METHOTREXATE

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Safetychecker Summary for Methotrexate
(for details about the summarized interactions, read the full article)

May be Beneficial: Side effect reduction/prevention—Taking these supplements may help reduce the likelihood and/or severity of a potential side effect caused by the medication.	Beta-carotene* (mouth sores) Folic acid (for people with rheumatoid arthritis)* Folic acid* (for people with psoriasis) Glutamine* Spleen peptide extract* (see text) Zinc* (taste alterations) Eleuthero* (see text) Ginger* (nausea) Chamomile* (mouth sores)
May be Beneficial: Supportive interaction—Taking these supplements may support or otherwise help your medication work better.	Antioxidants* Glutamine* Melatonin* Milk thistle* PSK*
Avoid: Reduced drug absorption/bioavailability—Avoid these supplements when taking this medication since the supplement may decrease the absorption and/or activity of the medication in the body.	Folic acid*
Avoid: Adverse interaction—Avoid these supplements when taking this medication because taking them together may cause undesirable or dangerous results.	Folic acid (for people with cancer) PABA*
Check: Other—Before taking any of these supplements or eating any of these foods with your medication, read this article in full for details.	Echinacea* Multivitamin-mineral* Vitamin A* Vitamin C*
Depletion or interference	None known

Interactions with Dietary Supplements

Antioxidants
Chemotherapy can injure cancer cells by creating oxidative damage. As a result, some oncologists recommend that patients avoid supplementing antioxidants if they are undergoing chemotherapy. Limited test tube research occasionally does support the idea that an antioxidant can interfere with oxidative damage to cancer cells.¹ However, most scientific research does not support this supposition.

A modified form of vitamin A has been reported to work synergistically with chemotherapy in test tube research.² Vitamin C appears to increase the effectiveness of chemotherapy in animals³ and with human breast cancer cells in test tube research.⁴ In a double-blind study, Japanese researchers found that the combination of vitamin E, vitamin C, and N-acetyl cysteine (NAC)—all antioxidants—protected against chemotherapy-induced heart damage without interfering with the action of the chemotherapy.⁵

A comprehensive review of antioxidants and chemotherapy leaves open the question of whether supplemental antioxidants definitely help people with chemotherapy side effects, but it clearly shows that antioxidants need not be avoided for fear that the actions of chemotherapy are interfered with.⁶ Although research remains incomplete, the idea that people taking chemotherapy should avoid antioxidants is not supported by scientific research.

A new formulation of selenium (Seleno-Kappacarrageenan) was found to reduce kidney damage and white blood cell–lowering effects of cisplatin in one human study. However, the level used in this study (4,000 mcg per day) is potentially toxic and should only be used under the supervision of a doctor.⁷

Glutathione, the main antioxidant found within cells, is frequently depleted in individuals on chemotherapy and/or radiation. Preliminary studies have found that intravenously injected glutathione may decrease some of the adverse effects of chemotherapy and radiation, such as diarrhea.⁸

Folic acid
In cancer treatment, methotrexate works by blocking activation of folic acid. Folic acid-containing supplements may interfere with methotrexate therapy in people with cancer.⁹ Methotrexate therapy can lead to folic acid deficiency. People using methotrexate for cancer treatment should ask their prescribing doctor before using any folic acid-containing supplements. There is no concern about folic acid supplementation for people with cancer using chemotherapy drugs other than methotrexate.

