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Methotrexate side effects and how to avoid them

Learn about methotrexate side effects, restrictions, drug interactions, and more

Methotrexate side effects | Serious side effects | How long do side effects last? | Warnings | Interactions | How to avoid side effects

Methotrexate, available generically or under the brand names Trexall, Otrexup, and Rasuvo, is a prescription drug used in chemotherapy for various types of cancer such as lymphoma and leukemia. It is also prescribed as an immunosuppressant to treat conditions such as rheumatoid arthritis, psoriasis, and juvenile idiopathic arthritis (JIA). 

Methotrexate is an antifolate antimetabolite that prevents the growth of fast-growing cancer cells by blocking their ability to use folic acid to grow and divide. As an immunosuppressant, methotrexate dials down the immune response during attacks of autoimmune disorders. Unfortunately, methotrexate side effects are commonly experienced even at low doses. In preparing for methotrexate treatment, it helps to fully understand side effects, restrictions, drug interactions, and how to manage possible side effects. 

RELATED: Learn more about methotrexate

Common side effects of methotrexate

The most common side effects of methotrexate involve digestive system problems. However, because methotrexate affects vital cellular functions, a wide range of side effects are possible. These side effects include:

  • Nausea
  • Vomiting
  • Swelling and ulcers in the mouth (stomatitis)
  • Loss of appetite
  • Liver dysfunction
  • Hair loss
  • Abdominal discomfort
  • Diarrhea
  • Tiredness
  • Fever
  • Sore throat
  • Rash
  • Itching
  • Dizziness
  • Dry cough
  • Low blood cell counts
  • Photosensitivity (sunburn recall)

Serious side effects of methotrexate

Methotrexate prevents tissue growth because it blocks fundamental cellular functions. Severe adverse effects can affect many vital systems in the body including the bone marrow, liver, kidneys, lungs, digestive system, and lymphatic system. Additionally, by suppressing the immune system, methotrexate makes patients more vulnerable to infections. 

Serious side effects of methotrexate include:

  • Blood disorders
  • Liver damage, cirrhosis (scarring), and fibrosis (extensive scarring)
  • Lung swelling (pneumonitis) and lung scarring (pulmonary fibrosis)
  • Kidney damage and kidney failure
  • Intestinal bleeding and perforation
  • Severe mouth ulcers
  • Severe diarrhea
  • Opportunistic infections
  • Tumor lysis syndrome (poisoning from extensive cancer cell death)
  • Uncontrolled growth of white blood cells
  • Leukoencephalopathy (in people receiving radiation treatments to the head)
  • Severe allergic skin reactions

How long do methotrexate side effects last?

Gastrointestinal side effects and some mild side effects such as dizziness, headache, and rash typically start early and resolve after a few hours. However, other common side effects, such as recall sunburn, which is an inflammatory reaction that occurs after certain anticancer drugs are taken, may take a few days to resolve. More extensive side effects, such as hair loss or low blood cell counts, usually don’t improve until methotrexate therapy is stopped or the dose is reduced.

Serious side effects typically take days to weeks to resolve. Many of these side effects, such as organ damage, intestinal damage, blood problems, tumor lysis syndrome, or severe allergic reactions, will require treatment or even hospitalization. Some side effects, such as fibrosis, are lifelong, chronic conditions.

Methotrexate contraindications & warnings

Methotrexate is a very powerful and potentially toxic drug that disrupts human cell growth and partly shuts down the immune system. Many may experience problems or get very sick while taking methotrexate. All people undergoing methotrexate treatment will be monitored closely for side effects and other problems. The good news is that most serious adverse reactions, if detected early, can be reversed by lowering the dosage, discontinuing the drug, or treating the side effect. 

Abuse and dependence

Methotrexate does not cause dependence, withdrawal, or abuse.


Methotrexate overdose is a serious and potentially fatal medical emergency that will require immediate medical attention. There is an antidote for methotrexate called leucovorin that can help counteract the effects of methotrexate poisoning, but treatment may require intensive medical care.

Because methotrexate injections are administered by healthcare professionals, methotrexate overdose occurs primarily in those taking methotrexate tablets. In most cases, the overdose is not due to taking too many pills at once, but rather taking the weekly dose of methotrexate every day instead. 

The symptoms of an oral overdose are the same as the side effects of a normal dose. Some people who have overdosed on methotrexate, however, may experience no overdose symptoms.

Contraindications and Restrictions

People with some medical conditions will never be given methotrexate because of the risk of severe adverse reactions.

  • Pregnant or breastfeeding women: Methotrexate can cause birth defects and kill a fetus. Women of childbearing age will undergo a pregnancy test before methotrexate is administered. Contraception should be used while taking methotrexate and after discontinuing it for up to three months in men and up to six months in women. Methotrexate should also be avoided while nursing because it is present in breast milk and could harm a baby. 
  • Kidney disease: Because methotrexate can damage the kidneys, people with significant kidney dysfunction will not be given methotrexate for any condition.
  • Alcoholism, alcohol-related liver disease, and chronic liver disease: Because methotrexate affects liver function, methotrexate will not be used to treat diseases other than cancer in people who drink or have chronic liver problems.
  • Immune system problems: People with a suppressed immune system will not be given methotrexate treatment for diseases other than cancer. Extra caution is required in anyone with an active infection.
  • Blood problems: Methotrexate suppresses bone marrow, the tissue that generates blood cells. Anyone with pre-existing blood problems, such as anemia, will not receive methotrexate for diseases other than cancer.
  • People older than 65 are at a higher risk of serious side effects and will be monitored carefully. Methotrexate should be used with extreme caution in debilitated patients.
  • Because of the risk of bleeding or perforation in the digestive system, methotrexate requires careful monitoring in people with peptic ulcer disease or ulcerative colitis.
  • People receiving cranial radiation therapy will need to be watched carefully for leukoencephalopathy, a progressive loss of white matter in the brain. 
  • People with significant third-space accumulations, such as pleuritis, ascites, or other conditions in which fluid builds up between tissues, will need to have excess fluid in these spaces corrected before receiving methotrexate.

