Drug & supplement interaction

Melatonin + Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride brand name: Hycofenix.

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

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride falls into 4 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
Interactions4
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

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. Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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

CNS DEPRESSANTS

1 of 4

Why this applies to Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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

Here's the thing to keep in mind with Hycofenix: it contains hydrocodone, an opioid that can already make you drowsy and slow your breathing a bit. Melatonin has mild sedative effects of its own, so stacking the two could leave you feeling more sleepy, foggy, or sluggish than you'd expect. This isn't about one drug speeding up or blocking another in your liver. It's simply two things that can make you tired adding up together.

To be fair, this is a theoretical concern based on how these work, not strong proof, so the effect may be modest. Still, go easy until you know how the combo hits you, don't drive on it, and skip alcohol. If you're unsure whether melatonin is okay alongside your cough medicine, a quick chat with your pharmacist or doctor is the safest move.

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
Moderate

SEIZURE THRESHOLD LOWERING DRUGS

2 of 4

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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

Hycofenix is a combination cough and cold product that pairs an opioid (hydrocodone), a decongestant (pseudoephedrine), and an expectorant (guaifenesin). The concern here isn't about melatonin changing how your body breaks this medicine down. Instead, it's a theoretical worry that melatonin might slightly lower the seizure threshold, meaning the brain could become a touch more prone to seizure activity in people who are already vulnerable.

To be honest, this is a low-level, on-paper concern. The strongest signal comes from certain children with neurological conditions, not from healthy adults using melatonin for sleep. For most people taking Hycofenix short-term, this combination isn't a major red flag. Still, if you or your child has a seizure history, it's worth a quick chat with your pharmacist or doctor before combining them.

Contact Dr. Brian directly if you have additional questions on this interaction
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
Minor

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

3 of 4

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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 piece worth knowing about Hycofenix: the hydrocodone in it is actually a prodrug for pain relief. Your body uses an enzyme called CYP2D6 to convert hydrocodone into hydromorphone, which is the stronger painkiller. Some lab studies suggest melatonin might slow down that same enzyme.

So in theory, blocking CYP2D6 could mean less of the active painkiller is formed, not more, which could blunt the cough or pain relief slightly. But honestly, this is weak, test-tube-level evidence rated as minor, and most people won't notice any difference. The more practical concern is that both melatonin and hydrocodone can make you drowsy, so together they may leave you extra sleepy. If you're using both, just mention it to your pharmacist or doctor.

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

4 of 4

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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 practical side of mixing melatonin with Hycofenix. The hydrocodone part of this combo is partly broken down by a liver enzyme called CYP3A4. Some lab studies hint that certain batches of melatonin could slow that enzyme down a bit. In theory, that might let a little more hydrocodone build up, which could mean more drowsiness, dizziness, or slowed breathing than you'd expect.

That said, this is only based on test-tube research, not real people, so the actual risk looks small. The bigger thing I'd watch for is the obvious overlap: both melatonin and hydrocodone make you sleepy. Stacking them can leave you extra groggy. Don't start or stop anything on your own, but do check with your pharmacist or doctor first.

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, 346 minor known drug interactions in our database — the Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride one above is among them. If you take anything else, check it against the full list below.

Moderate 1,116 Minor 346 No known interaction 1,368 (incl. Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride)
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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride, 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride page lists 241 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), Beer (major), Ephedra (major) and Gamma-hydroxybutyrate (ghb) (major).

By severity: 13 major · 190 moderate · 38 minor.

From our pharmacist’s overview on the Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride page

“Hycofenix combines guaifenesin with hydrocodone, an opioid, and pseudoephedrine, a decongestant, so supplements can collide with it from two directions at once. That is why this list of 241 ingredients deserves real caution, starting with the 13 rated major.”

Reviewed by 2 · Jul 18, 2026

Open the Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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%

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

29 days ago today
Medication Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride
Top 25%

#536 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
346Minor
1,367No known interaction
1,116 Moderate 346 Minor 1,367 No interaction
Moderate

1,116 interactions

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

Minor

346 interactions

Showing 60 of 346 minor interactions — see all 346 on the Melatonin page.

No interaction 1,367 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 1,367 medications checked with no known interaction — see the full Melatonin list.

See the full Melatonin interactions page
See every supplement checked against Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride, 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride supplement interactions › Every supplement checked against Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride, 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride Together: Common Questions

Can you take Melatonin with Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride?
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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride?
Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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 Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride 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.