Methotrexate and Vitamin B9: what the research found
PubMed indexes 8 records that name Methotrexate and Vitamin B9 together, either in the title or in an interaction, co-administration, or pharmacokinetic context. The key findings come first, in the authors’ own words, followed by every study with its design and PubMed link.
A summary of published research, not medical advice. A pharmacist can check any combination against your full list of medicines and supplements.
Reviews and human studies first. Each quote is the authors’ own conclusion about their study, not a NutriStack assessment, and a single study is not a consensus.
“Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity.”
“The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any…”
“The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.”
The research
8 studies naming Methotrexate and Vitamin B9.
Strongest relevance first: papers naming both substances in the title, then human trials and systematic reviews.
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases · 2019 · PMID 29975207
Systematic ReviewHuman subjects
“Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity.”
Names both Methotrexate and Vitamin B9 in its title.
The Journal of rheumatology · 2014 · PMID 24737913
Systematic ReviewHuman subjects
“The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.”
Names both Methotrexate and Vitamin B9 in its title.
The Cochrane database of systematic reviews · 2000 · PMID 10796393
Systematic ReviewHuman subjects
“The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.”
Names both Methotrexate and Vitamin B9 in its title.
Research Support, U.S. Gov't, Non-P.H.S.Research Support, N.I.H., ExtramuralHuman subjects
“Here we present cryo-electron microscopy structures of hRFC in the apo state and captured in complex with methotrexate. Combined with molecular dynamics simulations and functional experiments, our study uncovers key determinants of hRFC transport selectivity among folates and antifolate drugs while shedding light on important features of anion recognition by hRFC.”
Names both Methotrexate and Vitamin B9 in its title.
Bulletin of the Hospital for Joint Disease (2013) · 2018 · PMID 31513516
ReviewHuman subjects
“There are, however, more potential strategies in a rheumatologist's armamentarium to ameliorate side effects and improve adherence, including vitamin A supplementation and dextromethorphan. Herein, we will provide a review of the literature (both rheumatologic and oncologic) and expert opinion in terms of managing methotrexate toxicity and improving adherence in rheumatic diseases.”
Names both Methotrexate and Vitamin B9 in its title.
“In this work, we used two fluorescently labeled conjugates of methotrexate, differently linked at the terminal groups, to clarify the uptake mechanism by folate receptor-α. The results demonstrate the importance of methotrexate amino groups in the interaction with folate receptor-α.”
Names both Methotrexate and Vitamin B9 in its title.
“Although daily use of folic acid does not appear to affect methotrexate efficacy, dosing of folinic acid close to methotrexate administration may hinder methotrexate efficacy. Therefore, folic acid should be used daily with methotrexate to ameliorate side effects, whereas folinic acid should only be used for methotrexate toxicity.”
Names both Methotrexate and Vitamin B9 in its title.
Limitations
What this evidence cannot tell you.
Search-based evidence indexes have real limits, and it is worth being explicit about them:
Selection. These records were found by searching PubMed titles and abstracts for both substance names alongside interaction and pharmacokinetic terms. Relevant work that phrases things differently, or is not indexed in PubMed, will be missing.
No effect size. The quoted conclusions are the authors’ words about their own study. We have not extracted effect direction or magnitude, and a single study’s conclusion is not a consensus.
Population mismatch. Findings in healthy volunteers, animals, or a specific patient group may not transfer to you, your dose, or your formulation.
Absence is not safety. Few published studies means the combination is under-studied, which is not the same as established as safe.
How to read this page
A literature summary, not guidance.
A study listed here is not proof that Methotrexate and Vitamin B9 interact. Two substances can be named together in a paper that never tested them in combination, and a source listed as background may cover only one of them.
Findings are quoted from each abstract as the authors wrote them. NutriStack has not re-analysed, pooled, or reconciled them, and they may disagree with each other.
Decisions about prescription medication and supplements belong with your prescriber or pharmacist, who can see your full regimen. Our timing guide and forms guide explain the general mechanisms.
Nearby evidence
Other pairs with published research.
Pages covering Methotrexate or Vitamin B9 alongside a different substance.
NutriStack is a free iPhone app for organising a supplement routine: what you take, when, and what the published record says about it. Its exploratory interaction checker covers Methotrexate, Vitamin B9, and several hundred other substances.
Log your routine, get reminders at the times you choose, and scan a label to add a product. The checker is a research and organisation tool, not a clinical decision aid.
NutriStack is an informational and organizational tool, not a medical service, and not a substitute for professional advice. Always consult a qualified healthcare professional before starting, stopping, or changing any supplement or medication.
