Drug & supplement interaction

Melatonin + Aspirin, Caffeine

Aspirin, Caffeine brand name: Anacin.

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

Aspirin, Caffeine falls into 4 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
Interactions4
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Aspirin, Caffeine

These two interact in 4 distinct ways. Each one is explained separately below.

Why Are There 4 Interactions?

Melatonin interacts with whole categories of medication. Aspirin, Caffeine falls into 4 of those categories, so it can interact with Melatonin in 4 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 4

Why this applies to Aspirin, Caffeine

Aspirin, Caffeine 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

The piece of this combo product that matters here is the caffeine. Your liver clears caffeine using an enzyme called CYP1A2, and melatonin leans on that same enzyme. On paper, taking them together could slow caffeine's breakdown a little, letting it linger longer in your system. If that happens, you might feel the usual caffeine "too much" signs: jitteriness, a racing or pounding heart, trouble settling down, or a restless night, which is a bit ironic if you took melatonin to sleep.

Keep in mind this is a theoretical concern based on how these compounds are processed, not on strong real-world studies, so for most people it stays minor. The aspirin side isn't really involved here. If you use this regularly, just run it by your pharmacist or doctor before mixing.

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
Moderate

ANTICOAGULANT/ANTIPLATELET DRUGS

2 of 4

Aspirin, Caffeine also falls under ANTICOAGULANT/ANTIPLATELET DRUGS.

Theoretically, melatonin may have anticoagulant effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
There are isolated case reports of minor bleeding and decreased prothrombin activity in people taking melatonin with warfarin (Coumadin). The mechanism, if any, of this interaction is unknown. Taking melatonin orally seems to decrease coagulation activity within one hour of dosing in healthy men.
Severity Moderate Likelihood Possible Evidence B

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

This combo product pairs aspirin, which thins the blood by keeping platelets from sticking together, with a little caffeine for extra pain relief. Adding melatonin to the mix is the part worth watching. There's a theory that melatonin may have its own mild blood-thinning effect, and a few scattered reports describe minor bleeding when it was used alongside blood thinners. Stacked on top of aspirin, this could in theory nudge your bleeding risk a bit higher.

I want to be honest that this is mostly theoretical, and the evidence is thin. Still, keep an eye out for things like easy bruising, nosebleeds, bleeding gums, or a cut that's slow to stop. If you notice any of that, or you take aspirin regularly, check in with your pharmacist or doctor before pairing it with melatonin.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002;2:CD001520. PubMed
  2. Wirtz, P. H., Spillmann, M., Bartschi, C., Ehlert, U., and von Kanel, R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res 2008;44(2):127-133. PubMed
  3. U.S.Food and Drug Administration. Special Nutritionals Adverse Events Monitoring System: registered case reports.
Moderate

CAFFEINE

3 of 4

Aspirin, Caffeine also falls under CAFFEINE.

Theoretically, taking caffeine with melatonin might increase levels of melatonin.
Some evidence suggests that caffeine consumption can decrease endogenous melatonin levels, while other evidence suggests that caffeine increases endogenous melatonin levels. When administered in combination with melatonin supplements, caffeine seems to increase melatonin effects and levels. The reason for this discrepancy is not completely clear. Part of the discrepancy may result from the fact that caffeine can inhibit melatonin synthesis as well as inhibit melatonin metabolism. By functioning as an adenosine receptor antagonist, caffeine may indirectly inhibit the synthesis of melatonin. Conversely, because melatonin and caffeine are both metabolized by cytochrome P450 1A2 (CYP1A2) enzyme, concomitant use of melatonin and caffeine may reduce the metabolism of melatonin, resulting in higher serum levels.
Severity Moderate Likelihood Probable Evidence B

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 interesting twist with this combo. The caffeine in Anacin and melatonin both get cleared by the same liver enzyme (CYP1A2). When you take them together, the caffeine can slow down how fast your body breaks down the melatonin, so your melatonin levels may run a bit higher. In other words, the caffeine isn't the one that builds up here, the melatonin is.

