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Methotrexate for lupus: help it work better and prevent side effects

How to prevent and treat side effects from methotrexate:

We have been using methotrexate to treat rheumatic diseases such as rheumatoid arthritis and lupus since the 1990’s. It is generally a safe medication when used along with the other important treatments for lupus. However, methotrexate can occasionally cause nuisance side effects. There are things you can do to ensure methotrexate works better for you and how to prevent side effects. This blog post tells you how.

Note: methotrexate for lupus is a slow-working drug. It can take up to 3 months after being on the maximum dose to see the full effects. The maximum dose we sometimes need is up to 30 mg weekly of injectable methotrexate.

Ask your prescribing doctor about any of these before putting them into practice. However, I suspect your doctor will be very happy you are being so proactive. You have a better chance of doing well if you follow this advice (but I cannot give formal medical advice since I do not know your medical situation).

Tips on helping methotrexate for lupus work better for you:

  • Absorb pills better by taking them on an empty stomach.
  • If tolerating methotrexate well and still having active inflammation, you can ask your doctor about going up on the dose every few weeks (as long as you have your blood counts and liver enzymes checked regularly after dose increases). We can go as high as 30 mg injectable weekly.
  • Do not take with dairy products or calcium; dairy products and calcium decrease absorption
  • Stop caffeine for 3 months while taking methotrexate; caffeine can reduce its effects
  • If you take pills once a week, ask your provider about either splitting up the dose over 24 hours or switching to injections. Both are absorbed better.

Take folic acid or leucovorin:

It is important to either take folic acid every day (1 mg to 5 mg daily), or the stronger vitamin called leucovorin (also called folinic acid) once a week (10 mg to 25 mg) to help decrease the risk of getting any side effects from methotrexate. Leucovorin is best taken 8-12 hours after your methotrexate dose.

Drug monitoring with your doctor

Remember to see your healthcare provider every 4-12 weeks while taking methotrexate so that they can monitor your blood counts and liver enzymes. If you ever have to reschedule an appointment make sure you ask the phone person to put you in ASAP with any provider in their office if your doctor doesn’t have an appointment available right away. It is very important your health care provider see you before the 3-month point is up after your previous appointment.

What to do for methotrexate side effects

If you get sores in your mouth:

Take an over-the-counter vitamin A tablet 8000 IU daily. You can also split up your methotrexate dose over a 24-hour period (such as taking half the dose on one day and the other half the next day). If you split up the dose and if your doctor prescribed leucovorin, make sure to take your leucovorin 8-12 hours after your last dose of methotrexate.

If you get “the blahs”, headache, memory problems, fatigue, or tingling sensations:

Take one tablet of Mucinex DM with your methotrexate, then take another tablet 8 hours later. Dextromethorphan (the active ingredient) has been shown to decrease methotrexate side effects when it affects the central nervous system.

If you get stomach upset:

Split up your dose over 24 hours as mentioned above. However, make sure and repeat your blood work sooner than later (split dosing increases overall blood levels of methotrexate).

If you develop any symptoms that could be due to infection:

Cough, fever, sore throat, pain with urination, increased urine frequency, painful red skin: Call and see your primary care doctor right away. If it is a weekend or evening, go to your closest urgent care center to ensure you don’t have an infection. Do not take your methotrexate during active infections.

If you get hair thinning:

If you notice hair thinning; do not worry. Rarely do other people notice. It also grows back.

Ask your doctor if you could try taking 25 mg of leucovorin 25 mg eight to twelve hours after each dose. This usually helps a lot. Also, ask your doctor if you should lower your methotrexate dose. In addition, use minoxidil twice a day on your scalp. minoxidil stimulates the hair follicles and causes increased blood flow to the hair follicles.

Hair is slow to grow back. If taking these measures (or even if you need to stop methotrexate), it takes 6-12 months later before you will notice the results of increased hair growth.

If you get any vaccination, ask your doctor if you should stop your methotrexate for 1 week after the vaccine:

A 2018 study showed that rheumatoid arthritis patients who were under good control and stopped their methotrexate for 2 doses after their flu (influenza) vaccination had a significantly better response to the vaccine compared to those who kept taking their methotrexate. Then, a 2023 study showed that just stopping one dose of methotrexate after getting a flu shot worked well without causing many rheumatoid arthritis flares. Only do this if your inflammation is under good control.

Can you drink alcohol while taking methotrexate for lupus?

Ask your doctor first.

However, studies show that low to moderate alcohol use is not associated with any liver problems from methotrexate. In addition, low amounts of alcohol intake may actually reduce autoimmune problems from lupus.

COMMENT: Do you take methotrexate? How have you done on it? Any advice?

AUTHOR: Donald Thomas, MD


  1. I developed a massive blood clot while taking methotrexate. It was discontinued after my emergency admission to the hospital. Doctors agreed methotrexate was a contributing factor.

    • Hello Kathy,
      I’m sorry to hear you had a negative experience. I hope you are better now. could I ask, how many mg of methotrexate you were on weekly ?

  2. I avoided taking it for years because of the testing worries the liver. Finally, 10 years into a UCDT Diagnosis (with lupus like features), I tried it because nothing else had worked. I was astonished how good I felt. 5 pills a week weren’t enough so my Rhuemetologist recommended 1 more. Perfect! I’ve been on 6 for the last 4 months and I like the results.

  3. I took methotrexate and my lungs were
    affected. For years I had nodules all over my lungs since 2014. A diagnosis comes up that I have systemic lupus from hematologists.Along with bone marrow cancer,multimyloma,did bone marrow biopsy and was told that both are in remission but could come back.☹️My
    Bones in my body especially in my back
    hurts something awful. Now I have fibromyalgia,noted! Inflammation noted,
    Rheumatoid arthritis noted the electrical pains runs thru body. Can’t do much for
    dealing with pain daily. Taking metrothrexate cause me to be on oxygen.
    Now has to have a pacemaker .

  4. Hi , I took hydroxychloroquine for 14 years without any problems . Just recently started to feel itchy , no rash . So my Dr . Said to change to a different generic . It worked for a year and 1/2 but then the same thing happened . So I tried another one and I had the same issue itching . So I stopped taking it for awhile . So now the Dr. Ordered the brand so I wanted to know if it would be better to follow your tips on starting with 1/4 tablet for a few days and so on ? I can only get the 200 mg tablet . Any suggestions greatly appreciated .

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