Methotrexate – Medications for Rheumatoid Arthritis (RA)


Methotrexate (mtx) is the current ‘gold standard’ of Rheumatoid Arthritis treatment.   While it comes with a whole host of unpleasant side effects, it has the highest rate of continued long-term treatment.  In short, the side effects are worth it to most people, because it reduces their joint pain and inflammation effectively.

methotrexateHowever methotrexate is a double edged sword.  Most people who take the drug see it as a necessary evil.  Some people don’t experience side effects at all, but most experience some discomfort at least.  It’s a very individual thing.

For most people, the side effects will fade over time.  The body can adjust, particularly if the drug dose is tapered up slowly.

It takes time for methotrexate to work its magic – it usually takes 6-8 weeks to see any benefit, and it can take much longer.

Many people give up too soon because the side effects can be very unpleasant, and take time to adjust to, and the benefits are slow to appear.

How does methotrexate work?

From ‘Australian Prescriber’….’Methotrexate is a folic acid antagonist cytotoxic drug. By binding to dihydrofolate reductase, methotrexate interferes with DNA synthesis and cell replication.’

If that sounds scary, it is.  Methorexate is a chemotherapy agent, used to treat certain cancers.  It is used in much smaller doses in Rheumatoid Arthritis, however, and methotrexate is NOT considered ‘chemotherapy’ in the doses used in RA or other forms of inflammatory arthritis.  There is a lot written about methotrexate on the internet, and it can sound frightening.  And there is no doubt that it is a serious medication for a serious disease.  But rheumatologists consider it a DMARD (Disease Modifying Anti-Rheumatic Drug) in these much lower doses, and this should be reassuring.

Methotrexate dose

Methotrexate is taken once weekly and a usual dose would be between 7.5 to 30mg, most commonly between 15mg and 20mg. It can be taken orally or by self injection.  Nausea is a very common side effect, and many people find the injectable version reduces the nausea experienced.

Methotrexate Side effects

Nausea is the most commonly reported side effect and usually occurs the day after the dose is taken. Most people take their dose at night, to sleep away the worst of the side effects.  Many people plan their methotrexate dose, so that the day after they take it is a ‘down day’ and they plan to be resting/recovering all day from the side effects of the methotrexate.

Liver toxicity is the most serious adverse effect of methotrexate.  About 60% of patients will experience mild toxicity, but less than 30% stop taking the drug in the first year due to side effects.

Because methotrexate can cause liver problems, alcohol should be avoided while taking methotrexate.  Blood tests for liver function are taken monthly to check for any toxicity issues, so that they can be picked up early, before permanent damage is done.

Other common side effects include fatigue, mouth ulcers, reversible hair loss, rash, and increased rheumatoid nodule formation. Rarer adverse effects include bone marrow suppression, liver fibrosis/cirrhosis (increased with alcohol consumption) and pulmonary infiltrates/allergic pneumonitis.   Methotrexate can also cause mood changes.  Depression and/or anxiety caused by methotrexate therapy can be serious, and suicidal ideation is possible.

Folic acid should be taken along with methotrexate – but not on the same day as the methotrexate dose.  Some people only take it for 2 days 3 days before their methotrexate dose, others take it every day except methotrexate day.  Taking folic acid and drinking lots of water on the day of and the day after taking methotrexate can reduce the nausea and gastric side effects of methotrexate significantly.

For a complete list of methotrexate side effects click here

Methotrexate Contraindications

Methotrexate should not be used in patients with pre-existing bone marrow conditions, immunodeficiency, severe liver disorders, or active infectious disease.  Heavy drinkers will not be prescribed methotrexate.  Patients often ask about a safe level of drinking on methotrexate, but no studies have been done.  Opinion varies widely.  Some rheumatologists demand complete abstinence.  Some say 1-2 drinks a month is OK.  Some say 1-2 drinks per week is fine.

Ultimately, drinking alcohol is the choice of the patient, but it considerably increases the chances of liver toxicity.

Advice in pregnancy/breastfeeding

Methotrexate can not be used in pregnancy or while breast feeding.


  1. I find the mental side effects much worse than the nausea and migraines. I’m a 17 year old who has a great life (besides the RA and Chrones disease) but I feel like I have no reason to live anymore, I always feel anxious and unsteady mentally. Methotrexate has taken away the happiest parts of my youth, and I guess I can’t really get that back.


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