Drug & supplement interaction

Grape + Aspirin, Caffeine, Phenacetin, Propoxyphene

Aspirin, Caffeine, Phenacetin, Propoxyphene brand name: Margesic Comp. 65.

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

Aspirin, Caffeine, Phenacetin, Propoxyphene falls into 5 drug categories that Grape can interact with; the most serious is rated moderate. Theoretically, grape juice might reduce the levels of CYP1A2 substrates.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions5
EvidenceB
What do Severity, Likelihood & Evidence mean?
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Interaction report

Grape and Aspirin, Caffeine, Phenacetin, Propoxyphene

These two interact in 5 distinct ways. Each one is explained separately below.

Why Are There 5 Interactions?

Grape interacts with whole categories of medication. Aspirin, Caffeine, Phenacetin, Propoxyphene falls into 5 of those categories, so it can interact with Grape in 5 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

1 of 5

Why this applies to Aspirin, Caffeine, Phenacetin, Propoxyphene

Aspirin, Caffeine, Phenacetin, Propoxyphene falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES — the group Grape interacts with.

Theoretically, grape juice might reduce the levels of CYP1A2 substrates.
A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of CYP1A2.
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 pill includes phenacetin and caffeine, both of which your body partly clears using a liver enzyme called CYP1A2. In one small study, drinking about 200 mL of grape juice seemed to speed that enzyme up, which lowered phenacetin levels in the blood. If the same thing happens here, these ingredients could be cleared a little faster and feel slightly less effective.

Honestly, this is fairly minor and the evidence is thin. A glass of grape juice or eating grapes is very unlikely to cause a problem, though concentrated grape seed extract supplements are less studied. If you take this medication regularly, it never hurts to run a new grape supplement past your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Xiao Dong S, Zhi Ping Z, Zhong Xiao W, et al. Possible enhancement of the first-pass metabolism of phenacetin by ingestion of grape juice in Chinese subjects. Br J Clin Pharmacol 1999;48:638-40. PubMed
Moderate

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

2 of 5

Aspirin, Caffeine, Phenacetin, Propoxyphene also falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES.

Theoretically, grape seed extract may increase the levels of CYP2D6 substrates.
In vitro evidence suggests that grape seed extract might inhibit CYP2D6 enzymes. However, this interaction has not been reported in humans.
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

This combination product mixes aspirin, caffeine, phenacetin, and propoxyphene. The piece that matters here is propoxyphene, an opioid pain reliever that the liver processes partly through an enzyme called CYP2D6. In a test tube, grape seed extract has slowed that same enzyme down. If that happened in your body, propoxyphene could build up a bit, which in theory might mean more drowsiness, dizziness, nausea, constipation, or slowed breathing.

I want to be honest about the strength of this: it's only lab evidence, and it has never actually been reported in real people. Eating grapes is very unlikely to do anything. A concentrated grape seed supplement is the only real question mark. Before adding one, just run it by your pharmacist or doctor so they can check the whole product.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Nishikawa, M., Ariyoshi, N., Kotani, A., Ishii, I., Nakamura, H., Nakasa, H., Ida, M., Nakamura, H., Kimura, N., Kimura, M., Hasegawa, A., Kusu, F., Ohmori, S., Nakazawa, K., and Kitada, M. Effects of continuous ingestion of green tea or grape seed extra
Moderate

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

3 of 5

Aspirin, Caffeine, Phenacetin, Propoxyphene also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

It is unclear if grape seed extract inhibits or induces CYP3A4; research is conflicting.
In vitro evidence suggests that grape seed extract might inhibit CYP3A4 enzymes. However, evidence from animal research shows that grape seed extract may induce CYP3A4 in the liver. So far, these interactions have not been reported in humans.
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

This combo pill mixes aspirin, caffeine, phenacetin, and propoxyphene (an older opioid pain reliever). The concern on file is that grape seed extract might affect a liver enzyme called CYP3A4, which helps process propoxyphene. Here's the honest truth though: the research is genuinely mixed. Lab (test tube) studies hint it could slow that enzyme, while animal studies suggest it could speed it up. We really don't know the direction, and nothing like this has shown up in actual people.

So I wouldn't lose sleep over it, especially since eating grapes won't matter. Concentrated grape seed supplements are the real question mark. Because propoxyphene is a sedating opioid, just check with your pharmacist before adding one.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Nishikawa, M., Ariyoshi, N., Kotani, A., Ishii, I., Nakamura, H., Nakasa, H., Ida, M., Nakamura, H., Kimura, N., Kimura, M., Hasegawa, A., Kusu, F., Ohmori, S., Nakazawa, K., and Kitada, M. Effects of continuous ingestion of green tea or grape seed extra
  2. Etheridge, A. S., Black, S. R., Patel, P. R., So, J., and Mathews, J. M. An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constitu
Moderate

ANTICOAGULANT/ANTIPLATELET DRUGS

4 of 5

Aspirin, Caffeine, Phenacetin, Propoxyphene also falls under ANTICOAGULANT/ANTIPLATELET DRUGS.

Theoretically, grape extracts may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
In vitro evidence suggests that grape extracts might decrease platelet aggregation.
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

This combination product contains aspirin, which already thins the blood a bit by making your platelets less sticky. Grape supplements (think concentrated grape seed extract, not a handful of grapes) may do something similar in lab studies. Put the two together and you could, in theory, nudge your bleeding risk up a little higher than aspirin alone.

