Drug & supplement interaction

Melatonin + Aspirin, Caffeine, Hydrocodone

Aspirin, Caffeine, Hydrocodone brand name: Damason-P.

Moderate Interaction
The bottom line Moderate

Aspirin, Caffeine, Hydrocodone falls into 7 drug categories that Melatonin can interact with; the most serious is rated moderate. Theoretically, taking melatonin might increase the sedative effects of CNS depressants.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions7
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Aspirin, Caffeine, Hydrocodone

These two interact in 7 distinct ways. Each one is explained separately below.

Why Are There 7 Interactions?

Melatonin interacts with whole categories of medication. Aspirin, Caffeine, Hydrocodone falls into 7 of those categories, so it can interact with Melatonin in 7 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CNS DEPRESSANTS

1 of 7

Why this applies to Aspirin, Caffeine, Hydrocodone

Aspirin, Caffeine, Hydrocodone falls under CNS DEPRESSANTS — the group Melatonin interacts with.

Theoretically, taking melatonin might increase the sedative effects of CNS depressants.
Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation.
Severity Moderate 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

The piece of this combo pill that matters most here is the hydrocodone, an opioid painkiller that already makes many people feel drowsy, foggy, or relaxed. Melatonin nudges your body toward sleep too, so layering the two together could add up. The concern is mainly extra sleepiness, slowed thinking, or feeling more groggy than usual, especially when you first start.

To be fair, this caution is theoretical, based on how both products work rather than strong studies, so it is not a guaranteed problem. The caffeine in this pill may even blunt some drowsiness. Still, hydrocodone deserves respect. Be careful with driving until you know how you feel, and check with your pharmacist or doctor before combining them.

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
Moderate

SEIZURE THRESHOLD LOWERING DRUGS

2 of 7

Aspirin, Caffeine, Hydrocodone also falls under SEIZURE THRESHOLD LOWERING DRUGS.

Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.
Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities.
Severity Moderate 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 what's going on with your Damason-P combo (aspirin, caffeine, and the opioid hydrocodone) alongside melatonin. The piece that matters here is that certain medicines can slightly lower the seizure threshold, meaning they can make the brain a bit more prone to a seizure. Opioids like hydrocodone can do this, especially at higher doses, and the caffeine in this product is a mild stimulant too. The concern is that melatonin might add to that and make a seizure a little more likely.

I want to be honest: this is a theoretical caution based mostly on how these drugs behave, with some real-world reports in children who have neurological conditions. For most adults using this short-term, it's unlikely to cause a problem. Still, if you have a seizure history, check with your pharmacist or doctor before combining them.

References
  1. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254. PubMed
  2. Stewart LS. Endogenous melatonin and epileptogenesis: facts and hypothesis. Int J Neurosci 2001;107:77-85.. PubMed
Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

3 of 7

Aspirin, Caffeine, Hydrocodone also falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES.

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

In this combination product, the piece that actually connects to melatonin is the caffeine. Caffeine is cleared by a liver enzyme called CYP1A2, and the same enzyme helps break down melatonin. On paper, the two may slow each other down a bit, so caffeine could hang around a little longer (think jitteriness, a racing heart, or trouble settling to sleep, which is the opposite of what you want from melatonin), and melatonin levels could nudge upward too.

The good news: this is a theoretical concern based on how the enzyme works, not strong real-world proof, and the caffeine dose in these tablets is modest. The hydrocodone and aspirin parts are not really involved here. Still, since melatonin is taken for sleep, run it by your pharmacist or doctor before pairing them.

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

4 of 7

Aspirin, Caffeine, Hydrocodone 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 combination product (Damason-P) contains aspirin, which thins the blood a bit by making your platelets less sticky. Melatonin has its own mild blood-thinning signal in some early research, so pairing the two could, in theory, nudge your bleeding risk a little higher. With aspirin, that might show up as easier bruising, nosebleeds, or stomach upset, and rarely something more serious like blood in the stool.

Honestly, this concern rests on a few case reports and small studies, so it is more theoretical than proven. For most people taking occasional doses it is unlikely to cause trouble. Still, if you take aspirin daily, are on a higher dose, or have any history of bleeding or ulcers, check with your pharmacist or doctor before adding melatonin.

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

5 of 7

Aspirin, Caffeine, Hydrocodone 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 wrinkle with this combo: the medication you're asking about (Damason-P) is a mix that includes caffeine. The interaction on file is really between that caffeine and your melatonin. Both are cleared by the same liver enzyme (CYP1A2), so when they're taken together, the caffeine can slow how fast your body breaks down melatonin. The practical result is that your melatonin levels may run a bit higher, so you could feel extra drowsy or groggy.

This evidence is on the softer side and the effect is usually mild, but melatonin already nudges you toward sleep, and hydrocodone is sedating too. Stacking sleepiness on top of a narcotic is worth a quick chat with your pharmacist before combining them.

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 2D6 (CYP2D6) SUBSTRATES

6 of 7

Aspirin, Caffeine, Hydrocodone 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

This combo product (brand name Damason-P) mixes aspirin, caffeine, and hydrocodone for pain relief. The piece that matters here is the hydrocodone. It's a bit unusual: hydrocodone is partly turned into a stronger painkiller (hydromorphone) by a liver enzyme called CYP2D6. Some lab studies hint that certain batches of melatonin might slow that same enzyme down.

If that happened, you could in theory see a touch more drowsiness, dizziness, nausea, or constipation, especially since melatonin already makes you sleepy. But honestly, this is rated minor and rests only on test-tube data, so it may not show up in real life at all. Still, if you feel extra groggy taking them together, mention it to your pharmacist or doctor.

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

7 of 7

Aspirin, Caffeine, Hydrocodone 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 with this combo product, which pairs aspirin and caffeine with hydrocodone (an opioid pain reliever). The concern on file is purely theoretical: in lab dishes, some batches of melatonin appeared to slow down the CYP3A4 enzyme, one of the pathways that helps process hydrocodone. If that happened in real life, hydrocodone could build up a bit and feel stronger, which might mean more drowsiness, dizziness, slowed breathing, or constipation.

But take a breath. This is rated minor and comes only from test-tube and animal data, not from people. For most healthy adults, occasional melatonin for sleep isn't likely to cause a problem here. Since hydrocodone is a controlled opioid, it's still smart to mention your melatonin use to your pharmacist or doctor, especially if you notice extra grogginess.

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

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, Hydrocodone

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, Hydrocodone, 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, Hydrocodone

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Aspirin, Caffeine, Hydrocodone page lists 398 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), Asarabacca (major), Beer (major) and Danshen (major).

By severity: 17 major · 334 moderate · 47 minor.

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

“Damason-P packs three drugs into one tablet, the opioid hydrocodone, aspirin, and caffeine, so a supplement can collide with any one of them, and its list of 398 interacting ingredients earns real respect. More than 200 of those can add to aspirin's bleeding risk, while 78 can deepen the opioid's sedation.”

Reviewed by 2 · Jul 18, 2026

Open the Aspirin, Caffeine, Hydrocodone 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, Hydrocodone 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, Hydrocodone 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, Hydrocodone
Steady interest

#1,956 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
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
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
Pharmacist Counseling Corner

Taking Melatonin and Aspirin, Caffeine, Hydrocodone Together: Common Questions

Can you take Melatonin with Aspirin, Caffeine, Hydrocodone?
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 7 interactions listed for Melatonin and Aspirin, Caffeine, Hydrocodone?
Aspirin, Caffeine, Hydrocodone 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, Hydrocodone 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

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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.