Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and anxiety.

[15][16] Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, small fiber peripheral neuropathy, nausea and vomiting, diarrhea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paresthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia).

By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine.

By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body.

[28] GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety, stress, and depression.

As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which may be responsible for the occasional incidence of hepatitis and liver failure.

Still, it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitization of autoreceptors which generally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase.

Because of this, upon phenelzine treatment being ceased, its effects typically do not wear off until the body replenishes its enzyme stores, a process which can take as long as 2–3 weeks.

[41][42] Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.