Until recently, it was believed that methotrexate helped people with rheumatoid arthritis also by interfering with folic acid metabolism. However, this is not necessarily so, as some studies have shown that folic acid supplementation in amounts ranging from 5–50 mg per week did not alter the efficacy of methotrexate in the treatment of rheumatoid arthritis.^{10 11 12} Many doctors now believe that people with rheumatoid arthritis taking methotrexate should supplement large amounts of folic acid. In separate double-blind trials, 5 mg per week of folic acid and 2.5–5 mg per week of folinic acid (an activated form of folic acid) have substantially reduced side effects of methotrexate without interfering with the therapeutic action in rheumatoid patients.^{13 14} Folic or folinic acid was taken at a different time from methotrexate and sometimes only five days per week. Daily (as opposed to weekly) supplementation with folic acid (5 mg per day for 13 days) was found to reduce blood levels of methotrexate;¹⁵ however, the researchers in this study suggest that the reduction in blood methotrexate levels by folic acid does not necessarily mean that the folic acid is interfering with the therapeutic action of the drug. It is possible that the lower blood levels of methotrexate are simply an indication that the drug is being taken up more rapidly by the cells as a result of folic acid supplementation. In most of the studies cited here, folic acid supplementation was begun 24 hours after the administration of methotrexate. Because of the uncertainty regarding this interaction, persons taking methotrexate for rheumatoid arthritis who are considering supplementation with folic acid should first consult with their doctor.

People who are prescribed methotrexate to treat severe psoriasis experience fewer side effects if they also supplement high amounts (5 mg per day) of folic acid.¹⁶ As is the case with methotrexate and rheumatoid arthritis, supplementing folic acid did not interfere with the activity of methotrexate. Such high levels of folic acid should not be taken without clinical supervision.

Glutamine
Though cancer cells use glutamine as a fuel source, studies in humans have not found that glutamine stimulates growth of cancers in people taking chemotherapy.^{17 18} In fact, animal studies show that glutamine may actually decrease tumor growth while increasing susceptibility of cancer cells to radiation and chemotherapy,^{19 20} though such effects have not yet been studied in humans.

Glutamine has successfully reduced chemotherapy-induced mouth sores. In one trial, people were given 4 grams of glutamine in an oral rinse, which was swished around the mouth and then swallowed twice per day.²¹ Thirteen of fourteen people in the study had fewer days with mouth sores as a result. These excellent results have been duplicated in some,²² but not all²³ double-blind research. In another study, patients receiving high-dose paclitaxel and melphalan had significantly fewer episodes of oral ulcers and bleeding when they took 6 grams of glutamine four times daily along with the chemotherapy.²⁴

One double-blind trial suggested that 6 grams of glutamine taken three times per day can decrease diarrhea caused by chemotherapy.²⁵ However, other studies using higher amounts or intravenous glutamine have not reported this effect.^{26 27}

Intravenous use of glutamine in people undergoing bone marrow transplants, a procedure sometimes used to allow very high amounts of chemotherapy to be used, has led to reduced hospital stays, leading to a savings of over $21,000 for each patient given glutamine.²⁸

Animal studies have demonstrated that administration of methotrexate with intravenous or oral glutamine may enhance the ability of methotrexate to kill tumor cells, while decreasing methotrexate toxicity and improving survival.^{29 30 31 32 33 34} The effects of oral glutamine supplementation in humans taking methotrexate remains unknown.

Melatonin
High amounts of melatonin have been combined with a variety of chemotherapy drugs to reduce their side effects or improve drug efficacy. One study gave melatonin at night in combination with the drug triptorelin to men with metastatic prostate cancer.³⁵ All of these men had previously become unresponsive to triptorelin. The combination decreased PSA levels—a marker of prostate cancer progression—in eight of fourteen patients, decreased some side effects of triptorelin, and helped nine of fourteen to live longer than one year. The outcome of this preliminary study suggests that melatonin may improve the efficacy of triptorelin even after the drug has apparently lost effectiveness.

N-acetyl cysteine (NAC)
NAC, an amino acid–like supplement that possesses antioxidant activity, has been used in four human studies to decrease the kidney and bladder toxicity of the chemotherapy drug ifosfamide.^{36 37 38 39} These studies used 1–2 grams NAC four times per day. There was no sign that NAC interfered with the efficacy of ifosfamide in any of these studies. Intakes of NAC over 4 grams per day may cause nausea and vomiting.

