What are MAO Inhibitors (MAOIs)?

MAOIs, also known as MAO inhibitors or monoamine oxidase inhibitors, are a class of psychotropic medications used to treat mood and anxiety disorders. These medications work by increasing the levels of neurotransmitters or chemical messengers in the brain to improve mood or reduce anxiety is some patients. Several of these medications may also work through other mechanisms.

Food & Drug Administration (FDA) Indications for MAOI:

There are four FDA-approved MAOIs.

1. Tranylcypromine (Parnate) is approved for Major Depressive Disorder (MDD).
2. Phenelzine (Nardil) is approved for certain forms of Major Depressive Disorder.
3. Selegiline (generic version and Emsam) is approved for Major Depressive Disorder.
4. Isocarboxazid (Marplan) is approved for Major Depressive Disorder.

Studies have found that MAOIs may be effective in treating other mental health conditions outside of their FDA-approved indications. Use outside of the FDA-approved indications is considered “off-label” and thus has not been robustly studied and supported by the FDA.

Potential Benefits of Treatment:

Potential benefits of MAOI include improvements in mental health such as partial or complete remission of symptoms of mood and anxiety disorders.

Alternatives to MAO Inhibitor Treatment:

Some potential alternatives to treatment with a MAO inhibitor include:

• Doing nothing or a “watch and wait” approach.
• Adjustments in lifestyle including activities and locations
• Therapy
• Other psychotropic medications such as antidepressants, anxiolytics (anti-anxiety) medications, stimulants, antipsychotics, and mood stabilizers.
• Non-invasive procedures such as Transcranial Magnetic Stimulation (TMS) and Electroconvulsive Therapy (ECT).
• Invasive procedures such as Deep Brain Stimulation (DBS).

Each of these alternatives has different potential benefits and risks. While it is difficult to predict how any individual patient may respond to a specific intervention, some interventions are generally considered safer such as therapy and other non-medication and non-procedure options. Additionally, among medications and procedures, some are considered generally safer than others. Given certain risks associated with monoamine oxidase (MAO) inhibitors, they are typically not considered first-line treatment options among medications.

Typical Use of MAOIs:

Typical use of monoamine oxidase (MAO) inhibitors (with the exception of Emsam, a transdermal or skin patch form of selegiline) involve taking one or more tablets one or more times per day. The quantity of tablets required for adequate treatment is often difficult to predict. In general, the daily dose of a MAOI should not be increased by more than one tablet at a time and a waiting period, often of several days to several weeks, is necessary with each dose adjustment. Rapid increases in the daily dose of a MAOI may result in the use of unnecessarily high doses of a medication, increased or worsened side effects and serious adverse risks, and/or possible diminished effectiveness or apparent effectiveness of the drug. The FDA’s or manufacturer’s maximum daily dose recommendation for MAOIs is as follows:

• The recommended daily maximum dose of Tranylcypromine (Parnate) is 60 mg. Each tablet contains 10 mg.
• The recommended daily maximum dose of Phenelzine (Nardil) is 90 mg. Each tablet contains 15 mg.
• The recommended daily maximum dose of Selegiline in oral form is 10 mg. Above this dose, the risks associated with consumption of tyramine in one’s diet increase and may be similar to the other MAOIs when taken at a dose of 30-40 mg. There is evidence that daily doses of 10 mg or less may still carry increased risks of a reaction to tyramine. Each tablet contains 5 mg.
• The recommended daily maximum dose of Isocarboxazid (Marplan) is 60 mg. Each tablet contains 10 mg.

Typical use of Emsam involves placing a patch on the skin and replacing it every 24 hours. The FDA’s recommended daily maximum dose of Emsam is 12 mg per day. The Emsam patch comes in 6 mg, 9 mg, and 12 mg strengths. Above the 6 mg dose, the risks associated with consumption of tyramine in one’s diet increase. At a dose of 6 mg per day, there may still be risks of a reaction to tyramine. Of note, some factors may reduce the recommended maximum dose. For example, the FDA recommended maximum dose of Emsam for patients 65 years and older is 6 mg.

