Key takeaways

  • Methotrexate injection, a treatment for certain autoimmune diseases and cancers, can lead to various side effects. These range from common, mild reactions such as headache and nausea to serious, potentially fatal complications affecting organs such as the lungs, liver, and kidneys.
  • The risk and severity of some methotrexate side effects, particularly liver damage and low blood cell levels, are often dependent on the dosage, with higher doses typically increasing the likelihood of adverse reactions.
  • Patients undergoing methotrexate treatment should be aware of potential long-term side effects, including continued organ damage, and must avoid alcohol due to increased liver damage risk. Pregnant people should not use the drug due to significant fetal harm risks.

Methotrexate comes as an injection given under your skin, into the space surrounding your spinal cord, or into your muscle.

It also comes as a tablet you swallow and an intravenous (IV) infusion (an injection into your vein given over time). But these forms of methotrexate are not covered in this article.

Methotrexate may be used as a long-term treatment. This article describes the drug’s side effects, also referred to as adverse effects.

This drug has boxed warnings. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). It alerts doctors and patients about drug effects that may be dangerous.

Some people may experience mild to serious side effects during methotrexate treatment.

Examples of the drug’s commonly reported side effects include:

To learn more about some of these side effects, see the “Methotrexate’s side effects explained” section.

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Some people may have mild side effects while using methotrexate. Examples that have been reported with this drug include:

To learn more about some of these side effects, see the “Methotrexate’s side effects explained” section.

In most cases, these side effects should be temporary. And some may be easily managed. But if you have symptoms that are ongoing or bothersome, talk with your doctor or pharmacist. And do not stop using methotrexate unless your doctor recommends it.

Methotrexate may cause mild side effects other than those listed here. See the drug’s prescribing information for details.

Note: After the Food and Drug Administration (FDA) approves a drug, it tracks and reviews side effects of the medication. Sharing your experience helps make medication safer for everyone by giving doctors and researchers more information about how the drug works in real life. If you develop a side effect while taking methotrexate and want to tell the FDA about it, visit MedWatch or call 800-FDA-1088.

Serious side effects are possible with methotrexate. These include:

To learn more about some of these side effects, see the “Methotrexate’s side effects explained” section.

If you develop serious side effects while using methotrexate, call your doctor right away. If the side effects seem life threatening or you think you’re having a medical emergency, immediately call 911 or your local emergency number.

Get answers to some frequently asked questions about methotrexate’s side effects.

Eye-related and dental side effects weren’t reported in studies of methotrexate. But eye-related side effects have been reported since methotrexate became publicly available for use. It isn’t known for certain whether methotrexate was the cause, though.

Examples of eye-related side effects that have been reported with methotrexate include:

• damage to your optic nerve
• blurry vision
• eye irritation
• redness or swelling of your eyes
• xerophthalmia (a kind of dry eye)

Although dental side effects have not been reported, methotrexate may cause mouth sores. To learn more about this side effect, see the “Methotrexate’s side effects explained” section.

Talk with your doctor if have other questions about eye-related or dental side effects with this medication.

It’s not likely. Weight gain wasn’t reported as a side effect in studies of methotrexate.

Keep in mind that rheumatoid arthritis (RA), which methotrexate is used to treat, may result in weight gain. If you’re using methotrexate to treat RA, it’s possible you may have weight gain related to your condition.

To learn more about weight gain and methotrexate, talk with your doctor. They can recommend ways to maintain a weight that’s healthy for you.

Yes, certain side effects of methotrexate are dose dependent, meaning your risk is greater at higher doses. So your risk of certain side effects could be reduced by using a lower dose.

For example, in studies of methotrexate, the risk of liver damage was greater at higher doses of the drug. (See the “Methotrexate’s side effects explained” section for more information.) Also, the dosage of methotrexate for rheumatoid arthritis is usually below 20 milligrams (mg) per week. This is because dosages above 20 mg weekly can increase your risk of low blood cell levels as a side effect.

If you have any bothersome side effects with methotrexate, talk with your doctor. If they feel the side effect is dose related, they may lower your dosage slightly to see if the side effect eases. For example, they may lower your dosage by 2.5 mg per week for several weeks to see if the side effect goes away.

To learn more about methotrexate side effects in relation to its dosage, talk with your doctor or pharmacist.

It’s possible for methotrexate to cause long-term side effects. These include side effects that may start during treatment and continue for a long time. It’s possible certain side effects could continue after methotrexate treatment ends.

The following are a few examples of long-term side effects that can happen with methotrexate:

Methotrexate has a boxed warnings for the risk of these side effects. A boxed warning is the most serious warning from the FDA. For more information, see the following “Methotrexate’s side effects explained” section.

To learn more about long-term side effects with methotrexate, talk with your doctor or pharmacist.

Learn more about some of the side effects methotrexate may cause.

