MAO Inhibitors Are Oldies but Goodies for Stubborn Depression

Psychiatrists estimate that depression affects as many as 1 out of 10 Americans. Teenagers and young adults are even more vulnerable, with as many as 17% impacted. There are ongoing questions about the effectiveness of modern antidepressants. These are drugs like fluoxetine (Prozac) and sertraline (Zoloft). Should we reconsider older medications such as MAO inhibitors? What are the pros and cons of such drugs?

Have We Forgotten MAO Inhibitors?

A visitor to this website took us to task recently because we rarely discuss MAOIs. We plead guilty as charged.

Most physicians prescribe SSRIs (selective serotonin reuptake inhibitors) or SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors). You will recognize brand names such as Prozac (fluoxetine), Paxil (paroxetine), Zoloft (sertraline), Cymbalta duloxetine), Effexor (venlafaxine) or Pristiq (desvenlafaxine).

Before the SSRIs and SNRIs became widely available, doctors prescribed tricyclic antidepressants such as amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil) and nortriptyline (Pamelor). Such drugs were perceived as having more side effects than drugs like Prozac, though I am not sure researchers did really well-controlled head-to-head trials.

But before there were either of those two categories there were MAO inhibitors. And here is why we were spanked:

Q. I am disappointed that you never mention antidepressant medications called MAOIs. This class of drugs works extremely well for me.

Doctors may be reluctant to prescribe them for fear of food-drug interactions. That’s much less of a problem now because patients can search online for foods and drugs that might be incompatible.

A. Thank you for reminding us that monoamine oxidase inhibitors (MAOIs) are a viable option against depression. Drugs such as isocarboxazid (Marplan), phenelzine (Nardil) and tranylcypromine (Parnate) were introduced in the late 1950s and early 1960s. They fell out of favor because of concerns about interactions. A more recent MAOI called selegiline (Emsam skin patch) was FDA approved for depression in 2006.

These drugs can be helpful, especially against treatment-resistant depression (Journal of Affective Disorders, May 1, 2025). It is crucial, however, to be aware of side effects and interactions.

Discovering MAO Inhibitors in a TB Ward:

Doctors discovered the first antidepressant medications completely by accident. In the 1950s, they noticed that drugs designed to treat tuberculosis had unexpected benefits.

Patients being treated at Sea View Hospital on Staten Island were quite ill. When they took the experimental TB medicine iproniazid, though, some became surprisingly energized. In their JAMA report (Nov. 8, 1952), the investigators mentioned “mild euphoria” and “sexual stimulation” as side effects.

These observations piqued the interest of other scientists. It was discovered that the TB drug iproniazid was helpful for people who were depressed even if they did not have tuberculosis. At the same time, researchers were unraveling the mechanism of action of MAO inhibitors.

How Do MAO Inhibitors Work?

The TB medication blocked an enzyme called MAO (monoamine oxidase). This in turn boosted levels of brain neurotransmitters such as dopamine, serotonin and norepinephrine. Iproniazid raised liver enzyme levels, however, and was ultimately replaced by other MAO inhibitors. These included isocarboxazid (Marplan), phenelzine (Nardil) and tranylcypromine (Parnate).

Doctors prescribed MAOI antidepressants enthusiastically until the late 1980s. That’s when Prozac (fluoxetine) entered the market. This selective serotonin reuptake inhibitor (SSRI) and its chemical cousins preempted the MAO inhibitors.

MAO Inhibitors and Food Interactions:

MAOIs lost favor partly because of the enthusiasm surrounding new antidepressants. It was also because drugs like Marplan, Nardil and Parnate were dangerous when combined with some foods. These antidepressants can interact with cheddar cheese, pepperoni, salami, soy sauce and avocados, to name just a few foods with tyramine.

One classic MAOI story involves involves the cheese effect (Lancet, May 16, 1964):

“On September 3, 1963, a 40-year-old man was put on Parnate (tranylcypromine) for serious depression. A month later, he complained of a slight headache, but ate supper with his family. He consumed beef casserole, cheese, and crackers. The cheese was cheddar, Caerphilly (a Welsh cheese similar to cheddar) and some Danish blue. During the night, he felt much worse. He was dizzy, nauseated, and his headache was unbearable. By morning, he felt well enough to eat breakfast with his family and consumed two or three large slices of cheese. Shortly thereafter he became distressed and incoherent. He started bleeding from his nose, and was agitated, aggressive, and confused. By the time he got to the hospital, he was incoherent, his temperature was 104.5° F, and his pulse and blood pressure were elevated. He died at 8:30 P.M. On autopsy, his brain was found to be swollen with intense vascular congestion. The physicians concluded that it was the combination of the cheese and his medicine that killed him.”

