Selegiline 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
Selegiline
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) raises levels of chemical messengers like serotonin and norepinephrine in your brain. Selegiline (a type of drug called an MAOI) blocks the enzyme that normally breaks those messengers down. Put them together and those chemicals can climb dangerously high.
This can cause a serious reaction called serotonin syndrome, with high blood pressure, high fever, muscle jerking, confusion, and even seizures. It can come on fast and be life-threatening. The good news is this is well understood and completely avoidable. Please talk with your doctor or pharmacist before starting or stopping either one so they can plan a safe gap between them.
Contraindicated. Combining the TCA amitriptyline with the MAO-B inhibitor selegiline risks serotonin syndrome (hypertension, hyperthermia, myoclonus, altered mental status), seizures, hyperpyrexia, and death.
- Mechanism: altered catecholamine/serotonin uptake and metabolism; MAO inhibition plus TCA-mediated reuptake blockade produces excessive serotonergic and adrenergic activity.
- Onset: rapid. Evidence: established.
- Management: avoid concurrent use. Allow >=14 days after stopping selegiline before starting amitriptyline, or >=7 days after stopping amitriptyline before starting selegiline. If a TCA is later used, start low and titrate slowly.
- Monitor for autonomic instability, neuromuscular signs, and mental status changes if inadvertent overlap occurs.
What happens
Neurotoxicity, seizures, or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
The combined administration of TCAs and MAOIs has led to hyperpyrexia, seizures, and fatalities. There have additionally been reports that using MAOIs together with TCAs produces a state known as serotonin syndrome121021. This uncommon yet possibly lethal condition, caused by excessive serotonergic stimulation, presents with elevated blood pressure, raised body temperature, myoclonus, and alterations in mental status9. Giving amitriptyline alongside a MAOI is contraindicated22. At least 14 days must pass following selegiline discontinuation before amitriptyline is started, or alternatively at least 7 days must pass after stopping amitriptyline before selegiline is begun23.
Why it happens (mechanism)
Altered catecholamine uptake and metabolism
How to manage this interaction
These drugs are not used together. Your care team will avoid overlapping them and will build in a safe washout period when switching.
- A minimum of 14 days should pass after stopping selegiline before amitriptyline is started.
- A minimum of 7 days should pass after stopping amitriptyline before selegiline is started.
- If amitriptyline is used later, it is typically started at a low dose and gradually adjusted and individualized by your care team.
What to do: Do not start, stop, or change either medicine on your own. Tell your pharmacist and prescriber about every medicine you take so they can plan the switch safely, and seek urgent care if you develop fever, muscle twitching, agitation, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) In the past, giving monoamine oxidase inhibitors (MAOIs) together with tricyclic antidepressants (TCAs) was regarded as an absolute contraindication, and manufacturers continue to list it as such. The combination has been linked to reports of excitation, hyperpyrexia, convulsions, and possible death 345678. The underlying mechanism may involve the joint inhibition of catecholamine reuptake into the central nervous system along with inhibition of catecholamine metabolism 19.
b) Serotonin syndrome was reported to occur when a TCA was given following MAOI therapy. In a double-blind, crossover study that assessed clorgyline and clomipramine for treating obsessive-compulsive disorder, two subjects experienced severe reactions typical of serotonin syndrome. Over the course of the study, patients received clorgyline, followed by a washout period of about four weeks and then clomipramine. 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 after the first dose, presenting with upper motor neuron symptoms, myoclonic movements, and cardiac irritability. In both patients the symptoms resolved several hours later, and both were subsequently treated successfully with clomipramine without adverse effects 1.
c) A drug interaction was reported in a 76-year old woman who had been receiving clomipramine 50 mg daily for several months and was then switched 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 described as meeting the diagnostic criteria for serotonin syndrome and resolved a few days later after all antidepressant medications were discontinued 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 initiated at 50 mg daily, followed by two increases of imipramine to 200 mg and a reduction in moclobemide dosage to 150 mg twice daily. Five days after imipramine was raised 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 10.
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 been given MAOIs and TCAs individually without complications. Symptoms of mania appeared only when the drugs were used together, suggesting a synergistic effect 11.
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 12.
g) There is evidence that MAOIs and TCAs can be administered together in patients who previously did not respond to 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) using oral administration, c) avoiding clomipramine, imipramine, desipramine, and tranylcypromine in any combination, and d) closely monitoring patients 13561415. The combination may be used in one of two ways. Most commonly, the recommendation is to discontinue all prior antidepressants (five to ten days for TCAs and 14 days for MAOIs) and then start the combination simultaneously 16. Alternatively, in a patient already receiving a TCA, small doses of the MAOI may be slowly added 20. Some sources suggest the combination of amitriptyline and isocarboxazid is preferred 16. Numerous studies in patients with refractory depression or phobic anxiety states have successfully employed the combination of MAOIs and TCAs 17618.
Common questions
Can I take Selegiline and Amitriptyline together?
Amitriptyline and selegiline should never be taken together because the combination can trigger life-threatening serotonin syndrome or seizures; a washout period (14 days off selegiline before amitriptyline, or 7 days off amitriptyline before selegiline) is required, so let your care team manage any switch. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Selegiline and Amitriptyline interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How is the Selegiline and Amitriptyline interaction managed?
These drugs are not used together. Your care team will avoid overlapping them and will build in a safe washout period when switching. A minimum of 14 days should pass after stopping selegiline before amitriptyline is started. A minimum of 7 days should pass after stopping amitriptyline before selegiline is started. If amitriptyline is used later, it is typically started at a low dose and gradually… 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 Selegiline 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 (23)
- 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
- 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
- Sjoqvist F: Psychotropic drugs (2): interaction between monoamine oxidase (MAO) inhibitors and other substances. Proc R Soc Med 1965; 58:967-978. 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: Elavil(R), amitriptyline hydrochloride. Zeneca Pharmaceuticals, Wilmington, DE, 1998. DailyMed
- Product Information: EMSAM(R) transdermal patch, selegiline transdermal patch. Bristol-Myers Squibb Company, Princeton, NJ, 2006. DailyMed
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