Isocarboxazid and Amitriptyline: 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
Isocarboxazid
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.
These two medicines should not be taken together. Amitriptyline (Elavil) is a tricyclic antidepressant, and isocarboxazid (Marplan) is an older type of antidepressant called an MAO inhibitor. When they mix, they can push blood pressure dangerously high and overload the body with a brain chemical called serotonin. This can lead to a hypertensive crisis, severe seizures, dangerously high fevers, coma, or the circulation shutting down. These are serious, life-threatening reactions.
Please don't stop or change either medicine on your own. If you have been prescribed both, contact your doctor or pharmacist right away so they can safely sort out your treatment.
Contraindicated combination. Coadministration of a TCA (amitriptyline) with the MAOI isocarboxazid risks hypertensive crisis, severe seizures, hyperpyrexia, coma, circulatory collapse, and serotonin syndrome.
- Mechanism: altered catecholamine uptake and metabolism plus additive serotonergic activity; neither drug is a prodrug.
- Evidence: established.
- Management: avoid concurrent use. Allow a minimum 1-week washout after stopping the TCA before starting isocarboxazid; if then initiated, use one-half the normal starting dose for at least the first week.
- If concurrent use is unavoidable: avoid large doses, use only oral TCAs, avoid imipramine, clomipramine, desipramine, and tranylcypromine, and monitor closely.
What happens
An increased risk of hypertensive crisis, severe convulsive seizures, coma or circulatory collapse and an increased risk of serotonin syndrome
Interaction Deep Dive
Combining isocarboxazid with tricyclic antidepressants is contraindicated because it can trigger hypertensive crises, severe convulsive seizures, coma, or circulatory collapse. A gap of at least 1 week should elapse after stopping a tricyclic antidepressant before isocarboxazid is started. Once this one-week drug-free interval has passed, isocarboxazid should be started at half its usual initial dose for a minimum of the first week of treatment1. Simultaneous administration of an MAOI, such as isocarboxazid, together with TCAs has additionally been reported to produce a condition known as serotonin syndrome23. When TCAs and MAOIs have to be given together, avoid high doses, restrict use to oral TCAs, steer clear of imipramine, clomiPRAMINE, desipramine, and tranylcypromine, and keep patients under close monitoring716.
Why it happens (mechanism)
Unknown; altered catecholamine uptake and metabolism
How to manage this interaction
This pairing is one your care team will generally avoid. The safest approach is not to take amitriptyline and isocarboxazid at the same time.
- Keep taking exactly what you have been prescribed until your doctor or pharmacist guides you, but flag this combination with them promptly.
- Your team typically allows at least a one-week medication-free gap after stopping amitriptyline before starting isocarboxazid.
- When isocarboxazid is then started, they usually begin at half the normal starting dose for at least the first week and watch you closely.
Get urgent help for a severe headache, confusion, agitation, high fever, muscle stiffness, racing heart, or fainting.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
8 reports — tap to read
a) In the past, giving monoamine oxidase inhibitors (MAOI) together with tricyclic antidepressants (TCAs) was regarded as an absolute contraindication, and manufacturers still classify it this way. This combination has been linked to reports of excitation, hyperpyrexia, convulsions, and possible death 456789. The underlying mechanism may involve the simultaneous blockade of catecholamine reuptake into the central nervous system and inhibition of catecholamine metabolism 10.
b) Serotonin syndrome was reported to occur when a TCA was given after MAOI therapy. In a double-blind, crossover study evaluating the effects of clorgyline and clomiPRAMINE for treating obsessive-compulsive disorder, two participants developed severe reactions typical of serotonin syndrome. Over the course of the study, patients received clorgyline therapy, then a washout period of roughly 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 developed a comparable reaction following the first dose, with upper motor neuron symptoms, myoclonic movements, and cardiac irritability. The symptoms in both patients resolved several hours afterward, and both were subsequently treated successfully with clomiPRAMINE without adverse effects 2.
c) A drug interaction developed 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. She experienced somnolence, confusion, and fever, which subsequently progressed to further mental impairment, muscle stiffness, myoclonus, and convulsive attacks. Her symptoms were described as meeting the diagnostic criteria for serotonin syndrome and resolved a few days later after all antidepressant medications were discontinued 3. Serotonin syndrome is a rare but potentially fatal condition of serotonergic overstimulation marked by hypertension, hyperthermia, myoclonus, and changes in mental status 11.
d) 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 initiated at 50 mg daily, followed by two increases in imipramine to 200 mg daily and a reduction of moclobemide to 150 mg twice daily. Five days after imipramine was increased 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 days without further complications 12.
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 taken MAOIs and TCAs individually without complications. Manic symptoms only appeared when the drugs were combined, indicating a synergistic effect 13.
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 several doses, the patient developed nausea and profuse sweating, followed by pyrexia, dyspnea, and agitation. The hyperpyrexic state led to disseminated intravascular coagulation and eventually death 14.
g) There is evidence that MAOIs and TCAs can be administered together in patients who did not previously respond to the MAOI or TCA alone. A few 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) using oral administration c) avoiding clomiPRAMINE, imipramine, desipramine, and tranylcypromine in any combination, and d) monitoring patients closely 15671617.
h) The MAOI and TCA combination may be used 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); the combination is then started simultaneously 18. Alternatively, in a patient already receiving a TCA, small doses of the MAOI may be added slowly (Schoonover, 1983). Some sources indicate that the combination of amitriptyline and isocarboxazid is preferred 18. Numerous studies in patients with refractory depression or phobic anxiety states have successfully employed the combination of MAOIs and TCAs 19720.
Common questions
Can I take Isocarboxazid and Amitriptyline together?
Amitriptyline and isocarboxazid together can cause life-threatening reactions and should not be combined; a washout period of at least one week between them is needed, so contact your doctor or pharmacist before taking both. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Isocarboxazid and Amitriptyline interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Isocarboxazid and Amitriptyline interaction managed?
This pairing is one your care team will generally avoid. The safest approach is not to take amitriptyline and isocarboxazid at the same time. Keep taking exactly what you have been prescribed until your doctor or pharmacist guides you, but flag this combination with them promptly. Your team typically allows at least a one-week medication-free gap after stopping amitriptyline before starting isocar… 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 Isocarboxazid or Amitriptyline 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 (20)
- Product Information: MARPLAN oral tablets, isocarboxazid oral tablets. Validus Pharmaceuticals LLC (per Dailymed), Parsippany, NJ, 2023. 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
- 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
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