The newer anti-nausea drugs prescribed for people taking chemotherapy lead to greatly reduced nausea and vomiting for most people. Nonetheless, these drugs often do not totally eliminate all nausea. Natural substances used to reduce nausea should not be used instead of prescription anti-nausea drugs. Rather, under the guidance of a doctor, they should be added to those drugs if needed. At least one trial suggests that NAC, at 1,800 mg per day may reduce nausea and vomiting caused by chemotherapy.⁴⁰

Spleen Extract
Patients with inoperable head and neck cancer were treated with a spleen peptide preparation (Polyerga®) in a double-blind trial during chemotherapy with cisplatin and 5-FU.⁴¹ The spleen preparation had a significant stabilizing effect on certain white blood cells. People taking it also experienced stabilized body weight and a reduction in the fatigue and inertia that usually accompany this combination of chemotherapy agents.

Beta-carotene and Vitamin E
Chemotherapy frequently causes mouth sores. In one trial, people were given approximately 400,000 IU of beta-carotene per day for three weeks and then 125,000 IU per day for an additional four weeks.⁴² Those taking beta-carotene still suffered mouth sores, but the mouth sores developed later and tended to be less severe than mouth sores that formed in people receiving the same chemotherapy without beta-carotene.

In a study of chemotherapy-induced mouth sores, six of nine patients who applied vitamin E directly to their mouth sores had complete resolution of the sores compared with one of nine patients who applied placebo.⁴³ Others have confirmed the potential for vitamin E to help people with chemotherapy-induced mouth sores.⁴⁴ Applying vitamin E only once per day was helpful to only some groups of patients in another trial,⁴⁵ and not all studies have found vitamin E to be effective.⁴⁶ Until more is known, if vitamin E is used in an attempt to reduce chemotherapy-induced mouth sores, it should be applied topically twice per day and should probably be in the tocopherol (versus tocopheryl) form.

Vitamin A
A controlled French trial reported that when postmenopausal late-stage breast cancer patients were given very large amounts of vitamin A (350,000–500,000 IU per day) along with chemotherapy, remission rates were significantly better than when the chemotherapy was not accompanied by vitamin A.⁴⁷ Similar results were not found in premenopausal women. The large amounts of vitamin A used in the study are toxic and require clinical supervision.

Zinc
Irradiation treatment, especially of head and neck cancers, frequently results in changes to normal taste sensation.^{48 49} Zinc supplementation may be protective against taste alterations caused or exacerbated by irradiation. A double-blind trial found that 45 mg of zinc sulfate three times daily reduced the alteration of taste sensation during radiation treatment and led to significantly greater recovery of taste sensation after treatment was concluded.⁵⁰

Multivitamin-mineral
Many chemotherapy drugs can cause diarrhea, lack of appetite, vomiting, and damage to the gastrointestinal tract. Recent anti-nausea prescription medications are often effective. Nonetheless, nutritional deficiencies still occur.⁵¹ It makes sense for people undergoing chemotherapy to take a high-potency multivitamin-mineral to protect against deficiencies.

Taurine
Taurine has been shown to be depleted in people taking chemotherapy.⁵² It remains unclear how important this effect is or if people taking chemotherapy should take taurine supplements.

Thymus peptides
Peptides or short proteins derived from the thymus gland, an important immune organ, have been used in conjunction with chemotherapy drugs for people with cancer. One study using thymosin fraction V in combination with chemotherapy, compared with chemotherapy alone, found significantly longer survival times in the thymosin fraction V group.⁵³ A related substance, thymostimulin, decreased some side effects of chemotherapy and increased survival time compared with chemotherapy alone.⁵⁴ A third product, thymic extract TP1, was shown to improve immune function in people treated with chemotherapy compared with effects of chemotherapy alone.⁵⁵ Thymic peptides need to be administered by injection. People interested in their combined use with chemotherapy should consult a doctor.

PABA (para-aminobenzoic acid)
PABA can increase methotrexate levels, activity, and side effects.⁵⁶ The incidence and severity of this interaction remains unclear.

