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Antimetabolite, DMARD

Methotrexate

Methotrexate is a folate analog and dihydrofolate reductase (DHFR) inhibitor used as chemotherapy for malignancies, as a disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis and psoriasis, and for medical management of ectopic pregnancy. The most critical exam fact is that leucovorin (folinic acid) is the rescue agent for methotrexate toxicity, bypassing the DHFR block.

Practice questionsHigh-yield facts
Drug classAntimetabolite, folate analog, DMARD
MechanismInhibits dihydrofolate reductase, blocks DNA and RNA synthesis
Main usesRheumatoid arthritis, cancer, ectopic pregnancy, psoriasis
Key adverse effectMyelosuppression, hepatotoxicity, pulmonary fibrosis, mucositis
6 min readFor medical studentsUpdated 2026-10-14

Mechanism of action

Methotrexate is a folic acid analog that competitively and reversibly inhibits dihydrofolate reductase (DHFR), the enzyme that reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is essential for one-carbon transfer reactions required for the synthesis of purines and thymidylate, which are building blocks of DNA and RNA.

By depleting tetrahydrofolate, methotrexate blocks de novo synthesis of purines and pyrimidines, impairing DNA replication and cell division. This particularly affects rapidly dividing cells such as malignant cells, bone marrow cells, gastrointestinal epithelium, and hair follicles.

At low doses (used for rheumatoid arthritis and psoriasis), methotrexate also has anti-inflammatory and immunosuppressive effects through increased adenosine release, decreased cytokine production, and modulation of T-cell and B-cell function. The mechanism in autoimmune disease is distinct from its cytotoxic effect in cancer.

High-yield for exams
  • Methotrexate inhibits dihydrofolate reductase (DHFR), blocking purine and thymidylate synthesis.
  • Leucovorin (folinic acid) is the rescue agent for methotrexate toxicity, bypassing the DHFR block.
  • Methotrexate is dosed weekly for rheumatoid arthritis and psoriasis; daily dosing is a fatal medication error.
  • Major toxicities: myelosuppression, mucositis, hepatotoxicity, pulmonary fibrosis (pneumonitis), and teratogenicity.
  • Methotrexate pneumonitis is idiosyncratic, not dose-dependent; presents with cough, fever, dyspnea; treat by stopping drug and giving corticosteroids.
  • Methotrexate is absolutely contraindicated in pregnancy (category X); causes neural tube defects and craniofacial abnormalities.
  • NSAIDs reduce renal clearance of methotrexate and increase toxicity; interaction is especially dangerous with high-dose methotrexate.
  • High-dose methotrexate requires hydration, urinary alkalinization, and leucovorin rescue to prevent renal crystal precipitation.

Indications

Oncologic indications

  • Acute lymphoblastic leukemia (ALL)
  • Non-Hodgkin lymphoma
  • Osteosarcoma
  • Breast cancer
  • Head and neck cancers
  • Choriocarcinoma and gestational trophoblastic disease
  • Bladder cancer

Rheumatologic and dermatologic indications

  • Rheumatoid arthritis — first-line DMARD
  • Psoriasis and psoriatic arthritis — moderate to severe disease
  • Systemic lupus erythematosus
  • Dermatomyositis and polymyositis
  • Vasculitis (granulomatosis with polyangiitis)

Obstetric indication

  • Medical management of ectopic pregnancy — for hemodynamically stable patients with unruptured ectopic pregnancy and certain criteria (low β-hCG, small mass size)

Other indications

  • Crohn disease (steroid-sparing agent)
  • Severe asthma (steroid-sparing agent)

Dosing varies widely by indication and follows disease-specific protocols.

Pharmacokinetics

Absorption: Methotrexate can be administered orally, intramuscularly, intravenously, intrathecally, or subcutaneously. Oral bioavailability is dose-dependent and saturable; at low doses (< 30 mg/m²) bioavailability is approximately 60%, but decreases at higher doses.

Distribution: Widely distributed; does not cross the blood-brain barrier well when given systemically (hence intrathecal administration for CNS prophylaxis in leukemia). Approximately 50% protein-bound. Methotrexate is taken up into cells via the reduced folate carrier and converted to polyglutamate forms that are retained intracellularly and have prolonged activity.

Metabolism: Partially metabolized to 7-hydroxymethotrexate, which is less active and can accumulate in renal insufficiency, contributing to toxicity.

