Phenelzine is an FDA-approved drug for the management of depression in adults. Off label, the drug may be used for the management of treatment-resistant depression, panic disorder, and social anxiety disorder. Phenelzine is also specifically useful for young women who have depression and mood disorders. Research has not established the safety and efficacy for children or adolescents. 

MAO-inhibitors such as phenelzine can treat a variety of diseases including bulimia nervosa, PTSD, pain secondary to angina, atypical facial pain, migraine, and even ADD (attention deficit disorder). Phenelzine has also been found to help lower weight in patients with obesity and potentially help the L1 cell-mediated response for the neural generation, axon regrowth and sprouting, and myelination.[1][2]

Phenelzine is a nonselective monoamine oxidase A and B inhibitor (MAOI): phenelzine irreversibly blocks serotonin, norepinephrine, and dopamine from being broken down, allowing these neurotransmitters to have a more prolonged effect on their accompanying receptors. Phenelzine usually takes up to 2 to weeks to start showing some benefit. If by 6 to 8 weeks, therapy has not achieved the intended results, a higher dosage will be necessary.[3][4][5]

Phenelzine can only be administered orally via tablet form. Patients must avoid foods and beverages containing tyramine, tryptophan, and/or caffeine to prevent phenelzine drug-interaction. The starting dose is 15 mg/ day, which may be increased to 3 doses of 15 mg/day, making a total of 45 mg/day. The highest allowable concentration of phenelzine is up to 90mg/day for adults and geriatrics. 

If a patient has a depressive disorder, the recommended initial dose is 5 mg PO/day over a 2 to 6 week period to determine if the anti-depressive effect has occurred; if not, dose adjustment may be necessary.  

Patients with hepatic or severe renal impairment must avoid monoamine oxidase inhibitors to prevent toxicity or worsening of the condition.[6]

Although phenelzine's intended use is to block serotonin from being broken down, it can also have adverse effects on the GABA and melatonin receptors and thus can potentiate insomnia. The inhibition of norepinephrine from break down can also affect the vascular smooth muscles.  A profound decrease in blood pressure leading to orthostatic hypotension may also occur in patients taking phenelzine. To treat the orthostatic hypotension caused by phenelzine, a patient must avoid consumption of caffeine and drink up to 2 liters of water/day to prevent dehydration. Constipation, dry mouth, change in weight, anorgasmia, nausea, and weight gain are well-known side effects of this drug.[7][8][9]

Phenelzine may also cause drowsiness or dizziness; thus, the clinician should exercise caution in patients operating machinery or driving. Patients diagnosed with asthma must use discretion due to the drug's effect on sympathetic neurotransmission.[10]

Phenelzine’s worst, even potentially life-threatening reaction, is a hypertensive crisis that occurs when taking this drug is taken with tyramine-containing foods such as cheese and wine. Phenelzine must stop two weeks before the patient ingests any tyramine-containing substances to avoid an adverse reaction.[11][12]

This drug cannot be combined with tramadol because seizures may be potentiated. Also, phenelzine may not be combined with sympathomimetic drugs (e.g., amphetamines, cocaine, methylphenidate) because it can cause a hypertensive crisis with a headache, intracranial bleeding, and even the potential of death occurring.

The combination of MAOI with a tricyclic/tetracyclic antidepressant, such as amoxapine, is possible because it has 5HT2A protective properties. The most common side effects are weight gain and orthostatic hypotension when using this combination.

Phenelzine is contraindicated with these substances and medications: SSRI, SNRI, clomipramine, St. John’s Wort, MDMA (ecstasy), cocaine, methamphetamine, meperidine, tramadol, methadone, and fentanyl, non-subcutaneous sumatriptan, chlorpheniramine, brompheniramine, dextromethorphan, and procarbazine due to the high risk of serotonin syndrome.[13]

Phenelzine is especially contraindicated for pregnant women as a Category C risk because of the potential of fetal malformation during the first trimester. Also, while breastfeeding, if a baby becomes sedated or irritable, then the drug needs to be discontinued immediately. Phenelzine contraindications include individuals with renal impairment and hepatic impairment due to drug toxicity. Phenelzine administration is permissible in patients with cardiac abnormalities, but close monitoring is required.[14][15]