Amitriptyline and Tranylcypromine: 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
Tranylcypromine
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.
Combining amitriptyline (Elavil) with tranylcypromine (Parnate) is a serious combination that doctors avoid. Tranylcypromine is an MAOI, which slows down how your body breaks down certain brain chemicals. Amitriptyline raises the levels of some of those same chemicals. Taken together, they can push levels too high and cause a dangerous reaction called serotonin syndrome, with symptoms like high fever, high blood pressure, muscle twitching, confusion, and even seizures.
Because this can be life-threatening, these two are not meant to be used together, and a safe waiting period is needed when switching between them. The good news is your care team knows how to plan this safely, so talk with your doctor or pharmacist before any change.
Contraindicated combination. Amitriptyline (TCA with serotonergic and noradrenergic reuptake inhibition) plus tranylcypromine (nonselective MAOI) can produce excessive serotonergic/catecholaminergic activity, risking serotonin syndrome, hypertensive crisis, neurotoxicity, and seizures.
- Mechanism: altered catecholamine/serotonin uptake and metabolism; MAO inhibition plus reuptake blockade.
- Onset: delayed. Evidence: established.
- Management: Do not co-administer. If switching from tranylcypromine to amitriptyline, allow >=14 days after MAOI discontinuation, then titrate amitriptyline cautiously. If starting tranylcypromine after amitriptyline, allow >=4 to 5 half-lives (including active metabolites) to elapse.
- Monitor for hyperthermia, autonomic instability, clonus, and mental status changes.
What happens
Neurotoxicity, seizures, or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
Taking amitriptyline together with tranylcypromine (an MAOI), or administering the two agents in close sequence, is contraindicated because of the danger of serotonin syndrome, which can be life-threatening 22. Serotonin syndrome has been documented in certain patients following such combined use 231121. When amitriptyline is intended to take the place of tranylcypromine, a period of at least 14 days must pass after stopping tranylcypromine before amitriptyline is begun. Amitriptyline should be started with care, using slow upward adjustment of the dose 1. Conversely, when tranylcypromine is to be started after an antidepressant like amitriptyline has been stopped, wait for a minimum of 4 to 5 half-lives of the antidepressant (including any active metabolites) to pass before beginning tranylcypromine 22.
Why it happens (mechanism)
Altered catecholamine uptake and metabolism
How to manage this interaction
This pairing is not used together because of the risk of a serious reaction. Your care team manages this by keeping the two drugs apart in time:
- If tranylcypromine is stopped and amitriptyline is being started, a minimum 14-day gap is allowed first, then amitriptyline is started low and increased slowly.
- If amitriptyline is stopped before starting tranylcypromine, a wait of about 4 to 5 half-lives of amitriptyline (and its active metabolites) is allowed.
What you should do: Never start, stop, or overlap these on your own. Keep taking your medicines as prescribed and ask your pharmacist or prescriber to plan any switch. Seek urgent care for fever, sweating, muscle twitching, agitation, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) The simultaneous use of monoamine oxidase inhibitors (MAOIs) together with tricyclic antidepressants (TCAs) was previously regarded as an absolute contraindication and continues to be listed that way by the manufacturers. Cases of excitation, hyperpyrexia, convulsions, and possible death have been linked to this combination 456789. The underlying mechanism may involve the joint inhibition of catecholamine reuptake into the central nervous system along with inhibition of catecholamine metabolism 10.
b) Serotonin syndrome was reported to develop when a TCA was given following MAOI therapy. In a double-blind, crossover study evaluating clorgyline and clomipramine for treating obsessive-compulsive disorder, two subjects experienced severe reactions typical of serotonin syndrome. Over the course of the study, patients had received clorgyline therapy, then a washout interval of roughly four weeks, and afterward clomipramine therapy. Following the first 100 mg dose of clomipramine, one patient developed coarse myoclonic jerking in both legs, hyperreflexia, diaphoresis, and arrhythmia. A second patient developed a comparable reaction after the first dose, showing upper motor neuron symptoms, myoclonic movements, and cardiac irritability. The symptoms in both patients resolved several hours afterward, and both patients were subsequently treated successfully with clomipramine without adverse effects 2.
c) A drug interaction was reported in a 76-year old woman who had taken clomipramine 50 mg daily for several months and was then switched to moclobemide 300 mg daily. The patient experienced somnolence, confusion, and fever, which then progressed to further mental impairment, muscle stiffness, myoclonus, and convulsive attacks. The patient's symptoms were described as meeting the diagnostic criteria for serotonin syndrome and resolved a few days later after all antidepressant medications were discontinued 3.
d) A 39-year old woman with bipolar disorder developed serotonin syndrome after imipramine was added to moclobemide. The patient was receiving moclobemide 300 mg twice daily when imipramine was initiated at 50 mg daily, followed by two increases in the imipramine dose to 200 mg and a decrease of moclobemide to 150 mg twice daily. Five days after the imipramine increase to 200 mg per day, the patient developed serotonin syndrome symptoms, including sweating, shivering, confusion, fever, and spasms in the extremities. The patient was treated with chlorpromazine, and symptoms resolved over the following few days without additional complications 11.
e) Three patients with bipolar disorder developed manic symptoms while receiving concurrent therapy with isocarboxazid and amitriptyline. In all three cases, the patients had previously received MAOIs and TCAs individually without complications. Symptoms of mania appeared only when the drugs were combined, suggesting a synergistic effect 12.
f) 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, the patient developed nausea and profuse sweating, followed by pyrexia, dyspnea, and agitation. The hyperpyrexical state progressed to disseminated intravascular coagulation and eventual death 13.
g) There is evidence that MAOIs and TCAs can be administered together in patients who did not previously respond to either the MAOI or TCA alone. Several precautions must be observed, including: a) avoiding large doses (no more than 150 mg amitriptyline or its equivalent, 45 mg phenelzine, or 60 mg isocarboxazid) b) oral administration c) avoiding clomipramine, imipramine, desipramine, and tranylcypromine in any combination, and d) close patient monitoring 14671516. The combination can be employed in one of two ways. The most common recommendation is to discontinue all prior antidepressants (five to ten days for TCAs and 14 days for MAOIs), after which the combination is then started simultaneously 17. Alternatively, in a patient already taking a TCA, small doses of the MAOI may be added slowly 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 used the MAOI and TCA combination 18719.
Common questions
Can I take Amitriptyline and Tranylcypromine together?
Amitriptyline and tranylcypromine should not be used together because the combination can cause life-threatening serotonin syndrome; any switch between them requires a doctor-planned waiting period. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Tranylcypromine 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 Tranylcypromine interaction managed?
This pairing is not used together because of the risk of a serious reaction. Your care team manages this by keeping the two drugs apart in time: If tranylcypromine is stopped and amitriptyline is being started, a minimum 14-day gap is allowed first, then amitriptyline is started low and increased slowly. If amitriptyline is stopped before starting tranylcypromine, a wait of about 4 to 5 half-lives… 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 Tranylcypromine 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 (22)
- Product Information: amitriptyline HCl oral film coated tablets, amitriptyline HCl oral film coated tablets. Sandoz Inc. (per DailyMed), Princeton, NJ, 2010. DailyMed
- 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
- 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
- Neuvonen PJ, Pohjola-Sintonen S, Tacke U, et al: Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses (letter). Lancet 1993; 342:1419. PubMed
- Product Information: PARNATE(R) oral tablets, tranylcypromine oral tablets. Concordia Pharmaceuticals, Inc. (per FDA), Kansas City, MO, 2018. DailyMed
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