Amitriptyline and Safinamide: 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
Safinamide
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 antidepressant that raises serotonin, a chemical messenger in your brain. Safinamide (Xadago), used for Parkinson's, also affects serotonin. Taking both can cause too much serotonin, a dangerous condition called serotonin syndrome.
Warning signs can include agitation, a fast heartbeat, sweating, shaking, muscle stiffness, or fever. This can be serious, even life-threatening. Please do not start or stop either drug on your own. Talk with your doctor or pharmacist right away so they can pick a safer plan for you. If you were recently on safinamide, your team will usually wait at least 14 days before starting amitriptyline.
Contraindicated combination. Safinamide is a selective MAO-B inhibitor and amitriptyline is a tricyclic antidepressant with serotonergic activity (serotonin reuptake inhibition). Combined use produces additive serotonergic effects, raising the risk of potentially life-threatening serotonin syndrome (reported).
- Direction: additive PD interaction, increased serotonergic tone.
- Evidence: probable.
- Onset: unspecified; may occur early after co-administration.
- Management: avoid concurrent use. Allow at least 14 days after discontinuing safinamide before initiating a TCA. Monitor for hyperthermia, autonomic instability, clonus, hyperreflexia, and mental status changes if exposure occurs.
What happens
Increased risk of serotonin syndrome
Interaction Deep Dive
Because life-threatening serotonin syndrome has been documented, taking safinamide (an inhibitor of MAO type B) together with a tricyclic antidepressant is contraindicated. Before starting a tricyclic antidepressant, allow a minimum of 14 days to elapse following the discontinuation of safinamide1.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
This pairing is contraindicated, so the usual step is to avoid using them together. Your care team will typically choose an alternative rather than combine these drugs.
- Keep taking your current medication as prescribed, and do not start or stop either drug on your own.
- Tell your prescriber and pharmacist about both medicines so they can select a safer option.
- If switching from safinamide to amitriptyline, expect your team to wait at least 14 days after stopping safinamide before starting amitriptyline.
- Seek help right away for fever, sweating, fast heartbeat, muscle stiffness, shaking, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Instances of serotonin syndrome have been documented when a MAOI (including selective MAO type B inhibitors) is used together with tricyclic antidepressants 1.
Common questions
Can I take Amitriptyline and Safinamide together?
Do not take amitriptyline and safinamide together, as the combination can cause life-threatening serotonin syndrome; wait at least 14 days after stopping safinamide before starting amitriptyline, and let your doctor or pharmacist choose a safe plan. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Safinamide interaction?
It is rated contraindicated. These should generally not be used together.
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 Safinamide interaction managed?
This pairing is contraindicated, so the usual step is to avoid using them together. Your care team will typically choose an alternative rather than combine these drugs. Keep taking your current medication as prescribed, and do not start or stop either drug on your own. Tell your prescriber and pharmacist about both medicines so they can select a safer option. If switching from safinamide to amitri… 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 Safinamide 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: XADAGO(R) oral tablets, safinamide oral tablets. US WorldMeds, LLC (per FDA), Louisville, KY, 2017. DailyMed
Keep reading about Amitriptyline
Keep reading about Safinamide
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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:
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