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Day # 36: Monoamine Oxidase Inhibitors (MAOI's)

Today we will discuss the monoamine oxidase inhibitors (MAOIs) which include tranylcypromine, phenelzine, selegiline, and isocarboxazid. We will discuss mechanism of action, side effects, and unique characteristics to specific medications within this class.

Today's Content Level: Mostly Beginner and Intermediate (some Advanced due to general lack of familiarity with using MAOI's for most providers)


•MAOIs = Monoamine Oxidase Inhibitors

The monoamine oxidase enzymes (MAO-A and MAO-B) are responsible for the break down of biogenic amines which include serotonin, norepinephrine, dopamine, and tyramine. Tyramine is an intermediate in the conversion of tyrosine to norepinephrine.

  • MAO-A preferentially breaks down serotonin and norephinenhrine.

  • MAO-B preferentially breaks down phenethylamine.

  • Both also deactivate dopamine and tyramine.

•MAO enzymes are found in many parts of the body including the brain, GI tract, liver, platelets, and more.

•MAOIs are medications that irreversibly block the the enzymes MAO-A and MAO-B. This actions prevents the inactivation of these amines thus increase the number of these neurotransmitters in the synapse.

•History: MAOIs were first discovered in the 1950s when a medication used in the treatment of tuberculosis (iproniazid) was noted to have antidepressant qualities. This was the first antidepressant ever marketed but was removed from the market a few years later due to hepatoxicity.

•Currently, MAOIs available include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), rasagiline (Azilect), moclobemide (Manerix) and selegiline (Eldepryl).


•Generally reserved as third or fourth line option for treatment of refractory depression and refractory anxiety disorders. This is due to the increased safety and tolerability of newer agents like the SSRIs and SNRIs as well as significant potential for adverse affects with MAOIs (drug/food interactions -> hypertensive crisis, serotonin syndrome).

  • Refractory depressive and anxiety disorders: used rarely and reserved for treatment resistant cases of 2 or more unsuccessful trials of other antidepressants. Some data show that MAOIs are considered more effective than TCAs in depression with "atypical features" (hypersomnia, increased appetite, heavy sensation in extremities, increased sensitivity to personal rejection). Tranylcypromaine was included in the STAR*D trial. SSRIs would still be first line in these cases.

  • May treat bipolar depression better than TCAs with less hypomania/mania.

  • Some evidence for treatment of pain, migraines, and depression associated with TBI's.

  • Parkinson's disease: selegiline and rasagiline can be used in parkinson's disease. Remember that MAOIs decreased the breakdown of dopamine.

•Start low and go slow with dosing. Small dose increases are recommended while checking orthostatic vital signs for tolerability.


Serotonin syndrome

  • MAOIs have the greatest risk of serotonin syndrome among all antidepressants particularly if used in combination with an SSRI.

  • Wait at least two weeks before switching from an SSRI to MAOI (5 weeks if fluoxetine due to its long half life).

  • Serotonin syndrome was described in detail in a prior post.

  • In brief, important symptoms include mental status changes (lethargy, delirium), neuromuscular abnormalities (clonus, hyperreflexia), and autonomic hyperactivity (increased temperature, heart rate, and blood pressure).

Hypertensive crisis

  • This is a unique adverse reaction and important to understand as it is still commonly tested on licensing exams.

  • MAOIs when taken in combination with foods that are high in tyramine cause a build up of stored catecholamines which leads to the so-called hypertensive crisis.

  • MAO-A metabolizes tyramine in the gut. MAOI causes tyramine to build up which then enters the blood stream and acts as a false neurotransmitter which releases norepinephrine.

  • Foods that are tyramine-rich include red wine, fava beans, cured meats, fermented vegetables, over-ripe fruits, soy sauce, tofu, chicken liver, and certain types of cheese (all aged and fermented cheeses such as bleu, cheddar, gouda, muenster, and more).

  • Can also be precipitated by medications that activate the sympathetic nervous system (sympathomimetics) such as over the counter decongestants, amphetamines, and other stimulants (bupropion, meperidine).

  • Hypertensive crisis presents as markedly elevated blood pressure, headache, photophobia, nausea/vomiting, and sweating. In severe cases can cause autonomic instability, chest pain, arrhythmias, and death.

Miscellaneous / Common

  • Orthostatic hypotension and lightheadedness: the most common side effect of MAOIs.

  • Drowsiness

  • Sexual dysfunction

  • Weight gain

  • Dry mouth

  • Sleep dysfunction

  • Patients with pyridoxine deficiency can have numbness or paresthesias. These patients should supplement with vitamin B6.

  • Rare: liver toxicity, seizures, and edema.


Tranylcypromine (Parnate) & Phenelzine (Nardil) & Isocarboxazid (Marplan)

  • Irreversibly inactive MAOIs.

  • Short half lives in the serum (2-3 hours) but longer half lives in the tissues.

  • Medication effects can last up to two weeks even with a single dose.

Moclobemide (Amira, Depnil)

  • Reversibly inactivates MAOIs.

  • Less side effects and less dietary restrictions.

  • Not currently approved for use in the united states.

Selegeline (Emsam transdermal patch)

  • Does not require following the dietary restrictions when used in low dosages (below 6 mg daily).

  • Sympathomimetics, decongestants, opiates, and serotenergic drugs must still be avoided.

  • Used in the treatment of Parkinson's disease.

  • Transdermal delivery also used in depression.


This class of medications are not commonly used but still important to know about for licensing exams and as an option for patients that are treatment refractory.

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