MAOIs explained

What MAOIs are

MAOIs are a class of antidepressant named for what they do biochemically. They inhibit an enzyme called monoamine oxidase. That enzyme is what breaks down serotonin, norepinephrine, and dopamine after those messengers have done their job. Turn the enzyme down, and more of those messengers stay available.

MAOIs are the oldest antidepressants still in regular use, older even than the tricyclics. They were the standard treatment for depression alongside TCAs from the 1950s until the SSRIs arrived in the late 1980s. After that they moved into a specialist role, used mainly when several other antidepressants haven't been enough.

The MAOIs covered here are phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), and selegiline transdermal (Emsam). Selegiline as a patch is the newest of the group and was designed to sidestep the food restrictions the older MAOIs require.

How they work

Serotonin, norepinephrine, and dopamine are chemical messengers that nerve cells use to pass signals. After those messengers do their work, an enzyme called monoamine oxidase breaks them down inside the nerve cell. Monoamine oxidase comes in two forms, MAO-A and MAO-B. MAO-A is the one that mainly handles serotonin and norepinephrine. Both forms handle dopamine.

The older MAOIs (phenelzine, tranylcypromine, isocarboxazid) block both MAO-A and MAO-B, and they do it irreversibly. That means the enzyme has to be replaced by the body, and it takes about two weeks for enzyme activity to recover after the last dose. That's why so many of the interaction rules around MAOIs stretch fourteen days past the last dose.

Selegiline is a bit different. In pill form it's selective for MAO-B at low doses and is used for Parkinson's disease. As a patch (Emsam), it inhibits both MAO-A and MAO-B in the brain but delivers the drug in a way that partly spares the MAO-A in the gut. That's the reason the 6 mg patch doesn't require the same food restrictions the pills do.

Because MAOIs raise serotonin, norepinephrine, and dopamine, they're broad-acting in a way SSRIs and SNRIs aren't. That breadth is thought to be why they help some people no other class helps, and it's also why they interact with so many other medications and with tyramine in food.

How the class developed

The MAOIs came from an accident. In the 1950s, doctors were using a tuberculosis drug called iproniazid. They noticed that some patients on it became noticeably cheerful, sometimes to the point where staff commented on the mood change. Researchers followed the thread, figured out that iproniazid inhibited monoamine oxidase, and the idea of treating depression with medication began there. Iproniazid was pulled off the market for liver toxicity, but other MAOIs followed. Phenelzine, tranylcypromine, and isocarboxazid became the standard treatment for depression through the 1960s.

The tyramine reaction, sometimes called the cheese effect, came into focus in the early 1960s. Patients on MAOIs were showing up with severe headaches and dangerously high blood pressure, and the connection to aged foods was worked out over several years. That discovery is what shaped MAOI prescribing forever after.

MAOIs held their place until TCAs became easier to use, and then the SSRIs arrived. By the 1990s, MAOIs were a specialist option. The selegiline patch, approved in 2006, was designed to keep the mood benefit while removing the dietary restrictions at its lowest dose.

What they treat

MAOIs are used for a narrower set of conditions today than when they were first-line.

• Treatment-resistant depression, meaning depression that hasn't responded to two or more antidepressant trials at adequate dose and duration. This is where MAOIs still earn their keep. Some people who haven't improved on any SSRI, SNRI, or bupropion do improve on an MAOI.
• Atypical depression, meaning depression with mood reactivity, heavy limbs, oversleeping, and rejection sensitivity. Phenelzine has particular evidence here, going back to older studies.
• Social anxiety disorder. Phenelzine has evidence in older studies, though SSRIs are now the first-line choice.
• Panic disorder and other anxiety conditions, occasionally.
• Selegiline in pill form (not on this class page) is approved for Parkinson's disease. The transdermal form (Emsam) is approved for depression.

MAOIs aren't started early in the depression treatment ladder. The reason isn't that they don't work. It's that the interaction and food restrictions raise the stakes, and easier-to-use options usually go first.

