Antidepressant, irreversible non-selective monoamine oxidase inhibitor (MAO-A and MAO-B)
ATC code: N06AF03 (Phenelzine)
Brand names
Nardil
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.
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.
18 pairs found. Sorted from critical to minor.
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.
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.
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.
Mechanism
Escitalopram is an SSRI. Combined with phenelzine causes serotonin syndrome. Nardil Section 4.
Symptoms
Hyperthermia, myoclonus, tachycardia.
Management
Combination contraindicated. 2-week washout.
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).
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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).
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.
Opens the checker prefilled with this drug. Pick the second one from your regimen.
Pregnancy data are limited. In women planning pregnancy phenelzine is usually switched to an SSRI with a better safety profile.
Passes into breast milk. Breastfeeding is not recommended.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
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.
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.
FDA category C. Pregnancy data are limited. In women planning pregnancy phenelzine is usually switched to an SSRI with a better safety profile.
Passes into breast milk. Breastfeeding is not recommended.
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.