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Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) are an older type of antidepressant medication that has largely been phased out by newer drugs such as selective serotonin reuptake inhibitors (SSRIs). They have a number of side effects and can interact with several different drugs and foods.

However, they are effective in managing certain types of depression and continue to be prescribed for patients who do not respond to other antidepressant treatments. Certain MAOIs may also be used in conjunction with other medications to help treat Parkinson’s disease (PD) as well as depression associated with PD.

What Are MAOIs?

diet and pills

Monoamine oxidase inhibitors are a class of drugs primarily used as antidepressants. Their use has waned over the last several decades due to the availability of other medications for depression, their side effects, and their interactions with food and drugs (which may require a special diet by those who take them).1

However, they are still used to treat some cases of atypical depression with certain types of symptoms—including sensitivity to perceived rejection, chronic dysphoria, increased appetite/weight gain, associated anxiety, associated panic attacks, and hypersomnia (increased sleep time). They also have some off-label uses, such as in helping to manage bipolar depression and Parkinson’s disease.1

MAOIs work by inhibiting the action of monoamine oxidase (MAO)—an enzyme involved in the metabolism and inactivation of a number of neurotransmitters in the brain, including norepinephrine, serotonin, and dopamine. MAOI inactivation of this enzyme results in a greater amount of active neurotransmitters throughout the brain, which, over time, can lead to functional brain changes and a subsequent improvement in depression symptoms.1

Examples of MAOIs include:2

  • Isocarboxazid (Marplan).
  • Phenelzine (Nardil).
  • Selegiline (Emsam).
  • Tranylcypromine (Parnate).

Side Effects and Interactions of MAOIs

The most common side effects of MAOIs include:2

  • Headache.
  • Dry mouth.
  • Insomnia.
  • Gastrointestinal issues, such as nausea, diarrhea, and constipation.
  • Lightheadedness.
  • Dizziness.

Other side effects that have been observed less often include:2

  • Weight gain.
  • Low blood pressure.
  • Sexual dysfunction.
  • Difficulties urinating.
  • Tingling or prickling feeling in the skin.
  • Involuntary muscle jerks or twitching.
  • Muscle cramps.

A dangerous interaction can occur when a patient on MAOIs eats foods rich in the amino acid tyramine. Normally, the monoamine oxidase enzyme keeps tyramine at safe levels in the body. But when the enzyme is inhibited by MAOIs, tyramine metabolism is inhibited, and the amino acid may build up to excessive levels. As levels of tyramine rise, a person can experience high blood pressure, headaches, heart problems, nausea, vomiting, visual problems, and confusion.3

Therefore, according to the National Institutes of Health Clinical Center, special dietary restrictions must be followed from the day you start taking an MAOI until 3 to 4 weeks after you stop using it.3

Foods that must be avoided to prevent the effects of too much tyramine include:3

  • Air-dried meats, such as pepperoni, salami, and pastrami.
  • Alcoholic beverages, especially unpasteurized beers.
  • Sauerkraut.
  • Aged cheeses.
  • Fermented soy products, such as soy sauce, teriyaki, miso soup, and tempeh.

There are also numerous drugs that can react with MAOIs to cause dangerously high blood pressure and other effects. These include:3,4

  • Other antidepressants (SNRIs, tricyclic antidepressants).
  • Tramadol (an atypical opioid painkiller with norepinephrine reuptake blocking effects).
  • Certain cold and allergy medications.
  • Decongestants.
  • Stimulants (amphetamines, methylphenidate).
  • Dietary supplements and weight-reduction drugs.
  • Asthma inhalers.
  • Sinus, hay fever, or cold medicines.
  • Certain nose sprays or drops.
  • Some herbal supplements, especially St. John’s Wort and ginseng.

Withdrawal from MAOIs

Withdrawal symptoms often appear within 3 days of quitting a MAOI or starting a taper.

Regardless of how you are feeling, suddenly stopping MAOI treatment can bring on a variety of withdrawal symptoms. Even those who begin gradually lowering their dose may experience some of these symptoms, though they are usually more severe when stopping suddenly.

Symptoms can include:5,6

  • Insomnia.
  • Nightmares.
  • Drowsiness.
  • Headache.
  • Anxiety.
  • Irritability.
  • Pressured speech.
  • Sudden muscle contractions (myoclonus).

More serious side effects can include:5,6

  • Agitation.
  • Delirium.
  • Aggressiveness.
  • Profound cognitive impairment.
  • Psychotic features (delusions, hallucinations, paranoia).

