Drug & supplement interaction

Bitter Orange + Acetaminophen, Butalbital, Caffeine, Codeine

Acetaminophen, Butalbital, Caffeine, Codeine brand names: Esgic with Codeine, Fioricet w/ Codeine.

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

Acetaminophen, Butalbital, Caffeine, Codeine falls into 4 drug categories that Bitter Orange can interact with; the most serious is rated moderate. Bitter orange might increase levels of drugs metabolized by CYP3A4.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions4
EvidenceB
What do Severity, Likelihood & Evidence mean?
Know someone taking this? Share
Facebook Post Reddit Email
On this page
Interaction report

Bitter Orange and Acetaminophen, Butalbital, Caffeine, Codeine

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

Why Are There 4 Interactions?

Bitter Orange interacts with whole categories of medication. Acetaminophen, Butalbital, Caffeine, Codeine falls into 4 of those categories, so it can interact with Bitter Orange 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 3A4 (CYP3A4) SUBSTRATES

1 of 4

Why this applies to Acetaminophen, Butalbital, Caffeine, Codeine

Acetaminophen, Butalbital, Caffeine, Codeine falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES — the group Bitter Orange interacts with.

Bitter orange might increase levels of drugs metabolized by CYP3A4.
Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear. One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4.
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 thing with this combo pill (acetaminophen, butalbital, caffeine, and codeine): bitter orange can mildly block an enzyme in your gut called CYP3A4. That same enzyme helps process butalbital (the barbiturate part) and codeine. If less of the drug gets broken down early, slightly more can reach your bloodstream, which could nudge up the drowsy, dizzy, foggy, or slowed-breathing effects you'd expect from these sedating ingredients.

This is only possible, based on lower-quality studies, and culinary amounts likely matter little compared to concentrated supplements. One extra note: bitter orange is a stimulant, and this pill already has caffeine, so you may feel jittery or have a faster heartbeat. Please run this past your pharmacist or doctor before mixing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69:14-23. PubMed
  2. Penzak SR, Acosta EP, Turner M, et al. Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics. J Clin Pharmacol 2002;42:1165-70. PubMed
  3. Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999;65:237-44. PubMed
  4. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci 2002;71:1149-60. PubMed
  5. Abdelkawy KS, Donia AM, Turner RB, Elbarbry F. Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects. Drugs R D. 2016 Sep;16(3):271-278. PubMed
Moderate

STIMULANT DRUGS

2 of 4

Acetaminophen, Butalbital, Caffeine, Codeine also falls under STIMULANT DRUGS.

Theoretically, bitter orange might increase the risk of hypertension and adverse cardiovascular effects when taken with stimulant drugs.
Bitter orange appears to have stimulant effects.
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 thing to keep an eye on with this combo. Your Fioricet with Codeine product already contains caffeine, which is a stimulant. Bitter orange brings its own stimulant, synephrine, to the party. Stack the two together and you can nudge your heart rate up and raise your blood pressure more than either would alone. You might notice a racing or pounding heart, jitteriness, anxiety, or feeling wired.

This concern is mostly theoretical and rated moderate, so it's not a guaranteed problem, but it matters more if you have high blood pressure or any heart condition. Concentrated bitter orange supplements are the worry here, not a splash of orange in food. Please check with your pharmacist or doctor before pairing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Penzak SR, Jann MW, Cold JA, et al. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol 2001;41:1059-63. PubMed
  2. Keogh AM, Baron DW. Sympathomimetic abuse and coronary artery spasm. Br Med J 1985;291:940.
Moderate

CAFFEINE

3 of 4

Acetaminophen, Butalbital, Caffeine, Codeine also falls under CAFFEINE.

Bitter orange might increase blood pressure and heart rate when taken with caffeine.
Small clinical studies show that taking bitter orange in combination with caffeine can increase blood pressure and heart rate in otherwise healthy normotensive adults. Theoretically, this might increase the risk of serious cardiovascular adverse effects.
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 piece to pay attention to with this combo pill: one of its four ingredients is caffeine. Bitter orange supplements contain synephrine, a mild stimulant, and when you pair that with caffeine, small studies have shown a modest bump in blood pressure and heart rate in otherwise healthy people. So you'd essentially be stacking a stimulant on top of the caffeine that's already built into your medication.

