Amitriptyline and Pargyline: 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
Pargyline
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 should not be taken together. Amitriptyline (Elavil) is an older antidepressant, and pargyline is a type of drug called an MAOI. When you combine them, the amount of certain brain chemicals can climb too high. This can cause a dangerous reaction called serotonin syndrome, with high fever, high blood pressure, muscle twitching, confusion, and even seizures. In serious cases it has been life-threatening.
The good news is this is very preventable. Do not stop or change anything on your own, but please talk with your pharmacist or doctor right away so they can make sure you are never taking both at the same time.
Contraindicated: TCA + MAOI combination. Amitriptyline (TCA) with pargyline (an MAOI) risks serotonin syndrome, hyperpyrexia, convulsions, and death.
- Mechanism: altered catecholamine and serotonin uptake and metabolism; MAO inhibition plus TCA-mediated reuptake blockade produces serotonergic/adrenergic hyperstimulation.
- Direction: additive/synergistic increase in monoamine effect (neither is a prodrug here).
- Onset: delayed. Evidence: probable.
- Management: avoid concurrent use. Allow >=14 days after stopping the MAOI before starting amitriptyline. If initiated later, use low doses titrated to response. Monitor for hypertension, hyperthermia, myoclonus, and mental status changes.
What happens
Neurotoxicity, seizures, or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
The combination of TCAs and MAOIs has led to hyperpyrexia, seizures, and fatalities. There are also reports that using MAOIs together with TCAs can produce what is known as serotonin syndrome112201. This uncommon yet possibly lethal condition arises from excessive serotonergic stimulation and presents with hypertension, hyperthermia, myoclonus, and altered mental status10. Giving amitriptyline alongside a MAOI is contraindicated21.
Why it happens (mechanism)
Altered catecholamine uptake and metabolism
How to manage this interaction
These drugs are not used together. Your care team will keep them separated in time rather than overlapping them.
- If amitriptyline is going to replace the MAOI (pargyline), at least 14 days should pass after stopping the MAOI before amitriptyline is started.
- When amitriptyline is later started, your team typically begins at a low dose and increases it slowly to the right level for you.
- Keep taking your medicines exactly as prescribed, and do not stop either one on your own.
Contact your pharmacist or prescriber if you were given both, or if you notice fever, rapid heartbeat, muscle twitching, confusion, or agitation.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) Giving monoamine oxidase inhibitors (MAOIs) together with tricyclic antidepressants (TCAs) was previously regarded as an absolute contraindication and is still listed that way by the manufacturers. Cases of excitation, hyperpyrexia, convulsions, and possible death have been linked to this combination 345678. The mechanism could be tied to the joint inhibition of catecholamine reuptake into the central nervous system and inhibition of catecholamine metabolism 9.
b) Serotonin syndrome developed in two patients who were given a TCA following MAOI therapy. In a double-blind, crossover study evaluating the effects of clorgyline and clomipramine for treating obsessive-compulsive disorder, two subjects had severe reactions typical of serotonin syndrome. During the study, patients received clorgyline therapy, then a washout period of roughly four weeks, and afterward clomipramine therapy. After taking the initial 100 mg dose of clomipramine, one patient developed coarse myoclonic jerking in both legs, hyperreflexia, diaphoresis, and arrhythmia. Another patient had a comparable reaction after the first dose, with upper motor neuron symptoms, myoclonic movements, and cardiac irritability. Both patients' symptoms cleared several hours later, and both were subsequently treated successfully with clomipramine without adverse effects 1.
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 then 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 stopped 2.
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 started at 50 mg daily, followed by two dose increases of imipramine to 200 mg and a reduction of the moclobemide dose to 150 mg twice daily. Five days after imipramine was raised to 200 mg per day, she developed serotonin syndrome symptoms, including sweating, shivering, confusion, fever, and spasms in the extremities. She was treated with chlorpromazine and her symptoms resolved over the following days without further complications 11.
e) Three patients with bipolar disorder developed manic symptoms during concurrent therapy with isocarboxazid and amitriptyline. In all three cases the patients had received MAOIs and TCAs individually without complications. Manic symptoms emerged only when the drugs were used together, suggesting a synergistic effect 12.
f) In one case, clomipramine 10 mg twice daily was added to a stable regimen of tranylcypromine in a physically healthy 34-year old man. After several doses, he developed nausea and profuse sweating, followed by pyrexia, dyspnea, and agitation. The hyperpyrexical state led 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 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) oral administration, c) avoiding clomipramine, imipramine, desipramine, and tranylcypromine in any combination, and d) close patient monitoring 14561516. The combination can 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 17. 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 17. Numerous studies in patients with refractory depression or phobic anxiety states have successfully used the combination of MAOIs and TCAs 18619.
Common questions
Can I take Amitriptyline and Pargyline together?
Amitriptyline and the MAOI pargyline should not be taken together because of the risk of a dangerous, potentially fatal serotonin reaction; allow at least 14 days between stopping the MAOI and starting amitriptyline, and let your care team manage the switch. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Pargyline 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 Pargyline interaction managed?
These drugs are not used together. Your care team will keep them separated in time rather than overlapping them. If amitriptyline is going to replace the MAOI (pargyline), at least 14 days should pass after stopping the MAOI before amitriptyline is started. When amitriptyline is later started, your team typically begins at a low dose and increases it slowly to the right level for you. Keep taking… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
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 Pargyline 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
- 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: Elavil(R), amitriptyline hydrochloride. Zeneca Pharmaceuticals, Wilmington, DE, 1998. DailyMed
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