What might you notice? Possibly a little extra drowsiness or grogginess from the melatonin. The good news is this is mostly theoretical and based on lower-quality studies, so for occasional use it's usually minor. Just keep in mind the caffeine in Anacin can also work against melatonin's sleepy signal. If you take this regularly or feel unusually groggy, check with your pharmacist or doctor about timing.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Wright KP Jr, Myers BL, Plenzler SC, et al. Acute effects of bright light and caffeine on nighttime melatonin and temperature levels in women taking and not taking oral contraceptives. Brain Res 2000;873:310-7.
  2. Wright KP Jr, Badia P, Myers BL, et al. Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans. Brain Res. 1997;747(1):78-84. PubMed
  3. Peuhkuri K, Sihvola N, Korpela R. Dietary factors and fluctuating levels of melatonin. Food Nutr Res. 2012;56. doi: 10.3402/fnr.v56i0.17252. Epub 2012 Jul 20. PubMed
  4. Babkoff, H., French, J., Whitmore, J., and Sutherlin, R. Single-dose bright light and/or caffeine effect on nocturnal performance. Aviat.Space Environ.Med. 2002;73(4):341-350.
  5. Ursing, C., Wikner, J., Brismar, K., and Rojdmark, S. Caffeine raises the serum melatonin level in healthy subjects: an indication of melatonin metabolism by cytochrome P450(CYP)1A2. J.Endocrinol.Invest 2003;26(5):403-406. PubMed
  6. Hartter, S., Nordmark, A., Rose, D. M., Bertilsson, L., Tybring, G., and Laine, K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br.J.Clin.Pharmacol. 2003;56(6):679-682. PubMed
  7. 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

4 of 4

Aspirin, Caffeine 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 honest scoop on pairing melatonin with an aspirin and caffeine combo like Anacin. The concern on file is that some batches of melatonin may slow down a liver enzyme called CYP3A4. In theory, that could let certain medications build up a bit. But this is graded as a minor interaction, and it comes only from lab and animal research, not from real people. That's a big caveat.

Practically speaking, the caffeine in Anacin is mostly handled by a different enzyme (CYP1A2), and aspirin isn't heavily reliant on CYP3A4 either. So I wouldn't expect any real trouble here. Worst case, you might feel slightly more jittery or wired from the caffeine, which could fight melatonin's sleep signal. If you take this regularly, just run it by your pharmacist to be safe.

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 Aspirin, Caffeine 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. Aspirin, Caffeine)
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 Aspirin, Caffeine

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 Aspirin, Caffeine, 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 Aspirin, Caffeine

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Aspirin, Caffeine page lists 347 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), Danshen (major) and Ephedra (major).

By severity: 13 major · 285 moderate · 49 minor.

From our pharmacist’s overview on the Aspirin, Caffeine page

“Anacin combines aspirin with caffeine, so supplements can hit it from two directions, and a few of the 347 on this list deserve real respect. The biggest group, over 200 ingredients, can raise bleeding risk on top of aspirin's blood-thinning effect; beer and wine carry major ratings because alcohol plus an aspirin-type drug makes stoma…”

Reviewed by 2 · Jul 18, 2026

Open the Aspirin, Caffeine 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 Aspirin, Caffeine 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 Aspirin, Caffeine 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 Aspirin, Caffeine
Top 25%

#563 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
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 Aspirin, Caffeine, 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 Aspirin, Caffeine supplement interactions › Every supplement checked against Aspirin, Caffeine, ranked by severity 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 Aspirin, Caffeine Together: Common Questions

Can you take Melatonin with Aspirin, Caffeine?
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 4 interactions listed for Melatonin and Aspirin, Caffeine?
Aspirin, Caffeine 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 Aspirin, Caffeine 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 Aspirin, Caffeine 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.