MAO Inhibitors (MAOIs) for Depression and Anxiety: How They Work, Side Effects, and What to Expect

Monoamine oxidase inhibitors (MAOIs) are one of the earliest classes of antidepressant medications, first developed in the 1950s. Despite being among the oldest pharmacological treatments for depression, they remain some of the most effective antidepressants available — particularly for people who have not responded to newer medications.

MAOIs work by inhibiting the activity of an enzyme called monoamine oxidase, which exists in two forms: MAO-A and MAO-B. This enzyme is responsible for breaking down key neurotransmitters in the brain — specifically serotonin, norepinephrine, and dopamine. By blocking this enzyme, MAOIs allow these neurotransmitters to remain active in the brain for longer periods, which helps regulate mood, motivation, energy, and emotional processing.

The MAOIs currently approved for psychiatric use in the United States include:

• Phenelzine (Nardil) — an irreversible, non-selective MAOI widely used for depression and anxiety
• Tranylcypromine (Parnate) — an irreversible, non-selective MAOI with mild stimulant properties
• Isocarboxazid (Marplan) — an irreversible, non-selective MAOI less commonly prescribed
• Selegiline transdermal patch (Emsam) — a selective MAO-B inhibitor at low doses, delivered through the skin, which reduces (but does not eliminate) dietary restrictions at its lowest dose

The distinction between irreversible and reversible MAOIs is clinically important. Traditional MAOIs permanently deactivate the monoamine oxidase enzyme, meaning the body must synthesize entirely new enzyme molecules before normal function returns — a process that takes approximately two weeks. This is why strict washout periods are required when switching medications. Reversible inhibitors of MAO-A (RIMAs), such as moclobemide (available in Canada, Europe, and Australia but not the United States), bind temporarily to the enzyme, allowing it to resume normal function more quickly and posing a lower risk of dangerous food and drug interactions.

To understand how MAOIs exert their therapeutic effects, it helps to understand the role of monoamine oxidase in normal brain function.

Neurons communicate through chemical messengers called neurotransmitters. After a neurotransmitter like serotonin or norepinephrine is released into the synapse (the gap between neurons), it must eventually be cleared away to prevent continuous, unregulated signaling. The body uses two primary mechanisms for this cleanup: reuptake (pulling the neurotransmitter back into the sending neuron) and enzymatic degradation (breaking the neurotransmitter down chemically).

Monoamine oxidase is the primary enzyme responsible for that degradation. It exists in two subtypes:

• MAO-A preferentially breaks down serotonin, norepinephrine, and dopamine — the neurotransmitters most implicated in mood regulation
• MAO-B preferentially breaks down dopamine and phenylethylamine

When an MAOI blocks this enzyme, neurotransmitter levels increase throughout the brain. Unlike SSRIs or SNRIs, which primarily affect one or two neurotransmitter systems, MAOIs broadly elevate serotonin, norepinephrine, and dopamine simultaneously. This broad-spectrum mechanism is believed to account for their robust efficacy, particularly in treatment-resistant cases.

Additionally, MAOIs affect trace amines such as phenylethylamine, tyramine, and octopamine. The accumulation of tyramine, in particular, is responsible for the well-known dietary restrictions associated with these medications — a topic covered in detail below.

The selegiline transdermal patch (Emsam) takes a different pharmacological approach. By delivering the medication through the skin, it bypasses the gastrointestinal tract and liver on its first pass through the body. At its lowest dose (6 mg/24 hours), it selectively inhibits MAO-B in the brain while leaving MAO-A in the gut relatively intact, which is why the FDA does not require dietary modifications at this dose level.

MAOIs are FDA-approved for the treatment of major depressive disorder (MDD), but their clinical utility extends well beyond this single indication. In practice, psychiatrists prescribe MAOIs for several conditions, often after other treatments have proven inadequate.

