RESEARCH MONOGRAPH · KDC-MN-226
Phenelzine
Phenelzine (Nardil) is a first-generation, non-selective MAOI from 1961 that irreversibly destroys both forms of monoamine oxidase, the enzymes that break down serotonin, norepinephrine, and dopamine. The result is a powerful boost in all three neurotransmitters but with the famous catch: any food containing tyramine (aged cheese, cured meats, fermented soy, certain wines) can trigger a hypertensive crisis severe enough to cause stroke, because the gut enzymes that normally clear dietary tyramine are gone. Many drug interactions are similarly dangerous. Despite all this, phenelzine remains genuinely useful for atypical depression and treatment-resistant depression where SSRIs and SNRIs have failed, because the broad monoamine boost can succeed where narrower drugs have not. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Irreversible non-selective MAO inhibitor (hydrazine)
A first-generation hydrazine MAOI; a non-selective irreversible inhibitor still used for atypical and treatment-resistant depression.
Abstract
Phenelzine (2-phenylethylhydrazine; CAS 51-71-8; molecular formula C8H12N2; molecular weight 136.19) is a hydrazine class non-selective irreversible monoamine oxidase inhibitor approved by the FDA in 1961 under the trade name Nardil. The compound covalently inactivates both MAO-A and MAO-B by hydrazine-mediated cofactor adduction at the FAD prosthetic group; recovery requires de novo enzyme synthesis (approximately 14 to 21 days). The non-selective inhibition increases brain serotonin, norepinephrine, and dopamine concurrently, producing classical MAOI antidepressant pharmacology along with the well-known tyramine cheese-effect risk: dietary tyramine, normally degraded by intestinal MAO-A, accumulates and triggers hypertensive crisis through indirect sympathomimetic action. Plasma half-life is 11.6 hours, but the irreversible binding produces effective enzyme inhibition for 2 to 3 weeks. Hydrazine metabolism may produce hepatotoxic byproducts; chronic dosing requires hepatic monitoring. Approved for major depressive disorder; remains a benchmark for atypical depression with reverse vegetative features and for treatment-resistant cases where SSRIs and TCAs have failed.
Mechanism of action
Irreversible non-selective MAO-A and MAO-B inhibition via hydrazine adduction. Increases brain serotonin, norepinephrine, and dopamine.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Robinson DS, et al. A controlled study of phenelzine in atypical depression. Psychopharmacol Bull 1973.
- Krishnan KR. Revisiting monoamine oxidase inhibitors. J Clin Psychiatry 2007.
- Stewart JW, et al. Phenelzine in atypical depression. J Clin Psychiatry 1989.
Read the full monograph
Available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.
The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.