Drug & supplement interaction

Melatonin + Ondansetron

Ondansetron brand name: Zofran.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Ondansetron falls into 3 drug categories that Melatonin can interact with; the most serious is rated moderate. Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2.

Read the full interaction report
SeverityModerate
LikelihoodProbable
Interactions3
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Ondansetron

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Melatonin interacts with whole categories of medication. Ondansetron falls into 3 of those categories, so it can interact with Melatonin in 3 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

1 of 3

Why this applies to Ondansetron

Ondansetron falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES — the group Melatonin interacts with.

Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2. Also, other CYP1A2 substrates might decrease the metabolism of melatonin, increasing melatonin levels.
Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes. Theoretically, combined administration of melatonin with drugs metabolized by the CYP1A2 enzyme might reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP1A2 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Moderate Likelihood Probable Evidence D

Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports..

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist with melatonin and ondansetron (Zofran). Your liver uses an enzyme called CYP1A2 to help clear ondansetron, and in theory melatonin may slow that enzyme down a bit. If that happens, a little more ondansetron could linger in your system. Ondansetron is not a prodrug, so it stays active itself, meaning you might notice its usual side effects a touch more, things like headache, constipation, or feeling tired.

I want to be honest though: this concern is theoretical, based on how these substances behave on paper rather than on real cases of people running into trouble. For most folks taking ondansetron for nausea, occasional melatonin is unlikely to cause a real problem. Still, it's worth a quick mention to your pharmacist or doctor so they can weigh in for your situation.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Yeleswaram, K., Vachharajani, N., and Santone, K. Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. J Pineal Res 1999;26(3):190-191. PubMed
  2. Faber, M. S., Jetter, A., and Fuhr, U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134. PubMed
  3. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed
Minor

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

2 of 3

Ondansetron also falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES.

Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.
Laboratory research suggests that certain lots of melatonin inhibit CYP2D6. Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Minor Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the short version: your body uses an enzyme called CYP2D6 to help clear ondansetron (Zofran). Some lab studies hint that melatonin might slow that enzyme down a bit. If that happened, a little more ondansetron could linger in your system, which in theory could nudge up its usual side effects like headache, constipation, or feeling tired.

That said, I want to keep this in perspective. This is a minor, mostly theoretical concern based only on test-tube research, not real-world patient reports. Ondansetron is not a prodrug, so it still works fine. For most folks an occasional melatonin at bedtime is unlikely to cause trouble, but it's always worth a quick word with your pharmacist or doctor if you use both regularly.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed
Minor

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

3 of 3

Ondansetron also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.
Laboratory research shows that certain lots of melatonin inhibit CYP3A4. Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Minor Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist for these two together. Your body partly clears ondansetron (Zofran) using a liver enzyme called CYP3A4. Some lab studies suggest melatonin might slow that enzyme down a bit. If that happened, ondansetron could clear a little slower and its levels could nudge upward, which in theory could mean more of its usual side effects like headache, constipation, or feeling drowsy.

That said, I don't want to worry you. This is only a theoretical concern based on test-tube research, not real patient cases, and it's rated as minor. For most people using ondansetron short-term for nausea, occasional melatonin at bedtime is unlikely to cause a real problem. Still, it's always worth a quick word with your pharmacist or doctor, especially if you take either one regularly.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Melatonin Also Interacts With Other Medications

Melatonin has 1,115 moderate, 345 minor known drug interactions in our database — the Ondansetron one above is among them. If you take anything else, check it against the full list below.

Moderate 1,115 Minor 345 No known interaction 1,370 (incl. Ondansetron)
Taking anything else?

Check Another of Your Medications Against Melatonin

Covers the 2,830 medications we’ve checked against Melatonin. Pick one to open its full report.

From our Q&A

Questions About Melatonin or Ondansetron

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Melatonin or Ondansetron, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Ondansetron

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Ondansetron page lists 195 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Grapefruit (major), Lithium (major), St. John's Wort (major) and 1,3-dmaa (moderate).

By severity: 4 major · 145 moderate · 46 minor.

From our pharmacist’s overview on the Ondansetron page

“Ondansetron (Zofran) often stands between you and relentless nausea from chemotherapy or surgery, so read this page carefully. Four of the 195 ingredients rate major.”

Reviewed by 2 · Jul 18, 2026

Open the Ondansetron interaction page

One more smart check

Taking Melatonin as Part of a Dietary Supplement Product? Check It for Interactions

We hold 2,885 real supplement products containing Melatonin, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Melatonin. Your product may carry other ingredients that interact with Ondansetron too, on top of Melatonin — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Melatonin and Ondansetron Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Melatonin
Top 5%

#55 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Ondansetron
Top 25%

#319 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Melatonin

What is Melatonin?

Melatonin
  • Trouble falling asleep (insomnia)
  • Jet lag
  • Delayed sleep phase syndrome
  • Non-24-hour sleep-wake disorder
  • Shift-work sleep problems
  • Sleep problems in some children with conditions like autism or ADHD

Melatonin is a hormone your body makes naturally to help control your sleep-wake cycle, and the supplement form is widely used to help with sleep timing problems and jet lag. The evidence is strongest for certain circadian (body-clock) disorders and is more mixed for everyday insomnia. It is generally well tolerated for short-term use, but talk with your pharmacist or doctor before starting, especially for children or during pregnancy.

Read the full Melatonin monograph & all interactions
Medication

About Ondansetron

What Is Ondansetron Used For?

Brand name: Zofran

Ondansetron is used to prevent nausea and vomiting in several situations. Oral forms (tablets, orally disintegrating tablets, and oral solution) are approved to prevent nausea and vomiting from highly or moderately emetogenic (nausea-causing) cancer chemotherapy, from radiation therapy to the abdomen or whole body, and from surgery.

Ondansetron injection (given intravenously or intramuscularly in a clinical setting) is approved to prevent nausea and vomiting from emetogenic cancer chemotherapy — including high-dose cisplatin — in adults and children as young as 6 months old, as well as to prevent postoperative nausea and vomiting.

See full Ondansetron drug information
Keep checking

Other Drugs & Melatonin

Browse every other medication we’ve checked against Melatonin — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
1,115Moderate
345Minor
1,369No known interaction
1,115 Moderate 345 Minor 1,369 No interaction
Moderate

1,115 interactions

Showing 60 of 1,115 moderate interactions — see all 1,115 on the Melatonin page.

Minor

345 interactions

Showing 60 of 345 minor interactions — see all 345 on the Melatonin page.

No interaction 1,369 drugs checked — show the list

We also checked Melatonin against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,369 medications checked with no known interaction — see the full Melatonin list.

See the full Melatonin interactions page
See every supplement checked against Ondansetron, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Melatonin monograph › Uses, safety, and every drug interaction in one place Ondansetron supplement interactions › Every supplement checked against Ondansetron, ranked by severity Ondansetron drug information › The full plain-English guide to this medication Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Melatonin and Ondansetron Together: Common Questions

Can you take Melatonin with Ondansetron?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 3 interactions listed for Melatonin and Ondansetron?
Ondansetron belongs to more than one drug category, and Melatonin interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Melatonin and Ondansetron interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Ondansetron and Melatonin?

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.