Phenelzine (Nardil)

What it treats

Phenelzine is approved by the U.S. Food and Drug Administration to treat depression, particularly depression that hasn't responded to other treatments and depression with atypical features.

Off-label uses include social anxiety disorder, panic disorder, and PTSD. Off-label means a purpose the label doesn't formally list even though evidence and practice support it.

How it works

Phenelzine blocks an enzyme called monoamine oxidase, or MAO. That enzyme breaks down serotonin, norepinephrine, and dopamine (and also tyramine from food). Blocking it raises levels of these messengers in the brain.

Phenelzine's block is irreversible: it permanently disables the MAO molecules it binds. New MAO has to be made from scratch by the body, which takes about two weeks. That's why the tyramine restriction and the drug-interaction restrictions have to hold for two weeks after the last dose, not just while a person is taking it.

Receptor mechanism (detail)

Phenelzine is an irreversible, non-selective inhibitor of MAO-A and MAO-B. MAO-A breaks down serotonin, norepinephrine, and dietary tyramine. MAO-B breaks down dopamine. Because both are blocked, tyramine that ordinarily gets neutralized in the gut can enter circulation and cause a hypertensive crisis. Because serotonin metabolism is blocked, other serotonergic drugs can cause serotonin syndrome.

Potency and typical dosing pattern

Ranges are typical framework only, not a prescription for any individual.

Starting is 15 mg three times a day. Titration goes to 60 to 90 mg per day divided. Some patients need longer trials at higher doses. MAO enzymes have to be substantially blocked (roughly 80% or more) before the drug consistently works, which usually takes a couple of weeks after reaching a full dose.

Safety monitoring

• Blood pressure at every visit. Both hypertensive crisis (with tyramine or sympathomimetics) and orthostatic hypotension are on the table.
• Tyramine-restricted diet. Avoid aged cheeses, cured or aged meats, tap or unpasteurized beer, sauerkraut, kimchi, soy sauce and other fermented soy products, fava beans, and overripe or spoiled foods. A pharmacist or dietician can give the complete list.
• 14-day washout before starting most other antidepressants and 14 days after stopping phenelzine before starting them. For fluoxetine specifically, wait 5 weeks after stopping it before starting phenelzine because of the long half-life.
• Avoid serotonergic drugs during and for 14 days after: SSRIs, SNRIs, tramadol, meperidine, dextromethorphan, triptans, linezolid, methylene blue, St. John's wort, MDMA.
• Suicidality in the first 4 weeks, especially under age 25 (FDA boxed warning).
• Weight gain, sexual dysfunction, edema, vitamin B6 depletion can develop over time. Some clinicians supplement B6.

What to expect

Common side effects

Common side effects include:

• Dizziness on standing.
• Dry mouth.
• Constipation.
• Weight gain.
• Sexual side effects (reduced desire, delayed orgasm, erectile difficulty).
• Sleep disturbance (insomnia or vivid dreams).
• Edema.
• Muscle twitches.

If a side effect is severe, or it isn't improving, that's a conversation to have with the prescriber rather than a reason to stop on your own.

Serious side effects and warnings

Serious problems are uncommon, but a few really matter.

Boxed warning. Like all antidepressants, phenelzine carries an FDA boxed warning that it can increase suicidal thoughts and behaviors in children, teenagers, and young adults under 25, especially in the first weeks of treatment or after a dose change.

• Hypertensive crisis. Eating tyramine-rich foods, or taking sympathomimetic drugs (some cold medications, ephedra, some ADHD stimulants, cocaine, amphetamine), can drive blood pressure to dangerous levels. Warning signs are severe pounding headache, chest pain, nausea and vomiting, sweating, and a racing heart. This is a medical emergency.
• Serotonin syndrome. Combining phenelzine with SSRIs, SNRIs, tramadol, meperidine, dextromethorphan, triptans, linezolid, methylene blue, or St. John's wort can cause severe agitation, fever, muscle rigidity, and altered mental status. Also a medical emergency.
• Orthostatic hypotension. A drop in blood pressure on standing can cause dizziness or falls.
• Liver injury. Elevated liver enzymes and, rarely, hepatitis have been reported.

