Abstract
With many cancer patients now taking herbs and nutrients as dietary supplements, the potential for supplement–drug and related types of adverse interactions is growing. Several of these have been investigated and published in the scientific literature. These include drug–herb interactions, drug–nutrient interactions, herb–nutrient interactions, herb–herb interactions, and nutrient–nutrient interactions as well as the related topic of contraindications of herbs and or nutrients in particular clinical conditions. A few examples are given of each of these interactions, but coverage of them is not exhaustive in this summary. These interactions are usually thought of as unfavorable, and this is certainly true in most cases; there can, however, be favorable interactions as well.
Drug–Herb Interactions
Significant potentials for interactions between herbs and oncology-related drugs have been identified. The best-known herb–drug interactions involve the use of St John’s wort. St John’s wort, used for depression, is known to have a clinically relevant interaction with cytochrome P450 (cyp450) enzymes, specifically as an inducer of the enzyme cyp450 3A4, increasing the level of the enzyme in the liver and intestine. 1 The cyp450 enzymes are responsible for the normal breakdown and removal of drugs from the body. When cyp450 enzymes are overexpressed, drugs can be broken down abnormally, and sometimes removed too quickly from the body, resulting in inadequate levels of the drug in the bloodstream. This has been observed with St John’s wort and many drugs, including the cancer chemotherapy drug irinotecan. 2 St John’s wort may also accentuate the effects of conventional antidepressants, which could lead to serotonin syndrome. Any patient wanting to use St John’s wort with a medication should request a screening for herb–drug interactions. A similar type of interaction may be seen with the herb goldenseal, which affects cyp450 2D6, which may alter metabolism of tamoxifen. Large doses of green tea may inhibit cyp450 3A4 and cause increased blood levels of drugs metabolized by this enzyme, although there are some conflicting data.3,4 Laboratory studies suggest that green tea has several other interactions, including affecting other biochemicals that influence drug levels, such as the molecular pump p-glycoprotein that removes chemotherapy drugs from cancer cells, as well as apparently binding some of the newer molecular target drugs and reducing their absorption.5-7 Herbs that induce or inhibit drug-metabolizing enzymes will have different effects on drugs that are active in the body in the form in which they are absorbed versus prodrugs that are activated by the drug-metabolizing enzymes; several antineoplastic drugs are prodrugs, including tamoxifen.
It is not uncommon for cancer patients to experience problems with blood clots, such as deep vein thrombosis or pulmonary embolism. These problems are sometimes treated with warfarin (Coumadin). Warfarin has interactions with numerous drugs as well as foods, particularly those that contain vitamin K, which counteracts its activity. Many herbs have blood-thinning activity as well, and these may leave the blood overly thinned; others contain vitamin K. 8 In addition, some herbs, such as laxatives (senna, rhubarb root) and mucilaginous herbs (Iceland moss, comfrey), may decrease the absorption of warfarin from the intestine, counteracting its blood-thinning activity. A nutritionist can help screen for herb–warfarin interactions while counseling patients about the dietary adaptations necessary during warfarin treatment.
Drug–Nutrient Interactions
Certain drug–nutrient interactions are already well known in oncology. Methotrexate stops cancer cells from dividing by inhibiting the availability of folic acid, which is needed in cell division. Taking high levels of folic acid may counteract the effectiveness of this and related drugs; physicians will have information on drugs for which it is contraindicated. Some cases of increased treatment toxicity have been reported in patients taking folic acid along with another chemotherapy drug, 5-fluorouracil. In addition, some chemotherapy drugs deplete nutrients from the body. Cisplatin is known to reduce magnesium level, causing clinical problems such as convulsions and muscle weakness. Patients receiving cisplatin routinely receive magnesium supplementation. 9 Fish oil is another nutrient that has potential drug–nutrient interactions. It may increase the blood-thinning effect of warfarin and would also be contraindicated during chemotherapy-related thrombocytopenia. 10
Herb–Nutrient Interactions
Herb–nutrient, herb–herb, and nutrient–nutrient interactions are all much less common than interactions of herbs and nutrients with drugs, because both herbs and nutrients are much more moderate in their effects on the body than drugs. An example of an herb–nutrient interaction is the interaction of ginkgo and fish oil, which is theoretical and not so far supported even by published case reports. Both these have blood-thinning effects. Using ginkgo and fish oil together could result in excessive anticoagulation. However, this is unlikely to happen in persons with normal blood coagulation. It might become a problem for patients with genetic disorders of blood coagulation or patients taking anticoagulant drugs (in which case it is more accurately described as a supplement–drug interaction). It is also possible that this could happen with patients who have low platelets due to chemotherapy—again a supplement–drug interaction.
Herb–Herb Interactions
Use of multiple herbs with anticoagulant effects could theoretically result in excessive anticoagulation, but this is unlikely in persons with normal blood coagulation. Of more concern is possible liver toxicity from using multiple herbs that have toxic effects on the liver. These include chaparral (which is used by some cancer patients), usnic acid, and germander. Herbs containing toxic pyrrolizidine alkaloids have been associated with liver toxicity; this includes comfrey, which is suggested for external use only, as well as a number of herbs that are in less common use in the United States. Kava has also been associated with liver toxicity, though no hepatotoxic constituents have yet been found in the plant. High-dose green tea has been associated with elevated liver enzymes; animal studies suggest that this is more likely when it is taken in the fasting state. 11
Nutrient–Nutrient Interactions
Vitamin C improves the absorption of iron. This may be helpful for persons with iron deficiency, but use of high-dose vitamin C with iron supplements may aggravate situations involving clinical iron overload and excessive oxidative stress. 12 High levels of folate can mask underlying vitamin B12 deficiencies by correcting the megaloblastic anemia that is often used to diagnose B12 deficiency. However, folate does not address the neurological damage caused by vitamin B12 deficiency. 13 People eating strict vegan diets, which are often high in folate-containing vegetables but low in vitamin B12, particularly need to be aware of this possibility and use vitamin B12 supplements. Vitamin E supplements may reduce vitamin K activity in the body; this may play a role in the anticoagulant effect of vitamin E in patients taking anticoagulant drugs. 14
Positive Interactions
Fish oil may improve the effectiveness of chemotherapy, as was shown in a recent study of lung cancer patients. 15 Ginger ameliorates chemotherapy-induced nausea. 16 Probiotic supplements were observed to reduce diarrhea caused by 5-fluorouracil. 17 Several other supplements are also under investigation to reduce chemotherapy side effects.