Phenelzine

Antidepressant, irreversible non-selective monoamine oxidase inhibitor (MAO-A and MAO-B)

ATC code: N06AF03

Brand names: Nardil

Updated 4 Jun 2026 · Methodology

Indications

Treatment-resistant depression

Third line

Phenelzine is a third-line antidepressant for SSRI- and SNRI-resistant depression, especially with atypical features (hypersomnia, hyperphagia, rejection sensitivity). It requires a strict tyramine-free diet because aged cheeses, cured meats, fava beans and red wine can trigger hypertensive crisis. A 2-week SSRI washout (5 weeks for fluoxetine) is needed before starting. and SEPB restrict prescribing to psychiatrists.

Sources

ICD-10: F33 · ICD-11: 6A72

How to read tiers A–F

AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit

Mechanism of action

Irreversibly inhibits mitochondrial MAO-A and MAO-B. After withdrawal, enzyme activity returns over 2–3 weeks – the time needed to synthesise new enzymes. Serotonin, noradrenaline and dopamine accumulate at nerve endings; in parallel, dietary tyramine accumulates and may trigger hypertensive crisis.

Safety

Contraindications

SSRI, SNRI, tricyclic antidepressants, mirtazapine, clomipramine – serotonin syndrome
Tramadol, pethidine (meperidine), dextromethorphan, methadone – fatal serotonin syndrome
Triptans (sumatriptan, rizatriptan, zolmitriptan) – serotonin syndrome
Sympathomimetics (pseudoephedrine, ephedrine, phenylephrine) and levodopa – hypertensive crisis
Phaeochromocytoma, thyrotoxicosis
Severe hepatic impairment, cerebrovascular disease

Serious adverse effects

Tyramine-induced hypertensive crisis
Serotonin syndrome
Hepatotoxicity
Hyponatraemia

Common adverse effects

Orthostatic hypotension
Drowsiness
Dry mouth
Weight gain
Paresthesia
Insomnia

Pregnancy: can you take Phenelzine?

Pregnancy data are limited. In women planning pregnancy phenelzine is usually switched to an SSRI with a better safety profile.

Breastfeeding: can you take Phenelzine?

Passes into breast milk. Breastfeeding is not recommended.

Calculate RID

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Drug–drug interactions

18 pairs found. Sorted from critical to minor.

CriticalAlmotriptanSelective serotonin 5HT1B/1D agonists (triptans)

Mechanism

Almotriptan is CYP3A4 + CYP2D6 substrate. With phenelzine – fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

FDA: Axert (almotriptan) prescribing information (2009)

Pair details →Almotriptan →

CriticalCitalopramSSRI (selective serotonin reuptake inhibitor)

Mechanism

Citalopram is an SSRI. Combined with phenelzine causes serotonin syndrome. Nardil Section 4 strict contraindication.

Symptoms

Hyperthermia, myoclonus, tachycardia, hypertension.

Management

Combination contraindicated. 2-week washout.

Sources

Pair details →Citalopram →

CriticalEletriptanTriptan, selective 5HT1B/1D receptor agonist

Mechanism

Eletriptan is a serotonin agonist, CYP3A4 substrate. With phenelzine – fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

FDA: Relpax (eletriptan) prescribing information (2013)

Pair details →Eletriptan →

CriticalEscitalopramSelective serotonin reuptake inhibitors (SSRIs)

Mechanism

Escitalopram is an SSRI. Combined with phenelzine causes serotonin syndrome. Nardil Section 4.

Symptoms

Hyperthermia, myoclonus, tachycardia.

Management

Combination contraindicated. 2-week washout.

Sources

Pair details →Escitalopram →

CriticalFluoxetineSelective serotonin reuptake inhibitors

Mechanism

Phenelzine irreversibly inhibits MAO; fluoxetine blocks serotonin reuptake. Combined use causes synaptic serotonin accumulation and serotonin syndrome: hyperthermia, myoclonus, agitation, coma. Nardil Section 4 strict contraindication. A 5-week washout is required between fluoxetine and phenelzine (due to norfluoxetine's long T½).

