A monoamine oxidase inhibitor (MAOI) is a type of antidepressant that works by blocking an enzyme responsible for breaking down key mood-regulating chemicals in the brain. MAOIs were among the first antidepressants ever developed, and while newer options have largely replaced them as first-choice treatments, they remain a powerful tool for depression that hasn’t responded to other medications.
How MAOIs Work in the Brain
Your brain relies on chemical messengers called neurotransmitters to regulate mood, motivation, sleep, and attention. Three of the most important for mood are serotonin, norepinephrine, and dopamine. After these chemicals do their job, an enzyme called monoamine oxidase (MAO) breaks them down so they don’t accumulate. This cleanup process is normal and constant, happening on the outer membrane of mitochondria inside your cells.
MAOIs block this cleanup enzyme, which means serotonin, norepinephrine, and dopamine stick around longer and in greater quantities. The result is stronger signaling between nerve cells, which can lift depression, reduce anxiety, and stabilize mood over time.
Two Types of MAO Enzymes
The body produces two versions of this enzyme, and each one targets slightly different chemicals. MAO-A preferentially breaks down serotonin and norepinephrine, making it the more relevant target for treating depression. MAO-B preferentially breaks down dopamine and a compound called phenylethylamine, making it more relevant for conditions involving dopamine loss.
This distinction matters because it explains why different MAOIs are prescribed for different conditions. Drugs that primarily block MAO-A are used for depression. Drugs that primarily block MAO-B are used for Parkinson’s disease, where the core problem is dopamine depletion. By preventing MAO-B from breaking down dopamine, these inhibitors make more of it available to the brain, which can modestly improve movement symptoms. They’re sometimes used alone in early Parkinson’s or added to other medications to extend their effectiveness and reduce periods when symptoms break through.
What MAOIs Are Prescribed For
The FDA has approved three oral MAOIs for treating depression: isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). A fourth option, selegiline (Emsam), is available as a skin patch. MAOIs are most often tried when other antidepressants, like SSRIs or SNRIs, haven’t worked. Canadian clinical guidelines from CANMAT classify phenelzine and tranylcypromine as third-line treatments for major depression, meaning they’re reserved for people who haven’t improved on two or more other antidepressant trials.
That third-line status doesn’t reflect a lack of effectiveness. MAOIs can be remarkably effective for certain subtypes of depression, particularly atypical depression (characterized by mood reactivity, oversleeping, increased appetite, and a heavy feeling in the limbs). The reason they’re held in reserve is their safety profile: the dietary restrictions and drug interaction risks require careful management.
Irreversible vs. Reversible MAOIs
Most of the MAOIs approved in the U.S. bind permanently to the MAO enzyme, destroying its function until the body manufactures new enzyme molecules. This process takes roughly two weeks, which is why these drugs have such long-lasting effects even after you stop taking them. These are called irreversible MAOIs.
Reversible MAOIs, by contrast, attach temporarily to the enzyme and release it. This means their effects fade more quickly and the risk of dangerous food interactions is lower. Reversible MAOIs are available in some countries outside the U.S. but haven’t gained wide FDA approval for depression.
The Tyramine Problem
The most distinctive aspect of taking an MAOI is the dietary restriction. Tyramine is a naturally occurring compound found in many aged, fermented, and cured foods. Normally, the MAO enzyme in your gut and liver breaks tyramine down before it can affect your blood pressure. When you’re taking an MAOI that blocks this enzyme, tyramine enters your bloodstream unchecked and can cause a sudden, dangerous spike in blood pressure known as a hypertensive crisis. Symptoms include a severe headache, rapid heartbeat, nausea, and neck stiffness.
The list of foods to avoid or limit is substantial:
- Aged cheeses: cheddar, Swiss, Parmesan, blue cheeses like Stilton and Gorgonzola, brine-preserved cheeses like feta, and soft varieties like Camembert and brie
- Cured meats: dry sausages, pepperoni, salami, and other meats treated with salt and nitrate
- Fermented or artisan beverages: tap beer, home-brewed beer or wine, and spontaneously fermented varieties
- Yeast-extract spreads: Marmite, Vegemite, and brewer’s yeast
- Certain produce: fava beans (and their pods), snow peas, overripe bananas, dried fruits like raisins, and overripe avocados
- Sourdough bread: artisan or homemade varieties may contain higher tyramine levels than commercial versions
- Improperly stored food: leftovers and anything past its freshness date, since tyramine levels increase as food ages
Caffeinated beverages may also contain tyramine, so your prescriber will likely recommend limits on those as well.
The Skin Patch Exception
The selegiline patch (Emsam) offers one notable advantage. At its lowest dose of 6 mg per 24 hours, it delivers the drug directly through the skin into the bloodstream, largely bypassing the gut. FDA data supports the recommendation that dietary modification is not required at this dose. At higher doses (9 mg or 12 mg per 24 hours), the standard tyramine-restricted diet applies. If you step down from a higher dose to 6 mg or stop the patch entirely, you still need to avoid tyramine-rich foods for two weeks after the change.
Drug Interactions
Beyond food, MAOIs interact dangerously with a wide range of medications. Combining an MAOI with drugs that increase serotonin levels, including SSRIs, SNRIs, and certain pain medications, can trigger serotonin syndrome. This is a potentially life-threatening condition involving agitation, high fever, muscle rigidity, and seizures. Some over-the-counter cold and cough medications, particularly those containing dextromethorphan, also pose risks.
Because of these interactions, switching between an MAOI and another antidepressant requires a washout period. The general guideline is to stop the MAOI and wait at least 14 days before starting a new antidepressant, giving the body time to produce fresh MAO enzyme. For certain medications, the wait extends to 21 days. Switching in the other direction also requires waiting: if you’re coming off an SSRI, you typically need to allow that drug to clear your system fully before starting the MAOI. The exact timeline depends on the specific drugs involved.
Common Side Effects
Like other antidepressants, MAOIs come with side effects unrelated to tyramine. The most common include dizziness when standing up (caused by a drop in blood pressure), weight gain, difficulty sleeping, and daytime drowsiness. Sexual side effects, dry mouth, and constipation also occur. Many of these are manageable and tend to stabilize after the first few weeks, but the blood pressure changes can be persistent and sometimes limit the dose a person can tolerate.
Why MAOIs Still Matter
Despite their complications, MAOIs occupy an important niche in psychiatric treatment. For people with treatment-resistant depression, particularly those who have cycled through multiple newer antidepressants without relief, MAOIs can be genuinely transformative. Some clinicians argue they’re actually underprescribed, with their reputation for difficulty scaring off both doctors and patients who might benefit from them. The dietary and drug interaction requirements are real, but for someone living with severe, unrelenting depression, they represent a manageable trade-off for a medication class with decades of proven effectiveness.