Inc. - Vol. 82 Exp. 12/94

Tyramine is an amino acid which is found in various foods, and is an indirect sympathomimetic that can cause a hypertensive reaction in patients receiving MAOI therapy. Monoamine oxidase is found in the gastrointestinal tract and inactivates tyramine; when drugs prevent the catabolism of exogenous tyramine, this amino acid is absorbed and displaces norepinephrine from sympathetic nerve ending and epinephrine from the adrenal glands. If a sufficient amount of pressor amines are released, a patient may experience a severe occipital or temporal headache, diaphoresis, mydriasis, nuchal rigidity, palpitations, and the elevation of both diastolic and systolic blood pressure may ensue (Anon [1989]; Da Prada et al [1988]; Brown & Bryant [1988]). Therefore, dietary restrictions are required for patients receiving MAOIs. Extensive dietary restrictions previously published were collected over a decade ago and due to changes in food processing and more reliable analytical methods, new recommendations have been published (Anon [1989]; McCabe [1986]). The tyramine content of foods varies greatly due to the differences in processing, fermentation, ripening, degradation, or incidental contamination. Many foods contain small amounts of tyramine and the formation of large quantities of tyramine have been reported if products were aged, fermented, or left to spoil. Because the sequela from tyramine and MAOIs is dose-related, reactions can be minimized without total abstinence from tyramine-containing foods. Approximately 10 to 25 mg of tyramine is required for a severe reaction compared to 6 to 10 mg for a mild reaction. Foods that normally contain low amounts of tyramine may become a risk if unusually large quantities are consumed or if spoilage has occurred (McCabe [1986]). Three lists were compiled (foods to avoid, foods that may used in small quantities, and foods with insufficient evidence to restrict) to minimized the strict dietary restrictions that were previously used and improve compliance and safety of MAOI therapy. The foods to avoid list consists of foods with sufficient tyramine (in small or usual serving sizes) that would create a dangerous elevation in blood pressure and therefore should be avoided (McCabe [1986]).

Foods to Avoid

Alcohol
Avoid Chianti wine and vermouth. Consumption of red, white, and port wine in quantities less than 120ml present little risk (Anon [1989]; Da Prada et al [1988]; McCabe [1986]). Beer and ale should also be avoided (McCabe [1986]), however other investigators feel major US brands of beer are safe in small quantities (<120 ml) (Anon [1989]; Da Prada et al [1988]), but imported beer should not be consumed unless a specific brand is known to be safe. Whisky and liqueurs such as Drambuie and Chartreuse have caused reactions. Alcohol-free beer and wines may contain tyramine and should be avoided (Anon [1989]; Stockley [1993]).
Banana peel
A single case report implicates a banana as the causative agent, which involved the consumption of whole stewed green banana, including the peel. Ripe banana pulp contains 7 mcg/gram of tyramine compared to a peel which contains 65 mcg/gram and 700 mcg of tyramine and dopamine, respectively (McCabe [1986]).
Bean curd
Fermented bean curd, fermented soya bean, soya bean pastes contain a significant amount of tyramine (Anon [1989]).
Broad bean (fava) pods
These beans contain dopa, not tyramine, which is metabolized to dopamine and may cause a pressor reaction and therefore should not be eaten particularly if overripe (McCabe [1986]; Anon [1989]; Brown & Bryant [1988]).
Cheese
Tyramine content cannot be predicted based on appearance, flavor, or variety and therefore should be avoided. Cream cheese and cottage cheese have no detectable level of tyramine (McCabe [1986]; Anon [1989], Brown & Bryant [1988]).
Fish
Fresh fish (Anon [1989]; McCabe [1986]) and vacuum-packed pickled fish or caviar contain only small amounts of tyramine and are safe if consumed promptly or refrigerated for short periods; longer storage may be dangerous (Anon [1989]). Smoked, fermented, pickled (herring) and otherwise aged fish, meat, or any spoiled food may contain high levels of tyramine and should be avoided (Anon [1989]]; Brown & Bryant [1988]).
Ginseng
Some preparations have resulted in a headache, tremulousness, and manic-like symptoms (Anon [1989]).
Protein extracts
Three brands of meat extract contained 95, 206, and 304 mcg/gram of tyramine and therefore meat extracts should be avoided (McCabe [1986]). Avoid liquid and powdered protein dietary supplements (Anon [1989]).
Meat, nonfresh or liver
No detectable levels identified in fresh chicken livers; high tyramine content found in spoiled or unfresh livers (McCabe [1986]). Fresh meat is safe, caution suggested in restaurants (Anon [1989]; Da Prada et al [1988]).
Sausage, bologna, pepperoni, and salami
contain large amounts of tyramine (Anon [1989]; Da Prada et al [1988]; McCabe [1986]). No detectable tyramine levels were identified in country cured ham (McCabe [1986]).
Sauerkraut
Tyramine content has varied from 20 to 95 mcg/gram and should be avoided (McCabe [1986]).
Shrimp paste
contains a large amount of tyramine (Anon [1989]).
Soup
should be avoided as protein extracts may be present; miso soup is prepared from fermented bean curd and contain tyramine in large amounts and should not be consumed (Anon [1989]).
Yeast, brewer's or extracts
Yeast extracts (Marmite) which are spread on bread or mixed with water, brewer's yeast, or yeast vitamin supplements should not be consumed. Yeast used in baking is safe (Anon [1989]; Da Prada et al [1988]; McCabe [1986]).

