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When should I take folic acid to reduce the side-effects of methotrexate?

Q) In Arthritis Today Spring 2009 Q & A I noted that on two occasions you mentioned 'taking folic acid on non-methotrexate days' and would like to know the reason for this specific note. I used to take 2.5 mg of methotrexate five days a week and folic acid once every day. Recently I saw a different member of the rheumatology team and he increased the methotrexate to six times a week and reduced the folic acid to six – to be taken on the non-methotrexate days – but no explanation was given. Please enlighten me!
JM Denyer, Ingatestone, Essex (Summer 2009)

A) Methotrexate suppresses cells which are metabolically active. One of the ways it does this is to antagonise an enzyme involved in the metabolism of folic acid. The enzyme is essential for cells to go about their business, and methotrexate in effect stops them doing this. This is fine when you're hoping to control the action of cells involved in inflammation but an unwanted spin-off is that it affects other active cells such as in the immune system, the stomach, the hair and the ovaries. In fact the drug suppresses any tissue which is ‘active’, that is, has metabolically active cells in it. Now, because of its action on the enzyme involved in the metabolism of folic acid, giving relatively large doses of folic acid acts as an antidote to the drug. If you were to take the folic acid on the same day as the methotrexate it would undoubtedly reduce the effectiveness of the methotrexate. But giving the folic acid on the other days of the week avoids this reduction in effectiveness and also prevents some of the side-effects (these can be guessed from the other target tissues listed above). Traditionally folic acid has been given on each of the six non-methotrexate days but there are some rheumatology departments now using folic acid only three times a week, or even only once a week. Incidentally, I presume you meant to write that you took methotrexate five tablets on one day a week, and this was then increased to six tablets on one day a week – methotrexate is normally a one-day-a-week treatment.

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