Drug & supplement interaction

Grapefruit + Phenobarbital, Phenytoin

Phenobarbital, Phenytoin brand name: Dilantin with PB.

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

Phenobarbital, Phenytoin falls into 2 drug categories that Grapefruit can interact with; the most serious is rated moderate. Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.

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

Grapefruit and Phenobarbital, Phenytoin

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

Why Are There 2 Interactions?

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

Moderate

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES

1 of 2

Why this applies to Phenobarbital, Phenytoin

Phenobarbital, Phenytoin falls under CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES — the group Grapefruit interacts with.

Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.
In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes. Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19.
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

Here's the basic idea: grapefruit can block an enzyme in your body called CYP2C19, which helps clear certain medicines. Phenytoin is partly handled by that pathway, so in theory grapefruit could slow its breakdown and let levels creep up. Since phenytoin is a narrow-therapeutic-index drug, even small shifts can matter. Higher levels might bring on side effects like dizziness, unsteady walking, slurred speech, double vision, or drowsiness.

That said, this is mostly theoretical and based on lab work, not strong human studies with phenytoin itself. An occasional grapefruit probably isn't a big deal, but regular grapefruit or grapefruit juice is worth a quick chat with your pharmacist or doctor before you make it a habit.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom 2004;1 PubMed
  2. Holmberg MT, Tornio A, Neuvonen M, Neuvonen PJ, Backman JT, Niemi M. Grapefruit juice inhibits the metabolic activation of clopidogrel. Clin Pharmacol Ther. 2014 Mar;95(3):307-13. PubMed
Moderate

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES

2 of 2

Phenobarbital, Phenytoin also falls under CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES.

Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.
In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes. So far, 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

Here's the gist with this combo. Your body uses a liver enzyme called CYP2C9 to help clear phenytoin out of your system. In lab and test-tube studies, grapefruit seems to slow that enzyme down. If that happened in a real person, phenytoin could build up a bit higher than expected. Since phenytoin has a narrow safety window, even small shifts can matter, possibly leading to dizziness, unsteady walking, slurred speech, double vision, or drowsiness.

That said, I want to be honest about the evidence. This effect has only been seen in the lab, not actually reported in people taking phenytoin. So it's more of a theoretical concern than a proven problem. Still, since phenytoin is so dose-sensitive, it's worth mentioning your grapefruit habit to your pharmacist or doctor so they can keep an eye on your levels.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom 2004;1 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

Grapefruit Also Interacts With Other Medications

Grapefruit has 776 major, 150 moderate, 63 minor known drug interactions in our database — the Phenobarbital, Phenytoin one above is among them. If you take anything else, check it against the full list below.

Major 776 Moderate 150 Minor 63 No known interaction 1,841 (incl. Phenobarbital, Phenytoin)
Taking anything else?

Check Another of Your Medications Against Grapefruit

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

From our Q&A

Questions About Grapefruit or Phenobarbital, Phenytoin

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Grapefruit or Phenobarbital, Phenytoin, 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 Phenobarbital, Phenytoin

This page covers Grapefruit only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Phenobarbital, Phenytoin page lists 229 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), Gamma-hydroxybutyrate (ghb) (major) and Kava (major).

By severity: 9 major · 192 moderate · 28 minor.

From our pharmacist’s overview on the Phenobarbital, Phenytoin page

“If your seizure medicine is the phenobarbital and phenytoin combination (Dilantin with PB), read this list carefully before you add any supplement. Nine of the 229 entries rate major, and most of the risk runs through two channels.”

Reviewed by 2 · Jul 18, 2026

Open the Phenobarbital, Phenytoin interaction page

One more smart check

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

We hold 1,144 real supplement products containing Grapefruit, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Grapefruit. Your product may carry other ingredients that interact with Phenobarbital, Phenytoin too, on top of Grapefruit — 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 Grapefruit and Phenobarbital, Phenytoin 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 Grapefruit
Top 10%

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

29 days ago today
Medication Phenobarbital, Phenytoin
Steady interest

#2,102 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 Grapefruit

What is Grapefruit?

Grapefruit
  • Source of vitamin C
  • Digestive complaints
  • Antimicrobial (seed extract)
  • Weight management
  • Skin and cosmetic uses

Grapefruit is a nutritious citrus fruit rich in vitamin C and other nutrients, and it is generally safe to eat. However, grapefruit is famous for serious interactions with many prescription medicines, so anyone taking medication should check with a pharmacist or doctor before consuming it regularly.

Read the full Grapefruit monograph & all interactions
Keep checking

Other Drugs & Grapefruit

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

776Major
150Moderate
63Minor
1,840No known interaction
776 Major 150 Moderate 63 Minor 1,840 No interaction
Major

776 interactions

Showing 60 of 776 major interactions — see all 776 on the Grapefruit page.

Moderate

150 interactions

Showing 60 of 150 moderate interactions — see all 150 on the Grapefruit page.

Minor

63 interactions

Showing 60 of 63 minor interactions — see all 63 on the Grapefruit page.

No interaction 1,840 drugs checked — show the list

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

Showing the 60 most looked-up of 1,840 medications checked with no known interaction — see the full Grapefruit list.

See the full Grapefruit interactions page
See every supplement checked against Phenobarbital, Phenytoin, 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
Grapefruit monograph › Uses, safety, and every drug interaction in one place Phenobarbital, Phenytoin supplement interactions › Every supplement checked against Phenobarbital, Phenytoin, 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 Grapefruit and Phenobarbital, Phenytoin Together: Common Questions

Can you take Grapefruit with Phenobarbital, Phenytoin?
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 Grapefruit and Phenobarbital, Phenytoin?
Phenobarbital, Phenytoin belongs to more than one drug category, and Grapefruit 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 Grapefruit and Phenobarbital, Phenytoin 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 Phenobarbital, Phenytoin and Grapefruit?

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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.