Amitriptyline and Bupropion: 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
Bupropion
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.
You've been prescribed amitriptyline (an antidepressant) and bupropion (another antidepressant, also used to quit smoking). There are two things to know here. First, bupropion can slow down how your body breaks down amitriptyline, so more of it can build up in your system, which may bring stronger side effects like drowsiness, dry mouth, constipation, or a fast heartbeat.
Second, both drugs can slightly lower the threshold for seizures, so together they may raise that risk a bit. This is mostly a theoretical concern, and your care team knows how to handle it by starting low, going slow, and watching how you do. Please don't stop either medicine on your own, just talk with your pharmacist or doctor.
Mechanism: Bupropion inhibits CYP2D6, reducing metabolism of amitriptyline (a CYP2D6 substrate), which can increase amitriptyline exposure (AUC/Cmax) and its active metabolite nortriptyline. Additive lowering of the seizure threshold also applies, as both agents are proconvulsant.
- Direction: Increased TCA exposure; increased seizure risk.
- Evidence: Theoretical; major severity. Onset unspecified.
- Management: Initiate the CYP2D6 substrate low and titrate gradually; if adding bupropion to existing amitriptyline, consider reducing the TCA dose. Use a low bupropion starting dose, titrate slowly, and respect max limits (IR 450 mg/day, SR 400 mg/day, XL 300 mg/day). Monitor for anticholinergic/cardiac effects; consider TCA levels. Discontinue bupropion if a seizure occurs.
What happens
Increased exposure of CYP2D6 substrates and an increased risk of seizure
Interaction Deep Dive
The seizure risk linked to buPROPion depends on dose, and combining it with other agents that lower the seizure threshold raises this risk further. BuPROPion also acts as a CYP2D6 inhibitor, so giving it together with a CYP2D6 substrate can raise the substrate's exposure. For this reason, a CYP2D6 substrate should be started at the low end of its dose range and increased slowly. When buPROPion is added to a regimen that already contains a CYP2D6 substrate, reducing the substrate dose should be considered, particularly for substrates with a narrow therapeutic index. Exercise extreme caution when buPROPion is combined with drugs that lower the seizure threshold; begin buPROPion at a low dose and titrate slowly to lessen seizure risk. Should a seizure occur, stop buPROPion and do not restart it1. Tablet dosing should not go above 450 mg/day. 2 The extended release form should not exceed 300 mg once daily 3. The sustained-release form should not exceed 400 mg/day 4.
Why it happens (mechanism)
Inhibition of CYP2D6-mediated metabolism of by buPROPion; additive lowering of the seizure threshold
How to manage this interaction
Your care team can manage this combination safely. Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise.
- Dosing: The amitriptyline dose may need to be adjusted and individualized by your care team, often starting low and increasing slowly.
- Bupropion: Your team may start it at a low dose and increase gradually, staying within safe daily limits.
- Monitoring: Expect closer follow-up for side effects like sedation, dry mouth, or a racing heart.
- Watch for: Report any seizure, fainting, or unusual jerking movements right away.
Bring up any questions with your pharmacist or prescriber before making changes.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) When buPROPion 150 mg administered twice daily was given together with a single 50 mg dose of desipramine (a CYP2D6 substrate) in healthy volunteers classified as extensive CYP2D6 metabolizers (n=15), desipramine Cmax rose 2-fold and its AUC rose 5-fold. This effect continued for 7 days after the final buPROPion dose 3425.
Common questions
Can I take Amitriptyline and Bupropion together?
Bupropion can raise amitriptyline levels and both drugs slightly increase seizure risk, so your care team may adjust doses and monitor you more closely. Keep taking both as prescribed and report any seizure or new side effects. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Bupropion 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 Bupropion interaction managed?
Your care team can manage this combination safely. Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise. Dosing: The amitriptyline dose may need to be adjusted and individualized by your care team, often starting low and increasing slowly. Bupropion: Your team may start it at a low dose and increase gradually, staying within safe daily limits. Monitoring: Exp… 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
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Questions for your pharmacist
- Does my dose of Amitriptyline or Bupropion 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 (5)
- Product Information: APLENZIN(R) oral extended-release tablets, bupropion hydrobromide oral extended-release tablets. Bausch Health US LLC (per FDA), Bridgewater, NJ, 2024. DailyMed
- Product Information: WELLBUTRIN(R) oral tablets, bupropion hydrochloride oral tablets. GlaxoSmithKline (per FDA), Durham, NC, 2024. DailyMed
- Product Information: WELLBUTRIN XL(R) oral extended-release tablets, bupropion hydrochloride oral extended-release tablets. Bausch Health US, LLC (per FDA), Bridgewater, NJ, 2024. DailyMed
- Product Information: WELLBUTRIN(R) SR oral sustained-release tablets, bupropion hydrochloride oral sustained-release tablets. GlaxoSmithKline (per FDA), Durham, NC, 2024. DailyMed
- Product Information: FORFIVO XL(R) oral extended-release tablets, bupropion hydrochloride oral extended-release tablets. TWi Pharmaceuticals USA, Inc (per FDA), Paramus, NJ, 2024. DailyMed
Keep reading about Amitriptyline
Keep reading about Bupropion
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