Methotrexate: Uses, Dosage & Side Effects
Disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis, psoriasis and Crohn's disease
Quick Facts About Methotrexate
Key Takeaways About Methotrexate
- Once-weekly dosing is critical: Methotrexate for autoimmune conditions must be taken once a week, not daily. Daily dosing can be fatal.
- Regular blood tests are essential: Complete blood counts and liver function tests are required before and throughout treatment to detect toxicity early.
- Folic acid reduces side effects: Most patients take folic acid supplements alongside methotrexate to reduce nausea, mouth sores and liver enzyme elevations.
- Strictly contraindicated in pregnancy: Methotrexate causes birth defects and miscarriage. Reliable contraception is required for women (6 months after stopping) and men (3 months after stopping).
- Avoid alcohol completely: Alcohol significantly increases the risk of liver damage during methotrexate treatment.
What Is Methotrexate and What Is It Used For?
Methotrexate is a disease-modifying antirheumatic drug (DMARD) that works by reducing inflammation and suppressing overactive immune responses. It is listed on the WHO Model List of Essential Medicines and is the cornerstone first-line therapy for rheumatoid arthritis worldwide. Methotrexate is also approved for severe psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and Crohn's disease.
Methotrexate belongs to a class of medications known as antimetabolites. Originally developed as a chemotherapy agent in the 1940s, it was later discovered that much lower doses have powerful anti-inflammatory and immunomodulatory effects. At the low weekly doses used for autoimmune and inflammatory conditions (typically 7.5–25 mg per week), methotrexate works through several mechanisms: it inhibits the enzyme dihydrofolate reductase, promotes the release of adenosine (a natural anti-inflammatory molecule), and modulates the production of inflammatory cytokines. These combined effects reduce joint inflammation, slow disease progression, and control abnormal skin cell growth.
The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) both recommend methotrexate as the first-choice DMARD for rheumatoid arthritis, either as monotherapy or in combination with other agents. Clinical trials consistently demonstrate that methotrexate reduces joint swelling, pain and stiffness, slows radiographic joint damage, and improves physical function and quality of life in RA patients.
Methotrexate is approved for the treatment of the following conditions:
- Rheumatoid arthritis (RA): First-line DMARD therapy for active RA in adults. Reduces inflammation, prevents joint damage and improves long-term outcomes.
- Juvenile idiopathic arthritis (JIA): Used in children and adolescents with polyarticular JIA who have not responded adequately to NSAIDs. Dosing is calculated based on body surface area.
- Psoriasis: Indicated for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Effective at controlling skin lesion extent and severity.
- Psoriatic arthritis: Treats both the skin manifestations and joint inflammation associated with severe psoriatic arthritis.
- Crohn's disease: Used to induce improvement in adults with moderate steroid-dependent Crohn's disease (in combination with corticosteroids) and as maintenance therapy in those who have responded to methotrexate.
The information on this page refers to low-dose methotrexate (7.5–25 mg once weekly) used for autoimmune and inflammatory conditions. High-dose methotrexate used in cancer treatment (hundreds to thousands of milligrams) follows entirely different protocols and is administered in hospital settings under close specialist supervision.
What Should You Know Before Taking Methotrexate?
Before starting methotrexate, your doctor will conduct blood tests, liver function assessments and screening for infections. You must not take methotrexate if you are pregnant, breastfeeding, have severe liver or kidney disease, active serious infections, or significant blood cell abnormalities. Several important drug interactions and precautions must be considered.
