Drug & supplement interaction

Sweet Orange + Methotrexate Sodium

Methotrexate Sodium brand name: Xatmep.

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

Sweet Orange has a major interaction with Methotrexate Sodium. Consuming sweet orange juice can decrease oral absorption of OATP substrates.

Read the full interaction report
SeverityMajor
LikelihoodLikely
EvidenceB
What do Severity, Likelihood & Evidence mean?
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Interaction report

Sweet Orange and Methotrexate Sodium

Here is the interaction we found between these two, with the evidence behind it.

Major

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP)

Why this applies to Methotrexate Sodium

Methotrexate Sodium falls under ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) — the group Sweet Orange interacts with.

Consuming sweet orange juice can decrease oral absorption of OATP substrates. Separate administration by at least 4 hours.
Clinical research shows that consuming sweet orange juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP. For example, sweet orange juice decreases bioavailability of fexofenadine, a substrate of OATP, by about 72% and of celiprolol, another OATP substrate, by up to 90%. Since sweet orange juice seems to affect OATP for a short time, recommend separating drug administration and consumption of sweet orange juice by at least 4 hours.
Severity Major Likelihood Likely Evidence B

Well-controlled human studies have demonstrated the likely existence of this interaction.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist: drinking sweet orange juice can temporarily block a transporter in your gut called OATP, and methotrexate relies on that same transporter to get absorbed when taken by mouth. So if you swallow your oral methotrexate around the same time as orange juice, less of the medicine may actually make it into your bloodstream. For something like methotrexate, where the dose is carefully calibrated, getting less than expected could mean your condition (whether it's rheumatoid arthritis, psoriasis, or another issue) isn't controlled as well.

The simple fix is timing. Researchers suggest keeping orange juice and your oral dose at least 4 hours apart, since the effect doesn't last long. This mainly applies to actual juice, not a single orange slice. Please run your routine by your pharmacist or doctor before changing anything.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Bailey DG, Dresser GK, Munoz C, et al. Reduction of fexofenadine bioavailability by fruit juices. Clin Pharmacol Ther 2001;69:P21.
  2. Lilja JJ, Juntti-Patinen L, Neuvonen PJ. Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol. Clin Pharmacol Ther 2004;75:184-90.
  3. Greenblatt DJ. Analysis of drug interactions involving fruit beverages and organic anion-transporting polypeptides. J Clin Pharmacol 2009;49:1403-7. PubMed
  4. Bailey DG. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol 2010;70:645-55. 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

Sweet Orange Also Interacts With Other Medications

Sweet Orange has 47 major, 198 moderate known drug interactions in our database — the Methotrexate Sodium one above is one of them. If you take anything else, check it against the full list below.

Major 47 Moderate 198 No known interaction 2,585 (incl. Methotrexate Sodium)
Taking anything else?

Check Another of Your Medications Against Sweet Orange

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

Everything else you take

See Every Supplement That Interacts With Methotrexate Sodium

This page covers Sweet Orange only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Methotrexate Sodium page lists 82 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Apple (major), Beer (major), Grapefruit (major) and Siberian Cocklebur (major).

Open the Methotrexate Sodium interaction page

One more smart check

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

We hold 678 real supplement products containing Sweet Orange, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Sweet Orange. Your product may carry other ingredients that interact with Methotrexate Sodium too, on top of Sweet 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 Sweet Orange and Methotrexate Sodium 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 Sweet Orange
Top 25%

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

29 days ago today
Medication Methotrexate Sodium
Steady interest

#1,533 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 Sweet Orange

What is Sweet Orange?

Sweet Orange
  • Vitamin C source
  • Digestive upset
  • Stress and relaxation (aromatherapy)
  • Cold and respiratory support
  • Antioxidant support

Sweet orange is a common citrus fruit that is a good source of vitamin C, fiber, and antioxidants, and is enjoyed as a food worldwide. Its peel and essential oil are used in aromatherapy and traditional remedies, but strong scientific proof for most medicinal claims is limited. The fruit and juice are safe for most people as food, while concentrated oils and extracts deserve more caution.

Read the full Sweet Orange monograph & all interactions
Keep checking

Other Drugs & Sweet Orange

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

47Major
198Moderate
0Minor
2,584No known interaction
47 Major 198 Moderate 2,584 No interaction
Major

47 interactions

Moderate

198 interactions

Showing 60 of 198 moderate interactions — see all 198 on the Sweet Orange page.

No interaction 2,584 drugs checked — show the list

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

Showing the 60 most looked-up of 2,584 medications checked with no known interaction — see the full Sweet Orange list.

See the full Sweet Orange interactions page
See every supplement checked against Methotrexate Sodium, 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
Sweet Orange monograph › Uses, safety, and every drug interaction in one place Methotrexate Sodium supplement interactions › Every supplement checked against Methotrexate Sodium, 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 Sweet Orange and Methotrexate Sodium Together: Common Questions

Can you take Sweet Orange with Methotrexate Sodium?
This is rated a major interaction, so the combination is best avoided unless your doctor or pharmacist has specifically told you otherwise. Read the full details on this page and confirm with your pharmacist before combining them.
How serious is the Sweet Orange and Methotrexate Sodium interaction?
We rate it Major. This is a clinically significant combination that is generally best avoided, or used only under the direct supervision of your physician or pharmacist.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Methotrexate Sodium and Sweet Orange?

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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.