Prozac With Delsym Interaction

In our latest question and answer, the pharmacist discusses the interaction between Prozac (fluoxetine) and dextromethorphan.


Why is dextromethorphan not recommended for use while a patient is on fluoxetine? Is MedlinePlus not an accurate source of information about fluoxetine? I don't see any mention of dextromethorphan in that (VERY long) list of contraindicated medications.

Asked by Alex On Nov 03, 2022

Answered by
Medical Content Reviewed By HelloPharmacist Staff

Published Nov 03, 2022
Last updated Nov 03, 2022

Key points

  • There are a few concerns with combining Prozac (fluoxetine) and dextromethorphan, including the increased risk of dextromethorphan-related side effects and serotonin syndrome.


There is an interaction between Delsym (dextromethorphan) and Prozac (fluoxetine), and they generally should not be combined unless recommended by your doctor.

In fact, there are actually two concerns with combining dextromethorphan and fluoxetine:

  • Fluoxetine inhibits an enzyme (CYP2D6) that is responsible for metabolizing dextromethorphan, potentially increasing the concentration of the cough medicine in your system and increasing the risk of side effects.
  • Fluoxetine and dextromethorphan both have serotonergic effects and can increase the risk of serotonin syndrome.

I can't speak for why MedlinePlus, which provides patient-centric drug information, doesn't have precautions regarding this drug combination. It may be due to the fact that there haven't been many large-scale studies evaluating the risk of serotonin syndrome while taking dextromethorphan and drugs like fluoxetine.

MedlinePlus generally sticks to the information reported in the FDA-approved prescribing information, which does not warn about an interaction with dextromethorphan (although it does discuss issues with the metabolizing enzyme CYP2D6).

There certainly are a few studies regarding dextromethorphan-induced serotonin syndrome, but they are generally very small scale, or only have case reports documenting serotonin syndrome in a handful of individuals.

Most online 'drug interaction checkers' will have at least a moderate warning regarding the combination, mostly based on the interaction-mechanisms described above and the case reports that have been published.

Interaction Details

As mentioned, there are two concerns with combining fluoxetine with dextromethorphan. The first concern is that fluoxetine can increase dextromethorphan concentrations.

Fluoxetine is a strong CYP2D6 inhibitor, something the prescribing information for the drug states explicitly:

Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution.
Prozac Prescribing Information

Since fluoxetine inhibits CYP2D6, it needs to be used cautiously with other drugs metabolized by the enzyme. Dextromethorphan is extensively metabolized by this enzyme.

There have been several studies that have specifically shown that fluoxetine can raise dextromethorphan concentrations, with some suggesting that concentrations of dextromethorphan can be raised 2-3 fold when co-administered with it.

Now, the next, related issue, is concerning serotonin syndrome.

Serotonin syndrome is a rare, but serious condition that can occur when taking drugs that affect the neurotransmitter serotonin. It is a condition characterized by several symptoms, including:

  • Muscle spasms
  • Hyperthermia
  • Sweating
  • Mental status changes
  • Confusion
  • Tremors
  • Increased heart rate
  • Increased blood pressure

Studies have reported cases of serotonin syndrome occurring in a small number of individuals who have combined SSRIs (selective serotonin reuptake inhibitors), like fluoxetine, and dextromethorphan.

One of the problems with fully understanding this interaction, and how likely it is to occur, is that studies evaluating the issue have been small, generally only contain a small number of case reports, and overall conclusions have been mixed.

Some studies have even suggested that the risk of serotonin syndrome is only really present when someone takes over the recommended doses of dextromethorphan. One such study stated the following:

Our cases suggest supra-therapeutic dextromethorphan doses with a therapeutic amount of a SSRI are required for serotonin syndrome. More work is needed to answer this question more completely.
Clin Toxicol (Phila) . 2008 Sep;46(8):771-3.

However, and this is an important point, we may be more concerned with fluoxetine versus many other SSRIs due to the fact that fluoxetine inhibits CYP2D6, as I talked about above.

Managing The Interaction

Since we don't quite understand what the overall risk is of combining fluoxetine and dextromethorphan, they generally shouldn't be used together. There is a theorical risk at the very least to be concerned about.

Alternatives to this combination should be considered, but if they are used together (under your doctor's supervision), you should start on lower doses of dextromethorphan and monitor for side effects.

Final Words

I hope you found this helpful! This situation is certainly a great example of why it is important to always ask your healthcare provider about potential interactions with new medications.

Thank you for your question!


  • The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease, PubMed
  • Serotonin syndrome caused by drug to drug interaction between escitalopram and dextromethorphan, PubMed
  • Serotonin syndrome induced by dextromethorphan (Medicon) administrated at the conventional dose, PubMed
  • Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition, PubMed
  • Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6, PubMed
  • CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline, PubMed
  • Inhibition by fluoxetine of cytochrome P450 2D6 activity, PubMed
  • Prozac Prescribing Information, AccessFDA

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