Amitriptyline and Phenelzine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Phenelzine
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Amitriptyline (Elavil) and phenelzine (Nardil) are not meant to be taken together. Phenelzine is an older antidepressant called an MAO inhibitor, and amitriptyline is a tricyclic antidepressant. When these two are combined, they can push serotonin and other brain chemicals too high. That can lead to a dangerous reaction called serotonin syndrome, with high fever, high blood pressure, muscle twitching, confusion, seizures, and in rare cases it has been fatal.
The good news is that this is well known and completely avoidable. If you have been prescribed both, or you are switching from one to the other, please talk with your pharmacist or doctor right away so they can guide the timing safely.
Contraindicated combination (MAOI + TCA). Phenelzine's irreversible MAO inhibition combined with amitriptyline's inhibition of serotonin/norepinephrine reuptake produces excessive serotonergic and catecholaminergic activity, plus additive CNS depression.
- Risk: serotonin syndrome (hyperthermia, hypertension, myoclonus, altered mental status), seizures, hyperpyrexia, and potential death.
- Onset: delayed; Evidence: established.
- Management: avoid coadministration. Allow at least 14 days after stopping phenelzine before starting a dibenzazepine TCA (MAO enzyme regeneration). If any overlap is contemplated, counsel patient and monitor closely for serotonergic/autonomic toxicity.
Neither agent's activity depends on prodrug conversion; the interaction is pharmacodynamic and additive.
What happens
An increased risk of CNS depression, an increased risk of neurotoxicity, seizures, and an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
The simultaneous use of monoamine oxidase inhibitors (MAOIs) alongside tricyclic antidepressants (TCAs), including dibenzazepine derivatives, was historically regarded as an absolute contraindication and continues to be classified that way by manufacturers. The combination has been linked to reports of excitation, hyperpyrexia, convulsions, and potential fatality345. Furthermore, taking phenelzine together with dibenzazepine derivatives may elevate the risk of serotonin syndrome. When dibenzazepine derivatives are intended to replace phenelzine therapy, a minimum interval of 14 days should elapse after stopping phenelzine before initiating the dibenzazepine derivatives. Likewise, should a choice be made to use phenelzine (an MAOI) together with other antidepressants, such as a dibenzazepine derivative drug, or within fewer than 10 days following the cessation of antidepressant treatment, the patient should be cautioned about the potential for an adverse drug interaction21.
Why it happens (mechanism)
Additive CNS depression; altered catecholamine uptake and metabolism; additive serotonergic effects
How to manage this interaction
This pairing is generally avoided. Your care team will typically not use amitriptyline and phenelzine at the same time because the combined effect on brain chemicals can be dangerous.
- If you are switching from phenelzine to amitriptyline, a washout of at least 14 days after stopping phenelzine is standard before the new drug is started.
- Keep taking your medications exactly as prescribed for now, and do not stop anything on your own.
- Contact your pharmacist or prescriber promptly if you find both on your list, and get emergency care for fever, agitation, muscle jerking, racing heart, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
9 reports — tap to read
a) Serious reactions have been described (such as hyperthermia, rigidity, myoclonic movements, and death) when serotoninergic agents (for example, dexfenfluramine, FLUoxetine, fluvoxaMINE, PARoxetine, sertraline, citalopram, venlafaxine) have been used together with an MAO inhibitor 21.
b) The simultaneous use of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) was regarded in the past as an absolute contraindication and continues to be labeled as such by the manufacturers. Cases of excitation, hyperpyrexia, convulsions, and possible death have been linked to this combination 345678. The proposed mechanism may involve the joint blockade of catecholamine reuptake into the central nervous system together with inhibition of catecholamine metabolism 9.
c) Serotonin syndrome was reported to occur when a TCA was given following MAOI therapy. In a double-blind, crossover study assessing clorgyline and clomiPRAMINE for the treatment of obsessive-compulsive disorder, two participants experienced severe reactions typical of serotonin syndrome. Over the course of the study, patients received clorgyline therapy, then a washout interval of about four weeks, followed by clomiPRAMINE therapy. After the first 100 mg dose of clomiPRAMINE, one patient developed coarse myoclonic jerking in both legs, hyperreflexia, diaphoresis, and arrhythmia. A second patient had a comparable reaction after the first dose, involving upper motor neuron symptoms, myoclonic movements, and cardiac irritability. In both patients the symptoms resolved several hours afterward, and both were subsequently treated successfully with clomiPRAMINE without adverse effects 1.
d) A drug interaction was described involving a 76-year old woman who had been taking clomiPRAMINE 50 mg daily for several months and was changed to moclobemide 300 mg daily. She experienced somnolence, confusion, and fever, which then advanced to further mental impairment, muscle stiffness, myoclonus, and convulsive attacks. Her symptoms were reported as meeting the diagnostic criteria for serotonin syndrome and resolved a few days later after all antidepressant medications were stopped 2.
e) A 39-year old woman with bipolar disorder developed serotonin syndrome after imipramine was added to moclobemide. She was taking moclobemide 300 mg twice daily when imipramine was begun at 50 mg daily, followed by two increases in the imipramine dose to 200 mg and a decrease in the moclobemide dose to 150 mg twice daily. Five days after the imipramine increase to 200 mg per day, she developed symptoms of serotonin syndrome, including sweating, shivering, confusion, fever, and spasms in the extremities. She was treated with chlorproMAZINE and the symptoms resolved over the following few days without further complications 11.
f) Three patients with bipolar disorder developed manic symptoms during concurrent treatment with isocarboxazid and amitriptyline. In all three of these cases the patients had received MAOIs and TCAs individually without complications. Symptoms of mania appeared only when the drugs were combined, suggesting a synergistic effect 12.