Contraindications
Methotrexate must not be used if you have any of the following conditions:
- Allergy to methotrexate or any of the excipients in the formulation
- Severe kidney disease – methotrexate is primarily eliminated by the kidneys, and impaired function leads to dangerous accumulation
- Severe liver disease – including active hepatitis, cirrhosis, or significantly elevated liver enzymes
- Blood disorders – pre-existing bone marrow suppression, significant anaemia, leukopenia or thrombocytopenia
- Excessive alcohol consumption – alcohol combined with methotrexate dramatically increases hepatotoxicity risk
- Immunodeficiency – congenital or acquired immunodeficiency syndromes
- Serious active infection – including tuberculosis, HIV, and systemic fungal infections
- Active peptic ulcer disease
- Pregnancy or breastfeeding – methotrexate is teratogenic and is excreted in breast milk
- Concurrent live vaccination – live attenuated vaccines must be avoided during treatment
Warnings and Precautions
Even at low doses, methotrexate can cause serious and potentially life-threatening side effects. Your doctor will arrange regular monitoring to detect problems early. You should be aware of the following important warnings:
Methotrexate for rheumatic diseases, skin conditions and Crohn's disease is taken once a week only. Accidental daily dosing instead of weekly dosing has caused fatal toxicity. Always confirm your dosing schedule with your doctor or pharmacist. Choose a specific day of the week and take your dose only on that day.
Discuss the following with your doctor before starting methotrexate:
- Diabetes mellitus treated with insulin – dose adjustments may be needed
- Inactive chronic infections such as tuberculosis, hepatitis B or C, or herpes zoster (shingles) – methotrexate can reactivate dormant infections
- Pre-existing liver or kidney disease – even mild impairment may require dose reduction or more frequent monitoring
- Lung problems – methotrexate can rarely cause pneumonitis (lung inflammation), and pre-existing lung disease increases risk
- Significant obesity – may affect drug distribution and toxicity risk
- Fluid collections – ascites (abdominal fluid) or pleural effusions can act as reservoirs for methotrexate, prolonging its effects and increasing toxicity
- Dehydration – can significantly increase methotrexate toxicity; adequate hydration is essential during treatment
- Sun sensitivity – methotrexate can increase photosensitivity; use appropriate sun protection and avoid sunbeds
Pulmonary haemorrhage (coughing up blood) has been reported in patients with underlying rheumatic disease who are taking methotrexate. If you experience blood in your saliva or bloody coughing, seek immediate medical attention. Enlarged lymph nodes (lymphoma) may occur during treatment and require discontinuation. Diarrhoea can be a sign of methotrexate toxicity and may also require treatment interruption.
Monitoring requirements: Before treatment begins, your doctor will order baseline blood tests including a complete blood count, liver function tests, kidney function tests, serum albumin, and screening for hepatitis B and C. A chest X-ray and lung function test may also be performed. During treatment, these tests are repeated regularly – typically every 1–2 weeks initially, then every 2–3 months once stable. It is vital to attend all scheduled monitoring appointments.
Pregnancy, Breastfeeding and Fertility
Do not use methotrexate during pregnancy or if you are trying to become pregnant. Methotrexate can cause miscarriage and severe birth defects affecting the skull, face, heart, blood vessels, brain and limbs. A pregnancy test is required before starting treatment. Women of childbearing age must use reliable contraception during treatment and for at least 6 months after the last dose. If you discover you are pregnant while taking methotrexate, contact your doctor immediately for counselling about potential risks.
Breastfeeding: Methotrexate is excreted in breast milk and must not be used during breastfeeding. If your doctor considers methotrexate treatment essential, you must stop breastfeeding.
Male fertility: Available evidence does not suggest an increased risk of birth defects or miscarriage when the father takes methotrexate at doses below 30 mg per week. However, the risk cannot be completely excluded as methotrexate may be genotoxic and can affect sperm production. Men should avoid fathering a child or donating sperm during treatment and for at least 3 months after the last dose.
Driving and operating machinery: Methotrexate treatment may cause central nervous system side effects such as fatigue and dizziness. If you experience these symptoms, do not drive or operate machinery.
How Does Methotrexate Interact with Other Drugs?
Methotrexate has numerous clinically significant drug interactions. NSAIDs, certain antibiotics, proton pump inhibitors and other immunosuppressants can increase methotrexate levels or toxicity. Live vaccines must be avoided. Always inform your doctor about all medications, supplements and herbal products you are taking.