Now, I want to be honest with you: this concern comes only from test-tube research, so it's more of a caution than a proven problem. Still, keep an eye out for things like easy bruising, nosebleeds, bleeding gums, or a cut that takes longer to stop. Eating grapes as food isn't the issue here. If you're thinking about a grape supplement, just run it by your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. de Lange, D. W., Scholman, W. L., Kraaijenhagen, R. J., Akkerman, J. W., and van de Wiel, A. Alcohol and polyphenolic grape extract inhibit platelet adhesion in flowing blood. Eur.J Clin.Invest 2004;34(12):818-824. PubMed
  2. de Lange, D. W., Verhoef, S., Gorter, G., Kraaijenhagen, R. J., van de Wiel, A., and Akkerman, J. W. Polyphenolic grape extract inhibits platelet activation through PECAM-1: an explanation for the French paradox. Alcohol Clin.Exp.Res 2007;31(8):1308-1314 PubMed
Moderate

PHENACETIN

5 of 5

Aspirin, Caffeine, Phenacetin, Propoxyphene also falls under PHENACETIN.

Grape juice might decrease phenacetin absorption.
A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of cytochrome P450 1A2 (CYP1A2).
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 pill contains phenacetin, an old pain reliever. The interaction we have on file involves grape juice and that phenacetin component specifically. In a small study, drinking about a cup of grape juice lowered phenacetin blood levels, likely because grape juice can speed up a liver enzyme (CYP1A2) that breaks it down. In plain terms, grape might clear the phenacetin out a little faster, so you could get less pain relief from it than expected.

Honestly, this is fairly minor and the evidence is limited and low quality. Everyday grapes or a glass of juice are unlikely to cause real trouble. Still, if you rely on this medicine for pain, mention any grape supplements to your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Xiao Dong S, Zhi Ping Z, Zhong Xiao W, et al. Possible enhancement of the first-pass metabolism of phenacetin by ingestion of grape juice in Chinese subjects. Br J Clin Pharmacol 1999;48:638-40. 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

Grape Also Interacts With Other Medications

Grape has 867 moderate, 42 minor known drug interactions in our database — the Aspirin, Caffeine, Phenacetin, Propoxyphene one above is among them. If you take anything else, check it against the full list below.

Moderate 867 Minor 42 No known interaction 1,921 (incl. Aspirin, Caffeine, Phenacetin, Propoxyphene)
Taking anything else?

Check Another of Your Medications Against Grape

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

From our Q&A

Questions About Grape or Aspirin, Caffeine, Phenacetin, Propoxyphene

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Grape or Aspirin, Caffeine, Phenacetin, Propoxyphene, 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, Phenacetin, Propoxyphene

This page covers Grape only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Aspirin, Caffeine, Phenacetin, Propoxyphene page lists 414 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 · 350 moderate · 47 minor.

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

“Margesic Comp. 65 packs four drugs into one tablet, aspirin, caffeine, phenacetin, and the sedating opioid propoxyphene, which is why 414 supplement ingredients appear on this page and why I would slow down before adding any of them.”

Reviewed by 2 · Jul 18, 2026

Open the Aspirin, Caffeine, Phenacetin, Propoxyphene interaction page

One more smart check

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

We hold 8,053 real supplement products containing Grape, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Grape. Your product may carry other ingredients that interact with Aspirin, Caffeine, Phenacetin, Propoxyphene too, on top of Grape — 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 Grape and Aspirin, Caffeine, Phenacetin, Propoxyphene 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 Grape
Top 5%

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

29 days ago today
Medication Aspirin, Caffeine, Phenacetin, Propoxyphene
Top half

#1,114 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 Grape

What is Grape?

Grape
  • Antioxidant support
  • Heart and circulation health
  • Vein problems (such as varicose veins)
  • Eye health
  • General anti-inflammatory support

Grapes and grape products like grape seed extract contain antioxidant compounds such as resveratrol and proanthocyanidins that may support heart and blood vessel health. While the food is healthy and generally safe, the supplement evidence for treating specific conditions is mostly limited or preliminary. Talk with your pharmacist or doctor before starting a grape supplement.

Read the full Grape monograph & all interactions
Keep checking

Other Drugs & Grape

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

0Major
867Moderate
42Minor
1,920No known interaction
867 Moderate 42 Minor 1,920 No interaction
Moderate

867 interactions

Showing 60 of 867 moderate interactions — see all 867 on the Grape page.

Minor

42 interactions

No interaction 1,920 drugs checked — show the list

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

Showing the 60 most looked-up of 1,920 medications checked with no known interaction — see the full Grape list.

See the full Grape interactions page
See every supplement checked against Aspirin, Caffeine, Phenacetin, Propoxyphene, 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
Grape monograph › Uses, safety, and every drug interaction in one place Aspirin, Caffeine, Phenacetin, Propoxyphene supplement interactions › Every supplement checked against Aspirin, Caffeine, Phenacetin, Propoxyphene, 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 Grape and Aspirin, Caffeine, Phenacetin, Propoxyphene Together: Common Questions

Can you take Grape with Aspirin, Caffeine, Phenacetin, Propoxyphene?
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 5 interactions listed for Grape and Aspirin, Caffeine, Phenacetin, Propoxyphene?
Aspirin, Caffeine, Phenacetin, Propoxyphene belongs to more than one drug category, and Grape 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 Grape and Aspirin, Caffeine, Phenacetin, Propoxyphene 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 Aspirin, Caffeine, Phenacetin, Propoxyphene and Grape?

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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.