Excretion: Primarily renal excretion via glomerular filtration and active tubular secretion. The elimination half-life is typically 3 to 10 hours for low doses and 8 to 15 hours for high doses. Elimination is prolonged in patients with renal impairment, pleural effusions, or ascites (third-spacing).

Clinical implications: Hydration and urinary alkalinization are used with high-dose methotrexate to enhance renal clearance and prevent crystal precipitation in renal tubules. Monitoring of methotrexate levels is standard with high-dose regimens.

Adverse effects

Hematologic

  • Myelosuppression — dose-limiting toxicity; leukopenia, thrombocytopenia, anemia
  • Megaloblastic anemia (folate deficiency effect)

Gastrointestinal

  • Mucositis and stomatitis — very common with high doses
  • Nausea, vomiting, diarrhea
  • Hepatotoxicity — transaminase elevations, hepatic fibrosis, cirrhosis with chronic use (especially in psoriasis patients and with alcohol use)

Pulmonary

  • Methotrexate-induced pneumonitis — potentially life-threatening; presents with cough, dyspnea, fever, and pulmonary infiltrates; can progress to pulmonary fibrosis. This is an idiosyncratic reaction, not dose-dependent, and requires discontinuation.

Renal

  • Acute kidney injury — high-dose methotrexate can precipitate in renal tubules, causing crystal nephropathy
  • Chronic use can cause renal impairment

Dermatologic

  • Alopecia
  • Photosensitivity
  • Skin rash

Neurologic

  • Intrathecal administration can cause arachnoiditis, transverse myelitis, leukoencephalopathy

Teratogenicity

  • Methotrexate is highly teratogenic — causes neural tube defects, craniofacial abnormalities, limb defects (methotrexate embryopathy)
  • Pregnancy category X — absolutely contraindicated in pregnancy except for life-threatening maternal conditions

Other

  • Infections due to immunosuppression
  • Tumor lysis syndrome (in hematologic malignancies)
  • Rarely, secondary malignancies

Contraindications and warnings

Absolute contraindications

  • Pregnancy — methotrexate is teratogenic and abortifacient
  • Breastfeeding
  • Severe renal impairment (creatinine clearance < 30 mL/min for low-dose use)
  • Severe hepatic impairment or active liver disease
  • Alcoholism or alcohol abuse
  • Severe immunodeficiency or active serious infections
  • Pre-existing blood dyscrasias (severe bone marrow suppression)

Warnings and precautions

  • Renal function monitoring — methotrexate is renally excreted; dose adjustments required in renal impairment
  • Hepatotoxicity monitoring — baseline and periodic liver function tests; liver biopsy may be recommended with long-term use in psoriasis
  • Pulmonary monitoring — educate patients to report cough or dyspnea immediately; discontinue if pneumonitis suspected
  • Folic acid supplementation — in rheumatoid arthritis and psoriasis, concomitant folic acid (1–5 mg/day) or leucovorin reduces toxicity without compromising efficacy
  • Pleural effusions and ascites — third-spacing prolongs methotrexate half-life and increases toxicity; drain effusions before high-dose therapy
  • Fertility — can impair fertility in both sexes; contraception required during and after therapy

Black box warnings (US FDA)

  • Can cause severe or fatal toxicities including myelosuppression, hepatotoxicity, pulmonary toxicity, renal toxicity, and GI toxicity
  • Should only be used by clinicians experienced in antimetabolite therapy
  • Fetal death and teratogenicity
  • Tumor lysis syndrome in hematologic malignancies

Drug interactions

Drugs that increase methotrexate toxicity

  • NSAIDs — reduce renal clearance of methotrexate and increase toxicity; particularly dangerous with high-dose methotrexate. Even low-dose NSAIDs with chronic low-dose methotrexate can increase risk, though often used cautiously together in rheumatoid arthritis.
  • Penicillins and cephalosporins — decrease renal tubular secretion of methotrexate
  • Proton pump inhibitors (PPIs) — especially high-dose PPIs can reduce methotrexate clearance
  • Salicylates (aspirin) — displace methotrexate from protein binding, increase toxicity
  • Sulfonamides (trimethoprim-sulfamethoxazole) — additive folate antagonism and bone marrow suppression
  • Probenecid — blocks renal tubular secretion of methotrexate

Drugs with additive toxicity

  • Other hepatotoxic drugs (alcohol, azathioprine, retinoids, sulfasalazine)
  • Other myelosuppressive agents
  • Radiation therapy

Other interactions

  • Live vaccines — avoid during immunosuppression
  • Theophylline — methotrexate may decrease theophylline clearance

Clinical pearl: Always review concomitant medications before initiating methotrexate, especially NSAIDs and antibiotics.