Drug interactions with methotrexate are common and can be dangerous. Some medications reduce methotrexate clearance from the body, leading to toxic accumulation. Others compound its toxic effects on the liver, bone marrow or immune system. The following table summarises the most important interactions:
Major Interactions
| Drug / Drug Class | Interaction Effect | Clinical Advice |
|---|---|---|
| NSAIDs (ibuprofen, naproxen, diclofenac) | Reduce renal clearance of methotrexate; increase risk of bone marrow suppression and GI toxicity | Use with caution; may need dose adjustment and more frequent monitoring |
| Trimethoprim/Sulfamethoxazole (Co-trimoxazole) | Additive folate antagonism; significantly increases risk of pancytopenia | Avoid combination; use alternative antibiotics |
| Leflunomide | Additive hepatotoxicity and myelosuppression | Combination requires close monitoring of liver function and blood counts |
| Live vaccines (MMR, varicella, yellow fever) | Risk of disseminated infection due to immunosuppression | Contraindicated during methotrexate treatment; use inactivated vaccines |
| Ciclosporin | Additive immunosuppression and nephrotoxicity | Requires close monitoring if combination is necessary |
| Penicillins (amoxicillin, ampicillin) | Reduce renal excretion of methotrexate; increase toxicity risk | Monitor methotrexate levels and blood counts closely |
| Probenecid | Inhibits tubular secretion of methotrexate; increases plasma levels | Avoid combination or reduce methotrexate dose |
Other Notable Interactions
| Drug / Drug Class | Interaction Effect | Clinical Advice |
|---|---|---|
| Proton pump inhibitors (omeprazole, pantoprazole) | May reduce renal elimination of methotrexate | Use with caution; monitor for methotrexate toxicity signs |
| Phenytoin, carbamazepine, valproate | Complex interaction; methotrexate may reduce anticonvulsant levels; anticonvulsants may alter methotrexate effect | Monitor anticonvulsant levels and methotrexate response |
| Theophylline | Methotrexate may reduce theophylline clearance | Monitor theophylline levels during concurrent use |
| Retinoids (acitretin) | Additive hepatotoxicity | Avoid combination; increased risk of liver damage |
| Nitrous oxide | May potentiate antifolate effects of methotrexate | Inform your anaesthetist if undergoing procedures requiring general anaesthesia |
| Cholestyramine | May bind methotrexate in the gut and reduce absorption | Separate administration times if used together |
You must not drink alcohol during methotrexate treatment, as it significantly increases the risk of liver damage. Avoid excessive consumption of coffee, caffeinated soft drinks and black tea, as caffeine may reduce methotrexate's effectiveness or amplify side effects. Ensure you drink plenty of water during treatment, as dehydration increases methotrexate toxicity.
What Is the Correct Dosage of Methotrexate?
Methotrexate is given once weekly, not daily. The typical starting dose for rheumatoid arthritis is 7.5 mg per week, which may be gradually increased to 15–25 mg per week based on clinical response. Dosing varies by indication and patient group. Methotrexate is administered subcutaneously (under the skin) or orally, and the exact dose and route are determined by your doctor.
Methotrexate for autoimmune conditions must only be used once a week. Taking methotrexate more frequently than once weekly can cause life-threatening toxicity including fatal bone marrow suppression. Choose a specific day of the week for your dose and never change the frequency without medical advice.
Adults – Rheumatoid Arthritis
Rheumatoid Arthritis Dosing
Starting dose: 7.5 mg once weekly.
Dose adjustments: Your doctor may gradually increase the dose if the initial dose is insufficient but well tolerated. The average weekly maintenance dose is 15–20 mg. The maximum weekly dose should generally not exceed 25 mg.
Onset of action: Clinical improvement typically begins within 4–8 weeks. Once methotrexate achieves its full effect, your doctor may gradually reduce the dose to the lowest effective maintenance dose.
Duration: Methotrexate therapy for RA is a long-term treatment. Symptoms may return if treatment is discontinued.
Adults – Psoriasis and Psoriatic Arthritis
Psoriasis / Psoriatic Arthritis Dosing
Test dose: Your doctor will typically start with a test dose of 5–10 mg to assess tolerability.
