Drug & supplement interaction

Bitter Orange + Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine

Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine brand name: Colrex.

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

Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine falls into 3 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
Interactions3
EvidenceB
What do Severity, Likelihood & Evidence mean?
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Interaction report

Bitter Orange and Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Bitter Orange interacts with whole categories of medication. Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine falls into 3 of those categories, so it can interact with Bitter Orange in 3 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 3

Why this applies to Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine

Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine 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

This Colrex combo has a few moving parts, but the one that matters here is codeine. Codeine is a prodrug, meaning your body has to convert it into morphine before it does much. A big part of that handling involves the CYP3A4 enzyme, and bitter orange may mildly slow that enzyme down in your gut. In theory, that could shift how much codeine sticks around, which can nudge up side effects like drowsiness, dizziness, constipation, or feeling foggy.

Honestly, the evidence here is on the weaker side and mostly involves fresh-squeezed bitter orange juice, not the concentrated synephrine in weight-loss pills. I'd still flag those supplements, since their stimulant effect can rub against the codeine and the decongestant phenylephrine. Please run it by your pharmacist or doctor first.

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 3

Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine 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 piece I'd zero in on: your Colrex combo contains phenylephrine, which is itself a stimulant-type decongestant that tightens blood vessels to clear a stuffy nose. Bitter orange brings its own stimulant, synephrine, to the party. Stacking the two can add up, and the worry is a bump in blood pressure and heart rate, sometimes with jitteriness, a racing or pounding heartbeat, or headache.

This is rated as a theoretical, moderate concern, so it's not a guarantee, but it's a reasonable caution, especially if you have high blood pressure or any heart issues. If you're considering a weight-loss or energy product with bitter orange while taking Colrex, please run it by your pharmacist or doctor first.

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.
Minor

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

3 of 3

Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine 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

This combination cold and pain product (Colrex) contains codeine, which is a prodrug. Your liver uses an enzyme called CYP2D6 to turn codeine into morphine, the part that actually relieves pain and suppresses cough. Bitter orange contains a compound (octopamine) that may weakly block CYP2D6. In theory, blocking that enzyme could mean less codeine gets converted, so you might get less pain and cough relief from this medicine.

Here's the reassuring part: this is based only on lab (test-tube) research and has never been shown to happen in real people, so I wouldn't lose sleep over it. Still, bitter orange is a stimulant that can raise heart rate and blood pressure, and the phenylephrine here does the same. That's the bigger reason to check with your pharmacist before pairing them.

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, Chlorpheniramine, Codeine, Phenylephrine 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, Chlorpheniramine, Codeine, Phenylephrine)
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, Chlorpheniramine, Codeine, Phenylephrine

This page covers Bitter Orange only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine page lists 338 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: 18 major · 275 moderate · 45 minor.

From our pharmacist’s overview on the Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine page

“Someone taking Colrex is usually fighting a miserable cold, and cold season is also when people reach for herbal sleep aids and energy boosters, which is exactly where this list bites hardest. Colrex combines acetaminophen, chlorpheniramine, codeine, and phenylephrine, and 18 of its 338 supplement interactions rate major, enough to war…”

Reviewed by 2 · Jul 18, 2026

Open the Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine 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, Chlorpheniramine, Codeine, Phenylephrine 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, Chlorpheniramine, Codeine, Phenylephrine 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%

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

29 days ago today
Medication Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine
Top 10%

#279 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, Chlorpheniramine, Codeine, Phenylephrine, 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, Chlorpheniramine, Codeine, Phenylephrine supplement interactions › Every supplement checked against Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine, 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, Chlorpheniramine, Codeine, Phenylephrine Together: Common Questions

Can you take Bitter Orange with Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine?
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 3 interactions listed for Bitter Orange and Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine?
Acetaminophen, Chlorpheniramine, Codeine, Phenylephrine 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, Chlorpheniramine, Codeine, Phenylephrine 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.