Skipping folic acid while taking methotrexate significantly increases your risk of side effects, and it makes you far more likely to stop treatment altogether. In one major study, 38% of patients taking methotrexate without folic acid had to quit the medication because of toxicity, compared to just 17% of those who took folic acid alongside it. Folic acid doesn’t just make methotrexate more tolerable; for many people, it’s what makes staying on the drug possible.
Why Methotrexate Depletes Your Folate
Methotrexate works by blocking an enzyme your body uses to convert folate (vitamin B9) into its active form. That active form is essential for cell division, growth, and producing new red blood cells. When methotrexate shuts down this process, it slows the rapid cell turnover that drives conditions like rheumatoid arthritis and psoriasis. But it also disrupts folate activity in healthy tissues, especially fast-dividing cells like those lining your mouth, gut, and bone marrow.
Folic acid supplementation replenishes the folate your body loses through this process. Because folic acid and methotrexate enter cells through the same transport system, timing matters. Most prescribers recommend taking folic acid on all the days you’re not taking your methotrexate dose, or at least 24 hours after it, so the two don’t compete directly.
Side Effects You’re More Likely to Experience
Without folic acid, the most common problems are the ones tied to folate depletion in fast-growing tissues. Mouth ulcers are one of the hallmark complaints. Nausea, vomiting, and diarrhea affect roughly 30% of methotrexate users even with folic acid on board, and the rate is higher without it. Hair thinning is another frequent issue.
A year-long placebo-controlled study found that folic acid supplementation (5 mg daily) significantly reduced discontinuation of methotrexate caused by mouth ulcers, nausea, vomiting, and low white blood cell counts. These aren’t minor improvements. If you’ve been dealing with persistent nausea or painful sores inside your mouth while on methotrexate, missing folic acid could be the reason.
Liver Damage Risk Increases
Methotrexate is processed through the liver, and one of its well-documented effects is elevating liver enzymes, a sign of liver stress or damage. Taking about 1 mg of folic acid daily has been shown to decrease the rate of these liver test abnormalities without reducing how well methotrexate works. That last point is important: folic acid protects your liver without undermining the reason you’re on the drug in the first place.
Without folic acid, you’re more likely to see abnormal results on the routine blood tests your doctor orders to monitor liver function. Persistently elevated liver enzymes can lead to dose reductions or discontinuation, which interrupts treatment for your underlying condition.
Blood Cell Counts Can Drop
Because methotrexate suppresses cell division, your bone marrow (where blood cells are made) is vulnerable. Without adequate folate, you may develop lower-than-normal counts of red blood cells, white blood cells, or platelets. Low red blood cells leads to anemia, causing fatigue and pale skin. Low white blood cells increases your infection risk, and you might notice unusual frequency of sore throats, fevers, or infections that linger. Low platelets can cause unusual bruising or bleeding.
These hematologic effects are among the more serious consequences of taking methotrexate without folate support, and they’re part of why regular blood monitoring is standard during treatment.
More People Quit Treatment Without It
The clearest evidence for folic acid’s importance comes from discontinuation rates. In a 48-week randomized, double-blind, placebo-controlled trial, 38% of patients on placebo (no folate supplement) stopped methotrexate because of side effects. Only 17% of those taking folic acid dropped out, and 12% of those taking folinic acid (a naturally occurring form of folate) did. That means folic acid cut the dropout rate by more than half.
This matters practically. Methotrexate often takes weeks to reach full effectiveness for conditions like rheumatoid arthritis. If side effects force you off the drug before it has time to work, you lose that investment and have to start over with a different medication. Folic acid is one of the simplest interventions in medicine: an inexpensive vitamin that dramatically improves your chances of staying on a treatment that takes time to pay off.
Folic Acid vs. Folinic Acid
You may see references to folinic acid (sometimes called leucovorin), which is a naturally occurring form of folate that your body can use without needing the enzyme methotrexate blocks. In theory, this makes it more efficient. In practice, a Cochrane systematic review found no significant difference between folic acid and folinic acid for reducing methotrexate side effects. Both reduce abnormal liver tests and overall treatment withdrawal at similar rates. Since folic acid is cheaper and more widely available, it’s the standard recommendation for most people on low-dose methotrexate.
Folinic acid does play a specific role in emergency settings, where it’s used as a “rescue” agent after high-dose methotrexate in cancer treatment. But for the typical rheumatology or dermatology patient on weekly low-dose methotrexate, regular folic acid is sufficient.
Signs of Serious Toxicity
Most side effects from skipping folic acid are uncomfortable but manageable once you start supplementing. However, methotrexate toxicity can occasionally become dangerous. Watch for severe mouth sores that make eating difficult, persistent vomiting or diarrhea, black or bloody stools, yellowing of the skin or eyes, a dry cough with fever and difficulty breathing, or signs of serious infection like high fever with chills. Sudden vision changes, confusion, or seizures are rare but require immediate emergency care.
These severe reactions can happen even with folic acid supplementation, but the risk is higher without it. If you’ve been taking methotrexate without folic acid and are experiencing any of these symptoms, that’s information your doctor needs right away.