I have this conversation at least a few times a week. A patient comes in, we talk through a new diagnosis, I recommend starting methotrexate, they seem on board, and then they go home and Google it. They see words like chemotherapy and liver failure and decide they're not taking it. I completely understand the reaction. Those are scary things to read about. But I think it's worth setting the record straight, because methotrexate is one of the most misunderstood medications I prescribe.
A little background
Methotrexate has been around since the 1940s. It was originally developed as a chemotherapy drug, specifically to treat childhood leukemia, and it's still used for cancer today. That's where the reputation comes from, and it's not totally unfair. At high doses, methotrexate is a powerful chemotherapy agent with a serious side effect profile.
But here's the thing. When methotrexate is used for cancer, doses typically run 3 to 15 grams per square meter, given intravenously over several hours in a hospital setting with intensive monitoring. To put that in perspective, that's somewhere in the range of 300 to 500 times the dose I prescribe for RA. The drug shares a name, but in practice it's a completely different clinical situation.
The FDA approved low-dose methotrexate for rheumatoid arthritis in 1988, and it's been the backbone of RA treatment ever since. Decades of use in millions of patients. That long track record is actually reassuring — we know this drug really well.
How it actually works
At high doses, methotrexate works by blocking a key step in cell replication, which is why it's useful against fast-growing cancer cells. At the doses we use in rheumatology, something different is happening.
Methotrexate is structurally similar to folic acid, so it fits into an enzyme called dihydrofolate reductase (DHFR), which normally converts folate into its active form. Methotrexate binds to that enzyme and blocks it. At low doses, this triggers a chain reaction that causes adenosine to accumulate — a naturally occurring molecule in the body with potent anti-inflammatory properties. So rather than attacking cells the way chemotherapy does, low-dose methotrexate is essentially signaling the immune system to calm down.
The folate piece is also why we use folic acid alongside it. Because methotrexate blocks that folate pathway, it depletes active folate in normal tissues, and that's responsible for a lot of the side effects — nausea, mouth sores, liver enzyme changes. Taking folic acid daily helps replenish what methotrexate disrupts. The important thing is that folic acid reduces side effects without reducing how well the medication works, because the anti-inflammatory effect runs through that separate adenosine pathway. So there's really no reason not to take it.
Why we still use it
Methotrexate works, it's inexpensive, and we have more safety data on it than almost anything else in rheumatology. It's taken once a week — not daily — which is worth mentioning because that's a common point of confusion. A lot of patients do well on it alone and stay on it long term. I have patients who have been on it for years with well-controlled disease and no significant issues.
That said, biologics like Humira, Enbrel, and Rinvoq are often more effective and generally better tolerated from a physical side effect standpoint, though that's not always necessary depending on the situation. The catch is that insurance companies typically require a trial of methotrexate before they'll approve a biologic. So methotrexate usually comes first not because it's the most powerful tool I have, but because it works for many people and it's where the system requires us to start.
I don't consider methotrexate a major immunosuppressant. It does modestly reduce antibody production, which is why we hold it around vaccine administration, but the infection risk on methotrexate alone is relatively low compared to stronger medications. It's not in the same category as the heavier immunosuppression I sometimes prescribe.
What to actually expect
Side effects do happen. The ones I hear about most are post-dose fatigue (that "blah" feeling for 12 to 36 hours after your weekly dose), nausea, mouth sores, and hair thinning. That last one causes a lot of anxiety, particularly for women. It's worth knowing that significant hair loss at the doses we use is actually one of the less common side effects, affecting around 5 to 6% of patients. GI symptoms are more common, affecting roughly 1 in 3 people to some degree. Folic acid helps with a lot of this.
We monitor with labs: a CBC (blood counts), liver enzymes, and kidney function. I check these before starting, about a month in, and then every three months ongoing. Mild liver enzyme changes happen sometimes. They're usually minor and go away quickly when we reduce or stop the dose. In my years of practice, I haven't seen anything close to liver failure at the doses we use in rheumatology. We check kidney function because methotrexate is cleared by the kidneys, so if kidney function declined, drug levels could build up.
A few situations where I wouldn't use methotrexate: more than 4 to 5 alcoholic drinks per week, pre-existing liver disease, and pregnancy or plans to become pregnant in the near future.
The bottom line
Methotrexate has earned its place as a starting point. It's not the most powerful tool I have, and for patients who need more, there are better options we can get to. But it works for a lot of people, it's affordable, and 35-plus years of data in rheumatology means we understand it well. The reputation it has online doesn't match the reality of how it's used in this setting.
If you've been prescribed it and have questions, that's what I'm here for.