Drug Interactions:
Methotrexate

Alternate Names
  • Amethopterin, MTX
Trade Names
  • Immunex, Folex PFS, Rheumatrex

Methotrexate is used in cancer chemotherapy as well as for treating inflammatory diseases such as rheumatoid arthritis and psoriasis.

Potassium Citrate

Possible Harmful Interaction

Potassium citrate and other forms of citrate (e.g., calcium citrate, magnesium citrate) may be used to prevent kidney stones. These agents work by making the urine less acidic.

This effect on the urine may lead to decreased blood levels and therapeutic effects of methotrexate.¹

It may be advisable to avoid these citrate compounds during methotrexate therapy except under medical supervision.

Dong Quai, St. John's Wort

Possible Harmful Interaction

St. John's wort (Hypericum perforatum) is primarily used to treat mild to moderate depression.

The herb dong quai (Angelica sinensis) is often recommended for menstrual disorders such as dysmenorrhea, PMS, and irregular menstruation.

Methotrexate has been reported to cause increased sensitivity to the sun, amplifying the risk of sunburn or skin rash. Because St. John's wort and dong quai may also cause this problem, taking these herbal supplements during methotrexate therapy might add to this risk.

It may be a good idea to wear a sunscreen or protective clothing during sun exposure if you take one of these herbs while using methotrexate.

White Willow

Possible Harmful Interaction

The herb white willow (Salix alba), also known as willow bark, is used to treat pain and fever. White willow contains a substance that is converted by the body into a salicylate similar to aspirin.

Case reports suggest that salicylates can increase methotrexate blood levels and toxicity.² For this reason, you should avoid combining white willow with methotrexate.

Ipriflavone

Possible Harmful Interaction

The supplement ipriflavone is used to treat osteoporosis. A 3-year double-blind trial of almost 500 women, as well as a small study, found worrisome evidence that ipriflavone can reduce white blood cell count in some people.^3,4 For this reason, anyone taking medications that suppress the immune system should avoid taking ipriflavone.

Folate

Supplementation Possibly Helpful

Folate (also known as folic acid) is a B vitamin that plays an important role in many vital aspects of health, including preventing neural tube birth defects and possibly reducing the risk of heart disease. Because inadequate intake of folate is widespread, if you are taking any medication that depletes or impairs folate even slightly, you may need supplementation.

Methotrexate is called a "folate antagonist" because it prevents the body from converting folate to its active form. In fact, this inactivation of folate plays a role in methotrexate's therapeutic effects. This leads to an interesting Catch-22: methotrexate use can lead to folate deficiency, but taking extra folate might prevent methotrexate from working properly.

However, evidence suggests that individuals who take methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can use folate supplements to good effect.^5–9 Not only does the methotrexate continue to work properly, but its usual side effects may decrease also.

For example, in a 48-week double-blind placebo-controlled trial of 434 individuals with active rheumatoid arthritis, use of folate helped prevent liver inflammation caused by methotrexate.¹⁰ Other side effects did not improve. A slightly higher dose of methotrexate was needed to reach the same level of benefit as taking methotrexate alone, but researchers felt this was worth it.

Similar results have been seen in other studies of rheumatoid arthritis^11,12 as well as juvenile rheumatoid arthritis.¹³

In addition, another study found that folate eliminated the gastrointestinal side effects associated with oral methotrexate therapy for psoriasis, also without interfering with the drug's therapeutic benefits.¹⁴

Therefore, folate supplementation may be advisable in individuals taking methotrexate for psoriasis, rheumatoid arthritis, or juvenile rheumatoid arthritis.¹⁵

Note: This does not necessarily mean that it is safe to take folate supplements if you are using methotrexate for some other condition, such as cancer. We just don't know yet.

Last reviewed March 2002 by Medical Review Board

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