Does Zofran Interact With Wellbutrin (Bupropion)?

In our latest question and answer, the pharmacist discusses the potential interaction between Wellbutrin (bupropion) and Zofran (ondansetron).

Jul 16, 2018

Katie asked

I am tapering off of Xanax 0.5mg once daily and my Dr. prescribed Wellbutrin 150 mg XL to help with this. I am having nausea all day and of course side effects from Wellbutrin as well as stopping Xanax. Is it safe to take Zofran for the nausea?


There is a potential interaction, but on the whole, there is a low chance of any adverse effects when combining Xanax (alprazolam), Wellbutrin (bupropion) and Zofran (ondansetron). 

Zofran And Wellbutrin Interaction

Many online drug interaction checkers will note a major interaction between Zofran and Wellbutrin, stating there is an increased risk of serotonin syndrome. However, there are no documented reports of serotonin syndrome with both drugs and most studies note that neither Wellbutrin nor Zofran possess strong serotonergic effects capable of producing serotonin syndrome.

Zofran is classified as a 5-HT3 (serotonin) receptor blocker, which can theoretically increase serotonin levels. However, most large studies refute the fact that Zofran can cause serotonin syndrome. Per one study:

"[Zofran] Ondansetron and related compounds have been demonstrated not to possess these properties to a significant degree and are not reliably documented as causing ST [serotonin toxicity]. It is therefore highly doubtful that these drugs are capable of contributing to ST, a conclusion that can be confidently predicted from their pharmacological actions".

When it comes to Wellbutrin, it does not possess serotonergic activity. There have only been a few cases reports of Wellbutrin induced serotonin syndrome, which appear to caused by Wellbutrin inhibiting the metabolism of serotonergic drugs (which can increase their levels in the body).

Wellbutrin does inhibit the metabolizing enzyme CYP2D6, which Zofran is partially metabolized by, theoretically meaning that Zofran levels may be increased. However, Zofran is also metabolized by a variety of other enzymes. From the prescribing information for Zofran:

"...[Zofran] ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination."

Overall, the risk of serotonin syndrome is extremely low with Wellbutrin and Zofran, if a risk exists at all. Nevertheless, if Zofran was not specifically prescribed for you to resolve the nausea from Wellbutrin and Xanax, you should check with your doctor before taking.

Lastly, Zofran does not interact with Xanax.

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