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.

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.

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.

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.

Potassium citrate, sodium citrate, and potassium-magnesium citrate are sometimes used to prevent kidney stones. These supplements reduce urinary acidity, and can therefore lead to decreased blood levels and effectiveness of methotrexate.¹⁹

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 could theoretically prevent methotrexate from working properly.

However, evidence suggests that individuals who take methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can safely use folate supplements.^{5–9, 14} 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.

In the study just described, folate supplements did not help reduce the incidence of mouth sores and nausea. However, in other studies folate supplements did reduce these side effects, both in individuals receiving methotrexate for rheumatoid arthritis ^11-15 and in those with psoriasis.¹⁶

In addition, two studies of individuals with rheumatoid arthritis found that use of folate supplements corrected the methotrexate-induced rise in homocysteine without affecting disease control.^17-18

Note: Folate supplements have only been found safe as supportive treatment in the specific conditions noted above. It is not known, for example, whether folate supplements are safe for use by individuals taking methotrexate for cancer treatment.