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Methotrexate Usage and Side Effects

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Methotrexate Usage and Side Effects


Methotrexate is a DMARD or Disease Modifying Anti-Rheumatic Drug. These are a class of medications that are grouped by their ability to reduce inflammation and reduce joint damage caused by Rheumatoid Arthritis and Ankylosing Spondylitis. DMARDS work by adjusting the immune system’s responses over time. After NSAIDs (no non-steroidal anti-inflammatory drugs), methotrexate is the most prescribed medication for ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis.

Methotrexate was initially used as a chemotherapy drug for treating cancer, specifically leukemia. When cancer patients who also had autoimmune diseases, such as ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis, were treated with methotrexate, doctors noted severe improvements in their disease symptoms. Specifically, the patients experience reduced signs of inflammation and slowed disease progression (joint damage). This led to methotrexate’s development and implementation as one of the first-line defense drugs in treating autoimmune diseases. Fortunately, autoimmune diseases respond to a much lower dose of methotrexate than is required for cancer treatment. This treatment protocol is often referred to as low-dose chemotherapy.

Pill Form

Although methotrexate is a chemotherapy medication, the side effects experienced are relatively manageable compared to the long-term effects of untreated autoimmune disease. Introducing the medicines to the body largely determines how severe the side effects are. There are two options available to most patients. The first option is pill form. Although many doctors offer this option, it is not a good idea. In pill form, methotrexate does not bypass the digestive tract. This means that the most common side effect is nausea and digestive upset. This widespread side effect can last up to 24 hours for some patients.

Injectable Form

Although it may sound scary to patients at first, taking methotrexate via subcutaneous injection (just below the skin) really is the best option. The needle used is tiny, and the nausea is minimal and easily managed by most people. Regarding injections, the pain from the needle used during the actual injection is equal to or less than an insulin injection. When the site has an ice cube pressed to it for 4 minutes before injection, the pain from the needle is essentially non-existent. Luckily, unlike intramuscular injections, such as the flu shot and COVID vaccines, and basically every vaccine, subcutaneous injections do not cause long-lasting pain or soreness at the injection site. Occasionally there will be a tiny bruise, but apart from that, these injections are essentially painless and worth the effort to avoid awful nausea that tends to accompany pill forms of methotrexate.

Side effects

Methotrexate has both short-term and long-term side effects. Short-term side effects are temporary and will go away when the use of methotrexate is ceased. These include nausea, headache, digestive upset, some thinning of hair, or increased shedding. Doctors often prescribe an oral nausea medication called Zofran to help with the symptoms the day after the injection. Zofran is usually taken by women who experience morning sickness and is tolerated well by most people. Sometimes doctors will also prescribe folic acid. Folic acid can also help with the side effects of methotrexate. However, using too much folic acid can also counteract the effects of methotrexate. The medication leucovorin is a prescription-level dose of folic acid that is occasionally prescribed with methotrexate. However, leucovorin has such a high dose of folic acid that it can counteract the effects of methotrexate. This is something patients should discuss with their doctor.

Methotrexate can suppress the immune system, making patients more susceptible to viral, bacterial, and fungal infections. It is essential to get a flu shot and keep up to date with COVID boosters to minimize the likelihood of contracting a severe viral infection. Methotrexate can also affect liver function and cause hardening of the liver. This is rare, but rheumatologists monitor liver function with regular blood tests to ensure any changes are noticed immediately.

Long-term consequences of methotrexate use can sound frightening at first. They include osteoporosis or bone loss. It is essential that anyone taking methotrexate discuss a calcium regimen with their doctor. Calcium supplements plus a diet rich in calcium foods can help offset this risk.


Methotrexate cannot be taken by anyone who is or is attempting to become pregnant or anyone who is breastfeeding. Another off-label use of methotrexate is to end pregnancies where the embryo has implanted in a dangerous place, which would likely kill the mother, such as a tubal pregnancy (when the embryo attaches inside the fallopian tube). Methotrexate stops new cell development in embryos and causes the body to miscarry. Becoming pregnant when taking methotrexate is very dangerous as the embryo/fetus will not survive exposure to the medication. This can cause a serious risk of bleeding in the mother. It is critical that any woman capable of getting pregnant either take birth control or use other measures to ensure that she does not become pregnant when taking methotrexate. Similarly, nursing women should not take methotrexate as it can be transferred from breast milk to the infant.

Why Take Methotrexate?

Methotrexate has been used in treating autoimmune arthritis for decades and is considered a safe medication. This author has been using methotrexate for nearly 20 years. Although nausea can sometimes be challenging, the pain reduction and increased ability to function are worth any side effects. It is important to remember that your doctor would not prescribe medication if the risks outweighed the potential benefits. Most people tolerate methotrexate well and see a significant improvement in their disease symptoms.

Watch the YouTube video below from Johns Hopkins Rheumatology to understand how Methotrexate works if you have been recently prescribed the drug.

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