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).

3 min read Updated Jun 2026 Read by 14,149 people
Taking Zofran (Ondansetron) With Nyquil
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Courtney asked

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.

Nov 20, 2022
The quick answer
  • Zofran and NyQuil are generally safe to take together with no reported interactions between them.
  • Both medications can cause sedation and fatigue, so they should only be taken together at bedtime.
  • There is a theoretical but very minimal risk of serotonin syndrome when combining these drugs, especially if you are also taking other serotonergic medications like certain antidepressants.
A quick summary of Dr. Brian Staiger, PharmD's full answer below, condensed by AI from that answer only (not from any outside source). The pharmacist's answer is the source of record.

Answer

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, 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.

References & sources
  1. Ondansetron Monograph — PubChem
  2. Dextromethorphan Monograph — PubChem
  3. Dextromethorphan-induced serotonin syndrome — Taylor & Francis Online
Glossary — Terms in This Answer
Antagonizing
Blocking or inhibiting the action of a receptor or substance in the body.
Serotonin syndrome
A serious but rare condition caused by excessive serotonin levels in the brain that can produce confusion, sweating, and dangerously high body temperature.
Antihistamine
A medication that blocks the effects of histamine in the body to reduce allergy symptoms and promote drowsiness.
Expectorant
A medication that helps thin and clear mucus from the airways to make coughing more productive.
Serotonergic
Relating to drugs or substances that affect serotonin levels or function in the brain.
Supra-therapeutic
Doses of medication that are higher than the recommended amount listed on product labeling.
Antagonist
A substance that blocks or reduces the effect of another substance or receptor in the body.
Agonist
A substance that binds to and activates a receptor in the body to produce a specific effect.
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Dr. Brian Staiger, PharmD
About the pharmacist

Dr. Brian Staiger, PharmD

Clinical Pharmacy

Doctor of Pharmacy, board certified clinical pharmacist (BCPS), American Herbalist Guild, Medication Therapy Management certified

Brian Staiger, PharmD, BCPS, is a licensed pharmacist with more than 13 years of experience across retail pharmacy, clinical pharmacy, medication safety, pharmacy program development, and healthcare administration. He is the founder of HelloPharmacist.com, where he helps patients...

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