I want to address an email from a recent podcast listener regarding the appropriate way to take folic acid with methotrexate. Specifically, what is my take on methotrexate and folic acid same-day dosing? First, let’s start with some basics. 

Folic Acid (vitamin B9) or the active form (folinic acid, leucovorin) is a medication that is prescribed with methotrexate primarily in patients with rheumatoid arthritis to minimize adverse effects like mouth ulcers, and gastrointestinal disturbances like nausea and vomiting. Some more severe adverse effects that folic acid may help prevent include bone marrow toxicity and abnormal liver functions tests. Somewhat recent evidence from 2019 suggests that it reduces GI toxicity and hepatotoxicity. In that same study, mouth sores from methotrexate were unaffected by folic acid supplementation. One question that I’ve had in clinical practice is what is the best time to take folic acid in relation to the methotrexate dose?

The reason folic acid is to be taken with methotrexate is that methotrexate inhibits enzymes dihydrofolate reductase and thymidylate synthase. These enzymes are responsible for synthesizing thymine, a critical component for DNA synthesis. Folic acid likely plays a role in the production of thymine. 

A few organizations and experts suggest taking folic acid on a different day than the methotrexate dose. This is because methotrexate is a folate antagonist and because taking them at the same time could theoretically reduce the efficacy of methotrexate. The rationale for this is that methotrexate is an immunosuppressant and works by slowing DNA synthesis via inhibition of thymidylate synthase, dihydrofolate reductase, and the s cell cycle phase. However, if folic acid is given at the same time, it may affect methotrexate’s ability to inhibit these enzymes. Some organizations including the British National Formulary (BNF) and National Institute for Health and Care Excellence Clinical Knowledge Summary (NICE CKS) note that folic acid should not be given on the same day as methotrexate administration due to this concern. My concern with this theory is that there is no literature to support this practice. 

Do all experts believe that clinical improvement can happen if patients skip a dose of folic acid on the same day as methotrexate?

Some other experts believe that it does not matter when folic acid is taken in relation to the methotrexate dose. According to Dr. Amanda Steiman, who is a rheumatologist at Sinai Health Network in Toronto, Canada, there is no benefit to skipping folic acid on the same day when methotrexate is to be taken. However, Dr. Steiman also states that most doctors prescribe folic acid 6 days a week due to the theoretical risk of interaction. According to John Hopkins Medicine, there is no mention of skipping folic acid on the same day as methotrexate. In my practice, I mostly see folic acid being given 7 days per week and on the same day as methotrexate.

My Take: Should patients skip folic acid on the day they take methotrexate?

Until we have proof one way or another, I don’t think it matters. If a well-designed study was done, my educated guess is that it wouldn’t matter. We don’t have any strong evidence comparing the once-weekly skipped dose or the continuous 7-day dosing of folic acid. Currently, I’m not going to recommend any changes if RA (or another disease state) is under control and adverse effects aren’t an issue. If a patient was taking folic acid 6 days per week with their once-weekly methotrexate, I am unlikely to encourage them to switch this unless they wanted to. In the same respect, if the patient is taking folic acid seven days per week and with their methotrexate once weekly, I am unlikely to request that they do it differently. 

What is your opinion on methotrexate and folic acid same-day dosing?

Article written by Cody Springer PharmD Candidate, in collaboration with Eric Christianson, PharmD, BCPS, BCGP

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  1. Ince, Susan. “Taking Folic Acid with Methotrexate for Arthritis: 9 Things You Must Know.” CreakyJoints, 10 July 2019, creakyjoints.org/living-with-arthritis/treatment-and-care/medications/folic-acid-and-methotrexate/
  2. “Methotrexate Information.” Johns Hopkins Arthritis Center, 17 Aug. 2017, www.hopkinsarthritis.org/patient-corner/drug-information/methotrexate/
  1. “Using Folic Acid with Methotrexate in Rheumatoid Arthritis.” NHS Choices, NHS, 20 Feb. 2023, www.sps.nhs.uk/articles/using-folic-acid-with-methotrexate-in-rheumatoid-arthritis/#:~:text=Folic%20acid%20supplements%20are%20usually,protection%20against%20gastrointestinal%20adverse%20effects
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