Methotrexate in Cancer Care: High Dose, Leucovorin Rescue and Staying Safe

By the Oncol.net editorial team · Last updated November 1, 2026

Methotrexate is a chemotherapy drug that blocks the use of folic acid. It treats leukemia, lymphoma, osteosarcoma and other cancers. Doses of 500 mg/m² or more are high dose and need leucovorin rescue, IV fluids and daily blood levels. Arthritis and psoriasis use far lower doses taken only once a week, and taking those doses daily by mistake has been fatal.

Safety first: know your schedule. Low-dose methotrexate for arthritis or psoriasis is taken once a week, not once a day. Taking it every day by mistake has caused deaths. If you take methotrexate at home, know the exact day, the number of tablets, and who to call. If you took extra, call your doctor or Poison Control at 1-800-222-1222 now, even if you feel fine. Call 911 if someone has collapsed, had a seizure, is having trouble breathing, or cannot be woken.

What methotrexate is and how it works

Methotrexate is an antimetabolite, and more specifically an antifolate. Cells need folic acid, a B vitamin, to make and repair DNA. Methotrexate blocks that step, so fast-dividing cells cannot copy themselves. Cancer cells are the target. The bone marrow, mouth and gut lining also suffer, which explains the main side effects.

It is unusual because the same drug is used across a huge dose range. A person with rheumatoid arthritis may start with 7.5 mg a week. A person with osteosarcoma may receive 12 grams for each square meter of body surface in one dose, well over 1,000 times more. The two uses have different risks and different safety rules. Trexall and Xatmep are US brand names, and generic forms are widely used.

What it treats in cancer care

Methotrexate injection is approved for these cancers, mostly with other drugs:

Acute lymphoblastic leukemia (ALL) in adults and children
Meningeal leukemia, which is leukemia in the fluid around the brain and spinal cord, for prevention and treatment
Non-Hodgkin lymphoma
Osteosarcoma, a bone cancer
Breast cancer, for example in the CMF regimen with cyclophosphamide and fluorouracil
Squamous cell carcinoma of the head and neck
Gestational trophoblastic neoplasia, a rare tumor arising from pregnancy tissue

Outside cancer care, it is approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe psoriasis.

Cancer doses vs. low-dose weekly methotrexate

These figures show the scale of the difference. They are what a patient may see, not a guide to any person's dose. mg/m² means milligrams per square meter of body surface, worked out from height and weight.

Use	Typical dose in the label	Notes
Rheumatoid arthritis	Starts at 7.5 mg once a week	Above 20 mg a week raises the risk of serious reactions
Psoriasis	10 to 25 mg once a week	Do not exceed 25 mg a week
Head and neck cancer	40 to 60 mg/m² IV once a week	Given alone
Breast cancer	40 mg/m² IV	Part of a multi-drug regimen
Acute lymphoblastic leukemia	10 to 5,000 mg/m² IV	Depends on phase; high doses need leucovorin rescue
Non-Hodgkin lymphoma	10 to 8,000 mg/m² IV in combination	8,000 mg/m² alone for lymphoma in the brain
Osteosarcoma	Typically 12 g/m² over 4 hours (maximum 20 g a dose)	Needs leucovorin rescue

The danger of accidental daily dosing

This is one of the best-known medication errors. The Institute for Safe Medication Practices (ISMP) has listed oral methotrexate for non-cancer use as a high-alert medicine since 2003. It has published harmful and fatal cases of accidental daily dosing in more than 60 newsletters since 1996. An FDA review found 12 reports of daily instead of weekly dosing from 2010 through 2016, including 2 deaths.

Few medicines are taken weekly, so it is easy to slip into a daily habit. ISMP reports errors at every stage: at the prescriber, at the pharmacy, on hospital discharge lists and at home. Some patients have misread instructions. Methotrexate can also be confused with a similarly named water pill, metolazone.

Ways to protect yourself or someone you care for:

Say the schedule out loud with your pharmacist: which day, how many tablets.
Mark the day on a calendar. Pick a day that you will remember.
In hospital, tell staff that your home methotrexate is weekly, and check your discharge list.
If you miss a dose, call your doctor. Do not double up.

Cancer protocols use many schedules, and some are different from weekly. If you are on methotrexate for cancer, follow your written plan, and do not assume that what you read about arthritis applies to you, or the reverse. Mouth sores, vomiting, diarrhea, fever and unusual bruising after a possible mistake need a same-day call.

High-dose methotrexate and leucovorin rescue

High doses would seriously harm normal cells if left unchecked. So they are given with a planned rescue. The label calls doses of 500 mg/m² or more high dose, and requires leucovorin rescue. For 100 to under 500 mg/m², leucovorin should be considered.