Clinical pearls

  • Leucovorin (folinic acid) is the antidote for methotrexate toxicity. It bypasses the DHFR block by directly providing tetrahydrofolate. Leucovorin rescue is standard with high-dose methotrexate regimens and is used in overdose or severe toxicity.
  • Weekly dosing error: Methotrexate for rheumatoid arthritis and psoriasis is dosed once weekly, not daily. Daily dosing is a medication error that has caused fatalities. Always counsel patients clearly.
  • Monitoring in rheumatoid arthritis: Baseline CBC, liver enzymes, creatinine, hepatitis B/C serologies, and chest X-ray. Monitor CBC and liver/renal function every 2–4 weeks initially, then every 8–12 weeks once stable.
  • Methotrexate pneumonitis is an idiosyncratic hypersensitivity reaction, not dose-dependent. It can occur at any time. Symptoms: dry cough, fever, dyspnea. Diagnosis of exclusion. Treatment: discontinue methotrexate, corticosteroids.
  • Folate supplementation (folic acid 1 mg daily or 5 mg weekly) reduces methotrexate GI and hematologic side effects in autoimmune disease without reducing efficacy. It does not protect against hepatotoxicity or pneumonitis.
  • Exam association: Methotrexate for ectopic pregnancy management requires the patient to be hemodynamically stable, unruptured ectopic, β-hCG typically < 5,000 mIU/mL, and able to follow up. Single-dose or multi-dose protocols exist.
  • Teratogenicity: Pregnancy must be excluded before starting methotrexate in women of childbearing age. Effective contraception is mandatory. Both men and women should discontinue methotrexate at least 3 months before conception.
  • High-dose methotrexate protocols (e.g., for osteosarcoma, CNS lymphoma) require hydration, urinary alkalinization (sodium bicarbonate to keep urine pH > 7), and leucovorin rescue starting 24 hours after methotrexate. Serum methotrexate levels are monitored to guide leucovorin dosing duration.
  • Third-spacing: Ascites and pleural effusions act as reservoirs for methotrexate, causing prolonged release and increased toxicity. Drain before high-dose therapy.
  • Alcohol: Patients on methotrexate should avoid alcohol completely or minimize intake, as the combination greatly increases hepatotoxicity risk.
Mnemonic

Methotrexate toxicities — MAD HELP: Myelosuppression, Alopecia, Diarrhea/mucositis, Hepatotoxicity, Embryopathy (teratogenicity), Lung fibrosis/pneumonitis, Photosensitivity.

Practice questions

1. A 45-year-old woman with rheumatoid arthritis is started on methotrexate 15 mg once weekly along with folic acid supplementation. Three weeks later, she develops a dry cough, low-grade fever, and progressive dyspnea. Chest X-ray shows bilateral interstitial infiltrates. Laboratory tests show normal white blood cell count and no evidence of infection. What is the most appropriate next step in management?

Answer: B. This patient has methotrexate-induced pneumonitis, an idiosyncratic hypersensitivity reaction presenting with cough, fever, dyspnea, and pulmonary infiltrates. The key management steps are immediate discontinuation of methotrexate and administration of corticosteroids. This is not an infection (WBC normal, no infectious symptoms predominate) or a dose-related toxicity requiring leucovorin. Folic acid does not prevent or treat pneumonitis. Adding trimethoprim-sulfamethoxazole would worsen toxicity due to additive folate antagonism.

2. A 28-year-old woman with an unruptured ectopic pregnancy (β-hCG 3,200 mIU/mL) is treated with intramuscular methotrexate. Four days later, she develops severe mucositis, pancytopenia (WBC 1,200/μL, platelets 45,000/μL), and elevated liver enzymes. Which agent should be administered immediately to reverse these effects?

Answer: B. This patient has severe methotrexate toxicity manifested by mucositis and myelosuppression. Leucovorin (folinic acid) is the specific antidote, providing reduced folate that bypasses the DHFR block and rescues normal cells from methotrexate's effects. Folic acid requires reduction by DHFR and will not work when DHFR is inhibited. Pyridoxine and cyanocobalamin are unrelated vitamins. N-acetylcysteine is used for acetaminophen overdose, not methotrexate toxicity.