In real life that could mean feeling jittery, a racing or pounding heartbeat, or higher blood pressure. The evidence here is limited and the effect is usually moderate, but if you have heart issues or high blood pressure it's worth being cautious. Before combining them, please check with your pharmacist or doctor rather than adjusting anything on your own.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Haller CA, Benowitz NL, Jacob P 3rd. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med 2005;118:998-1003.. PubMed
  2. Ratamess NA, Bush JA, Stohs SJ, et al. Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study. Phytother Res. 2018;32(1):94-102.
Minor

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

4 of 4

Acetaminophen, Butalbital, Caffeine, Codeine also falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES.

Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.
In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes. This effect 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 wrinkle with this particular combo product: the codeine part is a prodrug. Your body has to use an enzyme called CYP2D6 to turn codeine into morphine, which is what actually relieves pain. Bitter orange may very weakly block that same enzyme. If it did, your body would make less morphine, so you might get less pain relief from the codeine, not more.

Now the reassuring part. This is only a theory based on lab dish studies, never shown in real people, and it's rated a minor interaction. Bitter orange also raises heart rate and blood pressure, and this medicine already has caffeine, so the bigger concern is feeling jittery or wired. Check with your pharmacist or doctor before pairing them, especially if you have heart issues.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Liu Y, Santillo MF. Cytochrome P450 2D6 and 3A4 enzyme inhibition by amine stimulants in dietary supplements. Drug Test Anal. 2016;8(3-4):307-10. 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

Bitter Orange Also Interacts With Other Medications

Bitter Orange has 10 major, 875 moderate, 71 minor known drug interactions in our database — the Acetaminophen, Butalbital, Caffeine, Codeine one above is among them. If you take anything else, check it against the full list below.

Major 10 Moderate 875 Minor 71 No known interaction 1,874 (incl. Acetaminophen, Butalbital, Caffeine, Codeine)
Taking anything else?

Check Another of Your Medications Against Bitter Orange

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

Everything else you take

See Every Supplement That Interacts With Acetaminophen, Butalbital, Caffeine, Codeine

This page covers Bitter Orange only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Acetaminophen, Butalbital, Caffeine, Codeine page lists 305 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 Ephedra (major).

By severity: 15 major · 245 moderate · 45 minor.

Open the Acetaminophen, Butalbital, Caffeine, Codeine interaction page

One more smart check

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

We hold 1,000 real supplement products containing Bitter Orange, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Bitter Orange. Your product may carry other ingredients that interact with Acetaminophen, Butalbital, Caffeine, Codeine too, on top of Bitter Orange — 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 Bitter Orange and Acetaminophen, Butalbital, Caffeine, Codeine 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 Bitter Orange
Top 25%

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

29 days ago today
Medication Acetaminophen, Butalbital, Caffeine, Codeine
Top half

#923 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 Bitter Orange

What is Bitter Orange?

Bitter Orange
  • Weight loss
  • Athletic performance and energy
  • Digestive upset
  • Appetite control
  • Aromatherapy for stress (neroli oil)

Bitter orange is a citrus fruit whose extracts contain synephrine, a mild stimulant often added to weight-loss and energy supplements. Evidence that it works for weight loss or performance is limited, and because it can raise heart rate and blood pressure, people with heart problems, high blood pressure, or who are pregnant should avoid it. Talk to your pharmacist or doctor before using it, especially if you take other stimulants.

Read the full Bitter Orange monograph & all interactions
Keep checking

Other Drugs & Bitter Orange

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

10Major
875Moderate
71Minor
1,873No known interaction
10 Major 875 Moderate 71 Minor 1,873 No interaction
Major

10 interactions

Moderate

875 interactions

Showing 60 of 875 moderate interactions — see all 875 on the Bitter Orange page.

Minor

71 interactions

Showing 60 of 71 minor interactions — see all 71 on the Bitter Orange page.

No interaction 1,873 drugs checked — show the list

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

Showing the 60 most looked-up of 1,873 medications checked with no known interaction — see the full Bitter Orange list.

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

Can you take Bitter Orange with Acetaminophen, Butalbital, Caffeine, Codeine?
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 Bitter Orange and Acetaminophen, Butalbital, Caffeine, Codeine?
Acetaminophen, Butalbital, Caffeine, Codeine belongs to more than one drug category, and Bitter Orange 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 Bitter Orange and Acetaminophen, Butalbital, Caffeine, Codeine 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 Acetaminophen, Butalbital, Caffeine, Codeine and Bitter Orange?

Our pharmacists answer your medication & supplement questions — free.

Ask a pharmacist

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.