Methotrexate (MTX) is a medication with a long history, originally developed in the 1940s as a treatment for cancer. It is a synthetic chemical that mimics folic acid, a B vitamin necessary for cell growth and DNA synthesis. The drug is used in two distinct ways depending on the dosage. High-dose methotrexate functions as a chemotherapy agent, attacking rapidly dividing cancer cells. Conversely, low-dose methotrexate (LD-MTX) is used to manage chronic inflammatory and autoimmune diseases. The typical weekly dose for inflammatory conditions is many times lower than that used in oncology, which changes how the drug works and its overall safety profile.
Conditions Treated
Low-dose methotrexate (LD-MTX) is considered the standard initial treatment for several chronic inflammatory conditions. It functions as a Disease-Modifying Anti-Rheumatic Drug (DMARD) by suppressing an overactive immune system that mistakenly attacks the body’s own tissues. This sustained inflammation can lead to pain, swelling, and permanent tissue damage if not controlled.
LD-MTX is widely used to treat Rheumatoid Arthritis (RA), where the immune system attacks the joints, leading to progressive destruction. It is also effective for Psoriasis, an autoimmune disorder characterized by the rapid buildup of skin cells resulting in thick, scaly patches. Furthermore, LD-MTX is a common treatment for Psoriatic Arthritis, a form of arthritis affecting people with psoriasis.
How Methotrexate Works
The mechanism by which low-dose methotrexate controls chronic inflammation is complex and distinctly different from its cancer-fighting action. When used for autoimmune diseases, the drug acts primarily as an anti-inflammatory and immunosuppressant.
Methotrexate is a folate antagonist, meaning it interferes with the body’s use of folic acid by binding to the enzyme dihydrofolate reductase. While high doses starve rapidly dividing cells, the low weekly doses used for inflammatory diseases primarily target and slow the proliferation of certain inflammatory immune cells.
The primary anti-inflammatory effect of LD-MTX involves the release of adenosine. Methotrexate promotes the intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which facilitates the release of adenosine from cells. Adenosine is a powerful, naturally occurring anti-inflammatory agent that acts on specific receptors found on immune cells.
By increasing the local concentration of adenosine at sites of inflammation, LD-MTX reduces the accumulation and activity of leukocytes (white blood cells) that drive the inflammatory process. This adenosine-mediated pathway is considered the main way low-dose methotrexate exerts its beneficial effect.
Administration and Safety Monitoring
Low-dose methotrexate must be taken only once per week, and specifying the exact day of administration is necessary to prevent serious harm. Accidentally taking the dose daily instead of weekly can lead to fatal toxicity because the body does not have enough time to clear the drug. The typical weekly dose ranges from 5 mg to 25 mg, and it is available in both oral tablet and subcutaneous injection forms.
The oral form is most common, but switching to subcutaneous injection can improve absorption and reduce gastrointestinal side effects for some patients. The choice of administration route depends on the dose, patient preference, and whether the patient experiences poor absorption from the tablets. Regardless of the route, the weekly schedule must be strictly maintained.
Because methotrexate can affect organs, particularly the liver and bone marrow, safety monitoring is required. Before starting treatment, baseline tests for liver and kidney function, as well as a complete blood count (CBC), are necessary. Throughout treatment, patients must undergo routine blood tests, often initially every two to four weeks, to check for signs of toxicity.
These blood tests monitor liver enzymes (such as AST and ALT) to detect potential hepatotoxicity. The CBC is checked for bone marrow suppression, which indicates a drop in white blood cells, red blood cells, or platelets. Regular monitoring allows clinicians to catch adverse changes early and adjust the dosage or pause treatment.
Patient Experience and Side Effect Management
While routine monitoring addresses potential organ toxicity, patients often experience immediate side effects related to the drug’s impact on rapidly dividing cells lining the mouth and gut. Gastrointestinal issues are the most common complaint, including nausea and sometimes vomiting. Other frequently experienced issues include mouth sores or ulcers, fatigue, and a general feeling of being unwell, often called “methotrexate fog,” which occurs a day or two after dosing.
These common side effects can often be reduced through the co-prescription of folic acid supplements. Folic acid is the synthetic form of folate, and taking it helps replenish the body’s folate stores depleted by methotrexate. Supplementation lowers the risk of patient-reported side effects like nausea and mouth sores, and helps prevent abnormalities in blood counts and liver tests.
The typical folic acid dosage is usually 1 mg daily or 5 mg once weekly, taken on a different day from the methotrexate dose to ensure it does not interfere with the drug’s effectiveness. For patients experiencing severe nausea, dividing the weekly oral dose into two smaller doses taken 12 hours apart, or switching to the injectable form, can improve tolerance. These strategies allow many patients to remain on the medication and benefit from its disease-modifying effects.