Individual medications in this class

• Phenelzine (Nardil). Irreversibly inhibits both MAO-A and MAO-B. Widely regarded as the classic MAOI for depression, atypical depression, and social anxiety. More sedating and more associated with weight gain than tranylcypromine.
• Tranylcypromine (Parnate). Irreversibly inhibits both MAO-A and MAO-B, and has a mild amphetamine-like structure that gives it some activating quality. Some people who don't respond to phenelzine do respond to tranylcypromine, and vice versa.
• Isocarboxazid (Marplan). Similar mechanism to phenelzine. Less commonly used today, and supply has been uneven at times.
• Selegiline transdermal (Emsam). A skin patch. At the 6 mg/24 hr dose, no dietary restrictions are required, because the patch bypasses the MAO-A in the gut that handles tyramine. At 9 mg and 12 mg, tyramine restrictions apply.

Common side effects across the class

The side effects that come up most often with MAOIs.

• Lightheadedness on standing, called orthostatic hypotension. This is the most common reason people struggle with MAOIs. It tends to peak in the first weeks and often improves with time and hydration.
• Insomnia. MAOIs can be quite activating, and taking the last dose earlier in the day usually helps.
• Weight gain, especially with phenelzine over months.
• Sexual side effects, including reduced desire and difficulty with orgasm. These can be significant.
• Dry mouth.
• Sedation with some MAOIs, especially phenelzine, alongside the insomnia.
• Peripheral edema, meaning swelling of the ankles.
• Muscle twitching or jerking (myoclonus), which can point to too much serotonergic activity.
• Skin reactions at the patch site with selegiline transdermal.

The tyramine and drug interaction concerns aren't listed here because they're serious warnings rather than typical side effects.

Serious warnings across the class

MAOIs carry more warnings than most antidepressants, and understanding them is part of the price of using the class.

Tyramine reaction (hypertensive crisis). Tyramine is a substance in aged and fermented foods. Normally, the MAO-A in the gut lining breaks it down before it enters the bloodstream. When MAO-A is inhibited, tyramine gets through, releases stored norepinephrine, and can cause a sudden, severe rise in blood pressure. Symptoms include severe headache, sweating, a pounding heart, nausea, and vomiting. In serious cases it can cause stroke. The foods that matter include aged cheeses, cured or fermented meats (salami, dry sausages), tap or unpasteurized beers, sauerkraut, soy sauce and other fermented soy products, aged pickled or smoked fish, fava beans, and some other items. A prescriber will provide a specific list. The 6 mg selegiline patch doesn't require these restrictions.

Serotonin syndrome. Combining an MAOI with another serotonergic medication can cause too much serotonin activity, which produces confusion, agitation, sweating, muscle rigidity, tremor, high fever, and rapid heart rate. It can be fatal. The medications to avoid, or to wash out first, include:

• SSRIs and SNRIs. A 14-day washout is required after stopping most SSRIs before starting an MAOI. Fluoxetine requires a five-week washout because its active metabolite takes that long to clear.
• Tricyclic antidepressants.
• Meperidine (Demerol). Absolutely contraindicated.
• Tramadol.
• Dextromethorphan, the common cough suppressant.
• Triptans (sumatriptan and others) for migraine.
• Linezolid, an antibiotic that itself has MAOI activity.
• Methylene blue, sometimes used in medical procedures, which has MAOI activity.
• St. John's wort.
• MDMA and cocaine.

A 14-day gap in either direction between an MAOI and any of the above is the general rule. Fluoxetine is the exception with its longer washout.

Interactions with sympathomimetic drugs. Medications and substances that release norepinephrine can cause hypertensive crisis with MAOIs. This includes pseudoephedrine and phenylephrine (common cold and allergy medications), amphetamines, methylphenidate, and some over-the-counter appetite suppressants. Reading labels becomes part of the routine.

Suicidal thoughts warning. Like other antidepressants, MAOIs carry the boxed warning about a possible increase in suicidal thoughts in people under 25, especially early in treatment.