Foods to use with caution
(less than 120ml)

This list categorizes foods that have been reported to cause a hypertensive crisis if foods were consumed in large quantities, stored for prolong periods, or if contamination occurred. Small servings (less than 120ml) of the following foods are not expected to pose a risk for patients on MAOI therapy (McCabe [1986]).

Alcohol
see under foods to avoid.
Avocados
contain tyramine, particularly overripe (Anon [1989]) but may be used in small amounts if not overripened (McCabe [1986]).
Caffeine
contains a weak pressor agent, large amounts may cause a reaction (Anon [1989]).
Chocolate
is safe to ingest for most patients, unless consumed in large amounts (Anon [1989]; McCabe [1986]).
Dairy products
Cream, sour cream, cottage cheese, cream cheese, yoghurt, or milk should pose little risk unless prolonged storage or lack of sanitation standards exists (Anon [1989]; McCabe [1986]). Products should not be used if close to the expiration date (McCabe [1986]).
Nuts
large quantities of peanuts were implicated in a hypertensive reaction and headache. Coconuts and brazil nuts have also been implicated, however no analysis of the tyramine content was performed (McCabe [1986]).
Raspberries
contain tyramine and small amounts are expected to be safe (McCabe [1986]).
Soy sauce
has been reported to contain large amounts of tyramine and reactions have been reported with teriyaki (Anon [1989]), however analysis of soy sauce reveals a tyramine level of 1.76mcg/ml and fermented meat may have contributed to the previously reported reactions (McCabe [1986]).
Spinach, New Zealand prickly or hot weather
large amounts have resulted in a reaction (Anon [1989]; McCabe [1986]).

More than 200 foods contain tyramine in small quantities and have been implicated in reactions with MAOI therapy, however the majority of the previous reactions were due to the consumption of spoiled food. Evidence does not support the restriction of the following foods listed if the food is fresh (McCabe [1986]).

Any protein FOOD, improperly stored or handled, can form pressor amines through protein breakdown. Chicken and beef liver, liver paté, and game generally contain high amine levels due to frequent mishandling. Game is often allowed to partially decompose as part of its preparation. Ayd [1986] reported that the freshness of the food is a key issue with MAOIs and that as long as foods are purchased from reputable shops and stored properly, the danger of a hypertensive crisis is minimal. Some foods should be avoided, the most dangerous being aged cheeses and yeast products used as food supplements (Gilman et al [1985]).

With appropriate dietary restrictions, the incidence of hypertensive crises has decreased to approximately 4% (Zisook [1985]). Treatment of a hypertensive reactions includes the administration of phentolamine (Anon [1989]) 2.5 to 5 milligrams intravenously (slow) titrated against blood pressure (Zisook [1985]; Lippman & Nash [1990]). One report has suggested that the use of sublingual nifedipine 10 milligrams was effective in treating 2 hypertensive reactions following the ingestion of a tyramine-containing food in a patient receiving MAOI therapy (Clary & Schweizerr [1987]). Chlorpromazine also has alpha-blocking properties and has been recommended as an agent for discretionary use (patient-initiated treatment) in the setting of dietary indiscretion (Lippman & Nash [1990]).

Conclusion

Dietary restrictions are required for individuals receiving monoamine oxidase inhibitor therapy to prevent a hypertensive crisis and other side effects. The foods listed in the dietary restrictions have been categorized into those foods that must be avoided, foods that may be ingested in small quantities, and those foods that were previous implicated in reactions but upon analyses of fresh samples only a small tyramine content was identified and should be safe to consume if freshness is considered.

References

Anon [1989] 'Foods interacting with MAOI inhibitors' Med Lett Drug Ther 31: 11-12
Ayd, F J [1986] 'Diet and monoamine oxidase inhibitors (MAOIs): an update' Int Drug Ther Newslett 21: 19-20
Brown, C S & Bryant, S G [1988] 'Monoamine oxidase inhibitors: safety and efficacy issues' Drug Intell Clin Pharm 22: 232-235
Clary, C & Schweizer, E [1987] 'Treatment of MAOI hypertensive crisis with sublingual nifedipine' J Clin Psychiatry 48: 249-250
Da Prada, M, Zurcher, G, Wuthrich, I et al [1988] 'On tyramine, food, beverages and the reversible MAO inhibitor moclobemide' J Neural Transm 26(Suppl): 31-56
Gilman, A G, Goodman, L S & Rall, T W et al (eds) [1985] Goodman and Gilman's The Pharmacological Basis of Therapeutics 7th edition, Macmillan Publishing, New York, NY
Lippman, S B & Nash, K [1990] 'Monoamine oxidase inhibitor update. Potential adverse food and drug interactions' Drug Safety 5: 195-204
McCabe, B J [1986] 'Dietary tyramine and other pressor amines in MAOI regimens: a review' J Am Diet Assoc 86: 1059-1064
Stockley, I [1993] 'Alcohol-free beer not safe for MAOI patients' Pharm J 250: 174
Zisook, S [1985] 'A clinical overview of monoamine oxidase inhibitors' Psychosomatics 26: 240-251

Author

Theodore G Tong, Pharm D/C Hansen
Assistant Clinical Professor of Pharmacy
University of California
San Franscisco, California 94143
10/79
Revised by DRUGDEX(R) Editorial Staff
Denver, Colorado 80204, 09/82
Revised by DRUGDEX(R) Editorial Staff, 09/83; 07/85;07/86; 09/89; 04/93; 01/94
(DC2763)


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