Amitriptyline and Dextromethorphan: 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
Dextromethorphan
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.
Amitriptyline (Elavil) is an antidepressant, and dextromethorphan is the cough suppressant found in products like Delsym. Both can raise levels of a brain chemical called serotonin. When taken together, they may slightly increase the chance of a rare reaction called serotonin syndrome. Signs to watch for include feeling agitated or restless, shivering, sweating, a fast heartbeat, muscle twitching, or fever.
Please know this is considered a theoretical concern, not something proven with these two drugs. The good news is your care team can manage it easily by keeping an eye out for symptoms. Talk with your pharmacist or doctor before starting a cough medicine so they can guide you.
Effect: Additive serotonergic activity, theoretically increasing serotonin syndrome risk when dextromethorphan is combined with the TCA amitriptyline.
- Mechanism: Additive CNS serotonin concentrations. Note dextromethorphan is a CYP2D6 substrate; a related TCA (desipramine) showed ~8-fold increased steady-state levels with dextromethorphan/quinidine, suggesting a PK component via CYP2D6 competition as well.
- Direction/magnitude: Increased serotonergic effect; magnitude not quantified for amitriptyline.
- Onset: Unspecified. Evidence: Theoretical.
- Management: Use caution; monitor for altered mental status, hypertension, myoclonus, hyperreflexia, hyperthermia, diaphoresis, shivering, tremor. Dose may be individualized and monitoring intensified.
What happens
Increased risk of serotonin syndrome
Interaction Deep Dive
Taking dextromethorphan together with a tricyclic antidepressant (for example amitriptyline) can raise the likelihood of serotonin syndrome. Although this pairing has not been evaluated specifically with amitriptyline, coadministration of desipramine 25 mg (a different tricyclic antidepressant) alongside the dextromethorphan 30 mg/quinidine 30 mg combination produced roughly an 8-fold rise in steady state desipramine concentrations relative to desipramine given by itself1. When amitriptyline and dextromethorphan are used at the same time, watch for indications of serotonin syndrome (for instance altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor).
Why it happens (mechanism)
Additive CNS serotonin concentrations
How to manage this interaction
If both medicines are needed, your care team can handle this safely.
- Keep taking your amitriptyline as prescribed and do not stop on your own.
- Before using any cough product, check whether it contains dextromethorphan and ask your pharmacist if it is okay for you.
- Your team may watch you more closely and adjust things as needed if the two are used together.
- Get prompt help if you notice restlessness, shivering, sweating, fast heartbeat, muscle twitching, fever, or confusion.
A quick call to your pharmacist can help you pick a cough remedy that fits your situation.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Amitriptyline and Dextromethorphan together?
Amitriptyline and dextromethorphan together may slightly raise the theoretical risk of serotonin syndrome, so check with your pharmacist before adding a cough medicine and watch for symptoms like agitation, shivering, sweating, or tremor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Dextromethorphan interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Amitriptyline and Dextromethorphan interaction managed?
If both medicines are needed, your care team can handle this safely. Keep taking your amitriptyline as prescribed and do not stop on your own. Before using any cough product, check whether it contains dextromethorphan and ask your pharmacist if it is okay for you. Your team may watch you more closely and adjust things as needed if the two are used together. Get prompt help if you notice restlessne… 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 Amitriptyline or Dextromethorphan 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 (1)
- Product Information: NUEDEXTA(TM) oral capsules, dextromethorphan hydrobromide and quinidine sulfate oral capsules. Avanir Pharmaceuticals, Inc, Aliso Viejo, CA, 2010. DailyMed
Keep reading about Amitriptyline
Keep reading about Dextromethorphan
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Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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