Major Depressive Disorder and Treatment-Resistant Depression: MAOIs are among the most effective antidepressants available, particularly for individuals who have failed to respond to multiple trials of SSRIs, SNRIs, and tricyclic antidepressants. Research consistently shows that a significant percentage of patients labeled "treatment-resistant" respond to MAOIs when switched from other medication classes. They are sometimes described as the "last line" of antidepressant therapy, though many experts argue this label unfairly delays access to a highly effective treatment.

Atypical Depression: MAOIs have a particularly strong evidence base for atypical depression — a subtype characterized by mood reactivity (mood brightens in response to positive events), increased appetite or weight gain, hypersomnia (excessive sleeping), leaden paralysis (a heavy, weighted-down feeling in the limbs), and heightened sensitivity to interpersonal rejection. Multiple controlled trials have demonstrated that phenelzine outperforms both tricyclic antidepressants and placebo for this presentation.

Social Anxiety Disorder (Social Phobia): Phenelzine has demonstrated significant efficacy in the treatment of social anxiety disorder, with some studies showing response rates superior to cognitive-behavioral therapy in the short term. It is considered a well-supported option for severe, treatment-resistant social anxiety.

Panic Disorder: MAOIs are effective for panic disorder, including cases with agoraphobia. They are typically reserved for individuals who have not responded adequately to SSRIs or other first-line treatments.

Other Uses: There is clinical evidence and expert consensus supporting MAOI use in certain cases of post-traumatic stress disorder (PTSD), bipolar depression (used cautiously, typically alongside a mood stabilizer), and treatment-resistant anxiety disorders. Selegiline, specifically, is also used in neurology for the treatment of Parkinson's disease at different dosing than its psychiatric formulation.

Starting an MAOI is a more involved process than beginning most other antidepressants, and it requires close collaboration between the patient and prescriber. Understanding what to expect can help reduce anxiety about the process and improve adherence.

Before Starting: Before prescribing an MAOI, a psychiatrist will conduct a thorough medication review. Because of dangerous interactions, all serotonergic medications — including SSRIs, SNRIs, certain tricyclics, tramadol, meperidine, dextromethorphan (found in many cough medicines), and St. John's Wort — must be fully cleared from the body. This washout period is typically two weeks for most medications and five weeks for fluoxetine (Prozac), due to its exceptionally long half-life.

Dietary Restrictions: Patients taking traditional oral MAOIs must follow a low-tyramine diet. Tyramine is an amino acid found naturally in many foods, particularly those that are aged, fermented, cured, or spoiled. Normally, MAO-A in the gut breaks down dietary tyramine before it enters the bloodstream. When this enzyme is inhibited, tyramine can accumulate and trigger a sudden, dangerous spike in blood pressure called a hypertensive crisis.

Foods to avoid or limit include:

• Aged cheeses (cheddar, Swiss, Parmesan, blue cheese — fresh cheeses like mozzarella and cottage cheese are generally safe)
• Cured or smoked meats (salami, pepperoni, smoked sausage, dry-aged beef)
• Fermented foods (sauerkraut, kimchi, soy sauce, miso, fermented bean curd)
• Certain alcoholic beverages (tap beer, red wine, vermouth — while many patients safely consume small amounts of certain alcoholic beverages, this should be discussed with the prescriber)
• Overripe or improperly stored foods (spoiled fruit, leftover meats stored too long)
• Concentrated yeast extracts (Marmite, Vegemite)

Notably, dietary restrictions are often exaggerated in outdated resources. Modern guidance, based on updated tyramine content analyses, is more permissive than the overly restrictive lists from the 1960s and 1970s. A knowledgeable psychiatrist can provide a current, evidence-based dietary guide.

Onset of Action: Like most antidepressants, MAOIs typically require two to six weeks to reach full therapeutic effect. Some patients notice early improvements in energy and sleep within the first week or two, while mood improvements tend to emerge more gradually.

Monitoring: Blood pressure monitoring is recommended during the early weeks of treatment, particularly when doses are being adjusted. Patients are typically advised to obtain a home blood pressure cuff and report any sudden severe headaches, which can be a warning sign of hypertensive crisis.

