What is an MAO (Monoamine Oxidase) inhibitor?

What is an MAO Inhibitor?

MAO inhibitors (MAOIs) are a class of antidepressant medications that work by inhibiting the enzyme monoamine oxidase, which breaks down neurotransmitters like norepinephrine, serotonin, and dopamine in the brain. 1, 2

Mechanism of Action

• MAOIs block the monoamine oxidase enzyme system, which is widely distributed throughout the body and normally metabolizes monoamines (neurotransmitters including norepinephrine, serotonin, and dopamine). 2
• By inhibiting this enzyme, MAOIs increase the availability of these neurotransmitters in the brain, which helps alleviate depression. 2
• The exact relationship between MAO inhibition and clinical effects is not fully understood—it may be due to MAO inhibition itself, other pharmacologic actions, or an interaction of both. 2

Available MAOI Medications

The specific medications classified as MAOIs include:

• Phenelzine (traditional MAOI) 3, 2
• Tranylcypromine (traditional MAOI) 3, 1
• Selegiline (available in transdermal formulation) 3, 4
• Isocarboxazid 3
• Linezolid (an antibiotic with MAOI properties) 3

Clinical Uses

• MAOIs are indicated for treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants. 1
• They are particularly effective for atypical depression, high levels of anxiety, treatment-resistant depression, and anergic bipolar depression. 4, 5
• For anxiety disorders, MAOIs are effective for agoraphobia, panic disorder, and mixed anxiety-depressive states. 3
• MAOIs are NOT indicated for initial treatment of MDD due to potential for serious adverse reactions, drug interactions, and dietary restrictions. 1

Treatment Guidelines and Positioning

Current treatment guidelines position MAOIs as third-, fourth-, or fifth-line treatments for depression due to safety concerns. 3, 4, 5

The 2022 VA/DoD guideline for major depressive disorder includes MAOIs in advanced care management algorithms for patients who have shown partial or no response to initial pharmacologic monotherapy after a minimum of 4 to 6 weeks. 6

Critical Safety Concerns

Absolute Contraindications

MAOIs are absolutely contraindicated with the following medications due to risk of life-threatening serotonin syndrome or hypertensive crisis:

• Other MAOIs (combining two MAOIs is strictly prohibited) 7
• SSRIs and SNRIs (selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) 3, 7
• Tricyclic antidepressants (TCAs) 3, 7
• Opioids, especially meperidine, tramadol, methadone, and fentanyl 3
• Stimulants including amphetamines, methylphenidate, and sympathomimetic agents 3
• Certain cough/cold medications containing dextromethorphan, pseudoephedrine, or phenylephrine 3

Required Washout Periods

When switching to or from MAOIs, strict washout periods are mandatory:

• Wait at least 2 weeks after stopping an MAOI before starting any SSRI, SNRI, or TCA 3, 7
• Wait 5 weeks after stopping fluoxetine before starting an MAOI due to fluoxetine's long half-life 3, 7
• Discontinue all stimulants at least 2 weeks prior to starting an MAOI 3
• Failure to maintain adequate washout periods is the most common cause of preventable serotonin syndrome 7

Dietary Restrictions

Patients on MAOIs must avoid foods containing tyramine to prevent hypertensive crisis. 6, 8

The 2013 ACC/AHA heart failure guideline specifically notes caution with MAOIs when using adrenergic agonists in the management of heart failure. 6

Signs of Dangerous Reactions

Hypertensive crisis can manifest as:

• Sudden, severe elevation in blood pressure 3
• Severe "thunderclap" headache 3, 7
• Chest pain, palpitations 3
• Stroke, seizures, hyperthermia, and death 3

Serotonin syndrome presents with:

• Mental status changes 9, 7
• Autonomic instability 9, 7
• Neuromuscular abnormalities 3, 9

Pharmacokinetics

• Phenelzine reaches peak plasma concentration (Cmax) of 19.8 ng/mL at approximately 43 minutes after a single 30 mg dose. 2
• Mean elimination half-life is 11.6 hours after a single 30 mg dose. 2
• Phenelzine is extensively metabolized, primarily by oxidation via monoamine oxidase, with 73% recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours. 2

Patient Education Requirements

Patients on MAOIs must be explicitly educated about:

• Avoiding all over-the-counter medications without consulting a healthcare provider, including cold/allergy medications, energy drinks, weight loss products, and supplements containing stimulants 3, 9
• Recognizing signs of serotonin syndrome and hypertensive crisis 3
• Informing ALL healthcare providers about MAOI use before receiving any new medications 3, 7
• Avoiding illicit drugs, particularly cocaine, methamphetamine, and MDMA 3

Safe Medications with MAOIs

For breakthrough anxiety while on MAOIs:

• Benzodiazepines are the only truly safe PRN option (lorazepam, clonazepam, alprazolam) as they work through GABA pathways without interaction risk 9

For allergy symptoms:

• Second-generation antihistamines (cetirizine, loratadine, fexofenadine) are safe 3
• Intranasal corticosteroids (fluticasone, mometasone) are safe 3
• Saline nasal sprays or rinses are safe alternatives to decongestants 3

Common Clinical Pitfalls

• Failure to maintain adequate washout periods when switching between MAOIs and other antidepressants is the most preventable cause of serious adverse effects 3, 7
• Prescribing over-the-counter cold medications without checking for sympathomimetic ingredients 3
• Not providing written instructions listing all contraindicated medications to patients 9
• Combining MAOIs with opioids in pain management without recognizing the contraindication 3