Continuing Education Activity

The FDA-approved indications for phenelzine include 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. This activity reviews the indications, action, and contraindications for phenelzine as a valuable agent in treating and managing treatment-resistant depression. This activity will highlight the mechanism of action, adverse effects, and other key factors such as dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for members of the interprofessional team in the treatment and care of patients with depression and related conditions.


  • Identify the mechanism of action of phenelzine.
  • Describe the potential adverse effects of phenelzine.
  • Review the appropriate monitoring and toxicity of phenelzine.
  • Discuss interprofessional team strategies for improving care coordination and communication to advance phenelzine and improve outcomes.


Phenelzine is an FDA-approved drug for the management of depression in adults. Off label, the drug may be used to manage treatment-resistant depression, panic disorder, obsessive-compulsive 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 neural generation, axon regrowth and sprouting, and myelination.[1][2]

Mechanism of Action

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 their condition.[6]

Adverse Effects

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 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 caffeine consumption 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 using this drug for patients who operate machinery or drive frequently. 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]


A clinician must be cautious when giving phenelzine to children under the age of 16 because it can increase the risk of suicide or bipolar disorder.

If the depression is resistant to all other antidepressants, an MAOI can be combined with D-amphetamine or methylphenidate, lithium, and mood-stabilizing anti-convulsive to augment the best response.

Children require monitoring in-person to assess if the proper achievement of the antidepressant effects of phenelzine.

The onset of the antidepressant effects of phenelzine takes 2 to 3 weeks to manifest. There is no need to taper off phenelzine because the effects naturally wear off within the same 2 to 3 week time period.

If orthostatic hypotension occurs, the dosing can split to four times/day to lower the drug's concentration administered each dose. The hepatic function and renal function must be monitored at each clinic visit to prevent liver or kidney toxicity.[16]


For patients who overdose on phenelzine, the symptoms can range from agitation to comatose status. Sympathetic overflow effects can also be observed, such as hypertension, tachypnea, tachycardia, and dilated pupils. There may be observable involuntary movements of the face and jaw.   

If phenelzine overdose is suspected, dialysis and acidification of the urine must take place immediately. Chlorpromazine is another option if a hypertensive crisis secondary to suspected phenelzine overdose.[8][5]

Enhancing Healthcare Team Outcomes

Phenelzine is used for treatment-resistant depression and is used less frequently because of its many side effects. Most clinicians prescribe newer and better-tolerated medications with fewer side effects. A clinician can take a gas chromatography of 5 ml of a blood sample to test the level of phenelzine in the body. An interprofessional healthcare team of clinicians, nurses, and pharmacists will be needed before medication administration and monitoring. Hepatologists may be necessary to test hepatic function because phenelzine may cause hepatotoxicity. Primary care clinicians and psychiatrists must monitor for serotonin syndrome, tyramine-induced hypertensive crisis, and dose-related orthostatic hypotension. A pediatric psychiatrist consult should take place before administering phenelzine to a child: benefits vs. potential side effects merit consideration. Nurses can provide patient counseling and caution regarding adverse effects. The pharmacist can verify dosing, monitor drug-drug interactions, and provide additional medication counseling for the patient. This interprofessional approach will increase therapeutic success while helping minimize adverse events. [Level 5] If any acute crises develop, the patient must report to the emergency department for monitoring and resuscitation. 

Article Details

Article Author

Gursharan Sidhu

Article Editor:

Raman Marwaha


2/26/2021 11:36:56 AM

PubMed Link:




Phenelzine . 2012     [PubMed PMID: 31643721]


Antidepressant Agents . 2012     [PubMed PMID: 31643899]


Fred SM,Laukkanen L,Brunello CA,Vesa L,Göös H,Cardon I,Moliner R,Maritzen T,Varjosalo M,Casarotto PC,Castrén E, Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2. The Journal of biological chemistry. 2019 Nov 29     [PubMed PMID: 31631060]


Baker G,Matveychuk D,MacKenzie EM,Holt A,Wang Y,Kar S, Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine. Chemico-biological interactions. 2019 May 1     [PubMed PMID: 30857888]


Mercader J,Sabater AG,Le Gonidec S,Decaunes P,Chaplin A,Gómez-Zorita S,Milagro FI,Carpéné C, Oral Phenelzine Treatment Mitigates Metabolic Disturbances in Mice Fed a High-Fat Diet. The Journal of pharmacology and experimental therapeutics. 2019 Nov     [PubMed PMID: 31270215]


Carpéné C,Gómez-Zorita S,Chaplin A,Mercader J, Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice. International journal of molecular sciences. 2018 Sep 25     [PubMed PMID: 30257452]


Carpéné C,Boulet N,Chaplin A,Mercader J, Past, Present and Future Anti-Obesity Effects of Flavin-Containing and/or Copper-Containing Amine Oxidase Inhibitors. Medicines (Basel, Switzerland). 2019 Jan 15     [PubMed PMID: 30650583]


Mustafa AG,Al-Shboul O,Alfaqih MA,Al-Qudah MA,Al-Dwairi AN, Phenelzine reduces the oxidative damage induced by peroxynitrite in plasma lipids and proteins. Archives of physiology and biochemistry. 2018 Dec     [PubMed PMID: 29256275]


Shao W,Brown T,Ayub S, Phenelzine Withdrawal-Associated Psychosis and Mania. Journal of clinical psychopharmacology. 2017 Aug     [PubMed PMID: 28609305]


[REM sleep deprivation in normal humans. Changes in anxiety, depression and aggressiveness, and HVA and 5-HIAA levels in the lumbar cerebrospinal fluid]., Puca FM,Livrea P,Genco S,Specchio LM,Bandiera L,DiReda L,, Bollettino della Societa italiana di biologia sperimentale, 1976 Jun 15     [PubMed PMID: 5676040]


Ultrastructure of abnormal membrane inclusions in nuclei of human myocardial cells., Engedal H,Jensen H,Saetersdal TS,, British heart journal, 1977 Feb     [PubMed PMID: 20652662]


Effect of pretreatment with immune serum on murine sarcoma virus (Moloney) tumour induction and growth., Guiliani F,Casazza AM,Soranzo C,Di Marco A,, British journal of cancer, 1977 Feb     [PubMed PMID: 25903219]


Lung cancer in Hong Kong Chinese: mortality and histological types, 1960-1972., Chan WC,MacLennan R,, British journal of cancer, 1977 Feb     [PubMed PMID: 25861278]


Histochemical and histological effects of lead on the liver and kidney of the dog., White DJ,, British journal of experimental pathology, 1977 Feb     [PubMed PMID: 25884531]


Magnetic resonance and kinetic studies of the role of the divalent cation activator of RNA polymerase from Escherichia coli., Koren R,Mildvan S,, Biochemistry, 1977 Jan 25     [PubMed PMID: 20445015]


Fluorescence and nucleotide binding properties of Escherichia coli uridine diphosphate galactose 4-epimerase: support for a model for nonstereospedific action., Wong SS,Frey PA,, Biochemistry, 1977 Jan 25     [PubMed PMID: 10683640]