Monoamine Oxidase Inhibitors (MAOI)

Monoamine Oxidase Inhibitors (MAOIs) are antidepressants most commonly used in the treatment of major depressive disorder.

  • MAOIs such as tranylcypromine and phenelzine, were among the first drugs used to treat major depressive disorder.
  • MAOIs are thought to be more effective than newer antidepressants because they collectively block the catabolism (breakdown) of multiple neurotransmitters, including: serotonin, norepinephrine and dopamine in the brain (rather than say just serotonin in SSRIs).
  • However, these early MAOIs were problematic because they are non-selective and have an irreversible binding profile.
    • This meant early MAOIs caused severe hypertensive crisis when patients ate food and or drank beverages that were high in tyramine.
    • This is because tyramine is a vasoactive substance (thus would not be broken down due to the presence of the MAOIs) and could cause a hypertensive crisis.
    • Due to these concerns, MAOIs have been largely been replaced by modern antidepressants such as SSRIs and SNRIs.
    • However, they can still be effective medications for patients who do not respond to other antidepressants.

Monoamine Oxidase Functions

Monoamine oxidase A (MAO-A) Monoamine oxidase B (MAO-B)
Substrates • Dopamine
• Tyramine
• Serotonin
• Norepinephrine
• Dopamine
• Tyramine
• Phenylethylamine
Tissue Distribution Brain, gut, liver, placenta, skin Brain, platelets, lymphocytes

Reversible and Irreversible Inhibitors of Monoamine Oxidase

Irreversible Reversible
Medication Class MAOI Reversible Inhibitors of Monoamine Oxidase-A (RIMAs)
Examples Phenylzine (Nardil) 15-90 mg (divided into TID dosing for acute)
Tranylcypromine (Parnate) 10-60 mg (divided into BID dosing for acute)
Selegiline (Eldepryl)
• Isocarboxazid (Marplan)
Moclobemide (Manerix) 300-600mg, doses of 600-900 mg can be used, but dietary restrictions become an issue
Diet Restrictions Yes. Dietary restrictions are an issue as drugs bind MAO irreversibly and body must produce more MAO. Dietary restriction is less of an issue. Binds and unbinds MAO at low/moderate doses. However, at high doses can mimic an MAOI.
Dosing Acute dosing often requires elevated doses, which can then be decreased during maintenance

Length of Irreversible Inhibition

The irreversible inhibition lasts about 10 days.[1]
  • MAOIs inhibit both MAO-A and MAO-B.
  • The inhibition increases levels of the three primary amine neurotransmitters (norepinephrine, serotonin, dopamine)
  • When switching from a serotonergic antidepressant (e.g. - SSRI) to an MAOI, it is recommended to wait at least 7 days for the drug to wash out from the system.
    • For patients on fluoxetine, which has an extremely long half-life, a minimum of 5 weeks washout is recommended before starting.

There have been reports of serious, sometimes fatal reactions when MAOIs are given before, with, or shortly after discontinuation with some SSRIs or SNRIs. It is recommended that MAOIs are not used in combination with SSRIs or SNRIs. The following washout periods are recommended:

  • If on an MAOI, and considering switching to an SSRI or SNRI - 2 week wash out recommended
  • If on an SSRI (not fluoxetine), and considering switching to an MAOI - 2 week wash out recommended
  • If on fluoxetine and considering switching to an MAOI - 5 week wash out recommended
  • If on an SNRI, and considering switching to an MAOI – 1 week wash out recommended
  • Contraindicated with SSRIs, TCAs (e.g. - clomipramine), St. John’s wort, meperidine, dextromethorphan, linezolid (to avoid precipitating serotonin syndrome).
  • For these medications which have norepinephrine reuptake, caution is warranted (but not an absolute contraindication):
    • Decongestants: phenylephrine, pseudoephedrine
    • Stimulants: amphetamine, methylphenidate, modafinil, armodafinil
    • Local anaesthetics: tramadol, cocaine, phentermine.
  • This is particularly important for patients who have the cold/flu, or have an upcoming dental or surgical procedure.
  • Although a hypertensive crisis related to a high tyramine diet is a common concern. Hypotension is equally important to be aware of in MAOIS.[2]
  • It is thought this occurs since MAOIs result in the increased production of octopamine, which is a “false neurotransmitter” that has little alpha or beta adrenergic activity. However, it displaces noradrenaline, therefore rendering sympathetic nerve transmission non-functional, resulting in hypotension.
  • Hypotensive episodes can be managed via patient education and telling the individual to rise slowly when moving from supine to standing position.
  • Most patients will have a homeostatic adrenergic re-adaptation of their blood pressure over time.[3]
  • MAOIs have been reported to cause or worsen insomnia, and dosing it during the day may be helpful.

MAOIs and Diet

While dietary restrictions are minimal (in particular for moclobemide), it is very important to do patient counselling about dietary intake prior to use MAOIs!
  • Tyramine is a pressor agent (i.e. - increases blood pressure) and is normally metabolized by MAO-A in the gut and the liver.
    • If an individual takes both an MAOI and eats foods with high tyramine content, tyramine levels can quickly reach dangerous and cause a hypertensive crisis that requires emergency treatment (see History and Mechanism of Action section above).
    • This is because tyramine enters the nerve terminal via norepinphrine transporters (NET) and then displaces NE from vesicles (similar to amphetamines). Thus, the following foods should not be taken:

MAOI Diet: Foods to Avoid and Safe Foods when on an MAOI

Foods to Avoid OK Foods
Cheeses All matured or aged cheeses, and dishes made with these cheeses (e.g. - lasagna). This is pretty much all the good cheese! :( Only the following cheeses are safe to eat: fresh cottage cheese, cream cheese, ricotta cheese, and processed cheese slices. Fresh milk products such as sour cream, yogurt, and ice cream are also safe.
Meat, Fish, Poultry Fermented and dry sausages such as salami, mortadella, and summer sausages. Improperly stored meat, fish, or poultry. Improperly pickled herring. Any fresh packaged or processed meat (e.g. - chicken pot pie, hot dogs), poultry, or fish. Fresh products should always be stored in a fridge and/or eaten immediately.
Fruits and Vegetables Fava or broad bean pods (other beans are OK), banana peels Banana pulp and all other fruits and vegetables are OK
Beverages On-tap beer No more than two bottled or two canned beers or two 4 fluid ounce (oz) glasses or red or white wine per day.
Miscellaneous Marmite (concentrated yeast extract), sauerkraut, soy sauce, soy bean condiments Other yeast extracts (e.g. - Brewer's yeast), pizzas without aged cheeses added, soy milk, tofu
  • The most well-known and dangerous adverse event is serotonin syndrome.
  • The combination of an SSRI or SNRI and an MAOI inhibits results the two different inhibitory mechanisms
    • The blocking of reuptake of serotonin by the SSRI/SNRI, plus the blocking of the destruction of serotonin by MAOIs can result in extremely dangerous levels of serotonin!
  • MAOis, and phenelzine in particular can reduce vitamin B6 (pyridoxine) levels.[4][5]
    • Symptoms of B6 deficiency include seizures, hyperirritability, peripheral neuropathy, and sideroblastic anemia.
  • Many clinicians recommend that their patients wear medical alert bracelets stating they are taking MAOIs in case they become unconscious in an emergency and receive medications such as pressors.
  • Insomnia (tranylcypromine > phenelzine)
  • Weight gain (phenelzine > tranylcypromine)