Drug & supplement interaction

Melatonin + Acetaminophen

Acetaminophen brand names: Tylenol Ex Strength, Children's Tylenol, Tylenol, Children's Tylenol Meltaways.

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

Melatonin has a moderate interaction with Acetaminophen. Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2.

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

Melatonin and Acetaminophen

Here is the interaction we found between these two, with the evidence behind it.

Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Why this applies to Acetaminophen

Acetaminophen 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 for taking melatonin with Tylenol (acetaminophen): the concern on file is that melatonin might slow down a liver enzyme called CYP1A2, which is one of the pathways that helps your body process acetaminophen. In theory, that could let a little more acetaminophen linger in your system.

The honest truth is this interaction is purely theoretical, based on lab pharmacology rather than real-world reports of people running into trouble. Acetaminophen is also not a prodrug, so it doesn't need that enzyme to work. For normal, occasional Tylenol use, this combo is very unlikely to cause you any problems. The bigger thing to watch with acetaminophen is always staying under the daily dose limit to protect your liver. If you use both regularly, just mention it to your pharmacist.

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

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 Acetaminophen one above is one of them. If you take anything else, check it against the full list below.

Moderate 1,115 Minor 345 No known interaction 1,370 (incl. Acetaminophen)
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 Acetaminophen

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 Acetaminophen, 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 Acetaminophen

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Acetaminophen page lists 155 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Asarabacca (major), Beer (major), Siberian Cocklebur (major) and Wine (major).

By severity: 5 major · 114 moderate · 36 minor.

From our pharmacist’s overview on the Acetaminophen page

“Acetaminophen (Tylenol) feels harmless because it sits on every shelf, but this list deserves real attention, mostly because of your liver. Of the 155 supplements and herbs on file, five carry a major rating, and the largest serious group, 38 ingredients, adds liver strain on top of acetaminophen's own well-known potential to harm the…”

Reviewed by 2 · Jul 18, 2026

Open the Acetaminophen 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 Acetaminophen 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 Acetaminophen 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%

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

29 days ago today
Medication Acetaminophen
Top 1%

#26 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 Acetaminophen

What Is Acetaminophen Used For?

Brand names: Tylenol Ex Strength, Children's Tylenol, Tylenol, Children's Tylenol Meltaways

Acetaminophen temporarily relieves minor aches and pains caused by headaches, the common cold, backaches, muscle aches, toothaches, minor arthritis pain, and premenstrual or menstrual cramps. It also temporarily reduces fever.

These uses apply across oral tablet, suspension, and oral liquid products. The intravenous (IV) injection form is used in clinical settings to treat acute pain and fever, including in pediatric patients 2 years and older.

See full Acetaminophen 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 Acetaminophen, 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 Acetaminophen supplement interactions › Every supplement checked against Acetaminophen, ranked by severity Acetaminophen 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 Acetaminophen Together: Common Questions

Can you take Melatonin with Acetaminophen?
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.
How serious is the Melatonin and Acetaminophen 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 Acetaminophen 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.