Maintenance dose: If the test dose is well tolerated, treatment continues after one week at approximately 7.5 mg per week, with gradual increases as needed.
Onset of action: Improvement in psoriasis usually appears within 2–6 weeks. Your doctor will assess whether to continue based on clinical response and monitoring results.
Adults – Crohn's Disease
Crohn's Disease Dosing
Induction dose: 25 mg once weekly, usually administered subcutaneously.
Response time: Clinical response is generally expected after 8–12 weeks.
Maintenance dose: Once remission is achieved, your doctor may reduce the dose to 15 mg once weekly for maintenance therapy.
Children and Adolescents
Juvenile Idiopathic Arthritis Dosing
Dose calculation: The dose for children with polyarticular juvenile idiopathic arthritis is calculated based on body surface area (BSA), expressed as mg/m².
Age restriction: Methotrexate is not recommended for children under 3 years of age due to insufficient clinical experience in this age group.
Monitoring: Children and adolescents require particularly close medical supervision to identify side effects at the earliest possible stage.
Elderly Patients
In elderly patients, the methotrexate dose should be reduced due to age-related decline in liver and kidney function. Elderly patients require more frequent monitoring and should be observed particularly carefully for signs of toxicity.
Missed Dose
If you forget to take your weekly dose, do not take a double dose to compensate. Continue with your next scheduled dose as normal and contact your doctor for advice. Never take extra methotrexate to make up for a missed dose.
Overdose
If you suspect an overdose of methotrexate, contact your doctor immediately or go to the nearest emergency department. Bring the medication packaging with you. Signs of overdose include unusual bruising or bleeding, weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood, and decreased urine output. The antidote for methotrexate overdose is folinic acid (leucovorin), which must be administered as quickly as possible.
If your doctor has prescribed subcutaneous methotrexate (pre-filled pen or syringe), you will receive training on how to self-inject. Key steps include: (1) washing hands thoroughly, (2) checking the solution is clear and yellow with no particles, (3) choosing and cleaning the injection site on your abdomen or thigh, (4) pinching a skin fold and injecting as instructed, (5) rotating injection sites each week, and (6) disposing of the used device in a sharps container. If the injection site shows persistent redness, swelling or pain, contact your healthcare provider.
What Are the Side Effects of Methotrexate?
Like all medicines, methotrexate can cause side effects, though not everyone experiences them. The most common side effects are nausea, loss of appetite, mouth inflammation and elevated liver enzymes. Folic acid supplementation can reduce many gastrointestinal side effects. Serious but rare side effects include bone marrow suppression, liver toxicity, lung inflammation and severe infections. Report any concerning symptoms to your doctor promptly.
Pneumonia symptoms (general malaise, dry cough, shortness of breath, chest pain, fever), blood in saliva or coughing, severe skin peeling or blistering, unusual bleeding or bruising, severe diarrhoea, mouth sores, black tarry stools, blood in urine, small red spots on the skin, yellowing of the skin (jaundice), difficulty urinating, seizures, blurred vision, or loss of consciousness.
