By Naomi Carr

Last updated: 21 March 2024 & medically reviewed by Dr. David Miles

Monoamine oxidase inhibitors (MAOIs) are antidepressant medications that are no longer commonly prescribed due to their potential risks and side effects. In some instances, they can be an effective medication, in which case close monitoring and dietary restrictions will be necessary.

MAO Inhibitors (MAOIs)

What are MAO Inhibitors (MAOIs)?

Monoamine oxidase inhibitors (MAOIs) are a type of antidepressant medication that was first developed and used in the 1950s. Today, they are not commonly prescribed as a first-line treatment, as they require dietary restrictions, and have potentially severe effects and overdose risks. Other antidepressants can be used with fewer side effects and risks. [1]

MAOIs are approved to treat major depressive disorder (MDD) that has not responded to other medications. They are generally effective in the treatment of depressive or anxiety disorders with atypical features. [2]

MAOIs are also used to treat neurological conditions such as Parkinson’s disease and multiple system atrophy. [3]

How MAOIs work

MAOIs work by preventing the activity of monoamine oxidase enzymes. These enzymes break down neurotransmitters in the brain, causing reduced levels and activity of dopamine, serotonin, and norepinephrine. Although not the sole cause of depression or mood disorders, it is thought that reduced levels of these neurotransmitters play a part in the development of these conditions. [1][4]

For example, serotonin is responsible for regulating several functions, including mood, appetite, and sleep. Low serotonin levels are found to be linked to depressive symptoms. As such, by preventing monoamine oxidase enzyme activity, MAOIs can increase serotonin levels and improve mood by preventing these neurotransmitters from being broken down. [1][4]

Some MAOIs are irreversible inhibitors, which means that the effects continue to be seen for several days or weeks after stopping the medication, while the body reinstates the activity of the enzymes. It can also take several weeks or months for the full effects of the medication to occur. [3]

Types of MAOIs

MAOIs that are used in the treatment of depression, along with their most commonly known brand names, include: [5]

  • Isocarboxazid (Marplan)

  • Phenelzine (Nardil)

  • Tranylcypromine (Parnate)

  • Selegiline (Emsam) skin patch

MAOI side effects

It is common when commencing a new treatment or increasing the dosage to experience some side effects. Often, these side effects will be alleviated within several days or weeks. However, if they persist or become problematic, consult with a doctor immediately, as a change of medication or dosage may be required.

Common side effects of MAOIs include: [3][5][6][7]

  • Nausea

  • Constipation

  • Diarrhea

  • Stomach pain

  • Dry mouth

  • Drowsiness

  • Fatigue

  • Sedation

  • Insomnia

  • Lightheadedness

  • Dizziness

  • Weakness

  • Shaking

  • Headaches

  • Weight gain

  • Anxiety

  • Chills

  • Sexual dysfunction

Rare or severe side effects of MAOIs can include: [6][7]

  • Severe agitation

  • Euphoria

  • Extreme changes in mood and behavior

  • Hot flushes

  • Fever

  • Extreme changes in blood pressure or heart rate

  • Palpitations

  • Abnormal physical sensations

  • Blurred vision

  • Rash or itching

  • Seizures 

  • Urinary retention

MAOI risks and interactions

Food interactions

MAOIs prevent monoamine oxidase enzymes from breaking down the neurotransmitter tyramine, which helps regulate blood pressure. Blocking the breakdown of this neurotransmitter can cause an excess of tyramine in the body, resulting in dangerously high blood pressure. [1]

Tyramine occurs naturally in the body and is also found in several foods. Because of this, it is necessary to restrict dietary intake while using an MAOI, to prevent excessive tyramine and high blood pressure. Foods high in tyramine include certain fruits, fermented meats, beer, some cheeses, and certain yeast products. [2]

Serotonin syndrome

Serotonin syndrome is a dangerous and potentially fatal condition that occurs when levels of serotonin become too high. This can occur when an MAOI medication is used in combination with another serotonergic medication, such as another antidepressant. [1]

Symptoms of serotonin syndrome include sweating, fever, confusion, muscle stiffness and shaking, restlessness, and seizures. Signs of serotonin syndrome should be reported to a professional immediately for appropriate treatment and intervention. [6][7]