Allergic reaction, including severe allergic reaction

Like most drugs, methotrexate can cause a hypersensitivity reaction — such as an allergic reaction — in some people. While this side effect wasn’t reported in studies, it has occurred since the drug was approved for use. Symptoms can be mild to serious and can include:

  • skin rash
  • itchiness
  • flushing (temporary warmth, redness, or deepening of skin color)
  • swelling under your skin — usually in your eyelids, lips, hands, or feet
  • swelling of your mouth, tongue, or throat, which can make it hard to breathe

Risk of severe allergic reaction

Methotrexate has a boxed warning for the risk of severe allergic reaction. A boxed warning is the most serious warning from the FDA.

An example of a severe allergic reaction that could occur with methotrexate is anaphylaxis. It’s important to note that anaphylaxis wasn’t seen during studies of methotrexate. There have been reports of this side effect in people using the drug, but it’s unclear how often this has happened or if methotrexate was the cause.

What might help

If you have mild symptoms of an allergic reaction, such as a mild rash, call your doctor right away. They may suggest a treatment to manage your symptoms. Examples include:

  • an antihistamine you take by mouth, such as diphenhydramine (Benadryl)
  • a product you apply to your skin, such as hydrocortisone cream

If your doctor confirms you’ve had a mild allergic reaction to methotrexate, they’ll decide if you should continue using it.

If you have symptoms of a severe allergic reaction, such as swelling or trouble breathing, call 911 or your local emergency number right away. These symptoms could be life threatening and require immediate medical care.

If your doctor confirms you’ve had a serious allergic reaction to methotrexate, they may have you switch to a different treatment.

Risk of serious side effects, including death

Methotrexate has a boxed warning for the risk of serious side effects, including death. A boxed warning is the most serious warning from the FDA.

The following are details about serious side effects that may occur with methotrexate.

Lung damage: This includes conditions such as interstitial lung disease (scarring and inflammation around the lungs). In rare cases, lung damage with methotrexate may be fatal.

Liver damage: This includes conditions such as cirrhosis (liver scarring) and liver failure. In rare cases, liver failure with methotrexate may be fatal. Your risk of this side effect may be greater at higher doses of the drug.

Kidney damage: This includes conditions such as kidney failure. Your risk of this side effect may be greater at higher doses of the drug or if you already have kidney damage before starting methotrexate treatment.

Nerve damage: This side effect may lead to seizures or symptoms that mimic those of a stroke. Examples include confusion, loss of vision, and weakness on one side of the body. In rare cases, nerve damage with methotrexate may be fatal.

Serious infection: Examples of serious infections that may occur include shingles and cytomegalovirus. Methotrexate may also reactivate hepatitis B or tuberculosis (TB) in people who already have the hepatitis B virus or TB bacterium in their bodies. In rare cases, serious infections with methotrexate may be fatal.

Low level of certain blood cells: These include white blood cells, platelets, and red blood cells. Your doctor may check the levels of these blood cells before you start methotrexate. And they may continue checking them from time to time throughout your treatment. They’ll tell you what to do if your blood cell levels become low during your treatment with this drug.

Severe problems with your digestive system: This may lead to diarrhea, vomiting, and mouth sores. In rare cases, methotrexate may cause a tear in your stomach or intestines, which could be fatal. Your risk of severe digestive problems is higher if you have peptic ulcers or ulcerative colitis.

Severe skin-related side effects: Examples include erythema multiforme and the death of skin tissue. In rare cases, skin-related side effects with methotrexate may be fatal. For details, see the “Skin-related side effects” section.

What might help

If you develop any of the side effects listed above during methotrexate treatment, tell your doctor about them right away. But if your symptoms feel severe or life threatening, immediately call 911 or a local emergency number.

If you have serious side effects with methotrexate, your doctor will recommend what to do. In some cases, serious side effects may not go away, even after you’ve stopped treatment with the drug. For details, see the “Can methotrexate cause long-term side effects?” section.

Risks of using methotrexate containing benzyl alcohol

Methotrexate has a boxed warning for the risk of using formulations containing benzyl alcohol in certain situations. A boxed warning is the most serious warning from the FDA.

Methotrexate formulations containing benzyl alcohol as a preservative carry a serious warning against use in the following:

  • newborns and low birth-weight infants
  • intrathecal injections (those given into the space surrounding your spinal cord)
  • high-dose administration

Using methotrexate formulations containing benzyl alcohol in these instances can cause fatal gasping syndrome, severe central nervous system toxicity, or metabolic acidosis. Only preservative-free formulas of methotrexate should be used in these situations.

What might help

Doctors will not prescribe or administer methotrexate containing benzyl alcohol in these situations. Talk with your doctor or pharmacist if you have any questions about this warning.

Hair loss

Hair loss was a less common side effect in studies of methotrexate. Keep in mind that rheumatoid arthritis (RA) and psoriasis, which methotrexate is used to treat, may cause hair loss. So it’s possible you may have hair loss due to your condition while using methotrexate.

What might help

To help reduce hair loss, treat your hair gently while using methotrexate. This includes not using styling tools that are harsh on your hair, such as a curling iron. For more tips, see this hair loss prevention article.

If you have bothersome hair loss from methotrexate, talk with your doctor. They can help determine if your hair loss may be caused by the drug, your condition, or something else. They can also suggest more ways to help manage this side effect.

