Thanks Sumpup. Also, methotrexate is a potent inhibitor of dihydrofolate reductase enzyme, leads to depletion of cellular folic acid pools, and thus requires concomitant folic acid supplementation. Here's a good article on the side effects of methotrexate use and folic acid supplementation in rheumatoid arthritis patients, who are often prescribed low-dose methotrexate. The reduced CVD incidence in this population was the basis for CIRT.