MAO Inhibitors: Dangerous Interactions with Common Medications

MAO inhibitors are among the most powerful antidepressants ever developed-but also the most dangerous if used carelessly. These drugs, first discovered in the 1950s, work by blocking an enzyme that breaks down key brain chemicals like serotonin, norepinephrine, and dopamine. That’s why they help people with severe, treatment-resistant depression. But that same mechanism turns them into ticking time bombs when mixed with everyday medicines, supplements, or even foods you’d never suspect.

What Happens When MAOIs Mix with Other Drugs?

MAOIs don’t just affect your mood-they affect your entire nervous system. When you take one, your body can’t clear out excess neurotransmitters. That’s fine if you’re careful. But if you take another drug that also boosts serotonin or norepinephrine, your brain gets flooded. Two life-threatening reactions can happen: serotonin syndrome and hypertensive crisis.

Serotonin syndrome is like an overdose of your own brain chemicals. Symptoms start mild-shivering, sweating, diarrhea-but can explode into high fever (over 106°F), muscle rigidity, seizures, and organ failure. It kills 2 to 12% of people who develop it severely. This isn’t theoretical. In 2019, a 32-year-old man was rushed to the ICU after taking a single 50mg dose of tramadol while on selegiline. He needed a breathing tube. That’s not rare. The FDA has documented dozens of similar cases.

Hypertensive crisis is equally terrifying. It happens when tyramine-a compound in aged or fermented foods-builds up because MAOIs stop your body from breaking it down. Tyramine triggers a massive surge of norepinephrine, which can spike your blood pressure to 200-250 mmHg in under two hours. That’s enough to cause a stroke or heart attack. One patient in Cleveland Clinic’s records had a systolic pressure of 240 after eating just one ounce of strong blue cheese.

The Top 5 Most Dangerous Drug Interactions

Not all medications are created equal when you’re on an MAOI. Some are okay. Others are absolute no-go zones.

1. Dextromethorphan - Found in more than 100 cough syrups and cold medicines. Even a single 30mg dose has triggered serotonin syndrome in people taking phenelzine. The FDA issued a warning in 1992 after a 26-year-old woman was hospitalized following a single dose. Many people don’t realize it’s in their nighttime cold medicine.
2. SSRIs and SNRIs - Drugs like fluoxetine (Prozac), sertraline (Zoloft), and venlafaxine (Effexor) are common antidepressants. Mixing them with MAOIs is like pouring gasoline on a fire. You need at least 14 days between stopping one and starting the other. For fluoxetine, you need five weeks because it lingers in your system for weeks after you stop taking it.
3. Linezolid - This antibiotic treats stubborn infections like MRSA. But it also blocks MAO enzymes. In 2008, a 65-year-old woman died after taking linezolid while on phenelzine. The FDA added it to the contraindicated list in 2006. Many doctors don’t know this interaction exists.
4. Tramadol, Meperidine, Methadone - These are painkillers, but they’re also serotonin boosters. Tramadol alone has caused multiple fatal cases in MAOI users. There’s no safe dose. Even if you’re in severe pain, you cannot use these while on an MAOI.
5. Phenylephrine and Pseudoephedrine - These are in almost every cold and sinus medication. They’re decongestants that raise blood pressure. Combine them with an MAOI and you risk a hypertensive emergency. Look for “D” or “-D” on the label-like “Claritin-D” or “Sudafed PE.” Avoid them entirely.

Supplements You Think Are Safe (But Aren’t)

People assume natural means safe. That’s a deadly myth with MAOIs.

• St. John’s Wort - This herbal remedy for mild depression is a serotonin booster. One case report in 2018 described a patient who developed a fever of 40.5°C and blood pressure of 220/110 after taking it with phenelzine.
• 5-HTP - Sold as a sleep aid or mood booster, this is a direct precursor to serotonin. Taking it with an MAOI is like pouring fuel on a fire. There’s no safe amount.
• SAMe - S-adenosylmethionine is marketed for joint pain and depression. It also increases serotonin. The American Psychiatric Association explicitly warns against combining it with MAOIs.
• Ginseng - A 1985 case report linked ginseng to mania and tremors in someone on phenelzine. Even if the reaction was partly from caffeine contamination, the risk is real enough to avoid it.

Dietary Triggers You Can’t Ignore

You don’t need to eat like a monk. But you can’t ignore food either.

The rule: avoid anything aged, fermented, or cured. Tyramine builds up over time. Here’s what’s dangerous:

• Aged cheeses (Parmesan, blue cheese, cheddar over 6 months old)
• Tap beer and draft beer (bottled beer is usually okay)
• Soy sauce, miso, tempeh
• Cured meats: pepperoni, salami, pastrami
• Fermented tofu
• Red wine (especially Chianti)
• Overripe bananas, fava beans, sauerkraut

You don’t need to eliminate all of these forever. The threshold for crisis is around 10-25mg of tyramine. One ounce of aged cheese can hit 15mg. One tablespoon of soy sauce can be 30mg. A single bad bite can be enough.

But here’s the good news: the Emsam patch (selegiline at 6mg/24hr) is much safer. At this lowest dose, you can eat normal foods without restriction. Studies show no significant tyramine reactions. That’s why it now makes up 68% of all MAOI prescriptions in the U.S.

Why Are MAOIs Still Used at All?

If they’re so dangerous, why do doctors still prescribe them?

Because they work when nothing else does. For people with atypical depression-characterized by oversleeping, overeating, and heavy mood swings-MAOIs often produce results where SSRIs fail. They’re also effective for panic disorder, social anxiety, and treatment-resistant cases.

But they’re not first-line anymore. In 2022, MAOIs made up less than 1% of all antidepressant prescriptions in the U.S. Most are prescribed by psychiatrists-not primary care doctors. And even then, only after other treatments have failed.

Electronic health records now block prescriptions if an MAOI and a dangerous drug are ordered together. That’s because between 1998 and 2003, 127 interactions were reported, including 19 deaths. The FDA mandated those safety blocks in 2004.

Still, a 2021 study found 34% of family doctors didn’t know dextromethorphan was dangerous with MAOIs. That’s why patients are now encouraged to carry a wallet card listing all contraindicated drugs. About 78% of psychiatrists give them out.

What If You Accidentally Mix Them?

If you’ve taken a dangerous combination, don’t wait. Call emergency services immediately. Don’t try to “wait it out.”

Signs to watch for:

• Sudden, severe headache
• Blurred vision
• Fast heartbeat or chest pain
• High fever, sweating, confusion
• Stiff muscles or tremors
• Nausea, vomiting, diarrhea

There’s no antidote. Treatment is supportive: cooling the body, lowering blood pressure, sedating seizures. The faster you get to a hospital, the better your chance.

And if you’re on an MAOI, always tell every doctor, dentist, and pharmacist you see-even for a simple tooth extraction. A single dose of lidocaine with epinephrine can trigger a crisis.

Is There a Safer Alternative?

Yes-but it’s not available everywhere.

Moclobemide is a reversible MAO-A inhibitor used in Europe and Canada. It doesn’t cause the same dangerous food or drug interactions because it only temporarily blocks the enzyme. You can eat cheese. You can take some cold meds. But the FDA never approved it. Clinical trials in 2001 showed it was less effective than older MAOIs for severe depression.

So for now, if you’re prescribed an MAOI, your safety depends on you. Know your meds. Read every label. Ask your pharmacist. Keep a list. Carry a card. And never, ever assume something is safe just because it’s over-the-counter or natural.

MAOIs aren’t the problem. Ignorance is.