Symptoms

Within hours: agitation, confusion, tachycardia, hypertension, hyperthermia, tremor, myoclonus, hyperreflexia. Severe cases – seizures, coma, rhabdomyolysis, DIC.

Management

Combination contraindicated. Allow 5-week washout between stopping fluoxetine and starting phenelzine. Allow 2-week washout between stopping phenelzine and starting any SSRI (MAO resynthesis time).

Sources

Pair details →Fluoxetine →

CriticalFrovatriptanTriptan, selective 5HT1B/1D receptor agonist

Mechanism

Frovatriptan is a serotonin agonist, CYP1A2 substrate. With phenelzine – fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

Pair details →Frovatriptan →

CriticalLinezolidOxazolidinone antibiotic

Mechanism

Linezolid is a reversible MAO inhibitor. Combined with phenelzine causes cumulative MAO inhibition and fatal serotonin syndrome with tyramine load.

Symptoms

Hypertensive crisis, hyperthermia, myoclonus.

Management

Combination contraindicated. Alternative antibiotic: vancomycin or daptomycin for MRSA.

Sources

Pair details →Linezolid →

CriticalMeperidineOpioid analgesic, phenylpiperidine class

Mechanism

Meperidine inhibits serotonin reuptake. With phenelzine (MAOI) causes fatal serotonin syndrome. boxed warning.

Symptoms

Hyperthermia above 39°C, myoclonus, coma within hours.

Management

Combination contraindicated. At least 14 days between MAOI withdrawal and meperidine. Alternative – morphine or fentanyl.

Sources

Pair details →Meperidine →

CriticalMethadoneSynthetic opioid, full mu-receptor agonist

Mechanism

Methadone is an opioid with serotonergic activity and QT prolongation. Combined with phenelzine causes serotonin syndrome and additive QT effect.

Symptoms

Hyperthermia, myoclonus, respiratory depression, QT prolongation.

Management

Combination contraindicated. For OST in an MAOI patient, switch methadone to buprenorphine (less serotonergic).

Sources

Pair details →Methadone →

CriticalMirtazapineOther antidepressants (NaSSA)

Mechanism

Mirtazapine is a dual-mechanism antidepressant (α2 + 5-HT2 blockade). Combined with phenelzine causes serotonin syndrome.

Symptoms

Hyperthermia, myoclonus, tachycardia.

Management

Combination contraindicated. 2-week washout.

Sources

Pair details →Mirtazapine →

CriticalNaratriptanTriptan, selective 5HT1B/1D receptor agonist

Mechanism

Naratriptan is a serotonin agonist. With phenelzine – fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

FDA: Amerge (naratriptan) prescribing information (2014)

Pair details →Naratriptan →

CriticalParoxetineSelective serotonin reuptake inhibitor (SSRI)

Mechanism

Paroxetine is an SSRI with additional antimuscarinic activity. Combined with phenelzine causes serotonin syndrome plus additive sedation.

Symptoms

Hyperthermia, myoclonus, tachycardia, marked sedation.

Management

Combination contraindicated. 2-week washout.

Sources

Pair details →Paroxetine →

CriticalRizatriptanSelective 5-HT1B/1D serotonin receptor agonist

Mechanism

Rizatriptan is a MAO-A substrate. With phenelzine accumulation and fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

Pair details →Rizatriptan →

CriticalSertralineSelective serotonin reuptake inhibitors (SSRIs)

Mechanism

Sertraline is an SSRI. Combined with phenelzine causes serotonin syndrome. Nardil Section 4 contraindication. 2-week washout between stopping sertraline and starting phenelzine.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus within hours of co-administration.

Management

Combination contraindicated. Minimum 2-week washout. After phenelzine withdrawal – 2 weeks before any serotonergic drug.

Sources

Pair details →Sertraline →

CriticalSumatriptanSelective 5-HT1B/1D serotonin receptor agonist

Mechanism

Sumatriptan is a 5-HT1B/1D agonist, partly metabolised by MAO-A. Phenelzine irreversibly inhibits MAO – sumatriptan accumulates and excess serotonin triggers fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

Pair details →Sumatriptan →

CriticalTramadolOther opioids

Mechanism

Tramadol inhibits serotonin reuptake (secondary mechanism). Combined with phenelzine causes fatal serotonin syndrome – fatal cases reported. boxed warning on tramadol.

