MAOIs List: Types, Uses, and What Makes Them Different

MAOIs were discovered before anyone used the word antidepressant. In the early 1950s, a tuberculosis drug called iproniazid was found to have mood-elevating effects, and researchers traced the mechanism back to its inhibition of monoamine oxidase, an enzyme that breaks down mood-relevant neurotransmitters. The discovery launched the modern era of psychiatric medication.

Decades later, MAOIs are the least-prescribed antidepressant class. But they are not obsolete. They work through a fundamentally different mechanism than any other antidepressant, and for a specific population of patients, they produce responses that nothing else does.

What This Page Covers

• How MAOIs work and why the mechanism matters
• The four FDA-approved MAOIs for depression and their specific indications
• MAO-A vs MAO-B: why the distinction matters
• What conditions MAOIs treat particularly well
• The dietary restriction: what to avoid and why
• Drug interactions and washout requirements
• Why MAOIs are underused and what that costs patients

How MAOIs Work

Monoamine oxidase (MAO) is an enzyme found in the nervous system, liver, and gastrointestinal tract. Its job is to break down monoamine neurotransmitters including serotonin, norepinephrine, dopamine, and tyramine after they have served their function. By blocking this enzyme, MAOIs increase the stores of presynaptic monoamines available for release into the synapse, including not only serotonin and norepinephrine but also dopamine, a deficit of which may contribute to persistent depressive symptoms such as apathy, psychomotor retardation, and anhedonia.

This is a presynaptic mechanism. SSRIs, SNRIs, and most other antidepressants block reuptake, reducing how quickly neurotransmitters are removed from the synapse after release. MAOIs reduce how quickly neurotransmitters are broken down before they are even released, increasing the available pool. The two mechanisms complement rather than duplicate each other, which is why MAOIs can produce response in patients who have not responded to multiple reuptake inhibitors.

Two Types of MAO: A and B

There are two subtypes of monoamine oxidase:

• MAO-A is the primary enzyme responsible for breaking down serotonin and norepinephrine, as well as tyramine. MAO-A inhibitors produce the most pronounced antidepressant effect.
• MAO-B primarily acts on phenylethylamine and dopamine. Selective MAO-B inhibitors are used primarily for Parkinson’s disease. At standard doses, they do not significantly affect serotonin.

Traditional antidepressant MAOIs are nonselective, irreversible inhibitors of both subtypes. This gives them their potency and their dietary restriction requirement.

The FDA-Approved MAOIs

Phenelzine (Nardil)

A nonselective, irreversible MAOI. FDA-approved for depression including treatment-resistant presentations, panic disorder, and social anxiety disorder. In a series of six Columbia University studies in patients with atypical depression, phenelzine consistently outperformed both imipramine and placebo, with an overall response rate of 72% for phenelzine versus 44% for imipramine and 26% for placebo across 409 patients. Associated with sedation and weight gain.

Tranylcypromine (Parnate)

A nonselective, irreversible MAOI. FDA-approved for major depressive disorder including treatment-resistant cases. Its chemical structure is similar to amphetamine, providing some stimulant-like activation without the addictive profile, making it preferred for patients with psychomotor retardation. A systematic review reported an overall response rate of 58% to tranylcypromine in patients with TRD. Widely used in bipolar depression.

Isocarboxazid (Marplan)

A nonselective, irreversible MAOI approved for major depressive disorder. Less frequently prescribed than phenelzine or tranylcypromine. Used when other MAOIs are not tolerated or when clinical or formulary considerations apply.

Transdermal Selegiline (Emsam)

At oral doses, selegiline is a selective MAO-B inhibitor used for Parkinson’s disease. At the higher doses used in the transdermal patch for depression, it provides nonselective inhibition of both MAO-A and MAO-B. The patch delivers the drug through the skin, bypassing the gut where dietary tyramine is normally metabolized. At the lowest dose patch (6 mg per 24 hours), transdermal selegiline can often be used with fewer dietary restrictions than traditional oral MAOIs. At higher doses, the full dietary restriction applies.

What MAOIs Treat Best

Treatment-Resistant Depression

Estimates suggest that 15 to 20% of patients presenting for treatment of major depression require MAOI treatment for optimal response, but the prescription rate is less than 0.1%. MAOIs are mechanistically distinct from all other antidepressant classes, which is why they can produce response when multiple conventional agents have not. Their unique effect on dopamine stores may address persistent anhedonia and motivational symptoms that respond poorly to serotonin-focused agents.

Atypical Depression

MAOIs have been shown to have superior efficacy to tricyclic antidepressants for depression with atypical features, and earlier initiation of MAOI treatment is warranted when atypical features are present. Atypical features include mood reactivity, hypersomnia, increased appetite, significant fatigue, and rejection sensitivity. Multiple randomized controlled trials support this advantage.

Bipolar Depression

In a systematic review, tranylcypromine showed an overall response rate of 74% for bipolar depression compared to 28% for control conditions. For patients with bipolar depression who have not responded to mood stabilizers and atypical antipsychotics, MAOIs remain a meaningful option. They are used with caution due to potential mood-switching, though current evidence suggests this risk may be lower than with conventional antidepressants.

