Procarbazine 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
Procarbazine
No brand names on record
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 can be a dangerous pair. Amitriptyline (Elavil) is a tricyclic antidepressant, and procarbazine has weak MAOI (monoamine oxidase inhibitor) activity. When a drug like amitriptyline is combined with an MAOI, both can push up the body's natural chemical messengers too much. In the worst cases this has caused very high fevers, seizures, and even death.
The good news is that this is a well-known combination doctors and pharmacists watch for closely. If you have been prescribed both, please don't stop anything on your own. Reach out to your pharmacist or doctor right away so they can review your medicines and choose a safe plan for you.
Direction: Combining amitriptyline (TCA) with procarbazine (weak MAO inhibitor) risks excessive central and peripheral catecholamine/serotonergic activity via altered catecholamine uptake and metabolism.
- Effect: neurotoxicity, seizures; TCA+potent MAOI has produced hyperpyrexia, convulsions, death.
- Onset: delayed.
- Evidence: theoretical; procarbazine's MAOI action is weak and direct clinical data are lacking, but the combination remains contraindicated.
- Management: avoid concurrent use. Allow at least 14 days after stopping MAOI therapy before starting amitriptyline. When (re)initiating, use low doses titrated gradually. Monitor for autonomic instability, hyperthermia, and neuromuscular signs.
What happens
Neurotoxicity, seizures
Interaction Deep Dive
The combined use of tricyclic antidepressants with stronger MAOIs has led to hyperpyrexia, convulsions, and fatalities. Because procarbazine exhibits comparatively weak MAOI activity, an interaction between tricyclic antidepressants and procarbazine is theoretically possible, though clinical evidence is currently unavailable48. Giving amitriptyline together with a MAOI is contraindicated13.
Why it happens (mechanism)
Altered catecholamine uptake and metabolism
How to manage this interaction
This combination is generally avoided. Amitriptyline is contraindicated with MAOI therapy, and procarbazine has weak MAOI activity, so your care team will usually not use them together.
- Keep taking both exactly as prescribed until you speak with your prescriber or pharmacist. Do not stop anything on your own.
- If one medicine is replacing the other, your team typically allows at least 14 days after stopping the MAOI before starting amitriptyline.
- If amitriptyline is used, expect a low starting dose that is adjusted and individualized, with closer monitoring.
- Report any fever, confusion, muscle twitching, or seizures immediately.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) Although procarbazine is chiefly employed as an antineoplastic drug, it was initially studied as a monoamine oxidase inhibitor 10. Research in animals has shown procarbazine to act as a monoamine oxidase inhibitor (MAOI) 11, though in humans it seems to be a comparatively weak MAOI 10. Hypertensive reactions can nonetheless occur when it is given together with tricyclic antidepressants, sympathomimetics, and foods containing tyramine 109.
b) Giving monoamine oxidase (MAO) inhibitors at the same time as tricyclic antidepressants was previously regarded as an absolute contraindication and continues to be listed that way by the manufacturers. The combination has been linked to reports of excitation, hyperpyrexia, convulsions, and possible death 123456. A close review of these reports shows that most involved atypical circumstances, for example parenteral administration of a tricyclic. The proposed mechanism may involve the simultaneous inhibition of catecholamine reuptake into the central nervous system together with inhibition of catecholamine metabolism 7.
c) Procarbazine treatment should not be started until 7 days after tricyclic antidepressants have been stopped and 14 days after other MAO inhibitors have been stopped 1210.
Common questions
Can I take Procarbazine and Amitriptyline together?
Amitriptyline and procarbazine (a weak MAOI) are considered a contraindicated combination because of the risk of neurotoxicity and seizures; contact your pharmacist or doctor before taking both, and allow the recommended washout if switching between them. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Procarbazine and Amitriptyline 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 Procarbazine and Amitriptyline interaction managed?
This combination is generally avoided. Amitriptyline is contraindicated with MAOI therapy, and procarbazine has weak MAOI activity, so your care team will usually not use them together. Keep taking both exactly as prescribed until you speak with your prescriber or pharmacist. Do not stop anything on your own. If one medicine is replacing the other, your team typically allows at least 14 days after… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Procarbazine 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 (13)
- 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
- White K & Simpson G: The combined use of MAOIs and tricyclics. J Clin Psychiatry 1984; 45:67-69.
- 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
- Gilman AG, Goodman LS, Rall TW, et alGilman AG, Goodman LS, Rall TW, et al (Eds): Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 7th. MacMillan Publishing Co, New York, NY, 1985.
- DeVita VT, Hahn MA, & Oliverio VT: Monoamine oxidase inhibition by a new carcinostatic agent, n-isopropyl-alpha(2-methylhydrazino)-p-toluamide (MIH). Proc Soc Exp Biol Med 1965; 120:561-565.
- AMA Department of DrugsAMA Department of Drugs: AMA drug evaluations, subscription, Winter, American Medical Association, Chicago, IL, 1992.
- Product Information: Elavil(R), amitriptyline hydrochloride. Zeneca Pharmaceuticals, Wilmington, DE, 1998. DailyMed
Keep reading about Amitriptyline
Keep reading about Procarbazine
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