MAO inhibitors (MAOIs) are a class of medications that block an enzyme called monoamine oxidase, which normally breaks down key brain chemicals involved in mood regulation. By stopping this enzyme from doing its job, MAOIs allow serotonin, norepinephrine, and dopamine to build up in the brain, relieving symptoms of depression. They were the first antidepressants ever developed, introduced in the 1950s, and while newer options have largely replaced them as first-line treatments, MAOIs remain uniquely effective for people who haven’t responded to other antidepressants.
How MAO Inhibitors Work
Your brain relies on chemical messengers called neurotransmitters to regulate mood, motivation, sleep, and alertness. Three of the most important for mood are serotonin, norepinephrine, and dopamine. After these chemicals do their job, an enzyme called monoamine oxidase breaks them down so they don’t accumulate. In depression, levels of these neurotransmitters are often too low. MAOIs block the cleanup enzyme, allowing more of these mood-regulating chemicals to remain active in the brain for longer.
There are two forms of the monoamine oxidase enzyme: MAO-A and MAO-B. MAO-A primarily breaks down serotonin and norepinephrine, making it the main target for treating depression. MAO-B is the predominant form in the human brain and is primarily responsible for breaking down dopamine. This distinction matters because drugs that selectively target MAO-B are used to treat Parkinson’s disease, where dopamine loss is the core problem, while non-selective MAOIs that block both forms are used for depression.
Conditions MAOIs Treat
Four MAOIs are currently available in the United States, each with slightly different approved uses:
- Isocarboxazid and tranylcypromine are approved for major depressive disorder.
- Phenelzine is approved for treatment-resistant depression, panic disorder, and social anxiety disorder.
- Selegiline is approved for major depressive disorder (as a skin patch) and as an add-on treatment for Parkinson’s disease (in oral form).
In practice, MAOIs are most often prescribed after other antidepressants have failed. Their reputation as a “last resort” option undersells how well they can work. In one retrospective study of patients with treatment-resistant depression, 56% of MAOI trials resulted in patients rated “very much better” or “much better.” Even among patients with advanced treatment resistance who had already failed multiple medications, about 12% achieved the highest improvement rating. An earlier study of high-dose tranylcypromine in patients with advanced treatment-resistant depression found a 50% remission rate. The odds of a strong response do decrease by roughly 30% with each prior failed antidepressant, but MAOIs still offer meaningful relief for many people who have run out of options.
The Tyramine Problem
The biggest practical challenge with MAOIs is a required dietary restriction that most other antidepressants don’t have. Tyramine is a naturally occurring compound found in many common foods. Normally, the monoamine oxidase enzyme in your gut breaks down tyramine before it reaches your bloodstream. When you take an MAOI, that enzyme is blocked, so tyramine can build up rapidly and cause a dangerous spike in blood pressure. This reaction was historically called the “cheese effect” because it was first noticed in patients who ate aged cheese.
Foods high in tyramine are generally those that are aged, fermented, cured, overripe, or spoiled. The list is extensive:
- Aged and artisan cheeses: cheddar, Swiss, Parmesan, blue cheeses like Stilton and Gorgonzola, brie, Camembert, feta, Gruyere, and Edam.
- Cured and processed meats: pepperoni, salami, dry summer sausages, bologna, bacon, corned beef, and smoked fish.
- Fermented foods: sauerkraut, kimchi, pickles, pickled fish, caviar, tofu, kombucha, and kefir.
- Fermented sauces: soy sauce, fish sauce, miso, shrimp sauce, Worcestershire sauce, and teriyaki sauce.
- Certain vegetables: fava beans (broad beans), snow peas, and their pods.
- Caffeinated beverages: may also contain tyramine, so limits are often recommended.
Improperly stored or spoiled food of any kind can also develop high tyramine levels. A blood pressure spike from tyramine can require emergency treatment, so these restrictions are taken seriously.
The Selegiline Patch Exception
The selegiline skin patch (Emsam) was designed partly to get around the tyramine problem. Because the medication absorbs through the skin and enters the bloodstream directly, it bypasses the gut at lower doses. At the lowest dose of 6 mg per 24 hours, no dietary modifications are required. At higher doses (9 mg and 12 mg per 24 hours), tyramine-rich foods must be avoided, starting on the first day of treatment. If you step down from a higher dose to 6 mg or stop the patch entirely, you need to continue avoiding tyramine-rich foods for two weeks after the change.
Dangerous Drug Interactions
MAOIs interact dangerously with a wide range of medications, and these interactions can be life-threatening. The most serious risk is serotonin syndrome, a potentially fatal condition caused by too much serotonin flooding the brain at once. This can happen when MAOIs are combined with other antidepressants, including SSRIs (like fluoxetine or sertraline) and SNRIs (like venlafetine or duloxetine). It can also occur with certain pain medications, over-the-counter cold medicines containing decongestants, and other drugs that affect serotonin levels.
Because of these risks, switching between an MAOI and another antidepressant requires a washout period, typically 14 days, where you take no antidepressant at all. This applies when switching from an MAOI to an SSRI, SNRI, tricyclic antidepressant, or even to a different MAOI. Cross-tapering (gradually starting one while tapering the other) is not recommended because the risk of serotonin syndrome is too high. Anyone taking an MAOI needs to inform every healthcare provider, including dentists and pharmacists, about the medication before receiving any new prescription or over-the-counter drug.
MAO-B Inhibitors for Parkinson’s Disease
Selective MAO-B inhibitors like selegiline (in oral form) and rasagiline work differently from the non-selective MAOIs used for depression. MAO-B is the primary enzyme responsible for breaking down dopamine in the brain. By blocking it, these drugs preserve more dopamine, which helps with the movement problems that define Parkinson’s disease. Because they selectively target MAO-B and leave MAO-A in the gut largely intact, they carry a much lower risk of the tyramine reaction at standard doses. These medications are often used alongside other Parkinson’s treatments rather than as standalone therapy, and they can also help with some non-motor symptoms of the disease like fatigue and cognitive difficulties.
Why MAOIs Are Still Prescribed
The dietary restrictions, drug interactions, and required washout periods make MAOIs more demanding than newer antidepressants. This is why they’re rarely the first medication tried for depression. But for people who haven’t improved on SSRIs, SNRIs, or other standard options, MAOIs offer a genuinely different mechanism of action that can succeed where others have failed. They’re particularly well-regarded for atypical depression (characterized by oversleeping, overeating, and heavy feelings in the limbs), social anxiety, and panic disorder. For the right patient willing to manage the dietary and medication restrictions, MAOIs can be transformative after years of ineffective treatment.