MAO Inhibitors: Dangerous Interactions with Common Medications

What Are MAO Inhibitors?

MAO inhibitors are a class of antidepressants that block the monoamine oxidase enzyme, which normally breaks down neurotransmitters like serotonin, norepinephrine, and dopamine in the brain. First discovered in the 1950s, they were originally developed as tuberculosis drugs before their mood-lifting effects were noticed. Today, they’re used mainly for treatment-resistant depression, atypical depression, and certain anxiety disorders. But because they work so powerfully on brain chemistry, even small mistakes with other medications or foods can lead to life-threatening reactions.

Why MAO Inhibitors Are Risky

MAO inhibitors don’t just affect your mood-they affect your entire nervous system. When they stop the enzyme from breaking down neurotransmitters, those chemicals build up. That’s good for depression, but dangerous when combined with other substances that also boost those same chemicals. Two major dangers stand out: hypertensive crisis and serotonin syndrome.

Hypertensive crisis happens when tyramine-a compound found in certain foods-builds up in your body. Normally, your liver breaks it down. But MAO inhibitors block that process. Tyramine then triggers a massive release of norepinephrine, causing your blood pressure to spike. Cases have been documented where systolic pressure jumped from 120 to over 250 mmHg within two hours after eating aged cheese or drinking draft beer. That’s enough to cause stroke, heart attack, or death.

Serotonin syndrome is even more unpredictable. It occurs when too much serotonin accumulates in your system. Symptoms start mild-shivering, sweating, diarrhea-but can quickly turn deadly: fever above 41°C (106°F), muscle rigidity, seizures, organ failure. The mortality rate for severe cases is 2-12%. It doesn’t take much to trigger it. A single dose of an over-the-counter cough medicine can be enough if you’re on an MAOI.

Medications You Must Avoid

Many common drugs are absolutely off-limits with MAO inhibitors. The FDA and medical guidelines list these as contraindicated, meaning they should never be taken together.

• SSRIs like fluoxetine (Prozac), sertraline (Zoloft), and citalopram (Celexa) - combining these with MAOIs can cause serotonin syndrome. You need at least a 14-day gap between stopping one and starting the other. For fluoxetine, wait five weeks because it stays in your system so long.
• Dextromethorphan - found in more than 100 cough and cold products. A 26-year-old woman was hospitalized after taking just 30mg of it while on phenelzine. Her symptoms: agitation, high fever, confusion.
• Tramadol, meperidine, methadone - these painkillers are especially dangerous. A 32-year-old man needed intubation after taking 50mg of tramadol while on selegiline.
• Linezolid - an antibiotic used for resistant infections. It also inhibits MAO. There are documented deaths from combining it with MAOIs, including a fatal case in a 65-year-old woman.
• Phenylephrine - a common decongestant in cold medicines like Sudafed PE. It causes rapid, dangerous spikes in blood pressure when mixed with MAOIs.
• Ephedra - banned by the FDA in 2004, but still found in some supplements. Even small amounts can trigger hypertensive emergencies.

Supplements That Can Kill

People often think “natural” means safe. That’s not true with MAOIs. Several popular supplements carry serious risks:

• St. John’s Wort - used for mild depression, but it increases serotonin. Cases of serotonin syndrome have been reported after combining it with MAOIs.
• 5-HTP - a precursor to serotonin. One patient on phenelzine took 200mg of 5-HTP and developed a temperature of 40.5°C and blood pressure of 220/110 mmHg.
• SAMe - another serotonin booster. No safe dose has been established when used with MAOIs.
• Ginseng - early case reports from the 1980s linked it to mania and tremors in people on MAOIs. Some researchers suspect caffeine contamination played a role, but the risk remains.

Dietary Restrictions Are Not Optional

If you’re on an oral MAOI, you can’t just eat whatever you want. Tyramine is everywhere in aged, fermented, or cured foods:

• Aged cheeses (cheddar, blue, parmesan - especially if stored over six months)
• Tap beer and draft beer (bottled beer is usually safer)
• Soy sauce, miso, tempeh
• Cured meats: pepperoni, salami, pastrami
• Fermented tofu, sauerkraut
• Red wine, especially Chianti

As little as 10-25mg of tyramine can trigger a crisis. One ounce of strong aged cheese can contain 15mg. That’s why doctors tell patients to avoid these foods entirely. The rule isn’t about moderation-it’s about elimination.

There’s one exception: the selegiline patch (Emsam). At the lowest dose (6mg/24hr), it doesn’t block tyramine breakdown in the gut, so dietary restrictions are lifted. That’s why over two-thirds of new MAOI prescriptions today are for the patch. It’s safer, easier, and more practical.

What About Switching Medications?

Many people start on an SSRI and later switch to an MAOI-or vice versa. That transition is risky if not done right.

Doctors require a 14-day washout period between stopping an MAOI and starting an SSRI. But if you’ve been on fluoxetine, you need to wait five weeks. Why? Fluoxetine and its active metabolite, norfluoxetine, linger in your body for weeks after you stop taking it. Jumping ahead can mean serotonin syndrome even if you think you’ve stopped the drug.

Electronic health records now block doctors from prescribing MAOIs alongside contraindicated drugs. That’s thanks to a 2004 FDA mandate after 19 deaths were linked to these interactions between 1998 and 2003. But the system isn’t foolproof. A 2021 study found 34% of primary care doctors didn’t know dextromethorphan was dangerous with MAOIs. Patients often don’t know either.

What You Should Do

If you’re prescribed an MAOI:

• Get a wallet card listing all contraindicated medications and foods. About 78% of psychiatrists now give these to patients.
• Carry it with you at all times. Emergency responders need to know what you’re on.
• Always tell every doctor, dentist, or pharmacist you see that you’re taking an MAOI-even for a simple tooth extraction.
• Check every new medication, even OTC ones. Look for dextromethorphan, phenylephrine, or pseudoephedrine on the label.
• If you’re using the Emsam patch, confirm your dose. Only the 6mg/24hr version allows normal eating. Higher doses still require dietary restrictions.

MAO inhibitors still have a place in treating depression that hasn’t responded to anything else. But their use requires extreme caution. A single missed warning can be fatal.

Why Are MAOIs Still Prescribed?

They’re not first-line anymore. In the U.S., less than 1% of antidepressant prescriptions are for MAOIs. But they work where others don’t. For people with severe, treatment-resistant depression, they can be life-changing. Most prescriptions come from psychiatrists-not general doctors-because managing the risks requires expertise.

Research continues into safer versions. Moclobemide, a reversible MAO-A inhibitor, is used in Europe and has far fewer interactions. But it was never approved in the U.S. because clinical trials showed only modest benefits. Until something better comes along, MAOIs remain a high-risk, high-reward tool.

Final Warning

There’s no room for guesswork. If you’re on an MAOI, assume every new medication, supplement, or even cold remedy could be dangerous. Don’t rely on memory. Don’t ask a friend. Don’t Google it. Ask your doctor. Show them your list. Read every label. Your life depends on it.