Interactions with Herbs

Echinacea (Echinacea purpurea, Echinacea angustifolia)
Echinacea is a popular immune-boosting herb that has been investigated for use with chemotherapy. One study investigated the actions of cyclophosphamide, echinacea, and thymus gland extracts to treat advanced cancer patients. Although small and uncontrolled, this trial suggested that the combination modestly extended the life span of some patients with inoperable cancers.⁵⁷ Signs of restoration of immune function were seen in these patients.

Eleuthero (Eleutherococcus senticosus)
Russian research has looked at using eleuthero with chemotherapy. One study of patients with melanoma found that chemotherapy was less toxic when eleuthero was given simultaneously. Similarly, women with inoperable breast cancer given eleuthero were reported to tolerate more chemotherapy.⁵⁸ Eleuthero treatment was also associated with improved immune function in women with breast cancer treated with chemotherapy and radiation.⁵⁹

Milk thistle (Silybum marianum)
Milk thistle’s major flavonoids, known collectively as silymarin, have shown synergistic actions with the chemotherapy drugs cisplatin and doxorubicin (Adriamycin®) in test tubes.⁶⁰ Silymarin also offsets the kidney toxicity of cisplatin in animals.⁶¹ Silymarin has not yet been studied in humans treated with cisplatin. There is some evidence that silymarin may not interfere with some chemotherapy in humans with cancer.⁶²

Ginger  (Zingiber officinale)
Ginger can be helpful in alleviating nausea and vomiting caused by chemotherapy.^{63 64} Ginger, as tablets, capsules, or liquid herbal extracts, can be taken in 500 mg amounts every two or three hours, for a total of 1 gram per day.

German chamomile (Matricaria recutita)
A liquid preparation of German chamomile has been shown to reduce the incidence of mouth sores in people receiving radiation and systemic chemotherapy treatment in an uncontrolled study. ⁶⁵

PSK (Coriolus versicolor)
The mushroom Coriolus versicolor contains an immune-stimulating substance called polysaccharide krestin, or PSK. PSK has been shown in several studies to help cancer patients undergoing chemotherapy. One study involved women with estrogen receptor-negative breast cancer. PSK combined with chemotherapy significantly prolonged survival time compared with chemotherapy alone.⁶⁶ Another study followed women with breast cancer who were given chemotherapy with or without PSK. The PSK-plus-chemotherapy group had a 25% better chance of survival after ten years compared with those taking chemotherapy without PSK.⁶⁷ Another study investigated people who had surgically removed colon cancer. They were given chemotherapy with or without PSK. Those given PSK had a longer disease-free period and longer survival time.⁶⁸ Three grams of PSK were taken orally each day in these studies.

Although PSK is rarely available in the United States, hot-water extract products made from Coriolus versicolor mushrooms are available. These products may have activity related to that of PSK, but their use with chemotherapy has not been studied.

Interactions with Foods and Other Compounds

Food
Food can interfere with methotrexate absorption, and methotrexate causes stomach upset.⁶⁹

Fruit drinks
Often, people who undergo chemotherapy develop aversions to certain foods, sometimes making it permanently difficult to eat those foods. Exposing people to what researchers have called a “scapegoat stimulus” just before the administration of chemotherapy can direct the food aversion to the “scapegoat” food instead of more important parts of the diet. In one trial, fruit drinks administered just before chemotherapy were most effective in protecting against aversions to other foods.⁷⁰

Alcohol
Alcohol should be avoided during methotrexate therapy, due to concerns of increased risk of liver damage.⁷¹

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The information presented in Healthnotes is for informational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, or traditional usage as cited in each article. The results reported may not necessarily occur in all individuals. For many of the conditions discussed, treatment with prescription or over-the-counter medication is also available. Consult your doctor, practitioner, and/or pharmacist for any health problem and before using any supplements or before making any changes in prescribed medications. Information expires December 2003.

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