Methotrexate interactions

Methotrexate cannot be taken with a wide range of prescription and over-the-counter drugs and supplements. Other drugs should only be combined with methotrexate cautiously.

Because of potentially severe drug interactions, methotrexate is never used with certain drugs or vaccines:

  • Live vaccines could cause a serious infection.
  • Imlygic (talimogene laherparepvec), a genetically modified live herpes virus, can cause a serious or life-threatening herpes infection in anyone taking an immune-suppressing drug like methotrexate.
  • Acitretin, a retinoid used to treat psoriasis, raises the risk of liver damage when combined with methotrexate.
  • Cidofovir, an antiviral drug, is highly toxic to the kidneys and is never prescribed with any other drug, like methotrexate, that also can damage the kidneys.

Other drug interactions will require caution and careful monitoring. If there are problems, dosing or therapies may need to be adjusted. These drugs include:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) and antifolates
  • Antibiotics: Aminoglycosides like streptomycin are toxic to the kidneys, so doctors will avoid prescribing them with methotrexate. Penicillins interfere with the body’s ability to clear methotrexate from the body, raising the risk of side effects. Some antibiotics are toxic to the liver and others reduce the body’s ability to absorb methotrexate. They might require dose adjustments or sometimes should be avoided.
  • Immunosuppressants: Because methotrexate suppresses the immune system, taking it with other immune-suppressing drugs can seriously compromise immune function.
  • Retinoids and alcohol: Taking methotrexate with oral retinoids or alcohol increases the risk of liver damage.
  • Proton-pump inhibitors (PPIs): PPIs increase methotrexate levels in the blood, making side effects more likely.
  • Sulfonylureas and seizure medications: Sulfonylureas are drugs commonly used to treat Type 2 diabetes. Hydantoins, such as phenytoin, are used to prevent and control seizures. Both types of drugs increase the amount of methotrexate in the blood, increasing its toxicity.
  • Theophyllines: Theophyllines are more likely to produce serious side effects when combined with methotrexate. Healthcare providers are advised to avoid using them with methotrexate.
  • Colony-stimulating factors: Generally used after cancer chemotherapy, drugs like filgrastim stimulate bone marrow cells to grow. 
  • Photosensitizing agents: Over 100 different drugs, vitamins, and herbal supplements make tissues more sensitive to light damage. Methotrexate reactivates tissue damage due to light or radiation. Many other drugs, including diuretics, tricyclic antidepressants, antihistamines, and a host of others, make skin and tissues more vulnerable to sunlight damage. Using them with methotrexate will require extra caution with sun exposure.
  • Vaccines: Because methotrexate suppresses the immune system, vaccination may not be effective. Vaccines should be delayed until methotrexate treatment is ended.

How to avoid methotrexate side effects

Unfortunately, side effects are a common experience among people taking methotrexate. There are ways, however, to manage side effects.

1. Tell the doctor about all medical conditions and medications

The doctor prescribing methotrexate will perform a complete history and workup including blood tests. Even so, the best way to prevent side effects is to inform the doctor about all existing medical conditions and medications being taken. Once started on methotrexate, do not start or change any medications currently being taken until a doctor has been consulted.

2. Take methotrexate as directed

Follow all the directions on the prescription label or provided by a healthcare professional. Do not take more or less than prescribed until you’ve consulted with a doctor or healthcare professional.

3. Take methotrexate as scheduled

Adverse reactions and overdose are often due to people taking their methotrexate more often than scheduled. For people taking methotrexate for a disease other than cancer, methotrexate is taken only once per week, not once per day. For cancer treatment, take the dose as scheduled, which could be once a week to four times a week.

4. Take folic acid supplements as directed

People taking methotrexate to treat cancer may be instructed by their doctor not to take folic acid (vitamin B9), folinic acid, or any multivitamin containing folic acid. Folic acid supplements reduce methotrexate’s ability to fight off cancer. On the other hand, people taking methotrexate to treat diseases other than cancer may be instructed by their doctor to take folic acid supplements to prevent side effects. Folic acid does not reduce methotrexate’s ability to treat autoimmune diseases. In all cases, follow the doctor’s instructions to the letter.

5. Split the dose

For people taking methotrexate for diseases other than cancer, the weekly dose can be split to minimize digestive system side effects. Take half the dose in the morning and the other half in the evening.

6. Take methotrexate after a meal

Another way to minimize gastrointestinal side effects is to take the methotrexate dose after a meal.

7. Use a saltwater rinse for mouth sores

A saltwater rinse or mouthwash containing a topical anesthetic can help relieve mouth irritation and sores.