Symptoms

Within 1–6 hours: hyperthermia above 39°C, myoclonus, agitation, seizures. High mortality without tramadol withdrawal.

Management

Combination contraindicated. Alternative analgesic: paracetamol or gabapentin (no serotonergic effect). If opioid is needed, morphine with caution.

Sources

FDA: Nardil (phenelzine sulfate) prescribing information (2009)

Pair details →Tramadol →

CriticalVenlafaxineSNRI (serotonin-norepinephrine reuptake inhibitor)

Mechanism

Venlafaxine is an SNRI with strong serotonin effect. Combined with phenelzine causes severe serotonin syndrome.

Symptoms

Hyperthermia, myoclonus, tachycardia, rhabdomyolysis.

Management

Combination contraindicated. 2-week washout (1 week for venlafaxine due to short T½).

Sources

Pair details →Venlafaxine →

CriticalZolmitriptanTriptan, selective 5HT1B/1D receptor agonist

Mechanism

Zolmitriptan is MAO-A + CYP1A2 substrate. With phenelzine – fatal serotonin syndrome.

Symptoms

Agitation, tachycardia, hyperthermia, myoclonus, hyperreflexia within hours.

Management

Combination contraindicated. 14 days after MAOI withdrawal before starting triptan.

Sources

FDA: Zomig (zolmitriptan) prescribing information (2017)

Pair details →Zolmitriptan →

Label mentions33 mentions

Verbatim lines from the interaction sections, in the language of the label

From this drug’s label

CriticalBupropion
«CONTRAINDICATIONS: The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin®) is contraindicated. At least 14 days should elapse between discontinuation of an MAO…»
FDA, section 4 · Open on DailyMed
CriticalCitalopram
«CONTRAINDICATIONS: There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine…»
FDA, section 4 · Open on DailyMed
CriticalDextromethorphan
«CONTRAINDICATIONS: Phenelzine sulfate should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics. Excitation, seizures, delirium…»
FDA, section 4 · Open on DailyMed
CriticalFluoxetine
«CONTRAINDICATIONS: There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine…»
FDA, section 4 · Open on DailyMed
CriticalFluvoxamine
«CONTRAINDICATIONS: There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine…»
FDA, section 4 · Open on DailyMed
CriticalL-tryptophan
«CONTRAINDICATIONS: The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS ). Therefore, patients being treated with…»
FDA, section 4 · Open on DailyMed
CriticalL-tyrosine
«CONTRAINDICATIONS: The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS ). Therefore, patients being treated with…»
FDA, section 4 · Open on DailyMed
CriticalMeperidine
«CONTRAINDICATIONS: Phenelzine sulfate should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics. Excitation, seizures, delirium…»
FDA, section 4 · Open on DailyMed
CriticalMethyldopa
«CONTRAINDICATIONS: The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS ). Therefore, patients being treated with…»
FDA, section 4 · Open on DailyMed
CriticalMethylphenidate
«CONTRAINDICATIONS: The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS ). Therefore, patients being treated with…»
FDA, section 4 · Open on DailyMed
CriticalParoxetine
«CONTRAINDICATIONS: There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine…»
FDA, section 4 · Open on DailyMed
CriticalSertraline
«CONTRAINDICATIONS: There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine…»
FDA, section 4 · Open on DailyMed
Criticalsympathomimeticsclass named in the label
«CONTRAINDICATIONS: The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS ). Therefore, patients being treated with…»
FDA, section 4 · Open on DailyMed
CriticalTranylcypromine
«CONTRAINDICATIONS: pargyline hydrochloride pargyline hydrochloride and methylclothiazide furazolidone isocarboxazid procarbazine tranylcypromine»
FDA, section 4 · Open on DailyMed
CriticalVenlafaxine
«CONTRAINDICATIONS: There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine…»
FDA, section 4 · Open on DailyMed
MajorCNS depressantsclass named in the label
«CONTRAINDICATIONS: Phenelzine sulfate should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics. Excitation, seizures, delirium…»
FDA, section 4 · Open on DailyMed
ModerateCaffeine
«CONTRAINDICATIONS: The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS ). Therefore, patients being treated with…»
FDA, section 4 · Open on DailyMed

