The use of folates concomitantly with low-dose pulse methotrexate

Rheum Dis Clin North Am. 1997 Nov;23(4):969-80. doi: 10.1016/s0889-857x(05)70369-0.


Toxicities related to low-dose weekly methotrexate are largely due to its antifolate properties. Preexisting folate deficiency is associated with methotrexate toxicity in some patients. At the onset of methotrexate therapy and throughout therapy, the physician should be vigilant regarding one or more nutrient deficiencies. A multivitamin and, where appropriate, specific daily folic acid supplements should be employed. The only regimen known presently (through controlled trials) to treat side effects is the low-dose folinic acid (leucovorin) protocol outlined herein. Folic acid may be helpful to treat mild gastrointestinal symptoms. Folinic acid supplementation should be considered prophylactically in those requiring methotrexate who are at increased risk of hepatic disease. Other possible factors besides methotrexate should always be considered with the onset of new patient complaints or laboratory abnormalities. Claims that folic acid therapy is safer and more convenient than folinic acid seem unwarranted when one reviews the literature carefully. Cost differences between folic acid supplementation and folinic acid supplementation have been exaggerated.

Publication types

  • Review

MeSH terms

  • Antidotes / therapeutic use*
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Clinical Trials as Topic
  • Drug Therapy, Combination
  • Folic Acid Deficiency / prevention & control*
  • Humans
  • Leucovorin / therapeutic use*
  • Methotrexate / therapeutic use*


  • Antidotes
  • Antirheumatic Agents
  • Leucovorin
  • Methotrexate