Caerphilly and other aged cheeses contain tyramine. In the presence of MAO inhibitors, tyramine can push blood pressure to life-threatening levels. There are also other medications that can interact with these antidepressants.

Avoiding Interactions While Reaping the Benefits of an MAOI:

Q. You wrote recently about MAO inhibitors as antidepressants. I hope they become more widely available. No other antidepressant has worked for me for 25 years. I’ve tried virtually every drug category and most of the commonly prescribed meds.

You have to watch your diet with MAOIs. However, I eat an avocado every day and frequently have Cheddar cheese. I don’t care for aged meats, which I know can be a problem. I experienced a multi-day moderate headache from soy sauce, but I would get migraines from MSG and chocolate even prior to MAOIs.

Two doctors have prescribed meds that don’t mix well with Parnate – a urologist (doxazosin) and a pain doctor (duloxetine.) Since they enter all my meds into a program, I wonder why it’s not flagged. It’s important for the patient to be vigilant to avoid food and drug interactions. Please let others know this option can be helpful.

A. The monoamine oxidase inhibitors (MAOIs) were the first antidepressants to be developed. As we just discussed, they were discovered accidentally when the tuberculosis drug isoniazid was found to lift the mood of patients suffering from TB.

Many doctors abandoned drugs such as isocarboxazid (Marplan), phenelzine (Nardil) and tranylcypromine (Parnate) when different antidepressants became available. Concerns about drug and food interactions played a role in this shift. Because the problem is tyramine, though, foods like your fresh avocado do not pose much risk (Psychopharmacology Bulletin, May 31, 2022). Tyramine builds up in stored food, so you might want to skip the leftovers. Fermentation leads to an accumulation of tyramine, so sourdough bread, sauerkraut and fermented bean sauce should be added to your list of foods to avoid.

People who have not responded to other antidepressants may benefit from treatment with a MAOI-type medicine.  This will require very careful supervision by a physician familiar with such drugs and, as you suggested, patient vigilance to avoid dangerous interactions.

Should Psychiatrists Prescribe MAO Inhibitors?

It’s not surprising that this class of antidepressants fell into disfavor. Some psychiatrists are now reporting, however, that these drugs can be helpful when newer antidepressants are ineffective or stop working. We have heard from readers who report that MAO inhibitors can be surprisingly beneficial.

Here are two examples:

“I have tried many different medications for anxiety and depression, and Nardil is by far the most effective. However, the side effects were unbearable. I gained 40 pounds in just six weeks. Instead, my doctor switched me to Parnate. It works nearly as well for me without the unpleasant side effects.

“These are both old drugs but no psychiatrist would prescribe either one until I was referred to a university program for treatment-resistant depression. I am disappointed that psychiatrists are so reluctant to prescribe these MAO inhibitor medicines. I do need to be careful not to overdo on tyramine-containing foods. However, I worry more about interactions with other drugs. My doctor had to lower my doses of blood pressure medicines. Perhaps you could help spread the word about how valuable these MAOI medicines can be for severe depression.”

Another reader wrote:

“When I was 37, my psychiatrist prescribed Nardil, a MAO inhibitor. I’ve been on it for 40 years. It’s an old drug that is rarely used these days. This antidepressant transformed my life.”

The Pros and Cons of MAO Inhibitor Antidepressants:

For some people, a MAO inhibitor may be extremely helpful against depression. They work differently from tricyclic antidepressants such as amitriptyline (Elavil), desipramine (Norpramin) or imipramine (Tofranil). They are also quite different from more modern antidepressants such as citalopram (Celexa), desvenlafaxine (Pristiq), duloxetine (Cymbalta), escitalopram (Lexapro), sertraline (Zoloft) and venlafaxine (Effexor).

Learn More:

MAO inhibitor drugs require extra caution because of interactions and side effects. If physicians and pharmacists are vigilant, though, they can help protect patients against such dangers. That means providing a list of all foods and other medications that might interact. It also requires thoughtful counseling about adverse reactions. All antidepressants carry risks. But so does major depression. You can learn more about the pros and cons of MAOIs and other antidepressants in our eGuide to Dealing with Depression. You’ll find it under the Health eGuides tab.