From other drugs’ labels

CriticalBupropion
«MAO Inhibitors: Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions…»
FDA, section 7 · Open on DailyMed
CriticalLinezolid
«Linezolid no se debe usar en pacientes que estén tomando medicamentos que inhiban las monoamino oxidasas A o B (p.ej. fenelzina, isocarboxazida, selegilina, moclobemida) ni durante las dos semanas…»
AEMPS, section 4.3 · Open on CIMA
CriticalLinezolid
«Monoamine Oxidase Inhibitors: Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of…»
FDA, section 4 · Open on DailyMed
CriticalMeperidine
«Uso concurrente de inhibidores de la monoaminooxidasa (IMAOs) no selectivos (iproniazida, nialamida y fenelzina), selectivos A (moclobemida, toloxatona), selectivos B (selegilina)…»
AEMPS, section 4.3 · Open on CIMA
Fentanyl
«DRUG INTERACTIONS: Examples: phenelzine, tranylcypromine, linezolid»
FDA, section 7 · Open on DailyMed
Lamotrigine
«Interacciones de lamotrigina con agentes psicoactivos: Los estudios in vitro indican que la formación del principal metabolito de lamotrigina, el 2-N-glucurónido, se vio mínimamente inhibida por la…»
AEMPS, section 4.5 · Open on CIMA
Meperidine
«DRUG INTERACTIONS: Examples: Phenelzine, tranylcypromine, linezolid»
FDA, section 7 · Open on DailyMed
Mirtazapine
«DRUG INTERACTIONS: Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue»
FDA, section 7 · Open on DailyMed
Morphine
«DRUG INTERACTIONS: Examples: Phenelzine, tranylcypromine, linezolid.»
FDA, section 7 · Open on DailyMed
Oxycodone
«DRUG INTERACTIONS: Examples: phenelzine, tranylcypromine, linezolid»
FDA, section 7 · Open on DailyMed
Paroxetine
«DRUG INTERACTIONS: Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue»
FDA, section 7 · Open on DailyMed
Sertraline
«Clinically Significant Drug Interactions: Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue»
FDA, section 7 · Open on DailyMed
Tapentadol
«DRUG INTERACTIONS: Examples: phenelzine, tranylcypromine, linezolid»
FDA, section 7 · Open on DailyMed
Tramadol
«DRUG INTERACTIONS: Examples: phenelzine, tranylcypromine, linezolid»
FDA, section 7 · Open on DailyMed
Trazodone
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Examples: isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine»
FDA, section 7 · Open on DailyMed
Vortioxetine
«Drugs Having Clinically Important Interactions with TRINTELLIX: Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue»
FDA, section 7 · Open on DailyMed

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Frequently asked

What is Phenelzine used for?

Phenelzine is evaluated for the following indications with varying evidence strength: Treatment-resistant depression (evidence tier B). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Phenelzine?

Common side effects of Phenelzine (≥ 1 in 100): Orthostatic hypotension, Drowsiness, Dry mouth, Weight gain, Paresthesia, Insomnia. See the Safety section for uncommon and serious reactions.

Is Phenelzine safe during pregnancy?

Pregnancy data are limited. In women planning pregnancy phenelzine is usually switched to an SSRI with a better safety profile.

Is Phenelzine compatible with breastfeeding?

Passes into breast milk. Breastfeeding is not recommended.

Who should not take Phenelzine?

Phenelzine is contraindicated in: SSRI, SNRI, tricyclic antidepressants, mirtazapine, clomipramine – serotonin syndrome; Tramadol, pethidine (meperidine), dextromethorphan, methadone – fatal serotonin syndrome; Triptans (sumatriptan, rizatriptan, zolmitriptan) – serotonin syndrome; Sympathomimetics (pseudoephedrine, ephedrine, phenylephrine) and levodopa – hypertensive crisis; Phaeochromocytoma, thyrotoxicosis. Full list in the Safety section.

Official sources

Direct links to regulator labels. Open in a new tab.

FDA / DailyMedLabel dated 05/21/2026

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