MAO inhibitors (MAOIs) are a class of antidepressant that works by blocking an enzyme called monoamine oxidase, which normally breaks down mood-regulating brain chemicals like serotonin, norepinephrine, and dopamine. By stopping this enzyme, MAOIs allow these chemicals to build up in the brain, lifting mood and reducing anxiety. They were among the first antidepressants ever developed and remain some of the most effective options for depression that hasn’t responded to other medications.
How MAOIs Work in the Brain
Your brain produces chemical messengers (neurotransmitters) that regulate mood, motivation, and stress responses. After these chemicals do their job, an enzyme called monoamine oxidase breaks them down so they don’t accumulate. In people with depression, this cleanup process can leave too little of these chemicals available. MAOIs block that enzyme, keeping more serotonin, norepinephrine, and dopamine active in the spaces between nerve cells.
There are two forms of the enzyme. MAO-A has a stronger preference for serotonin and norepinephrine, which are closely tied to mood. MAO-B has a stronger preference for a stimulant-like compound called phenylethylamine, while dopamine is broken down roughly equally by both forms. This distinction matters because drugs that target one form over the other have different medical uses.
MAO-A vs. MAO-B Inhibitors
Blocking MAO-A raises serotonin and norepinephrine levels in the brain, which is what produces the antidepressant effect. The older, nonselective MAOIs block both forms of the enzyme at once, and this is the type most commonly prescribed for depression.
Blocking MAO-B primarily raises dopamine levels. Since Parkinson’s disease involves the progressive loss of dopamine-producing brain cells, MAO-B inhibitors are used to preserve the dopamine that remains. Rasagiline and safinamide are two MAO-B inhibitors approved specifically for Parkinson’s disease.
FDA-Approved MAOIs
The nonselective MAOIs approved for depression include:
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
- Isocarboxazid (Marplan)
Selegiline is a selective MAO-B inhibitor available both as an oral tablet (used for Parkinson’s disease) and as a skin patch (used for depression). The patch version delivers the drug directly into the bloodstream, bypassing the gut, which changes the safety profile in an important way covered below.
When MAOIs Are Prescribed Today
MAOIs are not typically the first antidepressant someone tries. Because of their dietary restrictions and interaction risks, they’re generally reserved for people whose depression hasn’t improved with newer antidepressants like SSRIs or SNRIs. Canadian treatment guidelines list phenelzine as a third-line option for depression, with a specific recommendation for atypical depression, where it has shown superiority over tricyclic antidepressants.
Atypical depression is marked by mood that temporarily brightens in response to good news, along with symptoms like oversleeping, increased appetite, heavy feelings in the arms and legs, and sensitivity to rejection. MAOIs also show benefits for certain anxiety disorders and possibly PTSD. For people who have genuinely exhausted other options, MAOIs can be remarkably effective medications that are underused largely because of their reputation for being difficult to manage.
The Tyramine Diet
This is the part that makes MAOIs unique among antidepressants. Tyramine is a compound found naturally in aged and fermented foods. Normally, monoamine oxidase in your gut breaks down tyramine before it enters your bloodstream. When you take an MAOI, that safety net is gone. Tyramine passes into the blood, triggers a surge of norepinephrine, and can cause a dangerous spike in blood pressure called a hypertensive crisis.
The threshold varies from person to person. Some people may notice a meaningful blood pressure increase after consuming just 10 mg of tyramine on an empty stomach, while others can tolerate 40 mg or more in a meal before reaching concerning levels. Because of this variability, anyone taking a nonselective MAOI needs to avoid high-tyramine foods consistently.
Foods With the Highest Tyramine Levels
Tyramine content varies widely even within the same food category, which makes simple lists somewhat misleading. That said, the foods most likely to contain dangerous amounts include:
- Aged cheeses: Cheeses matured for three to six months or longer, especially artisanal varieties. Some acid-curd cheeses have been measured at over 335 mg of tyramine per kilogram.
- Fermented sausages and cured meats: Salami, pepperoni, and similar products. One survey of European fermented sausages found most contained under 200 mg/kg, but some samples exceeded 600 mg/kg.
- Soy-based fermented products: Certain soybean pastes tested at over 1,000 mg/kg of tyramine, though other samples from the same category were nearly tyramine-free.
- Fish sauces: Korean fish sauces averaged around 350 mg/kg, with one anchovy-based sauce reaching 600 mg/kg.
- Yeast extracts: Products like Marmite have been measured between 322 and 650 mg/kg.
Fresh, unprocessed foods are generally safe. The key principle is that tyramine builds up over time through aging, fermentation, or bacterial action, so the older or more fermented a food is, the riskier it becomes.
The Selegiline Patch Exception
The selegiline transdermal patch at its lowest dose (6 mg/24 hours) does not require any dietary restrictions. Because the drug absorbs through the skin and enters the bloodstream directly, it largely avoids blocking monoamine oxidase in the gut, where tyramine would otherwise be a problem. At higher doses (9 mg and 12 mg/24 hours), dietary restrictions are required during treatment and for up to two weeks after stopping or reducing the dose. This makes the low-dose patch an appealing option for people who want the benefits of an MAOI without the dietary burden.
Dangerous Drug Interactions
The food restrictions get the most attention, but drug interactions with MAOIs are equally serious and arguably more dangerous. There are two categories of medications to avoid.
The first category includes drugs that raise serotonin levels. Combining an MAOI with an SSRI, SNRI, or another MAOI can trigger serotonin syndrome, a potentially fatal condition caused by excessive serotonin activity in the brain. Fatalities have been reported when SSRIs and MAOIs were combined, even at normal therapeutic doses. Less obvious serotonin-raising drugs include dextromethorphan (a common cough suppressant) and certain older antihistamines like chlorpheniramine and brompheniramine.
The second category includes drugs that raise blood pressure through stimulant-like effects. Over-the-counter decongestants containing phenylephrine, pseudoephedrine, or oxymetazoline can trigger a hypertensive crisis when combined with an MAOI. This is why reading labels on cold and flu medications is critical for anyone taking these drugs.
Recognizing Serotonin Syndrome
Serotonin syndrome typically produces three clusters of symptoms: neuromuscular excitation, autonomic nervous system overactivation, and mental state changes. The neuromuscular signs are the most distinctive. These include clonus (involuntary rhythmic muscle jerking, especially in the ankles and feet), exaggerated reflexes, tremor, and muscle rigidity. Autonomic signs include rapid heart rate, dilated pupils, and fever. Mental changes range from agitation and confusion to more severe disorientation.
Mild cases may involve only tremor and restlessness. Life-threatening cases are distinguished by high fever and increasing rigidity, particularly in the trunk, which can eventually impair breathing. The condition develops rapidly, often within hours of taking the offending drug combination, and requires emergency treatment.
Switching To or From an MAOI
Because MAOIs interact so dangerously with other antidepressants, switching medications requires a washout period where no antidepressant is taken. This gives the body time to clear the previous drug completely before starting the new one.
When stopping an irreversible MAOI (phenelzine, tranylcypromine, or isocarboxazid) and switching to another antidepressant, a washout of two to three weeks is standard. Moving in the other direction, from an SSRI or SNRI to an MAOI, requires at least 14 days off the first drug before cautiously starting the MAOI at a low dose. Some medications require even longer: switching from clomipramine (a tricyclic antidepressant) to an MAOI requires a 21-day gap in both directions.
These washout periods can be difficult for people with severe depression, since it means weeks without antidepressant coverage. This is one of the practical challenges that makes MAOIs harder to use, even when they may be the most effective option for a given person.