Drug & supplement interaction

Melatonin + Dextromethorphan, Guaifenesin, Psuedoephedrine

Dextromethorphan, Guaifenesin, Psuedoephedrine brand name: Aquatab C.

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

Dextromethorphan, Guaifenesin, Psuedoephedrine falls into 2 drug categories that Melatonin can interact with; the most serious is rated minor. Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.

Read the full interaction report
SeverityMinor
LikelihoodPossible
Interactions2
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Dextromethorphan, Guaifenesin, Psuedoephedrine

These two interact in 2 distinct ways. Each one is explained separately below.

Why Are There 2 Interactions?

Melatonin interacts with whole categories of medication. Dextromethorphan, Guaifenesin, Psuedoephedrine falls into 2 of those categories, so it can interact with Melatonin in 2 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Minor).

Minor

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

1 of 2

Why this applies to Dextromethorphan, Guaifenesin, Psuedoephedrine

Dextromethorphan, Guaifenesin, Psuedoephedrine falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES — the group Melatonin interacts with.

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

Out of the three ingredients in Aquatab C, only the cough suppressant dextromethorphan really matters here. It's cleared by a liver enzyme called CYP2D6, and some lab samples of melatonin have been shown to slow that enzyme down. In theory, that could let a little more dextromethorphan build up than usual, which might mean extra drowsiness, dizziness, or feeling a bit foggy. The guaifenesin and pseudoephedrine aren't affected this way.

Honestly, this one is very mild and only shows up in test-tube research, not in real people, so I wouldn't lose sleep over it. Since melatonin and dextromethorphan can both make you sleepy, the bigger practical point is just being careful with driving. If you have questions, your pharmacist can quickly check it with you.

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

2 of 2

Dextromethorphan, Guaifenesin, Psuedoephedrine 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 your Aquatab C (which combines dextromethorphan, guaifenesin, and pseudoephedrine). In some lab dishes, certain batches of melatonin slowed down a liver enzyme called CYP3A4. Of the three ingredients here, dextromethorphan is partly handled by that enzyme, so in theory melatonin could nudge its levels up a little. If that happened, you might feel a touch more drowsy or lightheaded from the dextromethorphan.

The honest truth is this is theoretical and only comes from test-tube research, not real people, so it's rated minor. For most folks taking a short course, this isn't something to lose sleep over. Still, since melatonin and dextromethorphan can both make you sleepy, go easy and check with your pharmacist if you take 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

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 1,116 moderate, 344 minor known drug interactions in our database — the Dextromethorphan, Guaifenesin, Psuedoephedrine one above is among them. If you take anything else, check it against the full list below.

Moderate 1,116 Minor 344 No known interaction 1,370 (incl. Dextromethorphan, Guaifenesin, Psuedoephedrine)
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 Dextromethorphan, Guaifenesin, Psuedoephedrine

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 Dextromethorphan, Guaifenesin, Psuedoephedrine, 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 Dextromethorphan, Guaifenesin, Psuedoephedrine

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Dextromethorphan, Guaifenesin, Psuedoephedrine page lists 197 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Ephedra (major), Grapefruit (major), Lithium (major) and Peyote (major).

By severity: 8 major · 148 moderate · 41 minor.

From our pharmacist’s overview on the Dextromethorphan, Guaifenesin, Psuedoephedrine page

“A cold and congestion remedy sounds low stakes, but Aquatab C (dextromethorphan, guaifenesin, and pseudoephedrine) earns real caution. Eight of the 197 supplements and herbs on file carry a major rating, and those deserve your attention first.”

Reviewed by 2 · Jul 18, 2026

Open the Dextromethorphan, Guaifenesin, Psuedoephedrine 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 Dextromethorphan, Guaifenesin, Psuedoephedrine 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 Dextromethorphan, Guaifenesin, Psuedoephedrine 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%

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

29 days ago today
Medication Dextromethorphan, Guaifenesin, Psuedoephedrine
Steady interest

#2,770 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
1,116Moderate
344Minor
1,369No known interaction
1,116 Moderate 344 Minor 1,369 No interaction
Moderate

1,116 interactions

Showing 60 of 1,116 moderate interactions — see all 1,116 on the Melatonin page.

Minor

344 interactions

Showing 60 of 344 minor interactions — see all 344 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 Dextromethorphan, Guaifenesin, Psuedoephedrine, 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 Dextromethorphan, Guaifenesin, Psuedoephedrine supplement interactions › Every supplement checked against Dextromethorphan, Guaifenesin, Psuedoephedrine, 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 Dextromethorphan, Guaifenesin, Psuedoephedrine Together: Common Questions

Can you take Melatonin with Dextromethorphan, Guaifenesin, Psuedoephedrine?
There is only a minor interaction, which is usually not serious. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 2 interactions listed for Melatonin and Dextromethorphan, Guaifenesin, Psuedoephedrine?
Dextromethorphan, Guaifenesin, Psuedoephedrine 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 Dextromethorphan, Guaifenesin, Psuedoephedrine interaction?
We rate it Minor. This interaction is generally not clinically significant, but it remains worth noting and discussing with your pharmacist.

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.