Drug & supplement interaction

Black Pepper + Aspirin, Butalbital, Caffeine, Codeine Phosphate

Aspirin, Butalbital, Caffeine, Codeine Phosphate brand name: Fiorinal w/ Codeine.

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

Aspirin, Butalbital, Caffeine, Codeine Phosphate falls into 4 drug categories that Black Pepper can interact with; the most serious is rated moderate. Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions4
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Black Pepper and Aspirin, Butalbital, Caffeine, Codeine Phosphate

These two interact in 4 distinct ways. Each one is explained separately below.

Why Are There 4 Interactions?

Black Pepper interacts with whole categories of medication. Aspirin, Butalbital, Caffeine, Codeine Phosphate falls into 4 of those categories, so it can interact with Black Pepper in 4 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

1 of 4

Why this applies to Aspirin, Butalbital, Caffeine, Codeine Phosphate

Aspirin, Butalbital, Caffeine, Codeine Phosphate falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES — the group Black Pepper interacts with.

Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.
In vitro research suggests that some constituents of black pepper inhibit CYP2D6. This 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

Here's the wrinkle with this combo: the codeine part of Fiorinal with Codeine is a prodrug. Your body has to convert codeine into morphine using a liver enzyme called CYP2D6 before it does much for pain. Lab studies hint that piperine, the active compound in black pepper, may slow that same enzyme down. If that happened, you might actually get less pain relief from the codeine, not more, because less of it turns into morphine.

The good news is this is theoretical, drawn from test-tube work and never shown in real people, so I wouldn't lose sleep over a peppery meal. Concentrated piperine supplements are a bigger question mark than food. If you take a piperine product regularly, just mention it to your pharmacist or doctor.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Subehan, Usia, T., Kadota, S., and Tezuka, Y. Mechanism-based inhibition of human liver microsomal cytochrome P450 2D6 (CYP2D6) by alkamides of Piper nigrum. Planta Med 2006;72(6):527-532.
  2. Usia, T., Iwata, H., Hiratsuka, A., Watabe, T., Kadota, S., and Tezuka, Y. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants. Phytomedicine. 2006;13(1-2):67-73. PubMed
  3. Subehan, Usia, T., Iwata, H., Kadota, S., and Tezuka, Y. Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants. J Ethnopharmacol. 5-24-2006;105(3):449-455. PubMed
Moderate

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

2 of 4

Aspirin, Butalbital, Caffeine, Codeine Phosphate also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

Theoretically, black pepper might increase levels of drugs metabolized by CYP3A4.
In vitro research and pharmacokinetic simulation data suggest that piperine, a constituent of black pepper, as well as the pepper fruit seem to inhibit CYP3A4. This 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 (Fiorinal with Codeine) has a few moving parts, but the piece that matters most here is butalbital, a barbiturate that the liver clears partly through the CYP3A4 enzyme. In lab and computer studies, piperine from black pepper appears to slow CYP3A4 down. If that happened in real life, butalbital could linger a bit longer, which might add to drowsiness, dizziness, or feeling foggy. The codeine side is more complicated, since codeine needs an enzyme (CYP2D6) to turn into its active form.

Here's the reassuring part: this is only a theoretical concern from test-tube research, not something reported in people, and the pinch of pepper on your food is very unlikely to matter. Concentrated piperine supplements are a different story. Since this medicine is already sedating, it's worth a quick chat with your pharmacist before adding any pepper-based supplement.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Bhardwaj RK, Glaeser H, Becquemont L, et al. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002;302:645-50. PubMed
  2. Usia, T., Iwata, H., Hiratsuka, A., Watabe, T., Kadota, S., and Tezuka, Y. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants. Phytomedicine. 2006;13(1-2):67-73. PubMed
  3. Lin F, Hu Y, Zhang Y, Zhao L, Zhong D, Liu J. Predicting Food-Drug Interactions between Piperine and CYP3A4 Substrate Drugs Using PBPK Modeling. Int J Mol Sci 2024;25(20):10955. PubMed
Moderate

ANTICOAGULANT/ANTIPLATELET DRUGS

3 of 4

Aspirin, Butalbital, Caffeine, Codeine Phosphate also falls under ANTICOAGULANT/ANTIPLATELET DRUGS.

Theoretically, black pepper might increase the risk of bleeding when taken with antiplatelet or anticoagulant drugs.
In vitro research shows that piperine, a constituent of black pepper, seems to inhibit platelet aggregation. This 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

Here's the simple version for Fiorinal with Codeine. This combo pill already contains aspirin, which thins the blood and makes platelets less sticky. Lab studies suggest piperine, the active part of black pepper, may also nudge platelets in that same direction. Stacked together, the theory is that your blood could become a touch slower to clot.

What that might look like in real life: easier bruising, nosebleeds, bleeding gums, or a small cut taking longer to stop. I'll be honest though, this is only seen in test-tube research and hasn't actually shown up in people, so it's a theoretical concern. A pinch of pepper on dinner is not the issue. Concentrated piperine supplements are where I'd pause and check with your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Raghavendra, R. H. and Naidu, K. A. Spice active principles as the inhibitors of human platelet aggregation and thromboxane biosynthesis. Prostaglandins Leukot.Essent.Fatty Acids 2009;81(1):73-78. PubMed
Minor

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

4 of 4

Aspirin, Butalbital, Caffeine, Codeine Phosphate also falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES.