Sexual side effects

Sexual side effects are common with phenelzine. Reduced desire, delayed orgasm, erectile difficulty, and anorgasmia all occur. Rates are similar to or higher than SSRIs. These are worth discussing early because they can be a leading reason for discontinuation.

Weight, appetite, and sleep

Phenelzine commonly causes weight gain, sometimes substantial. It can cause insomnia or, less often, sedation. Sleep architecture shifts on MAOIs, and vivid dreams are common.

Starting and dosing basics

This section is general background, not a dosing instruction for any individual. The right dose is a decision for a prescriber.

Phenelzine comes as tablets. Starting is at 15 mg three times a day, with steps up over days to weeks. The dose is often pushed to what a person can tolerate because sub-therapeutic dosing is a common cause of what looks like non-response. A prescriber comfortable with MAOIs will walk through the diet and drug rules in detail before the first dose.

Missed doses and interactions

If you miss a dose, take it when you remember, unless it's almost time for the next dose. Skip the missed dose and carry on. Don't take two doses to make up for one.

Interactions with phenelzine are extensive. Common categories:

• Do not combine with SSRIs, SNRIs, other MAOIs, tramadol, meperidine, dextromethorphan, triptans, linezolid, methylene blue, St. John's wort, MDMA, or amphetamines.
• Use with caution with sympathomimetic decongestants (pseudoephedrine, phenylephrine, over-the-counter cold medications), tyramine-rich foods, and any drug that raises blood pressure.
• Wait 14 days after stopping phenelzine before starting a serotonergic drug (5 weeks after fluoxetine before starting phenelzine).

Give every prescriber and pharmacist a full list of your medications and supplements, including over-the-counter ones. Carry a card that says you take an MAOI.

Stopping and tapering

Phenelzine isn't a controlled substance and isn't habit-forming in the usual sense.

The body does adjust to it, though, and stopping abruptly can cause discontinuation symptoms. The 14-day period after stopping is also when tyramine restrictions and drug interactions still hold, because MAO enzyme has to regenerate. A prescriber typically tapers phenelzine over weeks rather than stopping suddenly.

Pregnancy and breastfeeding

This is an area where individual circumstances matter and the decision belongs with a clinician. Data in pregnancy are limited, and MAOIs are generally avoided when there are alternatives. Untreated depression carries its own risks. Anyone who is pregnant, planning a pregnancy, or breastfeeding should talk it through with their prescriber so the specific risks and benefits can be weighed for their situation.

Cost and generic availability

Phenelzine is available as a generic and is inexpensive. Generic phenelzine contains the same active medication as Nardil and works the same way. Most insurance plans cover it.

Common questions

Why do MAOIs have such a strict diet? MAO in the gut normally breaks down tyramine from food. Blocking it lets tyramine enter circulation, where it can trigger a hypertensive crisis. Aged cheeses, cured meats, some beers, sauerkraut, and a few other foods have enough tyramine to matter.

Why 14 days between MAOIs and other antidepressants? Phenelzine irreversibly inactivates MAO. New enzyme has to be made, which takes about two weeks. During that window, combining MAOI activity with a serotonergic drug can cause serotonin syndrome.

Do MAOIs still work when SSRIs haven't? Yes, often. That's the specific niche for phenelzine and other MAOIs today: depression that hasn't responded to other trials.

Is a hypertensive crisis common? No. With careful diet counseling and drug review, it's uncommon. When it happens, though, it's serious.

Is phenelzine addictive? No. It's not a controlled substance and doesn't cause cravings. Stopping should still be planned with a prescriber.

Questions to ask your prescriber

• Is my prescriber comfortable with MAOIs, or should we consider a referral?
• Can we go through the tyramine diet together, and can I get a printed list?
• Which medications and supplements do I need to avoid, and which are safe?
• What warning signs should send me to the emergency room?
• If we decide to stop it later, how would we do that safely, and how long do the diet rules hold after stopping?

Sources

This guide draws on current prescribing information and public health references and current as of June 8, 2026. It is reviewed for clinical accuracy and updated as guidance changes.

• U.S. Food and Drug Administration. Phenelzine sulfate (Nardil) prescribing information.
• MedlinePlus, U.S. National Library of Medicine. Phenelzine.
• National Institute of Mental Health. Mental health medications.
• American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder.
• National Institute for Health and Care Excellence (NICE). NG222, Depression in adults.