MAOIs, or monoamine oxidase inhibitors, are one of the oldest classes of antidepressant medications. They work by blocking an enzyme in the brain that breaks down mood-regulating chemicals like serotonin, norepinephrine, and dopamine. First discovered in 1952, MAOIs are no longer a first-line treatment for depression, but they remain an important option for people who haven’t responded to newer antidepressants. They’re also used to treat Parkinson’s disease.
How MAOIs Work in the Brain
Your brain naturally produces chemicals called monoamines, including serotonin, norepinephrine, and dopamine. These chemicals help regulate mood, motivation, sleep, and attention. An enzyme called monoamine oxidase (MAO) breaks these chemicals down after they’ve done their job. In people with depression, this cleanup process can leave too little of these chemicals available.
MAOIs block the monoamine oxidase enzyme, which lets serotonin, norepinephrine, and dopamine build up to higher levels in the brain. The result is improved mood, energy, and emotional stability. There are actually two forms of this enzyme: MAO-A, which primarily breaks down serotonin and norepinephrine, and MAO-B, which primarily breaks down dopamine. Some MAOIs block both forms, while others target only one.
Types of MAOIs
MAOIs fall into a few categories based on which enzyme they target and whether their effects are permanent or temporary.
Nonselective, irreversible MAOIs block both MAO-A and MAO-B permanently. The enzyme doesn’t recover until your body produces new copies of it, which takes about two weeks. This group includes phenelzine, tranylcypromine, and isocarboxazid, all FDA-approved for depression. These are the “classic” MAOIs and the ones with the strictest dietary requirements.
Selective MAO-B inhibitors target only the MAO-B enzyme and are primarily used for Parkinson’s disease. Selegiline and rasagiline are irreversible MAO-B inhibitors, while safinamide is a reversible one. Because they leave MAO-A mostly untouched, selective MAO-B inhibitors carry less risk of the dangerous food interactions associated with the older drugs. Selegiline is unique in that it’s available as both an oral form (for Parkinson’s) and a skin patch (for depression).
Reversible inhibitors of MAO-A (RIMAs) block MAO-A temporarily and release their grip on the enzyme when competing substances like tyramine are present. This makes them significantly safer than the classic irreversible MAOIs, with much less potential to cause dangerous blood pressure spikes. Moclobemide is the best-known RIMA, though it is not available in the United States.
What MAOIs Treat
Four MAOIs are FDA-approved for depression in the U.S.: isocarboxazid, phenelzine, tranylcypromine, and selegiline (as a transdermal patch). They’re typically reserved for people with major depressive disorder who haven’t improved on other antidepressants. Isocarboxazid, for example, is specifically indicated for patients who have not responded to first-line therapy.
In Parkinson’s disease, MAO-B inhibitors play a different role. Selegiline is approved as an add-on therapy for patients already taking standard Parkinson’s medication who are experiencing a decline in their response. Rasagiline is approved for Parkinson’s disease and has been shown to improve motor symptoms in early-stage patients. Safinamide is used alongside other Parkinson’s drugs to help manage “off” episodes, those periods when medication wears off and symptoms return.
Common Side Effects
The most common early side effects of MAOIs include orthostatic hypotension (feeling dizzy or lightheaded when standing up), drowsiness, insomnia, and nausea. These tend to appear in the first weeks of treatment and often improve with time.
Side effects that develop later can include weight gain, swelling, muscle pain, involuntary muscle jerks, tingling or numbness, and sexual dysfunction. Weight gain can be a particular issue with phenelzine compared to other MAOIs. These later side effects are a common reason people stop taking the medication or switch to a different one.
The Tyramine Diet
The most well-known challenge of taking a classic MAOI is the dietary restriction. Your body uses the same monoamine oxidase enzyme to break down tyramine, a compound found naturally in many foods. When the enzyme is blocked by an MAOI, tyramine can accumulate in your bloodstream, triggering a dangerous spike in blood pressure called a hypertensive crisis. Symptoms include severe headache, rapid heartbeat, nausea, and vomiting.
The list of foods to avoid is long and centers on anything aged, fermented, cured, or overripe:
- Cheese: Aged varieties like cheddar, Swiss, Parmesan, blue cheeses (Stilton, Gorgonzola), brine-preserved cheeses like feta, and soft cheeses such as Camembert and brie
- Cured meats: Dry sausages, pepperoni, salami, and other meats treated with salt and nitrates
- Fermented foods: Yeast-extract spreads like Marmite and Vegemite, artisan or homemade sourdough bread, and brewer’s yeast
- Fruits and vegetables: Dried or overripe fruits (raisins, overripe bananas and their peels, overripe avocados), fava beans, and snow peas
- Alcohol: Tap or home-brewed beer, artisan wine, sherry, liqueurs, and some red wines
- Other: Meat tenderizers, improperly stored food, and leftovers past their freshness date
Doctors often recommend eating only fresh foods while on a classic MAOI. The selegiline skin patch at its lowest dose and the selective MAO-B inhibitors used for Parkinson’s generally carry a lower tyramine risk, though your prescriber will clarify what restrictions apply to your specific medication.
Dangerous Drug Interactions
MAOIs interact dangerously with a surprisingly wide range of medications, including many common over-the-counter products. These interactions fall into two categories: those that spike blood pressure and those that cause serotonin syndrome, a potentially life-threatening condition involving agitation, high fever, muscle rigidity, and seizures.
Medications that can trigger a blood pressure crisis include decongestants containing pseudoephedrine, phenylephrine, or ephedrine. These ingredients are found in many cold, flu, and sinus products sold without a prescription. Nasal sprays containing oxymetazoline (the active ingredient in several popular brands) also pose a risk.
The serotonin syndrome risk is equally serious. SSRIs and SNRIs, the most commonly prescribed antidepressants today, cannot be combined with MAOIs. Dextromethorphan, the cough suppressant found in many over-the-counter cough syrups, is also off-limits. Certain antihistamines like chlorpheniramine and brompheniramine carry the same risk. Some pain medications, particularly tramadol and methadone, should never be combined with MAOIs due to their serotonin-boosting properties.
Even medications you wouldn’t expect can cause problems. The antibiotic linezolid has MAOI properties of its own and can cause serotonin syndrome when combined with an MAOI antidepressant. Methylene blue, a dye sometimes used in medical procedures, is a potent reversible monoamine oxidase inhibitor and poses the same danger. If you take an MAOI, every new medication, including over-the-counter products, needs to be checked for interactions.
Why MAOIs Are Still Prescribed
Given all these restrictions, you might wonder why anyone takes an MAOI. The answer is that for some people, particularly those with treatment-resistant depression, MAOIs work when nothing else has. They affect a broader range of brain chemicals than most newer antidepressants, which tend to target only serotonin or serotonin and norepinephrine. That broader mechanism can make a real difference for patients who have tried multiple medications without relief.
The selegiline transdermal patch has also made MAOIs more accessible. By delivering the drug through the skin, it bypasses the gut, which reduces the tyramine interaction risk at the lowest dose. For Parkinson’s patients, MAO-B inhibitors remain a standard part of treatment with a relatively manageable side effect profile. MAOIs carry more complexity than newer options, but for the right patient, they can be genuinely effective.