Discontinuation: MAOIs should not be stopped abruptly. Gradual tapering under medical supervision is standard practice to minimize discontinuation effects. After stopping a traditional MAOI, the two-week dietary and medication restrictions remain in effect until new MAO enzyme has been synthesized by the body.

The evidence base for MAOIs is extensive, spanning over six decades of clinical research and use. While they are less frequently studied in modern randomized controlled trials compared to newer antidepressants — largely because they are all available as generics and lack pharmaceutical company sponsorship for new research — the existing evidence strongly supports their efficacy.

Efficacy in Major Depression: Multiple randomized controlled trials and meta-analyses have demonstrated that MAOIs are at least as effective as tricyclic antidepressants for the treatment of major depression and superior to placebo. For atypical depression specifically, the Columbia University group led landmark studies in the 1980s and 1990s showing that phenelzine was significantly more effective than both imipramine (a tricyclic) and placebo.

Treatment-Resistant Depression: Research suggests that approximately 50% to 70% of patients who have not responded to adequate trials of other antidepressant classes show meaningful improvement when switched to an MAOI. A widely cited study by McGrath and colleagues found that phenelzine produced remission in a substantial proportion of patients who had failed to respond to SSRIs and other modern antidepressants.

Comparative Effectiveness: Head-to-head trials comparing MAOIs with SSRIs are limited, but the available data suggest that MAOIs are at least as effective as SSRIs for moderate-to-severe depression and likely superior for atypical depression and treatment-resistant depression. The selegiline transdermal patch has demonstrated statistically significant superiority over placebo in large controlled trials, leading to its FDA approval in 2006.

Social Anxiety Disorder: Phenelzine has shown robust efficacy in multiple controlled trials for social anxiety disorder, with response rates often exceeding 65-70% in published studies. The Liebowitz Social Anxiety Scale, one of the most widely used measures in social anxiety research, was in fact developed in part during studies of phenelzine's effects.

Limitations of the Evidence: Most MAOI research was conducted before the modern era of clinical trial methodology. Many studies have relatively small sample sizes by today's standards, and direct comparisons with current first-line treatments are sparse. The lack of new industry-funded research means that clinicians often rely on older studies, clinical experience, and expert consensus when making prescribing decisions.

Like all medications, MAOIs carry risks and side effects that must be weighed against their substantial benefits. The most significant concerns are related to drug and food interactions, though everyday side effects are also important to consider.

Common Side Effects:

• Orthostatic hypotension — a drop in blood pressure upon standing, causing lightheadedness or dizziness. This is the most common limiting side effect, particularly with phenelzine, and tends to be worse in the first few weeks of treatment. Strategies such as increasing fluid and salt intake, rising slowly from seated positions, and wearing compression stockings can help manage this.
• Insomnia or sleep disturbance — especially with tranylcypromine, which has mild stimulant properties. Taking the medication earlier in the day often helps.
• Weight gain — particularly associated with phenelzine. This can be significant for some individuals and is a common reason for discontinuation.
• Sexual dysfunction — including difficulty achieving orgasm, reduced libido, or erectile dysfunction. This occurs at rates comparable to or sometimes higher than SSRIs.
• Edema (swelling in the extremities), dry mouth, and constipation
• Peripheral neuropathy — tingling or numbness in the hands and feet, associated primarily with phenelzine. This is caused by the medication's effect on pyridoxine (vitamin B6) metabolism and can often be prevented or treated with B6 supplementation.