Leucovorin is a form of folic acid that normal cells can use, which gets around the block. Timing is critical, because it works less well the longer it is delayed. Here is what usually happens:

Before the dose: IV fluids start, and medicine is given to make your urine alkaline, with a target pH of 7 or higher. This is part of protecting your kidneys. You may be asked to check or collect your urine. Your team needs to know about all your medicines.
During the infusion: the dose often runs over several hours. For osteosarcoma it is typically 4 hours.
After the dose: fluids continue. Kidney function, electrolytes and the methotrexate level in your blood are checked at least daily.
Leucovorin: one common label schedule starts 24 hours after the methotrexate begins, at 15 mg every 6 hours for 10 doses. If you are vomiting, it is given by IV or injection, because a missed or vomited dose matters.
Until the level is safe: leucovorin, fluids and urine alkalinization continue until the methotrexate level falls below 0.05 micromolar.

Because of these steps, high-dose methotrexate is usually a hospital treatment. Ask how long to expect to stay. Your stay depends on how fast your blood level falls, so it can change from cycle to cycle.

Blood level pattern (leucovorin label)	What it suggests	What usually changes
About 10 micromolar at 24 hours, 1 at 48 hours, under 0.2 at 72 hours	Normal clearance	Standard leucovorin
Above 0.2 at 72 hours, or above 0.05 at 96 hours	Delayed late clearance	Leucovorin continues until under 0.05
50 or more at 24 hours, 5 or more at 48 hours, or a doubling of creatinine at 24 hours	Delayed early clearance or kidney injury	Much higher leucovorin doses, more fluids, close monitoring

If kidney injury slows clearance and the level stays above 1 micromolar, glucarpidase may be used. This is an enzyme that breaks methotrexate down in the blood. High levels are serious but are something your team watches for and has treatment for.

Intrathecal methotrexate

Intrathecal means given into the fluid around the spinal cord, usually through a needle in the lower back (a spinal tap, or lumbar puncture). Intrathecal treatment is used to treat or prevent leukemia in the brain and spinal cord.

The dose goes by age, from 6 mg under age 1 up to 12 to 15 mg at age 9 and older.
Only preservative-free methotrexate may be used, because the preservative benzyl alcohol can cause severe nerve toxicity.
Spacing is set by the protocol. For prevention the label says no more than once a week, and for treatment it allows every 2 or more days, up to twice a week.
People with Down syndrome should receive leucovorin rescue after intrathecal doses.

Leucovorin must never be given intrathecally. Its label warns that this may be fatal.

Possible problems include chemical arachnoiditis, which is irritation of the membranes around the spinal cord. It causes headache, back pain, stiff neck and fever. A rarer problem, subacute myelopathy, is damage to the spinal cord. Leukoencephalopathy, a brain white-matter injury, is more likely after radiation to the head or spine.

After a spinal dose, call your team right away for: severe headache, back pain, stiff neck, fever, confusion or weakness. Call 911 for a seizure.

Side effects and when they happen

The most common effects are mouth ulcers, low white cells, nausea and stomach upset. Tiredness, chills, fever and dizziness are also frequent. See also mouth sores and nausea and vomiting.

Side effect	What to know
Mouth sores	Among the most common side effects. Call right away, because they can be a sign of toxicity.
Low blood counts	White cells, platelets and red cells can all fall, sometimes severely. The label we read gives no specific nadir timing. Ask your team which days to watch. See blood counts.
Kidney injury	Mainly with high doses. It slows clearance, which raises side effects.
Liver injury	Short-term rises in liver tests, and with long-term use fibrosis and cirrhosis. Blood tests are done during treatment.
Diarrhea, vomiting	Can lead to dehydration, which raises kidney risk. Rarely, serious bowel injury occurs.
Sun sensitivity and skin reactions	Use SPF 30 or higher, a hat and protective clothing. Earlier radiation burns can flare.
Hair loss	Can occur.
Stroke-like symptoms	With high doses, a temporary syndrome can occur. Any sudden weakness or speech problem needs urgent care.

Serious warnings and when to call

The label's boxed warning covers harm to a developing baby, severe allergic reactions, and serious reactions, including death, affecting the bone marrow, kidneys, liver, nerves, gut, lungs and skin. Serious infections can occur, including pneumocystis pneumonia and fungal infections. Hepatitis B, tuberculosis and shingles can flare. Lung inflammation can happen at any dose. Other concerns include tumor lysis syndrome, where fast tumor breakdown strains the body, and second cancers.