It is generally believed that treatment of many mental health conditions with medication requires the use of these medications for several months or longer. However, the risks of long-term use of MAOIs are not well-established. For example, it is not known if the risks of suicidality are increased with use of Tranylcypromine (Parnate) longer than 4 months or the risks with Isocarboxazid (Marplan) use past 6 weeks. Additionally, the risks of taking doses of a MAOI outside of the FDA’s or manufacturer’s maximum recommended daily dose are not well-known. Therefore, longterm use of a MAOI, use of a MAOI outside of the maximum recommended daily dose, or use of a MAOI in dose frequencies (for example, taking 40 mg once a day versus 20 mg twice a day versus 30 mg in the morning and 10 mg at night) outside of FDA or manufacturer guidelines requires patients to be informed by their providers of the potential for known and unknown risks and alternative treatment options. If these known and unknown risks are accepted by the patient and the patient desires to pursue this medication regimen instead of another treatment, repeat follow up evaluations to assess the effectiveness and safety of the medication.

Risks Associated with MAOI Use:

MAOIs are associated with some side effects or adverse reactions that are known and some that are not well-established. Below is a list of some potential adverse reactions associated with MAO inhibitors. This is not a complete list but instead is a representation of some common and some serious risks associated with MAOI use. A more complete list of side effects can be found on the FDA’s website, manufacturer’s website, packaging insert, or by contacting your pharmacist for a comprehensive list of side effects and adverse reactions. It is important to understand the potential risks prior to starting MAOI use and to discuss any side effects you experience with your provider.

Some Common Side Effects:

• Difficulty falling and/or staying asleep
• Fatigue
• Dizziness or lightheadedness especially when getting up from a lying or sitting position
• Sexual dysfunction
• Headache
• Increased appetite or weight gain
• Decreased appetite or weight loss
• Increased sweating
• Restlessness
• Dry mouth and dry eyes
• Nausea
• Palpitations
• Impaired vision
• Difficulty urinating (if unable to urinate at all for 8-10 hours, go to the urgent care or emergency room)
• Shakiness or trembling
• Muscle twitches
• Easy or excessive bruising
• Worsening mental health
• Increase or decrease in blood pressure

Uncommon But Serious Side Effects:

The following are some of the rare, but potentially fatal, reactions that may occur from MAOI use. This is not an all-inclusive list. Please seek emergency medical attention by calling 911 if you are or may be experiencing any of the following.

• Delirium or confusion.
• Delusions or unusual thoughts such as paranoia or believing others are acting against you or racing and repeated thoughts.
• Hallucinations or hearing, seeing, or feeling things that aren’t there.
• Homicidal or suicidal ideation, which present with thoughts of guilt, thoughts of lack of self-worth, and/or thoughts on causing self-harm or harm to others.
• Liver failure, which may present with one or more of these symptoms: dark urine, belly pain, unusual skin rashes, confusion, yellow eyes or skin, nausea and/or vomiting.
• Anaphylaxis, which often presents with skin rashes or hives, itchy skin, swelling of the face, and difficulty talking or breathing (This is most likely to occur the first time you take any medication or the first time you take a new ingredient and can become life-threatening within minutes and thus requires calling 911 immediately).

Other Serious Risks:

