Drug & supplement interaction

Milk Thistle + Tramadol, Acetaminophen

Tramadol, Acetaminophen brand name: Tramacet.

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

Tramadol, Acetaminophen falls into 2 drug categories that Milk Thistle can interact with; the most serious is rated moderate. Theoretically, milk thistle might affect the clearance of drugs that undergo glucuronidation.

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

Milk Thistle and Tramadol, Acetaminophen

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

Why Are There 2 Interactions?

Milk Thistle interacts with whole categories of medication. Tramadol, Acetaminophen falls into 2 of those categories, so it can interact with Milk Thistle in 2 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

GLUCURONIDATED DRUGS

1 of 2

Why this applies to Tramadol, Acetaminophen

Tramadol, Acetaminophen falls under GLUCURONIDATED DRUGS — the group Milk Thistle interacts with.

Theoretically, milk thistle might affect the clearance of drugs that undergo glucuronidation.
Laboratory research shows that milk thistle constituents inhibit uridine diphosphoglucuronosyl transferase (UGT), the major phase 2 enzyme that is responsible for glucuronidation. Theoretically, this could decrease the clearance and increase levels of glucuronidated drugs. Other laboratory research suggests that a milk thistle extract of silymarin might inhibit beta-glucuronidase, although the significance of this effect is unclear.
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 gist for Tramacet, which pairs tramadol with acetaminophen. Both of these get cleared in part through a liver process called glucuronidation. In test tube studies, milk thistle (silymarin) seems to slow down the enzymes that handle that step. The theory is that if those enzymes work slower, a little more of the drug could hang around in your body.

If that played out in real life, you might notice stronger tramadol effects like drowsiness, dizziness, nausea, or constipation, and theoretically less room for error with acetaminophen on your liver. But I want to be honest: this is only lab and animal data, not real people, so the actual risk is likely small. Still, since tramadol affects the brain, 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. Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000;28:1270-3. DOI
  2. Kim DH, Jin YH, Park JB, Kobashi K. Silymarin and its components are inhibitors of beta-glucuronidase. Biol Pharm Bull 1994;17:443-5. PubMed
  3. Sridar C, Goosen TC, Kent UM, et al. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 2004;32:587-94. PubMed
Minor

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

2 of 2

Tramadol, Acetaminophen also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

It is unclear if milk thistle inhibits CYP3A4; research is conflicting.
While laboratory research shows conflicting results, pharmacokinetic research shows that taking milk thistle extract 420-1350 mg daily does not significantly affect the metabolism of the CYP3A4 substrates irinotecan, midazolam, or indinavir. However, 8 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP3A4 substrates, including gefitinib, sorafenib, doxorubicin, and vincristine.
Severity Minor Likelihood Unlikely Evidence D

Interaction has been demonstrated in animal or in lab research but has been shown not to occur in humans..

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the honest picture with milk thistle and your Tramacet (tramadol plus acetaminophen): the worry is that milk thistle might slow down CYP3A4, one of the liver enzymes that helps break down tramadol. If that enzyme were blocked, a bit more tramadol could linger in your system, which in theory could nudge up effects like drowsiness, dizziness, nausea, or constipation.

That said, the actual evidence here is weak. It comes mostly from lab and animal studies, and human studies haven't shown milk thistle meaningfully changing how these CYP3A4 drugs are cleared. So for most people this is rated minor and unlikely. Still, since tramadol affects the brain, it's worth a quick word with your pharmacist or doctor before combining them, especially at concentrated supplement doses.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000;28:1270-3. DOI
  2. Piscitelli SC, Formentini E, Burstein AH, et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22:551-6. PubMed
  3. Sridar C, Goosen TC, Kent UM, et al. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 2004;32:587-94. PubMed
  4. van Erp NP, Baker SD, Zhao M, et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 2005;11:7800-6.
  5. Budzinski JW, Trudeau VL, Drouin CE, et al. Modulation of human cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell monolayers by selected commercial-source milk thistle and goldenseal products. Can J Physiol Pharmacol 2007;85:966-78.
  6. Doehmer J, Weiss G, McGregor GP, Appel K. Assessment of a dry extract from milk thistle (Silybum marianum) for interference with human liver cytochrome-P450 activities. Toxicol In Vitro 2011;25:21-7. PubMed
  7. Jalloh MA, Gregory PJ, Hein D, et al. Dietary supplement interactions with antiretrovirals: a systematic review. Int J STD AIDS. 2017 Jan;28(1):4-15. PubMed
  8. Kawaguchi-Suzuki M, Frye RF, Zhu HJ, et al. The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos. 2014;42(10):1611-6. PubMed
  9. Pochet S, Lechon AS, Lescrainier C, et al. Herb-anticancer drug interactions in real life based on VigiBase, the WHO global database. Sci Rep 2022;12(1):14178. 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