g) In one case, clomiPRAMINE 10 mg twice daily was added to a stable tranylcypromine regimen in a physically healthy 34-year old man. After taking several doses, he developed symptoms of nausea and profuse sweating, followed by pyrexia, dyspnea, and agitation. The hyperpyrexical state progressed to disseminated intravascular coagulation and eventual death 13. There is evidence that MAOIs and TCAs can be administered together in patients who were previously unresponsive to the MAOI or TCA used alone 145.
h) A few precautions should be observed when MAOIs and TCAs are given together, including: a) avoiding large doses (no more than 150 mg amitriptyline or its equivalent, 45 mg phenelzine, or 60 mg isocarboxazid) b) using oral administration c) avoiding clomiPRAMINE, imipramine, desipramine, and tranylcypromine in any combination, and d) monitoring patients closely 14561516.
i) The combination of MAOIs and TCAs may be applied in one of two ways. Most often, the recommendation is to discontinue all prior antidepressants (five to ten days for TCAs and 14 days for MAOIs), after which the combination is begun simultaneously 17. Alternatively, in a patient already receiving a TCA, small doses of the MAOI may be added gradually 20. Some sources indicate that the combination of amitriptyline and isocarboxazid is preferred 17. Numerous studies in patients with refractory depression or phobic anxiety states have successfully employed the combination of MAOIs and TCAs 18619. Serotonin syndrome is a rare but potentially fatal condition of serotonergic hyperstimulation marked by hypertension, hyperthermia, myoclonus, and changes in mental status 10.
Common questions
Can I take Amitriptyline and Phenelzine together?
Amitriptyline and phenelzine should not be taken together because of a serious, potentially life-threatening reaction; a 14-day gap is needed when switching, so check with your pharmacist or doctor right away. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Phenelzine interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Amitriptyline and Phenelzine interaction managed?
This pairing is generally avoided. Your care team will typically not use amitriptyline and phenelzine at the same time because the combined effect on brain chemicals can be dangerous. If you are switching from phenelzine to amitriptyline, a washout of at least 14 days after stopping phenelzine is standard before the new drug is started. Keep taking your medications exactly as prescribed for now, a… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Amitriptyline or Phenelzine need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (21)
- Insel TR, Roy BF, Cohen RM, et al: Possible development of the serotonin syndrome in man. Am J Psychiatry 1982; 139:954-955. PubMed
- Spigset O, Mjorndal T, & Lovheim O: Serotonin syndrome caused by a moclobemide-clomipramine interaction. Br Med J 1993; 306:248. PubMed
- Lockett MF & Milner G: Combining the antidepressant drugs (letter). Br Med J 1965; 1:921. DOI
- Brachfeld J, Wirtshafter A, & Wolfe S: Imipramine-tranylcypromine incompatibility. Near fatal toxic reaction. JAMA 1963; 186:1172. DOI
- Winston F: Combined antidepressant therapy. Br J Psychiatry 1971; 118:301-304. PubMed
- Schuckit M, Robins E, & Feighner JP: Tricyclic antidepressants and monoamine oxidase inhibitors. Combination therapy in the treatment of depression. Arch Gen Psychiatry 1971; 24:509-514. PubMed
- Sargent W: Combining the antidepressant drugs (letter). Br Med J 1965; 1:251. PubMed
- Spiker DG & Pugh DD: Combining tricyclic and monoamine oxidase inhibitor antidepressants. Arch Gen Psychiatry 1976; 33:828-830. PubMed
- Sjoqvist F: Psychotropic drugs (2). Interaction between monoamine oxidase (MAO) inhibitors and other substances. Proc R Soc Med 1965; 58:967-978. PubMed
- Sternbach H: The serotonin syndrome. Am J Psychiatr 1991; 148:705-713. PubMed
- Brodribb TR, Downey M, & Gilbar PJ: Efficacy and adverse effects of moclobemide (letter). Lancet 1994; 343:475. DOI
- de la Fuente JR, Berlanga C, & Leon-Andrade C: Mania induced by tricyclic-MAOI combination therapy in bipolar treatment-resistant disorder: case reports. J Clin Psychiatry 1986; 47:40-41.
- Tackley RM & Tregaskis B: Fatal disseminated intravascular coagulation following a monoamine oxidase inhibitor/tricyclic interaction. Anaesthesia 1987; 42(7):760-763. PubMed
- Kline NS: Experimental use of monoamine oxidase inhibitors with tricyclic antidepressants. JAMA 1974; 227:807.
- White K & Simpson G: The combined use of MAOIs and tricyclics. J Clin Psychiatry 1984; 45:67-69.
- Rom WN & Benner EJ: Toxicity by interaction of tricyclic antidepressant and monoamine oxidase inhibitor. Calif Med 1972; 117:65-66.
- Perry PJ, Alexander B, & Liskow BIPerry PJ, Alexander B, & Liskow BI: Psychotropic Drug Handbook, 6th. Harvey Whitney Books Company, Cincinnati, OH, 1991.
- Ponto LB, Perry PJ, Liskow BI, et al: Drug therapy reviews: tricyclic antidepressant and monoamine oxidase inhibitor combination therapy. Am J Hosp Pharm 1977; 34:954-961. DOI
- Ashcroft GW: Psychological medicine: management of depression. Br Med J 1975; 2:372-376. PubMed
- Schoonover SC: Depression In: Bassuk EL, Schoonover SC, & Gelenberg AJ (Eds): The Practitioner's Guide to Psychoactive Drugs, 2nd. Plenum Medical Book Company, New York, NY, 1983. DOI
- Product Information: NARDIL(R) oral film coated tablets, phenelzine sulfate oral film coated tablets. Parke-Davis Div of Pfizer Inc (per DailyMed), New York, NY, 2020. DailyMed
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