Very Common
- Loss of appetite (anorexia)
- Nausea
- Abdominal pain
- Inflammation of the mouth lining (stomatitis)
- Abnormal digestion (dyspepsia)
- Elevated liver enzymes (transaminases)
Common
- Reduced white blood cells (leukopenia), red blood cells (anaemia), platelets (thrombocytopenia)
- Headache, fatigue, drowsiness
- Pneumonia with dry cough, shortness of breath and fever
- Mouth ulcers
- Diarrhoea
- Skin rash, redness (erythema), itching (pruritus)
Uncommon
- Dizziness, confusion, depression
- Inflammation of blood vessels (vasculitis)
- Gastrointestinal ulceration and bleeding
- Inflammation of the pancreas (pancreatitis)
- Liver disease, diabetes, reduced blood protein
- Herpes-like skin eruptions, hives (urticaria), photosensitivity reactions
- Hair loss (alopecia), increased rheumatic nodules
- Joint or muscle pain, osteoporosis
- Bladder inflammation (cystitis), impaired kidney function
- Shingles (herpes zoster)
Rare
- Serious infections (including reactivation of dormant infections), sepsis
- Allergic reactions, anaphylactic shock
- Red eyes (conjunctivitis), visual disturbances
- Pericarditis (inflammation of the heart sac), pericardial effusion
- Low blood pressure, blood clots (thromboembolism)
- Pulmonary fibrosis, Pneumocystis jirovecii pneumonia
- Acute hepatitis (liver inflammation), gingivitis
- Skin hyperpigmentation, acne
- Bone fractures, kidney failure
- Mood changes, fever, slow wound healing
Very Rare
- Agranulocytosis (severe white blood cell depletion), severe bone marrow failure
- Liver failure
- Swollen lymph nodes (lymphadenopathy)
- Insomnia, pain, numbness or tingling (neuropathy), taste changes
- Seizures, meningitis symptoms, retinal damage
- Vomiting blood, toxic megacolon
- Stevens-Johnson syndrome, toxic epidermal necrolysis (severe skin reactions)
- Defective sperm production, decreased libido, erectile dysfunction
- Menstrual disturbances, vaginal discharge, infertility
- Lymphoproliferative disorders (abnormal white blood cell growth)
Methotrexate can reduce white blood cell counts and weaken resistance to infection. If you develop symptoms of infection such as fever, sore throat, mouth ulcers, or urinary problems, contact your doctor immediately for a blood test to check your white blood cell count.
It is known that methotrexate can cause bone-related problems including joint and muscle pain and osteoporosis. The risk of these effects in children is not fully established. Regular bone health assessments may be recommended for long-term users.
Your doctor will likely prescribe folic acid (typically 5 mg once weekly, taken on a different day to methotrexate) to reduce gastrointestinal side effects, mouth sores and liver enzyme elevations. Research shows folic acid supplementation reduces these side effects by approximately 40–80% without significantly reducing methotrexate's therapeutic efficacy.
How Should You Store Methotrexate?
Store methotrexate below 25°C (77°F), protected from light and out of reach of children. Do not freeze. Check the expiry date before each use and do not use if the solution is cloudy or contains particles.
Proper storage of methotrexate is important for maintaining its effectiveness and safety. Follow these guidelines:
- Store at temperatures not exceeding 25°C (77°F)
- Keep the pre-filled pen or syringe in its outer carton to protect from light
- Do not freeze – frozen methotrexate must be discarded
- Keep out of sight and reach of children
- Do not use after the expiry date printed on the label and carton
- Do not use if the solution is not clear or contains particles
- Methotrexate pre-filled pens and syringes are for single use only
- Dispose of used devices in an approved sharps container
- Do not dispose of methotrexate via household waste or wastewater – return unused medication to your pharmacy for safe disposal
If you accidentally get methotrexate solution on your skin or mucous membranes, rinse the affected area immediately with plenty of water. Methotrexate is a cytotoxic substance and should be handled with care.
What Does Methotrexate Contain?
The active substance is methotrexate. Each pre-filled pen or syringe contains methotrexate at a concentration of 25 mg/ml, available in strengths from 7.5 mg to 25 mg. Other ingredients include sodium chloride, sodium hydroxide and water for injection.
Active ingredient: Methotrexate. Each 1.0 ml of solution contains 25 mg of methotrexate.
Excipients (inactive ingredients): Sodium chloride, sodium hydroxide (for pH adjustment), and water for injections. The product contains less than 1 mmol sodium (23 mg) per dose and is therefore essentially sodium-free.
Available pre-filled pen/syringe strengths:
- 0.3 ml containing 7.5 mg methotrexate
- 0.4 ml containing 10 mg methotrexate
- 0.5 ml containing 12.5 mg methotrexate
- 0.6 ml containing 15 mg methotrexate
- 0.7 ml containing 17.5 mg methotrexate
- 0.8 ml containing 20 mg methotrexate
- 0.9 ml containing 22.5 mg methotrexate
- 1.0 ml containing 25 mg methotrexate
Appearance: Methotrexate solution for injection is a clear, yellow liquid. Pre-filled pens and syringes are supplied in packs of 1 or 4, each with an alcohol swab for injection site preparation.