Milk Thistle Also Interacts With Other Medications

Milk Thistle has 253 moderate, 700 minor known drug interactions in our database — the Tramadol, Acetaminophen one above is among them. If you take anything else, check it against the full list below.

Moderate 253 Minor 700 No known interaction 1,877 (incl. Tramadol, Acetaminophen)
Taking anything else?

Check Another of Your Medications Against Milk Thistle

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

From our Q&A

Questions About Milk Thistle or Tramadol, Acetaminophen

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Milk Thistle or Tramadol, Acetaminophen, 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 Tramadol, Acetaminophen

This page covers Milk Thistle only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Tramadol, Acetaminophen page lists 280 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 Gamma-hydroxybutyrate (ghb) (major).

By severity: 12 major · 224 moderate · 44 minor.

From our pharmacist’s overview on the Tramadol, Acetaminophen page

“The combinations I worry about most with tramadol and acetaminophen (Tramacet) involve anything that deepens drowsiness or strains the liver. Tramadol is an opioid, so sedating supplements like kava, along with alcohol in any form, can slow breathing on top of adding sleepiness, which is why this list deserves genuine care rather than…”

Reviewed by 2 · Jul 18, 2026

Open the Tramadol, Acetaminophen interaction page

One more smart check

Taking Milk Thistle as Part of a Dietary Supplement Product? Check It for Interactions

We hold 4,560 real supplement products containing Milk Thistle, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Milk Thistle. Your product may carry other ingredients that interact with Tramadol, Acetaminophen too, on top of Milk Thistle — 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 Milk Thistle and Tramadol, Acetaminophen 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 Milk Thistle
Top 5%

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

29 days ago today
Medication Tramadol, Acetaminophen
Top half

#921 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 Milk Thistle

What is Milk Thistle?

Milk Thistle
  • Liver health and protection
  • Hepatitis
  • Cirrhosis
  • Gallbladder problems
  • High cholesterol
  • Type 2 diabetes support

Milk thistle is a popular herbal supplement most often used for liver health, and its main active component is a group of compounds called silymarin. While it is generally well tolerated, the scientific evidence that it meaningfully improves liver disease or other conditions is mixed and far from conclusive. Talk with your pharmacist or doctor before using it, especially if you have a liver condition or take other medicines.

Read the full Milk Thistle monograph & all interactions
Keep checking

Other Drugs & Milk Thistle

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

0Major
253Moderate
700Minor
1,876No known interaction
253 Moderate 700 Minor 1,876 No interaction
Moderate

253 interactions

Showing 60 of 253 moderate interactions — see all 253 on the Milk Thistle page.

Minor

700 interactions

Showing 60 of 700 minor interactions — see all 700 on the Milk Thistle page.

No interaction 1,876 drugs checked — show the list

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

Showing the 60 most looked-up of 1,876 medications checked with no known interaction — see the full Milk Thistle list.

See the full Milk Thistle interactions page
See every supplement checked against Tramadol, Acetaminophen, 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
Milk Thistle monograph › Uses, safety, and every drug interaction in one place Tramadol, Acetaminophen supplement interactions › Every supplement checked against Tramadol, Acetaminophen, 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 Milk Thistle and Tramadol, Acetaminophen Together: Common Questions

Can you take Milk Thistle with Tramadol, Acetaminophen?
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 2 interactions listed for Milk Thistle and Tramadol, Acetaminophen?
Tramadol, Acetaminophen belongs to more than one drug category, and Milk Thistle 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 Milk Thistle and Tramadol, Acetaminophen 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.