Article Text

Download PDFPDF
What dose of folic acid to use with methotrexate in rheumatoid arthritis?
  1. Diane Bramley
  1. Pharmacy, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
  1. Correspondence to Diane Bramley, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; Diane.Bramley{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Key learning points

  • Folic acid supplementation during methotrexate therapy can reduce the risks of adverse effects including nausea, vomiting, abdominal pain, mouth ulcers, raised liver enzymes and bone marrow toxicity.

  • By reducing the risk of adverse effects, folic acid supplementation helps to reduce the number of patients who discontinue methotrexate treatment.

  • Folic acid should be taken for as long as the methotrexate therapy is continued.

  • There is no standard dose but at least 5 mg of folic acid once a week is recommended.

  • It is generally agreed that folic acid should not be taken on the same day as methotrexate.


Methotrexate is a first-line, conventional, synthetic, disease-modifying antirheumatic drug (DMARD) used in the management of rheumatoid arthritis.1 2 It is an antifolate agent with a chemical structure similar to that of folic acid and folinic acid, but its exact mechanism of action in treating this condition is unclear.3–5 Administered orally or by subcutaneous injection in low doses, methotrexate inhibits a number of folate dependent metabolic steps, including a very potent inhibition of dihydrofolate reductase which reduces folic acid to dihydrofolic acid and to tetrahydrofolate.3 This causes a depleted pool of reduced folates and produces a state of effective folate deficiency.6 The half-life of methotrexate in the serum is in the range of 6–8 hours for low-dose treatment and is undetectable in the serum by 24 hours.4 Therefore, the effects of methotrexate persist after it has been cleared from the serum.

It is likely that some of the adverse effects of methotrexate are due to folate antagonism, and the main factor affecting adherence to methotrexate is the occurrence of adverse effects, rather than lack of response.6 7 Between 7% and 30% of patients discontinue methotrexate in the first year due to toxicity.8 The common adverse effects associated with methotrexate …

View Full Text


  • Editor’s note This article is based on a UKMi Medicines Q&A document ‘What is the dose of folic acid to use with methotrexate therapy for rheumatoid arthritis?’

  • Competing interests None declared. Refer to the online supplementary files to view the ICMJE form(s).

  • Provenance and peer review Commissioned; externally peer reviewed.