Mouth sores

Mouth sores were one of the more common side effects in studies of methotrexate. With mouth sores, you may have small cuts or blisters that affect your gums, cheeks, tongue, or the inside of your lips. Other symptoms that can occur with mouth sores include peeling, swelling, or a burning sensation.

Mouth sores with methotrexate may occur on their own and be mild. Or they may occur along with more severe digestive system problems. (For details about more severe digestive problems with methotrexate, see “Risk of serious side effects, including death.”)

What might help

Tell your doctor if you have bothersome or painful mouth sores with methotrexate. They can suggest ways to manage this side effect. For example, they may recommend over-the-counter creams or other medications that can help relieve your discomfort.

Skin-related side effects

Skin-related side effects may occur with methotrexate. Mild skin-related side effects, such as skin rash and itchy skin, were common in studies of the drug. In rare cases, severe skin-related side effects may also occur and can be fatal.

Examples of severe skin-related side effects that may occur with methotrexate include:

Symptoms can include:

  • fever
  • blistering rash
  • peeling skin
  • painful skin

What might help

If you have skin-related side effects with methotrexate, tell your doctor right away. They can tell you how to manage them. But if your symptoms seem severe or life threatening, immediately call 911 or your local emergency number.

While using methotrexate, it’s important to limit your sun exposure as much as possible. Doing so can help reduce your risk of skin-related side effects. Be sure to wear a hat, long sleeves, long pants, and sunscreen while outdoors.

The following are several warnings for methotrexate.

Boxed warnings

Methotrexate has the following boxed warnings. Boxed warnings are the most serious warnings from the FDA.

  • Risk of severe allergic reaction: Methotrexate may cause a severe allergic reaction, including anaphylaxis. For details, see the “Methotrexate’s side effects explained” section.
  • Risk of fetal harm: Methotrexate is not safe to use during pregnancy. For details, see the “Methotrexate warnings” section.
  • Risks of using methotrexate containing benzyl alcohol as a preservative: Methotrexate formulations containing benzyl alcohol should not be used in newborns or low birth-weight infants, or for high-dose administration, or injections into the space surrounding the spinal cord. For details see the “Methotrexate’s side effects explained” section.
  • Risk of serious side effects, including death: Methotrexate may cause serious side effects that impact multiple organs and which may be fatal in rare cases. For details, see the “Methotrexate’s side effects explained” section.

Other warnings

Methotrexate may not be right for you if you have certain medical conditions. This is known as a drug-condition interaction. Other factors may also affect whether methotrexate is a good treatment option for you. Talk with your doctor about your health history before starting methotrexate. Factors to discuss with them include the following:

You should also talk with your doctor before receiving any live vaccines or any type of surgery with nitrous oxide anesthesia (also known as “laughing gas”).

Alcohol and methotrexate

You should not use methotrexate with alcohol. Drinking large amounts of alcohol with methotrexate can increase the risk of liver damage as a side effect of the drug. (To learn more about liver damage, see “Risk of serious side effects, including death” in the “Methotrexate’s side effects explained” section.)

If you have questions about methotrexate and alcohol, talk with your doctor.

Pregnancy and breastfeeding while using methotrexate

The following is information about using methotrexate during pregnancy and while breastfeeding.

Methotrexate and the risk of fetal harm during pregnancy

Methotrexate has a boxed warning about fetal harm (commonly known as birth defects) if the drug is used during pregnancy. A boxed warning is the most serious warning from the FDA.

Studies of methotrexate have shown that the drug may cause pregnancy loss. In addition, using this drug while pregnant can result in serious problems with fetal development including abnormalities of the brain, head, face, heart, arms, or legs.

Due to these risks, your doctor will likely recommend that you do not use methotrexate if you’re pregnant or planning a pregnancy. If you’re able to become pregnant, your doctor will confirm you aren’t by giving you a pregnancy test before you start methotrexate.

If you or your partner can become pregnant, you should use effective birth control throughout your methotrexate treatment. Females should continue to use birth control for at least 6 months after their last dose of the drug. And males should continue using birth control for at least 3 months after their last dose.

If you’re pregnant or planning a pregnancy, talk with your doctor before starting methotrexate. They may recommend a different drug for your condition.

Note: The use of binary terms such as “male” and “female” in this article reflects the language of the sources we’ve used. Unless otherwise noted, it’s unclear whether the research we reference included participants with expansive gender identities.

Methotrexate and breastfeeding

It’s recommended that you avoid breastfeeding while using methotrexate. This drug may pass into breast milk which could cause side effects in a child who is breastfed.

To be safe, you should avoid breastfeeding while using methotrexate and for at least 1 week after your last dose.

Before starting methotrexate, tell your doctor if you’re breastfeeding or planning to breastfeed. They may discuss other treatment options with you or suggest other healthy ways to feed your child.

Disclaimer: While Healthline strives for factual, comprehensive, and current information, this article is not a substitute for a licensed healthcare professional’s expertise. Always consult a doctor before taking or discontinuing any medication. Drug information is subject to change and may not cover all uses, directions, precautions, warnings, interactions, reactions, or adverse effects. The lack of a warning does not guarantee a drug’s safety, effectiveness, or appropriateness for all patients or specific uses. Learn more about our approach to content integrity.