Theoretically, black pepper might decrease levels and clinical effects of drugs metabolized by CYP1A2.
In vitro research suggests that black pepper induces CYP1A2. This has not been reported in humans.
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 that actually applies to your Fiorinal with Codeine: this combo contains caffeine, and caffeine is handled by a liver enzyme called CYP1A2. In lab (test tube) studies, black pepper's piperine seemed to speed that enzyme up a bit. If that happened in real life, your body might clear the caffeine a little faster, so you could get slightly less of its perk-up effect. Honestly, this is a minor, theoretical concern and has never been shown in actual people.

The aspirin, butalbital, and codeine parts aren't really driven by this enzyme, so I wouldn't expect a meaningful change there. Kitchen amounts of pepper are nothing to worry about. If you take concentrated piperine supplements, just mention it to your pharmacist or doctor.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Haron MH, Dale O, Martin K, et al. Evaluation of the Herb-Drug Interaction Potential of Commonly Used Botanicals on the US Market with Regard to PXR- and AhR-Mediated Influences on CYP3A4 and CYP1A2. J Diet Suppl 2022. 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

Black Pepper Also Interacts With Other Medications

Black Pepper has 975 moderate, 43 minor known drug interactions in our database — the Aspirin, Butalbital, Caffeine, Codeine Phosphate one above is among them. If you take anything else, check it against the full list below.

Moderate 975 Minor 43 No known interaction 1,812 (incl. Aspirin, Butalbital, Caffeine, Codeine Phosphate)
Taking anything else?

Check Another of Your Medications Against Black Pepper

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

From our Q&A

Questions About Black Pepper or Aspirin, Butalbital, Caffeine, Codeine Phosphate

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Black Pepper or Aspirin, Butalbital, Caffeine, Codeine Phosphate, 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, Butalbital, Caffeine, Codeine Phosphate

This page covers Black Pepper only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Aspirin, Butalbital, Caffeine, Codeine Phosphate page lists 398 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 · 334 moderate · 47 minor.

From our pharmacist’s overview on the Aspirin, Butalbital, Caffeine, Codeine Phosphate page

“Fiorinal with Codeine packs four active drugs into one capsule, and I would treat its supplement list with genuine wariness rather than a quick skim. The aspirin component is why roughly half of the 398 ingredients on file raise bleeding risk, while the codeine and butalbital explain a second large cluster that deepens sedation, someti…”

Reviewed by 2 · Jul 18, 2026

Open the Aspirin, Butalbital, Caffeine, Codeine Phosphate interaction page

One more smart check

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

We hold 5,528 real supplement products containing Black Pepper, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Black Pepper. Your product may carry other ingredients that interact with Aspirin, Butalbital, Caffeine, Codeine Phosphate too, on top of Black Pepper — 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 Black Pepper and Aspirin, Butalbital, Caffeine, Codeine Phosphate 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 Black Pepper
Top 5%

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

29 days ago today
Medication Aspirin, Butalbital, Caffeine, Codeine Phosphate
Steady interest

#1,766 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 Black Pepper

What is Black Pepper?

Black Pepper
  • Flavoring and culinary use
  • Digestive complaints like bloating and indigestion
  • Boosting absorption of other supplements
  • Antioxidant and anti-inflammatory support
  • Cold and congestion remedies

Black pepper is a common kitchen spice that is generally safe in the amounts used in food. Its extract, piperine, is mostly added to supplements to help the body absorb other ingredients (like curcumin from turmeric). Strong human evidence for black pepper treating specific health conditions is limited, so use supplement-strength products with care and check with your pharmacist.

Read the full Black Pepper monograph & all interactions
Keep checking

Other Drugs & Black Pepper

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

0Major
975Moderate
43Minor
1,811No known interaction
975 Moderate 43 Minor 1,811 No interaction
Moderate

975 interactions

Showing 60 of 975 moderate interactions — see all 975 on the Black Pepper page.

Minor

43 interactions

No interaction 1,811 drugs checked — show the list

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

Showing the 60 most looked-up of 1,811 medications checked with no known interaction — see the full Black Pepper list.

See the full Black Pepper interactions page
See every supplement checked against Aspirin, Butalbital, Caffeine, Codeine Phosphate, 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
Black Pepper monograph › Uses, safety, and every drug interaction in one place Aspirin, Butalbital, Caffeine, Codeine Phosphate supplement interactions › Every supplement checked against Aspirin, Butalbital, Caffeine, Codeine Phosphate, 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 Black Pepper and Aspirin, Butalbital, Caffeine, Codeine Phosphate Together: Common Questions

Can you take Black Pepper with Aspirin, Butalbital, Caffeine, Codeine Phosphate?
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 Black Pepper and Aspirin, Butalbital, Caffeine, Codeine Phosphate?
Aspirin, Butalbital, Caffeine, Codeine Phosphate belongs to more than one drug category, and Black Pepper 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 Black Pepper and Aspirin, Butalbital, Caffeine, Codeine Phosphate 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.