Pharmacology of monoamine oxidase inhibitors (MAOIs)

Moclobemide, a reversible MAO inhibitor, approved in Canada and the UK

MAOIs are generally considered the most effective class of antidepressant medications. Unfortunately, they pose the greatest risk in terms of frequency of potentially serious medical side effects and their use has fallen off in recent years.


The standard monoamine oxidase inhibitors are tranylcypromine (Parnate) and phenelzine (Nardil). These agents are irreversible inhibitors of the two main types (A and B) of the monoamine oxidase enzyme.  This enzyme breaks down monoamines, i. e., norepinephrine, serotonin, and dopamine.  MAO-A is the main enzyme responsible for metabolism of all types of monoamines, whereas MAO-B appears to be more specific to dopamine metabolism.  In addition to the standard irreversible MAOIs that affect both MAO-A and MAO-B, it is relevant that there is a MAOI that is specific to MAO-B: selegiline (Deprenyl).  This medication has a different profile of side effects due to this difference in mechanism.  A related class of medications, the reversible inhibitors of monoamine oxidase (RIMAs), inhibit both MAO-A and MAO-B, but they do so reversibly and possess a different side effect profile.  Moclobemide, the prototype RIMA, is not available in the US, but is in wide use in Canada, Europe, and other nations.

Rules of thumb: The MAOI diet

Basic rules of thumb regarding this class are as follows:  Phenelzine tends to be sedating, while tranylcypromine tends to be stimulating.  Both these agents can cause weight gain, hypertensive crisis, and potentially serious drug interactions.  Hypertensive crisis occurs with the ingestion of tyramine, which is chemically similar to tyrosine, the precursor to norepinephrine and dopamine.  Tyramine is catabolized by MAO; thus, excessive amounts of tyramine can remain in the body when MAO is inhibited.  This tyramine can lead to increased blood pressure through its effects on increased activity of the sympathetic nervous system.  Blood pressure can rise to dangerous levels, leading to stroke and possibly death.  Foods associated with the tyramine reaction are aged cheeses, wine, and certain beans (see below).  

MAOI use involves the paradoxical situation of being appropriate for severe refractory depression, but only in those persons who are not extremely impulsive, noncompliant, cognitively impaired, or otherwise unable to negotiate this complicated diet.  Further, while patients need to be severely depressed, they should not be extremely suicidal due to these risks.  Such patients do exist.  In fact, most depressed patients (even those who are severely depressed) are not suicidal, impulsive, irritable, or markedly impaired cognitively.  Good therapeutic alliance is also an important feature of MAOI use, since the clinician needs to trust that the patient will use these agents responsibly. 

Drug interactions

There are many drug interactions associated with MAOIs (see below), the two most serious being the combination with SSRIs and the combination with opioid derivates such as meperidine (Demerol).  Both combinations have proven fatal and are absolutely contraindicated.  In both cases, it appears that serotonin syndrome ensues with autonomic instability, fever, myoclonus, flushing, sweating, and abnormal laboratory tests.  Another major risk is hypertensive crisis, which can occur with stimulant agents such as phentermine, a common ingredient in over the counter cold remedies. 

Efficacy: Only 15%

Standard MAOIs have been proven to be the most effective antidepressant medications in existence.  They have proven effective in patients nonreponsive to other classes (such as TCAs and SSRIs), in the most difficult kinds of depression (such as melancholia).  Thus, short of ECT, MAOIs are probably the most powerful weapons in the clinician’s arsenal for treating severe depression. (Contrary to common belief, they are not proven more effective than mood stabilizers in bipolar depression; a head-to-head study of MAOI versus lithium, for instance, has never been conducted. Further, they do not have lower acute mania switch rates in bipolar depression than other agents. The only randomized study of this class in bipolar depression was versus placebo, without any mood stabilizers.)

Unfortunately, in the STAR*D study (also analyzed by the PT editor here), this notable efficacy of MAOIs in treatment-refractory depression led to only about 15% treatment response.  In other words, if patients fail multiple other antidepressants, they are 85% NOT likely to respond to MAOIs.  Given all the risks with these agents, PL recommends not using them in most circumstances due to the very low treatment response rate of true antidepressant-resistant unipolar depression.  Of course, in the PL view, most cases of treatment-resistant depression involve misdiagnosis of manic-depressive illness, as described here.  


Even if there were major benefits of these agents, their risks  weigh heavily in the other direction.  If MOIs are used, PL recommends starting with  selegiline as the first MAOI trial, following later with tranylcypromine or phenelzine.  PL takes this approach because selegiline is a selective MAO-B inhibitor, selective for dopamine metabolism.  Since the noradrenergic system is not involved, there is no significant risk of hypertensive crisis or drug interactions at low doses of selegiline (5-10 mg/d).  Though these low doses are indicated for the treatment of Parkinson’s disease, some persons will also experience antidepressant efficacy.  If so, they have the benefit of response to an MAOI without most of the risks.  Unfortunately, most persons require higher doses of selegiline for antidepressant efficacy (20-30 mg/d) and these doses irreversibly block both MAO-A and MAO-B.  However, even with this standard MAOI mechanism, selegiline appears to have a somewhat lower risk of hypertensive crisis with tyramine ingestion than do phenelzine or tranylcypromine and may be the safest MAOI available. The major disadvantage to its use is that it is less studied in treating depression than the other agents, although there are a few double-blind, controlled studies supporting selegiline’s use in depression.  A seligiline patch has been developed which bypasses gastrointestinal metabolism, thus reducing the risk of hypertensive crisis.  Given once daily at doses of 6, 9, and 12 mg/d (all shown more effective than placebo in acute unipolar depression), the patch does not require any special dietary considerations at 6-9 mg/d, though at higher doses the usual restrictions are necessary.  Nonetheless, even at the higher doses, the risk of  hypertensive crisis should be lower than with oral MAOI medications. 

Note that the selegiline patch at the FDA-indicated doses above is NOT more effective than other antidepressants.  Only higher doses of MAOI agents, i.e. Parnate and Nardil, are more effective than other antidepressants.  

Specific agents and doses

  • Tranylcypromine (Parnate) 20-60 Amphetamine-like, more tolerable than phenelzine
  • Phenelzine (Nardil) 15-45 Sedating, weight gain
  • Selegiline (Deprenyl) 5-30 Selective at lower doses, probably best tolerability
  • Selegiline patch (Em-Sam) 6-12 Bypasses GI metabolism, removing or reducing risk of hypertensive crisis, no diet needed at lower doses
  • Moclobemide 150-500 Reversible, no diet needed, not available in US

Dietary advice to avoid tyramine reaction with MAOIs

Avoid completely:  All matured or aged cheese, all aged/cured meat, fava beans, all tap beers or red wine, sauerkraut, soy sauce, other soy condiments, Marmite concentrated yeast extract 

May be safe in moderation:  Cottage cheese, cream cheese, fresh milk products, fresh meats, vodka, gin, white wine, canned or bottled beer (no more than one alcoholic beverage per day),  Brewer’s yeast, soy milk

Dangerous drug interactions with MAOIs

  • Hypertensive crisis:  L-DOPA, other MAOIs, phentermine (in OTC cold remedies)
  • Serotonin syndrome:  Meperidine, SSRIs, possibly TCAs
  • Morphine is associated with hypotension.  Codeine is somewhat safer though not definitively safe.

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