Call your care team now if you have: a temperature of 100.4°F (38°C) or higher; mouth sores; vomiting or diarrhea that stops you drinking; a dry cough or shortness of breath; unusual bruising or bleeding; yellow skin or eyes; less urine than usual or swelling; a new rash, blisters or peeling skin; or black or bloody stools. Call 911 for severe trouble breathing, swelling of the face or throat, a seizure, or loss of consciousness. See when to call your doctor.

Interactions and precautions

Methotrexate leaves the body through the kidneys, so anything that slows that route can raise levels. Before high-dose treatment, your team may stop some of your medicines. Never restart them without checking.

NSAIDs and aspirin: ibuprofen, naproxen and similar drugs may raise methotrexate levels. Severe and fatal gut toxicity has occurred, mainly with high doses.
Heartburn drugs called proton pump inhibitors: such as omeprazole. These may raise levels.
Certain antibiotics: penicillins and sulfa drugs, including trimethoprim-sulfamethoxazole, which also blocks folate. Tetracyclines are also listed.
Probenecid, a gout medicine.
Other drugs on the label's list: dapsone, pemetrexed, pyrimethamine, phenytoin, oral blood thinners, sulfonylurea diabetes drugs, mercaptopurine, imatinib and dasatinib. Methotrexate also raises theophylline levels.
Nitrous oxide (laughing gas): should be avoided. Tell your dentist and anesthesiologist.
Folic acid supplements: in cancer treatment, folate supplements can reduce methotrexate's effect. Check multivitamins too. Take folate only if your team says so. In arthritis the opposite is true: folic acid is recommended to reduce side effects.
Alcohol: heavy drinking raises the risk of liver damage. Ask about any alcohol use.
Live vaccines: avoid them during treatment.
Radiation: given at the same time, it raises the risk of tissue and bone damage.
Fluid around the lungs or in the belly: methotrexate can collect there and leak out slowly, so fluid is drained before dosing.

Pregnancy, breastfeeding and fertility

Methotrexate can cause birth defects and fetal death. A pregnancy test and birth control are needed. For non-cancer conditions, it must not be used in pregnancy. For cancer, your team will discuss the risks with you.

Women who could become pregnant: use effective birth control during treatment and for 6 months after the last dose.
Men with partners who could become pregnant: use effective birth control during treatment and for 3 months after the last dose.
Breastfeeding: do not breastfeed during treatment or for 1 week after the last dose, according to MedlinePlus.

Methotrexate can lower sperm counts and disturb periods. Ask your team about fertility before you start, and about how this may apply to your whole regimen.

Frequently asked questions

Is methotrexate for arthritis the same as chemotherapy?

It is the same drug, but at a very different dose. Arthritis doses are low and taken once a week. High cancer doses can be well over 1,000 times higher and may need hospital care with leucovorin rescue. Low-dose methotrexate still needs regular blood tests and care.

What happens if I take methotrexate every day by mistake?

This can be very dangerous, and deaths have occurred. Call your doctor or Poison Control at 1-800-222-1222 now, even if you feel fine. Do not wait for symptoms such as mouth sores, vomiting, fever or bruising. Bring your bottle and tell them exactly what you took. Call 911 for collapse, seizure or trouble breathing.

What is leucovorin rescue?

Leucovorin is a form of folic acid that normal cells can use while methotrexate is blocking the usual path. It is given on a set schedule after high doses, usually starting about 24 hours after methotrexate begins, and continues until the blood level is safe. Do not skip or delay a dose.

How long does methotrexate take to clear after a high dose?

Normally the level falls to about 10 micromolar at 24 hours, 1 at 48 hours and under 0.2 at 72 hours. Treatment continues until it is below 0.05 micromolar. Some people clear it more slowly, so your team checks a blood level at least daily.

Why do I need to avoid ibuprofen with methotrexate?

NSAIDs such as ibuprofen and naproxen can raise methotrexate levels, and severe and fatal gut toxicity has been reported, mainly with high doses. Ask your team what is safe for pain or fever. Check before taking any over-the-counter medicine, including heartburn drugs.

Can I take folic acid during methotrexate?

It depends on why you are taking methotrexate. In cancer treatment, folate supplements can reduce the effect of the drug, so avoid them unless your team tells you to take them. Check your multivitamin too. In arthritis and psoriasis, folic acid is usually recommended to lower side effects.

Does a spinal dose of methotrexate hurt?

A spinal tap can be uncomfortable, so ask your team how pain will be managed. Headache, back pain and stiff neck can happen afterward. Call your team right away for severe symptoms, fever, confusion or weakness.

Sources

This page is general information, not medical advice. Your care team knows your situation and should guide your decisions.