Can You Take Berberine With Methotrexate?
In our latest question and answer, the pharmacist discusses whether or not you can safely take berberine and methotrexate together.
Can I take a berberine supplement if I’m on 7.5 mg of methotrexate?
Jul 28, 2025- Methotrexate is not significantly broken down by the liver enzymes that berberine affects, so a direct interaction between these two is unlikely.
- Because methotrexate has a narrow therapeutic window, any changes in its blood levels can increase the risk of side effects, so you should discuss this combination with your doctor or pharmacist before use.
Answer
Hello, and thanks for contacting us!
This is a great question and one we’re happy to answer for you. Methotrexate is a versatile drug that is used for conditions like rheumatoid arthritis, psoriasis, and even certain types of cancer.
Due to its potency and complex metabolism, it’s incredibly important to review any potential interactions before combining it with supplements, especially something like berberine.
Understanding Methotrexate Metabolism
Methotrexate works by interfering with folate metabolism in cells, which slows the growth of certain immune and cancer cells.
It is primarily excreted unchanged by the kidneys, with only minor involvement from the liver and minimal contribution from gut flora. Most importantly, it is not significantly metabolized by the common liver enzymes known as cytochrome P450 (CYP) enzymes.
This point is very important because most supplement-drug interactions occur when a supplement affects these CYP enzymes...but the good news is that methotrexate mostly bypasses this interaction pathway, which is why we don't list an interaction on our website (Berberine - Methotrexate Interaction Details | HelloPharmacist).
So Where Does Berberine Come In?
Berberine is a compound found in several plants, including European barberry, goldenseal, goldthread, greater celandine, and Oregon grape. It's a very popular supplement due to its blood sugar–lowering effects and other potential health benefits.
However, it can carry risks, as it’s also known to interact with several CYP enzymes, specifically:
- CYP2C9
- CYP2D6
- CYP3A4
Inhibiting these enzymes can increase the blood levels of certain medications, potentially leading to stronger effects or side effects.
For example, one study reported that berberine was thought to be responsible for increasing cyclosporine concentrations due to CYP3A inhibition (Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients).
That said, methotrexate is not significantly metabolized by these CYP enzymes, so a direct interaction through this route is unlikely.
Should You Still Be Cautious?
Even though the risk of a direct interaction between berberine and methotrexate appears low, caution is still warranted for several reasons:
- Berberine may affect how drugs are processed in the body, even beyond CYP enzymes.
- Methotrexate has a narrow therapeutic window, meaning even small changes in blood levels can greatly increase the risk of side effects.
- There’s limited clinical research on combining methotrexate and berberine, so there may be unknown effects.
Final Words
While there's no strong evidence suggesting that berberine significantly affects methotrexate levels, their combination hasn't been well studied. As always though, it’s important to talk with your doctor or pharmacist before combining them.
References & sources
- Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study — PubMed
- Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins — PubMed
- Absorption Kinetics of Berberine and Dihydroberberine and Their Impact on Glycemia: A Randomized, Controlled, Crossover Pilot Trial — PubMed
- Immunoquantitative analysis for berberine and its related compounds using monoclonal antibodies in herbal medicines — PubMed
- Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study — PubMed
Glossary — Terms in This Answer
- Methotrexate
- A potent medication used to treat conditions like rheumatoid arthritis, psoriasis, and certain cancers by slowing the growth of specific immune and cancer cells.
- Folate metabolism
- The body's process of using and breaking down folate (a B vitamin), which methotrexate interferes with to achieve its therapeutic effects.
- Excreted
- Removed from the body, typically through urine or other bodily processes.
- Cytochrome P450 (CYP) enzymes
- Common liver enzymes responsible for breaking down many medications and supplements in the body.
- Berberine
- A compound found in certain plants that is taken as a supplement for its blood sugar-lowering effects and other potential health benefits.
- CYP3A4
- A specific liver enzyme that breaks down many medications and can be inhibited by berberine, potentially increasing drug levels in the body.
- Therapeutic window
- The safe range of medication dosage where the drug is effective without causing dangerous side effects.
- Clinical research
- Scientific studies conducted on human subjects to test the safety and effectiveness of medical treatments or combinations.
Dr. Brian Staiger, PharmD
Doctor of Pharmacy, board certified clinical pharmacist (BCPS), American Herbalist Guild, Medication Therapy Management certified
Brian Staiger, PharmD, BCPS, is a licensed pharmacist with more than 13 years of experience across retail pharmacy, clinical pharmacy, medication safety, pharmacy program development, and healthcare administration. He is the founder of HelloPharmacist.com, where he helps patients...
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