Frequently Asked Questions About Methotrexate
Methotrexate for autoimmune conditions (rheumatoid arthritis, psoriasis, Crohn's disease) is taken once a week only, not daily. This is critically important: taking methotrexate daily instead of weekly has caused fatal toxicity. Your doctor will choose a specific day of the week for your dose. The typical starting dose for rheumatoid arthritis is 7.5 mg once weekly, which may be increased to 15–25 mg weekly depending on response and tolerability.
Regular blood monitoring is essential. Before starting, you need a complete blood count, liver function tests, kidney function tests, and hepatitis B/C screening. During treatment, blood tests are typically done every 1–2 weeks for the first month, every 2–4 weeks for the next 2 months, then every 2–3 months once stable. Tests check for bone marrow suppression, liver damage and kidney function. It is vital to attend every scheduled blood test.
You should avoid alcohol entirely while taking methotrexate. Both methotrexate and alcohol are processed by the liver, and combining them significantly increases the risk of hepatotoxicity (liver damage). Most clinical guidelines recommend complete alcohol avoidance during treatment. Additionally, excessive caffeine intake may reduce methotrexate's effectiveness, so moderate your coffee and tea consumption.
Folic acid is prescribed alongside methotrexate to reduce common side effects including nausea, mouth sores, hair thinning and elevated liver enzymes. Methotrexate works by interfering with folate metabolism, and supplementing with folic acid (typically 5 mg once weekly, taken on a different day than methotrexate) helps protect healthy cells. Clinical studies show folic acid supplementation reduces gastrointestinal side effects by approximately 40–80% without significantly reducing methotrexate's therapeutic effect on inflammation.
No – methotrexate is strictly contraindicated during pregnancy. It can cause miscarriage and severe birth defects affecting the skull, face, heart, blood vessels, brain and limbs. Women must use reliable contraception during treatment and for at least 6 months after the last dose. Men should avoid fathering a child during treatment and for at least 3 months after stopping. A pregnancy test is required before starting treatment. If you become pregnant while on methotrexate, contact your doctor immediately.
Methotrexate has a delayed onset of action. For rheumatoid arthritis, clinical improvement typically begins within 4–8 weeks, with maximum benefit sometimes not achieved until 12 weeks or longer. For psoriasis, improvement may be seen within 2–6 weeks. For Crohn's disease, response is generally expected after 8–12 weeks. Because of this delay, your doctor may prescribe additional medications (such as corticosteroids) to manage symptoms while waiting for methotrexate to reach full effect.
References
This article is based on the following international medical guidelines and peer-reviewed sources:
- Fraenkel L, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 2021;73(7):924-939. doi:10.1002/art.41752
- Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18. doi:10.1136/ard-2022-223356
- World Health Organization. WHO Model List of Essential Medicines – 23rd List. Geneva: WHO; 2023.
- National Institute for Health and Care Excellence. Rheumatoid arthritis in adults: management (NG100). NICE; 2018 (updated 2020).
- European Medicines Agency. Methotrexate – Summary of Product Characteristics (SmPC). EMA; 2024.
- Lopez-Olivo MA, et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;(6):CD000957. doi:10.1002/14651858.CD000957.pub2
- British National Formulary (BNF). Methotrexate. NICE/BNF; 2025.
- Menter A, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486.
- Shea B, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;(5):CD000951.
- McDonald JW, et al. Methotrexate for induction and maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2014;(8):CD003459.
About This Article
Written by
iMedic Medical Editorial Team
Specialists in rheumatology, dermatology and clinical pharmacology with documented academic background and clinical experience.
Medically Reviewed by
iMedic Medical Review Board
Independent panel of medical experts reviewing content according to international guidelines (ACR, EULAR, NICE, WHO).
Evidence level: 1A – Based on systematic reviews of randomized controlled trials. Last fact-check: . This content follows the GRADE evidence framework and is free from commercial funding or pharmaceutical sponsorship.