Weight changes

Some antidepressants can contribute to changes in appetite and weight. Studies suggest that MAOIs are less likely to cause weight gain than tricyclic antidepressants (TCAs) like Doxepin, with very few reports of weight gain being caused by isocarboxazid and tranylcypromine treatment. Phenelzine is reportedly the most likely MAOI to cause weight gain. [7][8]

Physical health history

People with a history of heart, liver, or kidney disease, seizures, diabetes, severe headaches, or alcohol use disorder may not be able to safely take MAOIs or may be at increased risk of dangerous effects. If it is necessary for a high-risk individual to use an MAOI, the doctor may prescribe a reduced dose and monitor closely. [6]

Bipolar and mania

People with a history of bipolar disorder or manic symptoms may not be able to safely take antidepressants such as MAOIs, as they may cause or worsen episodes of mania. If it is necessary to prescribe an MAOI, adjunctive medications will also likely be prescribed and symptoms and behavior changes monitored closely. [6][7]

Drug interactions

MAOIs can interact with other substances and medications, causing a reduced effect of the medication or an increased risk of adverse effects. [2]

This can include other antidepressants, amphetamines, caffeine, antihistamines, cold medications, appetite suppressants, anticonvulsants, opioid analgesics, sedatives, tranquilizers, medicines containing alcohol, anxiolytics, diuretics, diabetes medications, beta-blockers, and St John’s wort. [1][6]

The prescribing doctor needs to be aware of all medications, prescribed or over the counter, that are being used before starting MAOI treatment. Also, MAOIs stay in the body for several weeks after stopping treatment, so it is also important to inform the prescribing doctor and wait at least 14 days before starting a new treatment after taking an MAOI. [3]

Alcohol

It is recommended not to consume alcohol while taking an MAOI. Alcohol can worsen symptoms of depression, increase the risk of side effects, and may cause high blood pressure when combined with MAOI treatment if the alcoholic beverage contains tyramine. [2]

MAOIs and suicidal ideation

Antidepressants are often prescribed to treat symptoms of depression, including suicidal thoughts. However, in some cases, particularly for individuals under 24 years old and when commencing treatment, antidepressants such as MAOIs can cause or worsen suicidal ideation. [6][7]

It is important for individuals taking MAOIs, along with their family members or caregivers, to be aware of these risks and to monitor for new or worsening thoughts of self-harm or suicide, or any concerning changes in mood or behavior. This should be reported to a professional to receive appropriate treatment and support. [2]

Alternative to MAOIs

Other antidepressants

Before being prescribed an MAOI, a different antidepressant will likely be prescribed first, such as: [5][9]

  • SNRIs: Serotonin and norepinephrine reuptake inhibitors (SNRIs) are also generally effective and well tolerated. This includes duloxetine and fluvoxamine.

  • TCAs: Tricyclic antidepressants (TCAs) are less commonly prescribed than SSRIs or SNRIs but might be utilized if other medications are ineffective. This includes imipramine and amoxapine.

  • Atypical: Atypical antidepressants include bupropion, mirtazapine, and trazodone. These medications work in slightly different ways from the other classes of antidepressants and can differ in their effects, which can be beneficial in certain cases.

  • Esketamine: Esketamine is a nasal spray containing ketamine that can be an effective treatment for some people with depression. It is often used alongside another antidepressant medication.

Psychedelic approaches

If other antidepressants have been prescribed with little or no effect, such as with treatment-resistant depression, alternative medicinal approaches may be used, such as: [10]

These approaches have been studied in recent years and are developing traction as effective treatments for depressive, mood, and trauma-related disorders. Psilocybin-assisted therapy may be available in some states and is typically administered alongside psychological interventions. [10]

Psychological interventions

Studies show that the most effective treatment for depression often includes the use of an antidepressant alongside psychological therapy. Evidence-based therapies for the treatment of depression include: [11][12]

Self-care and holistic approaches

Depression and other mental health conditions may also be improved by making lifestyle changes and engaging in holistic approaches. This can include changes in diet and exercise, improving sleep hygiene, creative therapies, yoga and meditation, and relaxation activities. [11][12]