Serious Risks:

• Hypertensive crisis — the most feared complication. This occurs when excessive tyramine enters the bloodstream or when MAOIs are combined with sympathomimetic drugs. Symptoms include sudden severe headache (often described as a pounding occipital headache), rapid heartbeat, nausea, vomiting, sweating, and dangerously elevated blood pressure. This is a medical emergency requiring immediate treatment. Patients are sometimes prescribed nifedipine as a rescue medication to carry in case of emergency, though the use of emergency protocols should be discussed with the prescribing physician.
• Serotonin syndrome — a potentially life-threatening condition caused by combining MAOIs with serotonergic medications. Symptoms include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle twitching or rigidity, hyperthermia, and in severe cases, seizures and organ failure. This is why strict washout periods are absolutely essential when transitioning to or from an MAOI.
• Dangerous drug interactions — beyond serotonergic antidepressants, MAOIs interact dangerously with stimulants, certain opioids (meperidine and tramadol), decongestants containing pseudoephedrine or phenylephrine, and numerous other medications. Patients must inform all healthcare providers, including dentists and emergency room physicians, that they are taking an MAOI.

It is worth emphasizing that while these risks are real, they are manageable and predictable when patients are properly educated and the diet and drug interaction guidelines are followed. The reputation of MAOIs as "dangerous" medications is largely a product of the 1960s, when the dietary restrictions were poorly understood. In the hands of a knowledgeable prescriber and an informed patient, MAOIs can be used safely and effectively.

One of the greatest practical challenges associated with MAOI treatment is finding a prescriber who is experienced and comfortable with these medications. Due to their declining use over recent decades, many psychiatrists — particularly those trained more recently — have limited experience prescribing MAOIs.

Seek a psychiatrist, not a general practitioner. MAOIs require specialized knowledge of drug interactions, dietary management, and dosing strategies that typically falls within psychiatric expertise. General practitioners and primary care providers rarely prescribe MAOIs and may not be equipped to manage their complexities.

Look for providers experienced in treatment-resistant depression. Academic medical centers, university-affiliated psychiatry departments, and treatment-resistant depression clinics are more likely to have clinicians familiar with MAOIs. Psychopharmacology specialists — psychiatrists who focus specifically on complex medication management — are particularly good candidates.

Useful strategies for finding a provider:

• Contact university-affiliated psychiatry departments and ask specifically about providers experienced with MAOIs
• Search for psychiatrists specializing in treatment-resistant depression or psychopharmacology
• The Psychology Today therapist finder and ABPN (American Board of Psychiatry and Neurology) verification tool can help identify board-certified psychiatrists in your area
• Patient advocacy organizations and online support communities focused on treatment-resistant depression sometimes maintain referral lists
• Consider telepsychiatry — remote psychiatric consultations have expanded access to specialists who may not practice in your geographic area

Be prepared to advocate for yourself. If you are experiencing treatment-resistant depression and believe an MAOI might be appropriate, it is reasonable to raise the topic with your psychiatrist. Some patients encounter resistance from providers unfamiliar with these medications. If your clinician is not comfortable prescribing an MAOI, ask for a referral to someone who is, rather than abandoning the possibility altogether.

Because all currently available MAOIs are available in generic form (with the partial exception of the selegiline patch), cost is generally not a prohibitive factor — though there are important nuances.

Generic Oral MAOIs: Phenelzine and tranylcypromine are available as generics and are typically affordable, with retail prices ranging from $30 to $100 per month depending on the pharmacy, dose, and geographic location. With insurance coverage or pharmacy discount programs (such as GoodRx), out-of-pocket costs can be significantly lower. However, some patients report intermittent supply chain issues — because demand for MAOIs is low, some pharmacies do not stock them routinely and must place special orders.

Selegiline Transdermal Patch (Emsam): The selegiline patch is considerably more expensive, with retail prices that can exceed $1,000 to $1,500 per month without insurance. A generic version became available, which has reduced costs somewhat, but it remains significantly more expensive than oral MAOIs. Insurance coverage varies, and prior authorization is frequently required — meaning your prescriber may need to document that other treatments have been tried and failed.

Pharmacy Availability: Because MAOIs are prescribed infrequently, not all pharmacies carry them in stock. Patients may need to:

• Call ahead to confirm availability or request that the pharmacy order the medication
• Use a mail-order pharmacy, which often has better stock of less commonly dispensed medications
• Work with a compounding pharmacy in rare cases of supply disruption

Insurance and Coverage: Most insurance plans cover generic oral MAOIs, but coverage for the selegiline patch may require prior authorization or step therapy (demonstrating failure of cheaper alternatives first). Patient assistance programs offered by manufacturers may be available for the patch formulation for those who are uninsured or underinsured.

