Toloxatone 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
Toloxatone
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 toloxatone is a type of medicine called an MAOI. When you combine an antidepressant like amitriptyline with an MAOI, your body can build up too much of certain brain chemicals like serotonin.
This can cause a dangerous reaction that includes high fever, high blood pressure, muscle twitching or jerking, confusion, and seizures. In serious cases it has been life-threatening. The good news is this is completely avoidable. Please talk with your doctor or pharmacist before taking both, and never start or stop either one on your own. Your care team can choose a safe plan for you.
Contraindicated combination. Amitriptyline (TCA) plus toloxatone (a reversible MAO-A inhibitor) risks serotonergic and catecholaminergic excess.
- Mechanism: altered catecholamine/serotonin uptake and metabolism; MAOI blocks monoamine breakdown while the TCA blocks reuptake, causing synaptic accumulation.
- Effect: serotonin syndrome (hypertension, hyperthermia, myoclonus, altered mental status), neurotoxicity, seizures, and reported fatalities.
- Onset: delayed. Evidence: probable.
- Management: avoid coadministration. Allow at least 14 days after stopping the MAOI before initiating amitriptyline; start low and titrate gradually to response. Monitor for autonomic instability, neuromuscular findings, and mental status changes.
What happens
Neurotoxicity, seizures, or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
The combined use of TCAs and MAOIs has led to hyperpyrexia, seizures, and fatalities. Reports also describe that taking MAOIs together with TCAs can produce serotonin syndrome112201. This uncommon yet possibly lethal state stems 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 meant to be used at the same time. Your care team will avoid combining them.
- Do not start, stop, or change either medicine on your own. Keep taking what is currently prescribed and raise this with your prescriber or pharmacist.
- If you are switching from the MAOI (toloxatone) to amitriptyline, your team will typically wait at least 14 days after stopping the MAOI before starting amitriptyline.
- When amitriptyline is started, expect a low dose that is slowly adjusted and individualized to your response.
- Seek urgent care for fever, fast heartbeat, 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 still label it that way. The combination has been linked to reports of excitation, hyperpyrexia, convulsions, and possible death 345678. The underlying mechanism may involve the simultaneous inhibition of catecholamine reuptake into the central nervous system and inhibition of catecholamine metabolism 9.
b) Two patients given a TCA following MAOI therapy experienced serotonin syndrome. In a double-blind, crossover study looking at 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 about four weeks, and then clomipramine therapy. After the first 100 mg dose of clomipramine, one patient developed coarse myoclonic jerking in both legs, hyperreflexia, diaphoresis, and arrhythmia. Another patient had a similar reaction after 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 later treated successfully with clomipramine without adverse effects 1.
c) An interaction was seen in a 76-year old woman who had taken clomipramine 50 mg daily for several months and was then changed 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 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 begun at 50 mg daily, followed by two imipramine dose increases to 200 mg and a reduction of moclobemide to 150 mg twice daily. Five days after the 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 symptoms resolved over the following few days without further complications 11.
e) Three patients with bipolar disorder developed manic symptoms while receiving concurrent isocarboxazid and amitriptyline. In all three cases the patients had been given MAOIs and TCAs individually without complications. Only when the drugs were combined did manic symptoms appear, pointing to 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 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 given 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 14561516. The combination can be used in one of two ways. Most often, the recommendation is to discontinue all previous antidepressants (five to ten days for TCAs and 14 days for MAOIs), and then start the combination simultaneously 17. Alternatively, in a patient already receiving a TCA, small doses of the MAOI may be added slowly (Schoonover, 1983). Some sources suggest 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 18619.
Common questions
Can I take Toloxatone and Amitriptyline together?
Do not take amitriptyline and toloxatone together, as the combination can cause a dangerous, sometimes fatal reaction; ask your doctor or pharmacist about safe timing and switching, and allow at least 14 days between them. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Toloxatone 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 Toloxatone and Amitriptyline interaction managed?
These drugs are not meant to be used at the same time. Your care team will avoid combining them. Do not start, stop, or change either medicine on your own. Keep taking what is currently prescribed and raise this with your prescriber or pharmacist. If you are switching from the MAOI (toloxatone) to amitriptyline, your team will typically wait at least 14 days after stopping the MAOI before starting… 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 Toloxatone 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 (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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