• Tyramine-Induced Hypertension. Individuals who are taking MAOIs may experience elevated blood pressure from consuming foods with significant amounts of tyramine such as pickled or fermented foods, aged cheeses, cured and smoked meats, soybeans, broad beans, fava beans, some supplements, and improperly stored or spoiled foods. Some potential symptoms of tyramine-induced hypertension include severe headache, nausea & vomiting, sweating, severe anxiety, fast or pounding heartbeat, chest pain or pressure, changes in vision, shortness of breath, and confusion.
• Serotonin Syndrome. Serotonin Syndrome is a potentially life-threatening medical condition due to an excess or imbalance in serotonin activity  often due to taking certain medications or supplements with a MAOI. Some common medications and supplements that can react with MAOIs include Tryptophan, 5-HTP, St. John’s Wort, Ergotamine, Caffeine, Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors (SSRI), Serotonin-Norepinephrine Reuptake Inhibitors (SNRI), Dopamine-Norepinephrine Reuptake Inhibitors (DNRIs), Mirtazapine, Trazodone, Lithium, Second Generation Antipsychotics, Phentermine, Fenfluramine, Dexfenfluramine, Dextromethorphan, Chlorpheniramine, Pseudoephedrine and Ephedrine, Fentanyl, Meperidine, Tramadol, rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig), Linezolid, Fluconazole, Ciprofloxacin, MDMA, LSD, Cocaine, Amphetamines, Amphetamine Derivatives, Methylene Blue, and Methylergonovine. This is not a comprehensive list. Patients should never take a supplement or over-the-counter medication without checking with their provider first and inform other providers involved in their health of all of their medications including MAOIs. Some potential symptoms of serotonin syndrome include agitation or restlessness, rigid muscles, diarrhea, fast or pounding heartbeat, hallucinations, fever, loss of muscle coordination, nausea and vomiting, overactive reflexes, and high blood pressure.

Discontinuing Treatment

In general, MAOIs should not be stopped abruptly. However, there are cases, such as when serious adverse effects are present, in which your provider may recommend abrupt discontinuation of treatment. When MAOIs are stopped, withdrawal symptoms may present. While withdrawal symptoms are varied, some common ones include headache, trouble sleeping, fatigue, high blood pressure, irritation, worsening mental health, and suicidal ideation. You should inform your provider of withdrawal symptoms you experience and seek immediate medical help by calling 911 if you experience any significant or severe symptoms.

Other Considerations:

• Use of MAOIs With Other Medications and Supplements. Often, monoamine oxidase (MAO) inhibitors may produce an inadequate therapeutic response or cause side effects, both of which may justify the use of additional treatment(s) such as additional medications. These medications have their own risks and benefits and may have additional risks and benefits when combined with a MAOI or other medications and supplements. As combination treatments involving MAOIs are not frequently well-studied, the risks of these multi-drug regimens may not be fully known. Therefore, repeat follow up evaluations to assess the effectiveness and safety of the medication. – Pregnancy and Breastfeeding. The risks associated with MAOI use in pregnancy are not well known. Patients must inform their provider if they believe they may be pregnant or are breastfeeding.
• Changes in Health. Patients must notify providers of any changes in health or changes in their life that may affect their physical or mental health or ability to receive and follow a treatment plan with their provider.
• Use of Alcohol, Prescription Medications in a Way Not Intended to be Used, and Use of Illicit or Recreational Substances. Patients must report use of alcohol use, use of prescription medications in a way not intended to be used, and use of illicit or recreational substances to their provider. Use of any of these may result in life-threatening reactions with MAOIs or may contribute to significant disease and side effects.
• Serotonin Syndrome Risk with Adjunctive Medications. Some medications that may be improve the effects of MAOIs or decrease the side effects associated with MAOIs such as buspirone (Buspar) and sleep aids including trazodone, doxepin, and mirtazapine (Remeron) may increase the risks of serotonin syndrome. Use of adjunct medications that increase the risk of dangerous adverse effects requires patients to be willing and able to understand how to monitor themselves and take appropriate precautions, seek emergency in-person medical attention when appropriate, communicate any effects of the medication regimen to their provider, and willingness to accept the risks despite the availability of reasonable alternative treatments that may not pose the same risks.

Termination of Care:

While patients may terminate care at any time, providers may opt to terminate care at their clinical discretion. Some situations in which providers may end care with a patient include frequently missing appointments or communication difficulties, disagreements on appropriate treatment plan, or when complicating factors that lead the provider to believe they are unable to adequately provide care are present.