Methotrexate

Is methotrexate safe?

Methotrexate is safe enough to be the first drug most rheumatologists reach for, provided three things hold: it is taken once a week, never daily; blood tests are kept up; and the prescriber knows about every other medicine. When one of those slips, it can kill. We score it 50, close to warfarin (49), another useful drug whose margin for error is small. A middling score is not a reason to stop: untreated rheumatoid arthritis destroys joints, so talk to your rheumatologist before any change.

Our score covers the low weekly doses used for rheumatoid arthritis, psoriasis and similar conditions, about 7.5 to 30 mg a week. The same drug is used for some cancers at much higher doses, often in hospital, sometimes with a rescue drug and specialist monitoring.

Why is methotrexate taken once a week?

Methotrexate blocks folate, which fast-dividing cells need. Once a week calms the immune system while giving the bone marrow, gut lining and liver time to recover. Taken every day, the same tablet becomes a poison: seven times the dose, with no gap. Blood cells crash, the mouth and gut ulcerate, and infection or bleeding follows.

The errors follow the same pattern. US FDA reports from November 1997 to 2001 included 106 medication errors involving methotrexate, with 25 deaths; confusion over the weekly schedule was the most common cause. In Australia, coroners recorded seven deaths in which daily dosing was documented, and poisons centres logged 92 cases between 2004 and 2015, some caused by pharmacists filling pill organisers wrongly. The UK had 11 serious Yellow Card reports of daily dosing between 2006 and mid-2020, some fatal.

Regulators have responded repeatedly. In 2019 the EMA required blister packs instead of bottles, prominent pack warnings and patient cards. The MHRA added a space on the box to write the dosing day. In February 2026 the US boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary was expanded to say that daily dosing by mistake has resulted in death.

What are the serious side effects?

The US label lists severe harm to the bone marrow, gut, liver, lungs, skin and kidneys, plus serious infections. At low doses most of these are uncommon, but they are real. The best measure comes from CIRT, a trial in which 4,786 people without arthritis took methotrexate (median 15 mg a week) or placebo for about two years:

In the arthritis trials behind the label, liver tests rose in 15% of patients and about 1% developed lung inflammation (pneumonitis). In psoriasis, liver scarring can develop without symptoms, more often after a total of 1.5 g or more. That is why regular blood tests matter: they catch falling blood counts and liver changes before you feel them.

Interactions to know about

The label's list is long. The ones that matter most day to day:

• Trimethoprim and co-trimoxazole (Bactrim, Septra): the NHS lists both, and the US label lists sulfonamide antibiotics. In an Ontario study of older adults on methotrexate, co-trimoxazole raised hospital admission by about half compared with a cephalosporin, though 30-day deaths were similar.
• NSAIDs and aspirin, such as ibuprofen, and proton pump inhibitors can raise methotrexate levels.
• Penicillins and other drugs that harm the liver or kidneys.
• Nitrous oxide (laughing gas) anaesthesia: the label says to avoid it.
• Live vaccines are not recommended.
• Alcohol: heavy drinking raises the risk of liver damage.

Carry the patient card and show it at every new doctor, dentist, pharmacy or hospital visit.

Who should be careful

• Anyone pregnant or planning a pregnancy: it is contraindicatedContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary for non-cancer use, with contraception needed for 6 months after the last dose in women and 3 months in men.
• People with liver disease, heavy drinking, kidney disease or low blood counts.
• Older people and anyone on many daily tablets, where a weekly pill is easy to mix up. Keep it in a separate place from daily medicines.
• Anyone who gets a sore throat, fever, mouth ulcers, a new cough or breathlessness, unusual bruising or diarrhoea: contact your doctor promptly.

How we scored it

Dependence (97) and track record (92) are strong. Overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (25), regulatory warnings (20) and interactions (35) are among the weakest on our list, because a simple dosing mix-up can be fatal and the boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary reflects that. Serious side effects (45) are less common at weekly arthritis doses than in cancer treatment, but frequent enough to need blood monitoring for as long as you take it. For a steroid often used alongside it in flares, see prednisone.