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Phenelzine, sold as Nardil, is a classic irreversible, non-selective monoamine oxidase inhibitor (MAOI), an older but powerful antidepressant. What sets it apart from other MAOIs is a second action: it also inhibits GABA-transaminase, the enzyme that breaks down GABA, so it raises brain GABA levels, and it metabolizes to phenylethylidenehydrazine (PEH), the compound thought to drive much of that GABA effect. That extra, calming mechanism is a big part of why phenelzine is unusually effective for anxiety as well as depression; it also raises phenylethylamine (PEA), a natural trace amine.
- Powerful antidepressant, including in treatment-resistant depression
- Unusually effective for anxiety and panic disorder
- Distinctive GABA-raising, calming action from GABA-T inhibition
- Helpful for atypical depression
- Dizziness or lightheadedness on standing (orthostatic hypotension)
- Insomnia or sedation and weight gain
- Sexual side effects
- Risk of hypertensive crisis from tyramine foods and serotonin syndrome with serotonergic drugs
Mechanism
Phenelzine's core action is irreversible, non-selective inhibition of monoamine oxidase, blocking both the MAO-A and MAO-B subtypes. MAO is the enzyme that breaks down , noradrenaline, and , so shutting it down lets these monoamines build up, which is the basis of its antidepressant effect; because the inhibition is irreversible, the effect persists until the body makes fresh enzyme, taking a couple of weeks.
Uniquely among the MAOIs, phenelzine also inhibits -transaminase (GABA-T), the enzyme that degrades GABA, which raises brain GABA and adds a distinct calming, anti-anxiety action; this is largely attributed to its phenylethylidenehydrazine (PEH). It additionally raises levels of phenylethylamine (PEA), an endogenous trace amine, and slows the metabolism of other amines the body normally clears through MAO, which is exactly why its dietary and drug interactions are so strict.
receptor fingerprint
Monoamine oxidase (MAO-A and MAO-B)Irreversible non-selective inhibitor
-transaminase (GABA-T)Inhibitor (largely via the metabolite PEH)
Phenylethylamine (PEA) levelsIncreases (via MAO-B inhibition)
Safetyrisks and cautions, not medical advice
Phenelzine carries the full, non-negotiable MAOI cautions. Because it blocks the MAO that normally breaks down tyramine in food, eating tyramine-rich aged or fermented foods (aged cheeses, cured and fermented meats, some fermented soy products, tap or aged beers, certain wines) can trigger a hypertensive crisis, a dangerous spike in blood pressure; this is the classic "cheese reaction." Combining it with serotonergic drugs (SSRIs and other antidepressants, certain migraine triptans, tramadol and other opioids, dextromethorphan, MDMA) can cause serotonin syndrome, a life-threatening overload of serotonin, and it must never be combined with other MAOIs or with many stimulants and decongestants. Adequate washout time is required when switching to or from other drugs. Common effects include dizziness on standing, insomnia or sedation, weight gain, and sexual side effects. Not medical advice.
Interactionsdocumented pairs only, not exhaustive
Phenelzine triggers a hypertensive crisis when combined with tyramine-rich foods (aged cheeses, cured meats, fermented products) through a pharmacodynamic mechanism; MAO inhibition prevents tyramine degradation, allowing accumulated tyramine to trigger norepinephrine release and severe blood pressure elevation [4]; [5]. This interaction has caused documented myocardial infarction in phenelzine users consuming cheese [4].
Phenelzine also produces serotonin syndrome when co-prescribed with serotonergic drugs (SSRIs, SNRIs, tramadol, meperidine), a pharmacodynamic interaction causing excessive serotonergic activity; combination with other antidepressants or stimulants requires expert supervision and is associated with both risks and some documented benefit in treatment-resistant cases [6]; [7]. What remains incompletely documented are the safety margins for selective serotonin reuptake inhibitors with phenelzine under expert monitoring, the threshold tyramine dose that triggers crisis (amounts vary by individual), and safe washout periods between phenelzine and other serotonergic agents.
Checking a whole stack? Run it through interactions + stacks.
Subjective profileweighing the evidence above
Still one of the most effective antidepressants available for treatment-resistant, atypical and anxious depression, and the GABA-raising action is part of why. It is also the least forgiving: tyramine-rich foods can cause a hypertensive crisis and serotonergic drugs serotonin syndrome, so it needs real medical management.
Resources
This entry is here for reference.
Research
- 1998first citedMonoamine oxidase inhibitors. A perspective on their use in the elderly.
- 2023most recentThe prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) f…
- 1.Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine
- 2.Effects of the antidepressant/antipanic drug phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular gamma-aminobutyric acid levels in the striatum
- 3.MAOIs - does the evidence warrant their resurrection?
- 4.Phenelzine-induced myocardial injury: a case report.
- 5.Monoamine oxidase inhibitors. A perspective on their use in the elderly.
- 6.The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.
- 7.Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression.
7 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Why does phenelzine need a special diet?
It irreversibly blocks monoamine oxidase, the enzyme that clears tyramine from food. Eating tyramine-rich aged or fermented foods while on it can spike blood pressure dangerously, the classic "cheese reaction," so the tyramine diet is strict and mandatory.
What makes phenelzine different from other MAOIs?
On top of inhibiting MAO, it also inhibits GABA-transaminase and raises brain GABA, an action largely credited to its metabolite phenylethylidenehydrazine. That extra calming effect is why it is unusually good for anxiety, not just depression.
What must never be combined with phenelzine?
Other MAOIs, and serotonergic drugs such as SSRIs, certain triptans, tramadol, dextromethorphan, and MDMA, because of serotonin syndrome. Many stimulants and decongestants are also off-limits, and switching drugs requires a washout period.
Adverse effects
- Dizziness or lightheadedness on standing (orthostatic hypotension)
- Insomnia or sedation and weight gain
- Sexual side effects
- Risk of hypertensive crisis from tyramine foods and serotonin syndrome with serotonergic drugs