Drug & supplement interaction

Kratom + 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 3 drug categories that Kratom can interact with; the most serious is rated moderate. Theoretically, concomitant use might increase the risk for adverse CNS depressant effects.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions3
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Kratom and Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Kratom interacts with whole categories of medication. Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride falls into 3 of those categories, so it can interact with Kratom in 3 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 3

Why this applies to Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride falls under CNS DEPRESSANTS — the group Kratom interacts with.

Theoretically, concomitant use might increase the risk for adverse CNS depressant effects.
Kratom contains mitragynine, a mu-receptor agonist that may cause respiratory depression. Although results from animal research suggest that mitragynine causes less respiratory depression than the CNS depressant codeine, fatalities have been reported for patients who ingested a combination of kratom and O-desmethyltramadol, another mu-receptor agonist. Additionally, observational research suggests that adverse effects such as drowsiness and coma are more likely to occur in individuals taking kratom in combination with agents such as opioids and sedatives. Theoretically, ingesting kratom along with other CNS depressants can increase the risk of adverse effects, including drowsiness, coma, and/or severe or fatal respiratory depression.
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 know about Hycofenix: it contains hydrocodone, an opioid pain reliever that quiets your breathing drive and makes you sleepy. Kratom works on those same opioid receptors in the brain. So when you stack the two, you're essentially doubling up on opioid-like activity, and the worry is they pile on each other.

What could that look like? Heavy drowsiness, confusion, very slow or shallow breathing, and in the worst cases, dangerously slowed breathing that can become life-threatening. This concern is theoretical and based on how these substances behave, not on hard studies of this exact pair, but real fatalities have happened when kratom was mixed with other opioids. Please don't combine them without talking to your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Backstrom BG, Classon G, Lowenhielm P, Thelander G. [Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]. Lakartidningen 2010;107(50):3196-3197.
  2. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol 2011;35(4):242-247. PubMed
  3. Jansen KL, Prast CJ. Ethnopharmacology of kratom and the Mitragyna alkaloids. J Ethnopharmacol 1988;23(1):115-119. PubMed
  4. Davidson C, Cao D, King T, et al. A comparative analysis of kratom exposure cases in Thailand and the United States from 2010-2017. Am J Drug Alcohol Abuse. 2020:1-10. PubMed
Moderate

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

2 of 3

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride also falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES.

Theoretically, kratom might increase the levels and clinical effects of drugs metabolized by CYP2D6.
In vitro research suggests that kratom extract inhibits CYP2D6 enzyme activity. However, human research shows that a single low dose of kratom tea 2 grams does not inhibit CYP2D6 activity. However, this kratom dose is lower than what is normally taken for psychoactive effects. In one case report, a 63-year-old male presented with possible serotonin syndrome after taking an unknown dose of kratom for up to 3 months along with serotonergic prescription medications bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone. It was hypothesized that kratom inhibited CYP2D6-mediated metabolism of buspirone and consequently increased systemic exposure to serotonin. In another case, a 37-year-old male stable for 15 years on amitriptyline presented with anticholinergic symptoms including xerostomia, dry eyes, and constipation, along with mildly elevated bilirubin and liver enzymes after taking progressively higher doses of up to 14 grams of kratom daily for 12 weeks. It was hypothesized that the adverse effects of amitriptyline were precipitated by CYP2D6 inhibition by kratom.
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 wrinkle with this combo: your Hycofenix contains hydrocodone, which the liver enzyme CYP2D6 turns into a more potent painkiller. Lab studies hint that kratom can block CYP2D6, but here's the twist. If that enzyme is slowed, your body makes less of the stronger active form, so you might actually feel less pain relief than expected. At the same time, kratom itself acts on opioid receptors, so stacking it with hydrocodone can pile on sedation, slowed breathing, and constipation.