Withdrawal symptoms often appear within 3 days of quitting a MAOI or starting a taper, but symptoms have been reported within hours of missing a dose. The symptoms of antidepressant withdrawal are often mild and fade after 1 to 2 weeks, but some MAOI withdrawal symptoms may be more severe and troublesome than those associated with other types of antidepressant discontinuation syndromes.6

Combining Talk Therapy With Antidepressants

Many people who take antidepressants continue to have some symptoms, which puts them at risk of depression relapse. Psychotherapy may augment the therapeutic effects of antidepressant medications and improve the long-term outlook for people with depression.6

Behavioral therapies may be able to target some symptoms that antidepressants may not—such as guilt, hopelessness, and low self-esteem—that, left unmanaged, might contribute to relapse. It also improves coping skills and promotes positive changes in the way people think and behave so that people can better manage their depression in the long term.6

According to the American Psychological Association, there is some evidence that shows that combining psychotherapy and antidepressant medications may be more effective than either treatment by itself. Specifically, cognitive behavioral therapy and interpersonal therapy have been shown to help. For anxiety, research suggests that psychotherapy may be even more effective than medications.7

History of MAOIs

pills bottle

Until the 1950s, if a person exhibited signs of depression, there were few medication options. The only treatment with any significant rates of effectiveness was electroconvulsive therapy.8

In 1952, a team at Northwestern University Medical School in Chicago observed that iproniazid (a member of the hydrazine class) was capable of inhibiting monoamine oxidase (MAO), which had been discovered 15 years earlier by researchers at Cambridge University. MAO is an enzyme that is responsible for breaking down neurotransmitters within the central nervous system. These neurotransmitters play important roles in the regulation of mood and energy, and discovering a way to inhibit their breakdown would lead to an ability to increase their levels in the brain.8

Iproniazid was designed to treat tuberculosis, but researchers at Sea View Hospital in New York City, observing the drug’s ability to stimulate the central nervous system, categorized this as a “side effect.” Soon, the doctors as Sea View began to notice that patients receiving treatment with iproniazid exhibited signs of an increase in mood and a more positive outlook. A new story from 1953 even showed a photo of patients dancing, with the caption, “A few months ago, the only sound here was the sound of victims of tuberculosis, coughing up their lives.”8

A group of clinicians recognized that this side effect could potentially be a primary effect to help other types of patients who were suffering from psychiatric disorders. Iproniazid’s initial success ushered in an era of treatment with more powerful MAO inhibitors, such as isocarboxazid, tranylcypromine, and phenelzine.8

Still Useful After All These Years

Almost 70 years ago, scientists took the first steps toward managing depression through medication and bringing some measure of relief to the millions of people who suffer from this mental health condition.

Those first antidepressants—miraculous as they seemed at the time—have mostly been replaced by better-tolerated options. Despite their rather antique status among pharmaceuticals, however, MAOIs can still provide significant relief for patients who can’t find it elsewhere.


[1]. Fiedorowicz, J., and Swartz, K. (2004). The Role of Monoamine Oxidase Inhibitors in Current Psychiatric Practice. Journal of Psychiatric Practice, 10(4), 239-248.

[2]. Mental Health America. Monoamine Oxidase Inhibitors (MAOI’s).

[3]. National Institutes of Health Clinical Center, Drug-Nutrient Interaction Task Force. (2011). Monoamine Oxidase Inhibitor (MAOI) Medications.

[4]. Stahl, S. and Felker, A. (2008). Monoamine Oxidase Inhibitors: A Modern Guide to an Unrequited Class of Antidepressants. Trends in Psychopharmacology.

[5]. Dilsaver, S. (1988). Monoamine oxidase inhibitor withdrawal phenomena: symptoms and pathophysiology. Acta Psychiatrica Scandinavica, 78(1), 1-7.

[6]. Warner, C., Bobo, W., Reid, S., and Rachal, J. (2006). Antidepressant Discontinuation Syndrome. American Family Physician, 74(3), 449-456.

[7]. Petersen, T. (2006). Enhancing the efficacy of antidepressants with psychotherapy. Journal of Psychopharmacology, 20(3).

[8]. American Psychological Association. How Do I Choose Between Medication and Therapy?

[9]. Lopez-Munoz, F. and Alamo, C. (2009). Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today. Current Pharmaceutical Design, 15, 1563-1586.

Last Updated on June 4, 2020
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