Understanding Methotrexate and Its Relationship with Folate
Methotrexate (MTX) is a powerful medication used to treat a variety of conditions, including certain cancers and autoimmune diseases like rheumatoid arthritis (RA) [1.2.6, 1.3.4]. It is classified as a disease-modifying antirheumatic drug (DMARD) and an antimetabolite [1.2.1, 1.2.2]. Its primary mechanism involves acting as a folate antagonist, specifically by inhibiting the enzyme dihydrofolate reductase (DHFR) [1.2.2, 1.7.6]. This enzyme is crucial for converting dietary folate into its active form, tetrahydrofolate, which is essential for DNA synthesis and cell replication [1.7.6, 1.4.4].
By blocking this pathway, methotrexate effectively slows the growth of rapidly dividing cells, which is beneficial in treating cancer and taming an overactive immune system in autoimmune disorders [1.2.2, 1.2.6]. However, this action also depletes the body's folate stores, leading to a state of folate deficiency [1.2.6, 1.2.1]. This deficiency is the root cause of many of methotrexate's common and debilitating side effects, which can affect the gastrointestinal (GI) tract, liver, and blood cell production [1.2.1, 1.2.3].
Common Side Effects of Methotrexate-Induced Folate Deficiency
The toxicity from methotrexate can manifest in several ways, often severe enough to make patients discontinue the treatment [1.2.3]. Common side effects include:
- Gastrointestinal Issues: Nausea, vomiting, and abdominal pain are among the most frequent complaints, affecting 20% to 65% of patients [1.2.5].
- Mouth Sores (Stomatitis): Painful ulcers in the mouth are a common occurrence [1.2.5, 1.6.3].
- Liver Toxicity (Hepatotoxicity): Methotrexate can cause elevated liver enzymes, and long-term use carries a risk of liver damage [1.2.1, 1.2.5]. Studies show that supplementation can reduce the risk of abnormal liver tests by over 76% [1.2.1].
- Bone Marrow Suppression: The drug can interfere with the production of new blood cells, potentially leading to anemia (low red blood cells), leukopenia (low white blood cells), and thrombocytopenia (low platelets) [1.2.2, 1.2.6].
- Fatigue and "Methotrexate Fog": Many patients report a general feeling of fatigue and cognitive cloudiness, especially the day after taking their weekly dose [1.2.5].
- Hair Loss: While less common at the lower doses used for arthritis, some hair thinning can occur [1.2.5, 1.6.2].
The Role of Vitamin B9 in Reducing Toxicity
To counteract these side effects, healthcare providers routinely prescribe a form of vitamin B9 alongside methotrexate therapy [1.3.3, 1.3.4]. This supplementation replenishes the body's folate levels, protecting healthy cells from the drug's effects without appearing to compromise its therapeutic efficacy in treating inflammatory conditions like rheumatoid arthritis [1.2.1, 1.3.5].
The two primary forms of vitamin B9 used are folic acid and folinic acid (also known as leucovorin) [1.2.1].
Folic Acid: The Standard Supplement
Folic acid is a synthetic, inactive form of vitamin B9 [1.2.6]. It is cost-effective and widely used. For it to be utilized by the body, it must be converted into the active form, tetrahydrofolate, by the DHFR enzyme—the very enzyme that methotrexate inhibits [1.7.6]. While this seems counterintuitive, providing an excess of folic acid helps to overcome the methotrexate blockade, allowing for enough active folate to be produced to protect healthy cells [1.2.1].
Supplementation with folic acid has been shown to significantly reduce GI side effects, liver toxicity, and the overall rate at which patients stop taking methotrexate [1.3.8, 1.2.1]. Dosing regimens vary, but a common approach is 5mg of folic acid taken once a week, on a different day than the methotrexate dose, to avoid interference with the drug's absorption and initial action [1.3.1, 1.3.3].
Folinic Acid (Leucovorin): The Active Form and Rescue Therapy
Folinic acid, or leucovorin, is a metabolically active form of folate [1.2.1]. Unlike folic acid, it does not require conversion by the DHFR enzyme to be used by the body [1.4.4]. This means it can directly bypass the metabolic block created by methotrexate, providing an immediate source of the necessary cofactors for DNA and RNA synthesis [1.4.2, 1.4.4].
Because it is already in an active state, folinic acid is often referred to as a "rescue" therapy, particularly in high-dose methotrexate regimens used in oncology to prevent severe, life-threatening toxicity [1.4.1, 1.5.2]. For patients with rheumatoid arthritis, it may be considered if folic acid is not sufficient to manage side effects [1.5.3]. While some studies suggest folinic acid may be more effective at reducing certain side effects like nausea, other comprehensive reviews have found both forms to be similarly effective at preventing liver toxicity and treatment discontinuation [1.5.1, 1.5.3]. Given that folinic acid is significantly more expensive, folic acid remains the first-line choice for routine supplementation [1.7.6, 1.5.1].
| Feature | Folic Acid | Folinic Acid (Leucovorin) |
|---|---|---|
| Form | Synthetic, inactive form of Vitamin B9 [1.2.1, 1.2.6] | Active form of folate (5-formyl tetrahydrofolate) [1.2.1, 1.4.4] |
| Mechanism | Requires conversion by the DHFR enzyme to become active [1.7.6] | Bypasses the DHFR enzyme block, directly providing active folate [1.4.2, 1.4.4] |
| Primary Use | Routine prevention of side effects in low-dose MTX therapy (e.g., for RA) [1.3.1] | "Rescue" therapy for high-dose MTX toxicity (oncology); second-line for RA [1.5.2, 1.5.3] |
| Efficacy | Significantly reduces liver, GI, and mucosal side effects [1.2.1, 1.3.8] | Also highly effective; may be better for some GI symptoms but overall similar to folic acid for major outcomes [1.5.1, 1.5.3] |
| Cost | Inexpensive [1.7.6, 1.5.1] | Substantially more expensive than folic acid [1.7.6, 1.5.1] |
| Dosing Schedule | Typically 1-5mg daily or 5mg weekly, taken on a day other than the MTX dose [1.3.1, 1.3.4] | Varies; often given 24 hours after MTX administration [1.4.1] |
Conclusion
Supplementation with vitamin B9, in the form of either folic acid or folinic acid, is a critical component of managing methotrexate therapy. By replenishing depleted folate stores, this intervention effectively mitigates many of the drug's most common and burdensome toxicities, particularly those affecting the liver and gastrointestinal system [1.2.1, 1.3.8]. This protective effect helps improve patient tolerance, reduces the rate of treatment discontinuation, and allows patients to continue benefiting from this important medication without compromising its efficacy in inflammatory diseases [1.2.1, 1.3.5]. While both forms are effective, the lower cost of folic acid makes it the standard choice for most patients on low-dose methotrexate regimens [1.7.6].
For more information, consult authoritative sources such as the Arthritis Foundation.