3. A 62-year-old man with osteosarcoma receives high-dose intravenous methotrexate. To prevent nephrotoxicity from methotrexate precipitation in the renal tubules, which intervention should be implemented?

Answer: C. High-dose methotrexate can precipitate in renal tubules, causing crystal nephropathy and acute kidney injury. Prevention requires aggressive intravenous hydration and urinary alkalinization (keeping urine pH > 7) with sodium bicarbonate, which increases methotrexate solubility. Acidification would worsen precipitation. Fluid restriction would increase precipitation risk. Prophylactic dialysis is not standard. Leucovorin rescue (typically starting 24 hours post-methotrexate) and monitoring serum methotrexate levels are also essential components of high-dose protocols.

Frequently asked questions

How does methotrexate work?

Methotrexate is a folate analog that inhibits dihydrofolate reductase (DHFR), an enzyme that converts dihydrofolate to tetrahydrofolate. Tetrahydrofolate is required for one-carbon transfer reactions in the synthesis of purines and thymidylate, which are necessary for DNA and RNA synthesis. By blocking DHFR, methotrexate impairs DNA replication and cell division, particularly affecting rapidly dividing cells such as cancer cells, bone marrow, and gastrointestinal epithelium. At low doses, methotrexate also has anti-inflammatory effects through increased adenosine release and cytokine modulation.

What are the side effects of methotrexate?

Common side effects of methotrexate include nausea, mouth sores (mucositis), fatigue, and elevated liver enzymes. Serious adverse effects include myelosuppression (low blood counts), hepatotoxicity (liver damage, fibrosis, cirrhosis with chronic use), pulmonary toxicity (methotrexate pneumonitis and fibrosis), renal toxicity, and severe infections due to immunosuppression. Methotrexate is highly teratogenic, causing birth defects and fetal death. Alopecia, photosensitivity, and gastrointestinal symptoms are also common. Patients should be monitored with regular blood tests and educated to report respiratory symptoms immediately.

What is the antidote for methotrexate toxicity?

The antidote for methotrexate toxicity is leucovorin (folinic acid), which is the reduced form of folic acid. Leucovorin bypasses the dihydrofolate reductase enzyme that methotrexate inhibits, directly providing tetrahydrofolate to cells for DNA and RNA synthesis. This allows normal cells to recover while cancer cells, which have taken up more methotrexate, remain affected. Leucovorin rescue is routinely used with high-dose methotrexate chemotherapy regimens and is administered in cases of overdose or severe toxicity to prevent life-threatening myelosuppression and mucositis.

Can you drink alcohol while taking methotrexate?

No, patients taking methotrexate should avoid alcohol or strictly limit intake. Both methotrexate and alcohol are hepatotoxic, and their combination significantly increases the risk of liver damage, including hepatic fibrosis and cirrhosis. Chronic alcohol use is an absolute contraindication to methotrexate therapy. Even occasional alcohol consumption can elevate liver enzymes and accelerate hepatotoxicity, particularly with long-term methotrexate use for conditions like rheumatoid arthritis or psoriasis. Patients with a history of alcoholism should not receive methotrexate.

Methotrexate vs leucovorin — what is the difference?

Methotrexate is a chemotherapy drug and immunosuppressant that inhibits dihydrofolate reductase, blocking folate metabolism and DNA synthesis to kill rapidly dividing cells. Leucovorin (folinic acid) is the rescue agent for methotrexate toxicity; it is a reduced form of folic acid that bypasses the enzyme methotrexate inhibits, providing cells with the folate cofactor they need for DNA synthesis. Leucovorin is given after high-dose methotrexate to protect normal cells from toxicity while allowing the drug to continue affecting cancer cells, which have taken up more methotrexate.

Conditions it is used for

Rheumatoid arthritisPsoriasisPsoriatic arthritisAcute lymphoblastic leukemiaNon-Hodgkin lymphomaEctopic pregnancyOsteosarcomaChoriocarcinoma
LeucovorinAzathioprineSulfasalazineHydroxychloroquine6-mercaptopurineCyclophosphamideAdalimumabInfliximab

Sources and further reading

DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: L01BA01WHO ATC/DDD index: L04AX03

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.