Discontinuation. Stopping abruptly can cause discontinuation symptoms similar to other antidepressants. A gradual taper matters.

Anesthesia. General anesthesia and some anesthetic drugs interact with MAOIs. Any surgery needs coordination with the prescribing team, sometimes with a plan to hold the MAOI in advance.

What tips the choice within the class

The choice between MAOIs is driven by a few things.

Prior response. If a specific MAOI has helped a family member, that can guide the choice. If phenelzine hasn't worked, a switch to tranylcypromine sometimes helps, and vice versa.

Diet flexibility. If dietary restrictions are the barrier, the selegiline patch at 6 mg avoids them. That can be the difference between using an MAOI and not.

Activation versus sedation. Tranylcypromine tends to be more activating, with an amphetamine-like feel that some people like and others don't. Phenelzine tends to be more sedating and more associated with weight gain.

Type of depression. Atypical depression, meaning mood reactivity, heavy limbs, oversleeping, and rejection sensitivity, has the most tradition around phenelzine specifically. Whether that pattern still steers choice today depends on the prescriber.

Anxiety symptoms. Phenelzine has more of a track record in social anxiety and panic than tranylcypromine, though the SSRIs are usually tried first for those.

Once someone is on an MAOI and doing well, the discussion usually shifts from which one to how to stay safe on it. That's where the patient education about foods, over-the-counter medications, and medical procedures matters most.

Common questions

Why are MAOIs still around if they're so hard to use? Because for some people, no other antidepressant works. Treatment-resistant depression is real, and MAOIs still help a meaningful fraction of people who haven't responded to SSRIs, SNRIs, bupropion, TCAs, or augmentation strategies. The dietary and interaction rules make MAOIs harder to use, but for someone who has been through several failed trials, hard to use is much better than not working.

What foods do I have to avoid on an MAOI? Aged cheeses (cheddar, blue, Parmesan, gouda), cured or dry sausages (salami, pepperoni), fermented soy products (soy sauce, miso), sauerkraut and kimchi, tap or unpasteurized beers, aged pickled or smoked fish, fava beans, and a few other items. The concern is tyramine, which is highest in foods that have been aged, cured, fermented, or spoiled. Fresh foods are generally safe. A prescriber will give a specific list. The 6 mg selegiline patch doesn't require these restrictions.

How long is the washout between an MAOI and an SSRI? Fourteen days after stopping the MAOI before starting an SSRI or SNRI, and fourteen days after stopping most SSRIs and SNRIs before starting an MAOI. Fluoxetine is the exception. Because its active metabolite has a long half-life, five weeks are required after stopping fluoxetine before starting an MAOI. That five-week gap isn't optional. Starting an MAOI too soon can cause serotonin syndrome.

Is the selegiline patch different from selegiline pills? Yes. Selegiline pills are used for Parkinson's disease and are selective for MAO-B at low doses. The selegiline patch (Emsam) is used for depression and delivers enough drug through the skin to inhibit both MAO-A and MAO-B in the brain. At 6 mg per 24 hours, it doesn't require dietary restrictions because it partly spares the MAO-A in the gut. At 9 mg and 12 mg, the tyramine restrictions apply.

Are MAOIs stronger than SSRIs? Stronger isn't quite the right word, but for treatment-resistant depression, MAOIs do help some people that SSRIs don't. On average, effectiveness across all depression is broadly similar between antidepressant classes. The difference is in who responds. When several first-line and second-line options haven't worked, an MAOI is worth considering because it acts on a broader set of targets than SSRIs or SNRIs.

Sources

This guide draws on current prescribing information and public health references. It's reviewed for clinical accuracy and updated as guidance changes. This isn't medical advice, and it doesn't replace a conversation with your own prescriber.

1. U.S. Food and Drug Administration. Prescribing information.
2. MedlinePlus, U.S. National Library of Medicine.
3. National Institute of Mental Health. Mental health medications.
4. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder.