Metaxalone 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
Metaxalone
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.
Both of these medicines can raise serotonin, a chemical messenger in your body. Amitriptyline (Elavil) is used for depression and nerve pain, and metaxalone (Skelaxin) is a muscle relaxer. When taken together, the extra serotonin can, in rare cases, build up too much and cause a reaction called serotonin syndrome.
Watch for things like feeling agitated or confused, shivering, a fast heartbeat, sweating, muscle twitching or stiffness, or an upset stomach. These usually show up within hours to a couple of days, especially when you first start or change a dose. This risk is theoretical, so please don't panic. Your care team can watch you closely and keep you safe.
Additive serotonergic effect from amitriptyline (serotonin reuptake inhibition) plus metaxalone, raising the theoretical risk of serotonin syndrome.
- Direction: additive pharmacodynamic effect; increased serotonergic tone (neither agent is a prodrug relevant here).
- Evidence: theoretical; case-level reports with metaxalone at therapeutic doses.
- Onset: typically several hours to a few days, occasionally later.
- Monitoring: watch for mental status changes, autonomic instability (tachycardia, hyperthermia, diaphoresis), neuromuscular findings (clonus, hyperreflexia, rigidity), and GI symptoms, especially at initiation and dose changes.
- Management: if co-use is required, observe closely; dose may be individualized and discontinue if serotonin syndrome develops.
What happens
Increased risk of serotonin syndrome
Interaction Deep Dive
Cases of serotonin syndrome have been documented when metaxalone (given within the standard therapeutic dose range) is taken together with serotonergic drugs. Manifestations including alterations in mental status, autonomic instability, neuromuscular abnormalities, and gastrointestinal effects generally appear within a few hours to a couple of days, though a later onset is possible. If this combined use cannot be avoided, close monitoring is advised, especially when therapy is started and when doses are being adjusted1.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with awareness and monitoring.
- Your care team may watch you more closely, especially when starting either drug or adjusting a dose.
- Doses may be adjusted and individualized by your team as needed.
- Tell your pharmacist or doctor right away if you notice agitation, confusion, fast heartbeat, sweating, shivering, muscle twitching or stiffness, fever, or stomach upset.
Ask your pharmacist to review your full medication list, since other serotonergic products can add to the effect.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Cases of serotonin syndrome have been documented when metaxalone (given at doses within the standard therapeutic range) was used together with serotonergic agents 1.
Common questions
Can I take Metaxalone and Amitriptyline together?
Taking amitriptyline and metaxalone together can add up serotonin and, rarely, trigger serotonin syndrome, so watch for agitation, fast heartbeat, sweating, or muscle twitching and call your care team if they appear. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Metaxalone and Amitriptyline 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 Metaxalone and Amitriptyline interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with awareness and monitoring. Your care team may watch you more closely, especially when starting either drug or adjusting a dose. Doses may be adjusted and individualized by your team as needed. Tell your pharmacist or doctor right away if you notice agitation, confusion, fast hear… 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 Metaxalone 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 (1)
- Product Information: SKELAXIN(R) oral tablets, metaxalone oral tablets. King Pharmaceuticals, Inc. (per FDA), Bristol, TN, 2018. DailyMed
Keep reading about Amitriptyline
Keep reading about Metaxalone
These medications also interact with supplements
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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