This is mostly theoretical and based on lab work, not strong human data, so I don't want to alarm you. Still, mixing two opioid-like substances is the bigger real-world worry. Please run this by your pharmacist or doctor before combining them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Kong WM, Chik Z, Ramachandra M, et al. Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assay. Molecules. 2011;16(9):7344-7356. PubMed
  2. Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents. J Pharm Pract 2022. PubMed
  3. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Clin Pharmacol Ther 2023;113(6):1315-1325. PubMed
  4. Vanani NB, Stevanovic SG, Stevanovic N. Adverse Drug Interaction Between Kratom and Amitriptyline With Gastrointestinal and Mild Hepatic Effects. Cureus 2023;15(1):e33809. PubMed
Moderate

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

3 of 3

Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

Kratom might increase the levels and clinical effects of drugs metabolized by CYP3A4.
In vitro research shows that kratom extract inhibits CYP3A4 enzyme activity. A pharmacokinetic study in adults shows that taking kratom tea 2 grams modestly increases the plasma concentration time-curve (AUC) and maximum concentration (Cmax) of CYP3A4 probe midazolam by 40-50% and its CYP3A4-mediated metabolites 18-27%. However, a lack of change in the half-life of midazolam and a simulation of the kratom-midazolam interaction suggest that kratom inhibits CYP3A4 enzymes in the small intestine but not the liver. Additionally, there is one case report of a 27-year-old male who died from neuroleptic malignant-like symptoms after concomitant use of kratom and quetiapine, a CYP3A4 substrate. Although it did not appear that the patient had consumed large quantities of quetiapine, postmortem plasma levels were in the lethal range, indicating possible inhibition of CYP3A4 by kratom. In another case report, a 63-year-old male presented with possible serotonin syndrome after taking an unknown dose of kratom for up to 3 months along with serotonergic prescription medications bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone. It is hypothesized that CYP3A4 inhibition by kratom reduced metabolism of desvenlafaxine, trazodone, and ziprasidone and consequently increased systemic exposure to serotonin.
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 hydrocodone piece of Hycofenix is the one I'd watch here. Your body relies partly on an enzyme called CYP3A4 to break hydrocodone down, and lab studies suggest kratom can slow that enzyme. If hydrocodone clears more slowly, it can build up and push its effects too far. That means stronger drowsiness, slowed or shallow breathing, confusion, and constipation. Both kratom and hydrocodone act on opioid receptors, so stacking them adds to that sedation risk.

To be fair, this is mostly theoretical, based on pharmacology and lab data rather than solid human studies, so I don't want to alarm you. Still, with an opioid involved, even a modest bump matters. Please check with your pharmacist or doctor before combining the two.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Kong WM, Chik Z, Ramachandra M, et al. Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assay. Molecules. 2011;16(9):7344-7356. PubMed
  2. Hughes RL. Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction. Forensic Sci Med Pathol. 2019 Mar;15(1):110-113. PubMed
  3. Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents. J Pharm Pract 2022. PubMed
  4. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Clin Pharmacol Ther 2023;113(6):1315-1325. 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

Kratom Also Interacts With Other Medications

Kratom has 983 moderate, 12 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 983 Minor 12 No known interaction 1,835 (incl. Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride)
Taking anything else?

Check Another of Your Medications Against Kratom

Covers the 2,830 medications we’ve checked against Kratom. Pick one to open its full report.

From our Q&A

Questions About Kratom 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 Kratom 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 Kratom 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 Kratom as Part of a Dietary Supplement Product? Check It for Interactions

We hold 8 real supplement products containing Kratom, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Kratom. Your product may carry other ingredients that interact with Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride too, on top of Kratom — 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 Kratom 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 Kratom
Top 25%

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

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

#495 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 Kratom

What is Kratom?

Kratom
  • Pain relief
  • Opioid withdrawal symptoms
  • Anxiety and stress
  • Low energy or fatigue
  • Mood enhancement

Kratom is a Southeast Asian plant whose leaves act on the brain's opioid receptors and can produce both stimulant-like and opioid-like effects. It is not approved or proven safe by health regulators, carries real risks of dependence and serious harm, and its legal status varies widely. Talk to a pharmacist or doctor before considering it.

Read the full Kratom monograph & all interactions
Keep checking

Other Drugs & Kratom

Browse every other medication we’ve checked against Kratom — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
983Moderate
12Minor
1,834No known interaction
983 Moderate 12 Minor 1,834 No interaction
Moderate

983 interactions

Showing 60 of 983 moderate interactions — see all 983 on the Kratom page.

Minor

12 interactions

No interaction 1,834 drugs checked — show the list

We also checked Kratom against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,834 medications checked with no known interaction — see the full Kratom list.

See the full Kratom 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
Kratom 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 Kratom and Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride Together: Common Questions

Can you take Kratom 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 3 interactions listed for Kratom and Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride?
Guaifenesin, Hydrocodone Bitartrate, Pseudoephedrine Hydrochloride belongs to more than one drug category, and Kratom 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 Kratom 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 Kratom?

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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.