An MAOI, or monoamine oxidase inhibitor, is a type of antidepressant that works by blocking an enzyme in your brain responsible for breaking down mood-regulating chemicals. MAOIs were among the very first antidepressants ever developed, introduced in the 1950s, and they remain effective options today, particularly for people whose depression hasn’t responded to newer medications. They come with unique dietary restrictions and drug interactions that make them less commonly prescribed than other antidepressants, but for the right person, they can be genuinely transformative.
How MAOIs Work in the Brain
Your brain relies on chemical messengers called neurotransmitters to regulate mood, motivation, and emotional stability. Three of the most important for mood are serotonin, norepinephrine, and dopamine. After these chemicals do their job carrying signals between brain cells, an enzyme called monoamine oxidase breaks them down and clears them away. In people with depression, this cleanup process can leave neurotransmitter levels too low.
MAOIs block that enzyme from doing its work. With monoamine oxidase out of the picture, serotonin, norepinephrine, and dopamine stay active longer and build up to higher levels. The result is a more sustained mood-boosting effect. The tradeoff is that monoamine oxidase also works in your gut and liver, where it breaks down other substances, so blocking it body-wide creates side effects and dietary concerns that don’t come with newer antidepressants.
Two Types of the Enzyme
There are actually two forms of monoamine oxidase in the body: MAO-A and MAO-B. They’re distributed differently and handle different tasks. MAO-A is found heavily in the gut, liver, and placenta, and it primarily breaks down serotonin and norepinephrine. It also plays a major role in dopamine breakdown in the brain’s movement-control circuits. MAO-B is concentrated in the brain (especially in certain support cells called astrocytes) and in platelets.
This distinction matters because medications can be designed to target one form or the other. Drugs that selectively block MAO-A tend to work as antidepressants, since they preserve serotonin and norepinephrine. Drugs that selectively block MAO-B are more commonly used to treat Parkinson’s disease, where preserving dopamine in movement circuits is the priority. Some older MAOIs block both forms, which makes them powerful but also increases their side effects.
MAOIs Approved for Depression
Four MAOIs are currently approved in the United States for treating depression:
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
- Isocarboxazid (Marplan)
- Selegiline transdermal patch (Emsam)
The first three are oral medications that irreversibly block both MAO-A and MAO-B. “Irreversible” means the enzyme is permanently disabled once the drug binds to it. Your body has to manufacture entirely new enzyme molecules to restore normal function, which is why these drugs have effects that linger well after you stop taking them.
The selegiline patch is a newer option that delivers medication through the skin. At its lowest effective dose of 6 mg per 24 hours, it inhibits MAO primarily in the brain while largely sparing the gut. This is a meaningful advantage because it eliminates the need for the strict dietary restrictions that come with the oral forms. At higher patch doses, however, the dietary rules apply again.
The Tyramine Problem
The most well-known drawback of MAOIs is the so-called “cheese effect.” Tyramine is a naturally occurring compound found in many aged, fermented, and overripe foods. Normally, monoamine oxidase in your gut breaks tyramine down before it can affect you. When that enzyme is blocked by an MAOI, tyramine passes into your bloodstream unchecked, where it can trigger a sudden and dangerous spike in blood pressure. This is called a hypertensive crisis, and it can require emergency treatment.
Foods you’d need to avoid or limit on an oral MAOI include:
- Aged cheeses: cheddar, Swiss, Parmesan, blue cheeses like Stilton and Gorgonzola, brie, Camembert, feta, Gruyere, and Edam. Fresh cheeses like cottage cheese, ricotta, cream cheese, and fresh mozzarella are generally safe.
- Cured meats: pepperoni, salami, dry sausages, and anything treated with salt and nitrates for preservation.
- Fermented products: soy sauce, fish sauce, miso, Worcestershire sauce, teriyaki sauce, kombucha, and kefir.
- Certain produce: fava beans (and their pods), snow peas, dried fruits, overripe bananas, and overripe avocados.
- Other items: yeast-extract spreads like Marmite and Vegemite, meat tenderizers, and fermented soybean paste.
The dietary restrictions are manageable once you learn them, but they do require real attention. Many people carry a list of safe and unsafe foods, especially early on.
Dangerous Drug Interactions
Beyond food, MAOIs interact dangerously with several common medications, and this is arguably the bigger safety concern in everyday life. The two main categories to watch are drugs that raise blood pressure through stimulant-like effects and drugs that increase serotonin levels.
Combining an MAOI with another antidepressant, particularly an SSRI or SNRI, can cause serotonin syndrome, a potentially fatal condition where serotonin builds up to toxic levels. Symptoms include agitation, rapid heart rate, high fever, muscle rigidity, and seizures. This combination is strictly avoided.
Less obvious but equally important: several over-the-counter medications are off-limits. Dextromethorphan, the cough suppressant found in many cold medicines, has serotonin-boosting properties and can trigger serotonin syndrome. Nasal decongestants containing phenylephrine or oxymetazoline can cause dangerous blood pressure spikes. Certain pain medications, including tramadol and meperidine, also carry serious interaction risks. Even some antihistamines like chlorpheniramine and brompheniramine can be problematic. This means you can’t just grab something off the pharmacy shelf without checking; you need to verify every new medication against your MAOI.
Why MAOIs Are Still Prescribed
Given all these precautions, you might wonder why anyone takes MAOIs at all. The answer is that they work, sometimes when nothing else does. MAOIs are typically reserved for treatment-resistant depression, meaning cases where newer antidepressants like SSRIs and SNRIs haven’t provided adequate relief. Some clinicians also consider them particularly effective for atypical depression, a subtype characterized by mood reactivity, excessive sleeping, increased appetite, and a heavy, leaden feeling in the limbs.
For people who have cycled through multiple antidepressants without success, an MAOI can be the medication that finally makes a difference. The dietary and drug restrictions are real, but many patients find them a worthwhile tradeoff for effective depression relief.
Switching To or From an MAOI
Because MAOIs interact so strongly with other antidepressants, switching medications requires a waiting period called a washout. If you’re stopping an irreversible MAOI like phenelzine or tranylcypromine and moving to an SSRI, SNRI, or most other antidepressants, the standard washout is at least 14 days. For certain drugs, the wait extends to 21 days. This gives your body enough time to produce fresh monoamine oxidase enzymes and restore normal metabolism before introducing a new medication that affects serotonin.
The reverse is also true. If you’re switching from an SSRI to an MAOI, you typically need to wait at least two weeks after stopping the SSRI (and five weeks for fluoxetine, which stays in the body much longer). During any washout period, the tyramine dietary restrictions still apply. This transition period can be difficult since you’re essentially going without antidepressant coverage, but skipping it risks serotonin syndrome.
Common Side Effects
Like all antidepressants, MAOIs come with side effects unrelated to food or drug interactions. Because they affect neurotransmitters throughout the body, not just in the brain, the effects can be wide-ranging. Dizziness when standing up quickly (from a drop in blood pressure) is one of the most common complaints. Weight gain, sleep disruption, dry mouth, and digestive issues also occur frequently. Sexual side effects, including difficulty with arousal or orgasm, are possible as well.
Many of these side effects overlap with what people experience on other antidepressants. The intensity varies from person to person and sometimes improves after the first few weeks of treatment. The selegiline patch tends to produce fewer of these issues compared to the oral forms, partly because it bypasses the digestive system entirely.