Taking Zofran (Ondansetron) With Nyquil

In our latest question and answer, the pharmacist discusses whether or not there is an interaction between Nyquil and Zofran (ondansetron).


Both my kids had the stomach flu over the weekend and now I feel very sick... extremely nauseous and bad headache. I already took a generic nighttime cold and flu medicine 2 hours ago and want to know if it would be safe to take Zofran.

Asked by Courtney On Nov 20, 2022

Answered by
Medical Content Reviewed By HelloPharmacist Staff

Published Nov 20, 2022
Last updated Dec 07, 2023

Key points

  • Zofran and NyQuil are generally considered safe to take with one another.
  • Dextromethorphan, the cough suppressant in NyQuil, has rarely been linked to an increase in the risk of serotonin syndrome when taken with other serotonergic drugs.
  • There have been no reports of serotonin syndrome with the combination of Zofran and NyQuil, but it is important to be aware of the signs and symptoms when combining any drugs that affect the neurotransmitter serotonin.


There is no listed or reported interaction between Zofran (ondansetron) and the common ingredients in nighttime cold medications (including NyQuil). They are generally considered to be safe to be taken together. 

However, there is a theoretical risk of serotonin syndrome when combining dextromethorphan, the cough suppressant in NyQuil, and Zofran, but this risk is thought to be very minimal in those not taking any other interacting drugs.

I discuss this in more detail below.

What Is In NyQuil?

NyQuil contains the following ingredients:

  • Acetaminophen (analgesic)
  • Doxylamine (sedating antihistamine)
  • Dextromethorphan (cough suppressant)

The ingredients in many generic cough/cold products can vary but the above are the most common ones included. Some do contain a nasal decongestant (e.g., phenylephrine) and an expectorant (e.g., guaifenesin) as well.

What Is Zofran?

Zofran (ondansetron) is a medication used to treat/prevent nausea and vomiting.

It works by antagonizing a specific serotonin receptor that is widely distributed throughout the body. Antagonizing this receptor is thought to decrease serotonin signal transmission to the central nervous system, lessening the symptoms of nausea and vomiting. The duration of action of Zofran is reported to be around 6 to 8 hours.

It should be noted that although there is no interaction (aside from what is discussed below) between Zofran and Nyquil, both can cause sedation and fatigue. It is important to only dose them together at bedtime.

Doxylamine, the sedating antihistamine in many cough/cold products begins to work in 30-60 minutes. Zofran similarly begins to work in about 30 minutes. Therefore you can expect the onset of sedation to begin rather quickly after taking the products together.

Dextromethorphan (From NyQuil), Zofran, And Serotonin Syndrome

There is a potential interaction between Zofran and high doses of dextromethorphan, the cough suppressant in Nyquil.

There is a theoretical risk of serotonin syndrome when both drugs are used together.

Symptoms of serotonin syndrome include:

  • Confusion
  • Hallucinations
  • Sweating
  • Chills
  • Hyperthermia
  • Hypertensive crisis

Serotonin syndrome is a rare but serious disorder that results from excess serotonin levels in the brain. If you ever experience symptoms of serotonin syndrome, you should seek medical attention right away. Those susceptible include individuals who are taking a combination of serotonergic drugs.

Dextromethorphan, while not acting directly to increase serotonin, has documented cases of increased serotonin levels when used in supra-therapeutic dosages (i.e. dosages more than indicated on product labeling). 

Zofran, although not a serotonin agonist, blocks serotonin binding to receptors, which could theoretically increase unbound/available serotonin, which may then bind to other serotonin receptors.

There are no case reports of serotonin syndrome between Zofran and dextromethorphan. Nevertheless, it is important to be aware of this theoretical interaction, especially if taking additional serotonergic medications or high doses of each (e.g., such as certain antidepressants, like Zoloft).

Final Words

I hope you found this helpful!

Reach back out anytime.


About the Pharmacist

Dr. Brian Staiger, PharmD

Dr. Brian has been practicing pharmacy for over 13 years and has wide-ranging experiences in many different areas of the profession. From retail, clinical, program development, and administrative responsibilities, he's your knowledgeable and go-to source for all your pharmacy and medication-related questions! Dr. Brian Staiger also has herbalist training and educational certificates in the field of medical ethnobotany. Feel free to send him an email at Hello@HelloPharmacist.com! You can also connect with Dr. Brian Staiger on LinkedIn.

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