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 first antidepressants ever developed, and while they’re prescribed far less often today than newer options, they remain a powerful tool for people whose depression hasn’t responded to other treatments.
How MAOIs Work in the Brain
Your brain naturally produces chemicals called monoamines that regulate mood, motivation, and alertness. The three most important ones are serotonin, dopamine, and norepinephrine. After these chemicals do their job, an enzyme called monoamine oxidase breaks them down and clears them away. In people with depression, this cleanup process can leave too little of these chemicals available.
MAOIs block that enzyme, which means serotonin, dopamine, and norepinephrine stick around longer and build up to higher levels. The result is a broader chemical boost than many newer antidepressants provide. Most modern antidepressants (like SSRIs) primarily target serotonin alone, while MAOIs affect multiple mood chemicals at once.
There are actually two forms of the monoamine oxidase enzyme. MAO-A primarily breaks down serotonin, while MAO-B has a stronger preference for other brain chemicals like phenylethylamine. Dopamine, norepinephrine, and several other monoamines are broken down by both forms. Different MAOI drugs target one or both of these enzyme types, which is why some MAOIs are used for depression while others treat conditions like Parkinson’s disease.
Approved MAOIs and What They Treat
The FDA has approved four MAOIs. Three are taken as pills: isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). A fourth, selegiline (Emsam), is applied as a skin patch. The oral forms are all approved for depression, while the selegiline patch delivers the drug through the skin to reduce some of the dietary concerns associated with the pill versions.
MAOIs are currently considered third-line medications for treatment-resistant depression. That means they’re typically tried after two or more other antidepressants have failed. This isn’t because they don’t work well. It’s because their side effects and dietary restrictions make them harder to live with day to day. For people who have been through multiple treatment failures, though, MAOIs can be genuinely transformative. Researchers have described them as “potentially lifesaving for severely affected individuals,” and many psychiatrists consider them markedly underutilized.
Beyond depression, selective MAO-B inhibitors like selegiline and rasagiline are used to treat Parkinson’s disease, where they help preserve dopamine levels in parts of the brain that control movement. These are technically MAOIs but serve a very different clinical purpose.
The Tyramine Problem: Why Diet Matters
The biggest practical challenge with MAOIs is food. Your gut contains the same monoamine oxidase enzyme that exists in your brain, and one of its jobs is breaking down a substance called tyramine that’s naturally present in many foods. When you take an MAOI, that gut enzyme gets blocked too. Tyramine can then build up rapidly in your body, causing a dangerous spike in blood pressure known as a hypertensive crisis.
The foods you need to avoid are generally those that are aged, fermented, overripe, or spoiled. The list is extensive:
- Aged and artisan cheeses: aged 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, smoked fish
- Fermented foods: sauerkraut, kimchi, pickles, pickled fish, tofu, caviar, kombucha, kefir
- Fermented sauces: soy sauce, fish sauce, miso, Worcestershire sauce, teriyaki sauce, shrimp sauce
- Certain produce: fava beans (broad beans) and their pods, snow peas, dried fruits like raisins, overripe bananas, overripe avocados
- Alcoholic beverages: especially tap beer, home-brewed beer or wine, and artisan or spontaneously fermented varieties
- Other: yeast-extract spreads like Marmite and Vegemite, meat tenderizers, brewer’s yeast
Your prescriber will likely recommend eating only fresh foods and avoiding leftovers or anything past its freshness date. Combination dishes that contain any high-tyramine ingredient also need to be avoided. The selegiline patch at its lowest dose may not require these restrictions because it bypasses the gut, but higher doses still carry the same risk.
Symptoms of a Hypertensive Crisis
A tyramine-triggered blood pressure spike can come on suddenly and requires emergency treatment. Warning signs include a severe headache (often at the back of the head), rapid heartbeat, nausea, vomiting, sweating, visual changes, and confusion. If you’re taking an MAOI and experience a sudden, intense headache after eating, treat it as urgent. This reaction is the main reason MAOIs carry such strict dietary guidelines, and it’s also why many doctors hesitate to prescribe them despite their effectiveness.
Drug Interactions to Be Aware Of
MAOIs interact dangerously with a wide range of other medications. The most serious risk is serotonin syndrome, a potentially life-threatening condition caused by too much serotonin building up in the brain. This can happen when an MAOI is combined with other antidepressants, including SSRIs, SNRIs, and certain tricyclics. Symptoms of serotonin syndrome include agitation, muscle twitching, rapid heart rate, high fever, and in severe cases, seizures.
Beyond antidepressants, many over-the-counter cold and cough medications contain ingredients that interact with MAOIs. Certain pain medications, stimulants, and herbal supplements like St. John’s wort also pose risks. If you’re prescribed an MAOI, you’ll need to check with a pharmacist before taking virtually any new medication, including ones you’d normally buy without a second thought.
Switching Between Antidepressants
One of the less obvious challenges with MAOIs is the waiting period required when switching to or from another antidepressant. Because the enzyme-blocking effects linger after you stop taking the drug, you typically need to wait at least 14 days after stopping an MAOI before starting most other antidepressants, including SSRIs, SNRIs, and other MAOIs. For certain tricyclic antidepressants like clomipramine or imipramine, the recommended wait is 21 days.
This washout period works in both directions. If you’re currently on an SSRI and your doctor wants to switch you to an MAOI, you’ll need to stop the SSRI and wait before the MAOI can safely begin. The exact timing depends on which SSRI you’re taking, since some stay in your system longer than others. This gap without medication can be difficult for people with severe depression, which is another reason the decision to use an MAOI involves careful planning.
Common Side Effects
Like all antidepressants, MAOIs come with side effects. The most frequently reported ones include dizziness when standing up (caused by a drop in blood pressure), weight gain, trouble sleeping, and dry mouth. Sexual side effects, including reduced desire and difficulty with arousal or orgasm, are also common. Some people experience swelling in the ankles or fingers, muscle twitching, or daytime drowsiness.
Many of these side effects overlap with what you’d experience on other antidepressants, but the blood pressure drops tend to be more pronounced with MAOIs. Standing up slowly, staying hydrated, and giving your body time to adjust can help manage the dizziness in the early weeks of treatment.
Why MAOIs Still Matter
Despite being older drugs with genuine inconveniences, MAOIs occupy an important place in psychiatry. They affect a broader range of brain chemicals than most newer antidepressants, which may explain why they work for some people when nothing else has. Certain subtypes of depression, particularly those involving heavy fatigue, oversleeping, increased appetite, and intense sensitivity to rejection, have historically responded well to MAOIs like phenelzine.
The dietary restrictions and drug interaction risks are real, but they’re manageable with planning. For someone who has tried multiple antidepressants without relief, the trade-off of watching what they eat in exchange for a medication that actually works can feel more than worthwhile. Researchers have argued that these drugs deserve a second look, noting they are “markedly underutilized” given how effective they can be for the right patient.