Panic Disorder and Social Anxiety Disorder

Phenelzine has FDA approval for panic disorder and social anxiety disorder. Prior to SSRIs, MAOIs were considered highly effective for both conditions. For patients who have not responded to first-line agents, MAOIs remain a legitimate option.

The Dietary Restriction

The critical safety consideration with traditional MAOIs is the tyramine interaction.

Tyramine is an amino acid found in many aged, fermented, cured, or spoiled foods. Normally, MAO-A in the gut breaks down tyramine before it can reach the bloodstream. When MAO-A is blocked, tyramine absorbed from food enters the circulation and can trigger a sudden, severe blood pressure increase called a hypertensive crisis. Symptoms include a sudden severe headache, stiff neck, palpitations, sweating, and nausea. It is a medical emergency requiring immediate evaluation.

High-tyramine foods to avoid include aged cheeses (cheddar, Parmesan, Gruyere, brie), cured and fermented meats (salami, pepperoni, prosciutto, smoked fish), fermented foods (miso, soy sauce, sauerkraut, kimchi), tap beer and certain wines, and overripe or fermented fruits. Patients receive a specific, updated food list from their prescriber.

The dietary restriction is real and important. It is also more manageable than its historical reputation suggests. Many patients on modern MAOI diets report the restriction list is narrow and largely avoidable in normal daily eating. The older lists that included items like bananas and avocados were overly conservative based on incomplete data.

Drug Interactions and Washout Requirements

MAOIs interact seriously with many medications:

• SSRIs and SNRIs: Combining an MAOI with any serotonergic antidepressant can cause serotonin syndrome. A washout period of at least 14 days is required after stopping most antidepressants before starting an MAOI, and after stopping an MAOI before starting another antidepressant. For fluoxetine, the washout period is 5 weeks.
• Opioids, particularly meperidine and tramadol: Can cause serotonin syndrome.
• Stimulants and sympathomimetics: Can cause hypertensive crisis.
• Certain anesthesia agents: Disclosure of MAOI use is required before any surgery.

Patients starting an MAOI need a complete medication review with their prescriber before the transition.

Why MAOIs Are Underused and What That Costs

A 1999 survey found that 40% of psychiatrists had not prescribed an MAOI in the previous 3 years, and only 2% prescribed them frequently. These numbers have certainly worsened since then as older psychiatrists have retired. The result is that many residency-trained psychiatrists lack practical knowledge to initiate or manage MAOI therapy.

The clinical cost is real. If 15 to 20% of patients with depression would achieve their best response with an MAOI, and less than 0.1% are being prescribed one, a significant number of people are spending years on inadequate treatments when the right medication is available.

“MAOIs are underused for a real reason, the safety requirements are not trivial,” says Daniel Montville, MD, Psychiatrist, of the SiggyMD clinical team. “But the reasons we don’t prescribe them are mostly about prescriber familiarity, not whether they work. For the right patient, particularly someone who hasn’t responded to multiple SSRIs and SNRIs and fits the atypical or treatment-resistant profile, the conversation about MAOIs is worth having.”

About SiggyMD

SiggyMD provides clinician-reviewed psychiatric care for anxiety and depression, with licensed prescribers who review every treatment decision. For patients who have worked through multiple antidepressant options without adequate response, start your anonymous intake with SiggyMD to connect with a prescriber who will review your full clinical history. Also see: Treatment-Resistant Depression Options and The Complete Antidepressant List.

What Members Are Saying

TB

T.B., 52

Treatment-Resistant Depression with Atypical Features

“I had been on five SSRIs over fifteen years. Each one helped with anxiety but not the exhaustion, the sleeping too much, or the total flatness. When my prescriber finally mentioned phenelzine, I was skeptical about the dietary restrictions. Two months in, I feel more like myself than I have in a decade. The cheese thing is real but it’s manageable.”

PL

P.L., 38

Bipolar Depression

“Tranylcypromine was the medication that finally worked for my bipolar depression after everything else had either failed or triggered hypomania. The prescriber managed the transition carefully. It wasn’t a casual choice, but it was the right one.”

Member stories reflect real experiences. Names and identifying details have been changed to protect privacy. Results vary. SiggyMD is currently invite-only.

Sources

1. Fiedorowicz JG, Swartz KL. The Role of Monoamine Oxidase Inhibitors in Current Psychiatric Practice. Journal of Psychiatric Practice. 2004;10(4):239-248.

2. Birkenhäger TK, Heijnen WT. Monoamine oxidase inhibitors: Seriously underused in the treatment of major depression. Acta Psychiatrica Scandinavica. 2024;150(6):497-499.

3. Psychiatry Online. Moving on With Monoamine Oxidase Inhibitors. FOCUS. 2021;19(1).

4. StatPearls. Monoamine Oxidase Inhibitors (MAOIs). NCBI Bookshelf. Updated 2024.

5. Mayo Clinic. Monoamine oxidase inhibitors (MAOIs). Reviewed January 2025.

6. Cleveland Clinic. Monoamine Oxidase Inhibitors (MAOIs). Accessed June 2026.

7. PubMed. MAOIs and depression treatment guidelines. Journal of Clinical Psychiatry. 2012.

Reviewed by Daniel Montville, MD, Psychiatrist | Last updated June 2026