For individuals who are not candidates for MAOI therapy — whether due to inability to adhere to dietary restrictions, dangerous medication interactions, or personal preference — several alternative treatments exist for depression and anxiety disorders.

Other Antidepressant Classes:

• SSRIs (fluoxetine, sertraline, escitalopram) — first-line treatments for depression and most anxiety disorders, with a favorable side effect profile and no dietary restrictions
• SNRIs (venlafaxine, duloxetine, desvenlafaxine) — effective for depression and anxiety, with dual action on serotonin and norepinephrine
• Tricyclic antidepressants (TCAs) such as nortriptyline, amitriptyline, and clomipramine — older medications with robust efficacy, sometimes used when SSRIs and SNRIs are insufficient
• Bupropion (Wellbutrin) — a norepinephrine-dopamine reuptake inhibitor useful for depression, with a lower risk of sexual side effects and weight gain
• Mirtazapine (Remeron) — a noradrenergic and specific serotonergic antidepressant, particularly useful when insomnia and appetite loss are prominent

Augmentation Strategies:

• Lithium augmentation — adding lithium to an existing antidepressant is one of the best-studied strategies for treatment-resistant depression
• Atypical antipsychotic augmentation — aripiprazole, quetiapine, and brexpiprazole are FDA-approved as adjuncts to antidepressants for treatment-resistant depression
• Thyroid hormone (T3) augmentation — adding low-dose liothyronine can enhance antidepressant response in some patients

Non-Pharmacological and Neuromodulation Treatments:

• Cognitive-behavioral therapy (CBT) — the most extensively studied psychotherapy for depression and anxiety, with strong evidence for sustained benefit
• Electroconvulsive therapy (ECT) — the most effective acute treatment for severe, treatment-resistant depression, with response rates of 50-70% even after medication failure
• Transcranial magnetic stimulation (TMS) — a non-invasive brain stimulation technique FDA-cleared for treatment-resistant depression
• Ketamine and esketamine (Spravato) — rapidly acting treatments for treatment-resistant depression, available through specialized clinics and REMS programs
• Vagus nerve stimulation (VNS) — an implanted device FDA-approved for chronic, treatment-resistant depression

The choice between these alternatives depends on the specific condition being treated, the severity of symptoms, prior treatment history, co-occurring medical conditions, and individual patient preferences. A thorough discussion with a psychiatrist can help identify the most appropriate next step.

If you are experiencing persistent symptoms of depression — such as sustained low mood, loss of interest in activities, changes in sleep or appetite, difficulty concentrating, feelings of worthlessness, or thoughts of death or suicide — it is important to seek evaluation from a qualified mental health professional.

Consider asking about MAOIs specifically if:

• You have tried multiple antidepressants from different classes without adequate improvement
• Your depression features atypical symptoms such as mood reactivity, oversleeping, overeating, leaden paralysis, or rejection sensitivity
• You have severe social anxiety that has not responded to first-line treatments
• You are interested in exploring all available treatment options with your psychiatrist

If you are currently taking an MAOI and experience a sudden, severe headache (especially at the back of the head), rapid heartbeat, nausea, vomiting, or neck stiffness, seek emergency medical care immediately — these may be signs of a hypertensive crisis. Inform emergency personnel that you are taking an MAOI.

If you are in crisis: Contact the 988 Suicide & Crisis Lifeline by calling or texting 988. You can also reach the Crisis Text Line by texting HOME to 741741. These services are free, confidential, and available 24/7.

Treatment-resistant depression is not a failure of willpower or character — it is a complex neurobiological condition, and effective treatments exist. MAOIs represent one of the most powerful tools available in psychiatry, and no one should be denied access to potentially life-changing treatment due to outdated fears or unfamiliarity.