Myths and Mistakes About Herb-Drug Interactions
Myths and Mistakes About Herb-Drug Interactions
May 1999; Volume 1: 44-46
Abstract & Commentary
Source: Miller LG. Herbal medicinals: Selected clinical considerations focusing on known or potential drug-herb interaction. Arch Intern Med 1998;158:2200-2211.
Synopsis: Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for.
COMMENT BY DENNIS AWANG, PhD, FCIC AND ADRIANE FUGH-BERMAN, MD
Herbs do contain pharmacologically active ingredients, some of which can potentially interact with medications. However, this article contains numerous errors, and thus is not a credible source of information. In our analysis, the publication of this review indicates deficiencies in both editorial judgment and the peer review process. What follows is a limited discussion of misleading statements in the abstract.
"If used beyond 8 weeks, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatoxic drugs, such as anabolic steroids, amiodarone, methotrexate, and ketoconazole. However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatotoxicity of pyrrolizidine alkaloids."
This assertion is not referenced in the text, for good reason. There are no reports of hepatotoxicity associated with echinacea alone, in combination with any of the drugs listed, or in combination with any pharmaceutical drug. There is one report of hepatotoxicity with a product purportedly containing echinacea and skullcap (Scutellaria lateriflora). Products purportedly containing skullcap have been implicated in several cases of hepatitis, and even here skullcap may not be the culprit. Some "skullcap" products have been found to contain germander (Teucrium chamaedrys),1 sometimes mistaken for skullcap. Germander has demonstrated hepatotoxicity in both rodents2 and humans.3,4 There is no evidence implicating echinacea as a contributing factor to hepatotoxicity.
It is not the "1,2 saturated necrine ring" but rather the 1,2-unsaturated necine ring that is associated with hepatotoxicity of pyrrolizidine alkaloids. While echinacea does not contain the dangerous unsaturated form of pyrrolizidine alkaloids, it does contain extremely low levels (0.006%) of isotussilagine and tussilagine, which are non-toxic saturated pyrrolizidine alkaloids.5 There are of course other mechanisms of hepatotoxicity, but echinacea causes none of them.
"Feverfew, garlic, Ginkgo, ginger, and ginseng may alter bleeding time and should not be used concomitantly with warfarin sodium."
There is a case report of ginseng reducing the international normalized ratio (INR) in a patient on warfarin.6 Garlic intake has been associated with excessive postoperative bleeding and spontaneous spinal hematoma but specific drug interactions have not been reported. Ginkgo alone7,8 and in combination with anticoagulants9,10 has been linked to bleeding episodes. Although both ginger and feverfew contain anticoagulant substances, there are no reports in the medical literature of bleeding episodes or alterations in bleeding time with feverfew or ginger. (See retated article on p. 46.)
"Ginseng should also not be used with estrogens or corticosteroids because of possible additive effects."
No such interactions have been reported. Ginseng has complex actions, including effects on corticosteroid action, so a theoretical interaction with corticosteroids is possible. Ginseng does not contain phytoestrogens (although interestingly, several cases of postmenopausal bleeding have been linked to ginseng ingestion11,12).
"Kyushin, licorice, plantain, uzara root, hawthorn, and ginseng may interfere with either digoxin pharmacodynamically or with digoxin monitoring."
Kyushin is a Chinese medicine containing dried toad venom, which does have cardiac glycoside activity. Toad venom, however, is not an herb. High chronic doses of licorice can cause hypokalemia, which of course can cause or contribute to cardiac arrhythmias, but there are no in vitro, in vivo, or clinical reports of licorice-digoxin interactions. The warning against plantain is apparently based on a plantain product that was contaminated with woolly foxglove (Digitalis lanata),13 a source of cardiac glycosides (and the original source of the digoxin we use in practice). Plantain itself has never been associated with cardiotoxicity or any interaction with digoxin.
Uzara root contains cardiac glycosides but is rarely used in herbal medicine today. There are no clinical reports of hawthorn interacting with digoxin, and the reference for the statement in the text that "Hawthorn berries purportedly potentiate the action of digoxin" actually states that hawthorn may be combined with digitalis.14
Ginseng (Panax species) has not been associated with elevated digoxin levels. The reference to this statement in the text of the article is incorrect; it refers to an article on sesquiterpene esters in echinacea. Perhaps the author meant to refer to an article about eleuthero (Eleutherococcus senticosus), which is also called "Siberian ginseng." Siberian ginseng is not ginseng, but belongs to an entirely different genus.
The eleuthero-digoxin case is interesting. A 74-year-old man whose digoxin levels had been maintained in a consistent range for many years experienced a sudden rise in digoxin levels to 5.2 nmol/L after taking capsules purportedly containing Siberian ginseng (concurrent medications included acetaminophen, cimetidine, oxazepam, aspirin, and magaldrate).15 Considering that the therapeutic range for digoxin is 0.6-2.6 nmol/L, the fact that this patient was completely asymptomatic with digoxin levels of 5.2 nmol/L (EKG was unchanged, and there were no other signs or symptoms of digoxin poisoning) suggests that the herb interfered with the assay for digoxin rather than actually increasing serum digoxin levels.
Although the implicated capsules were tested for the presence of digoxin and digitoxin (neither was found), the capsules were not tested to confirm that they actually contained eleuthero. Another herb known as Chinese silk vine (Periploca sepium) is commonly substituted for Eleutherococcus senticosus; periploca does contain cardiac glycosides.16
"Evening primrose oil and borage should not be used with anticonvulsants because they may lower the seizure threshold."
The text of the article states that "evening primrose oil contains gamolenic acid (GLA) that lowers the seizure threshold" and that "Neither evening primrose oil nor borage should be used with other drugs known to lower the seizure threshold (e.g., tricyclic antidepressants and phenothaizines [sic])." Miller’s own reference17 to the first statement (the second is unreferenced) states that epileptic events were reported only in patients treated with phenothiazines.
"Kava when used with alprazolam has resulted in coma."
There is no reported association between kava and coma. It is true that the reference for this statement is misleadingly titled, "Coma from the health food store: Interaction between kava and alprazolam,"18 but surely it is reasonable to expect the author of a review article to read beyond the title of a referenced article. The case actually reports only lethargy and disorientation, not unconsciousness.
"Numerous herbs (e.g., karela and ginseng) may affect blood glucose levels and should not be used in patients with diabetes mellitus."
While it is true that a number of herbs have hypoglycemic effects, in diabetics this effect may be an advantage, not a disadvantage. In fact, a double-blind, placebo-controlled, eight-week study of 36 newly-diagnosed NIDDM patients found that 100 mg or 200 mg ginseng extract reduced fasting blood glucose (the higher dose also significantly reduced HbA1c).19 Although Miller states in the text "that ginsenghas been associated with hyperglycemic properties," it is the opposite that is true (as her own reference states). Obviously blood glucose levels should be monitored carefully when herbs with hypoglycemic activity are used.
1. Huxtable RJ. The myth of beneficent nature: The risks of herbal preparations. Ann Intern Med 1992;117: 165-166.
2. Loeper J, et al. Hepatotoxicity of germander in mice. Gastroenterology 1994;108:464-472.
3. Larrey D, et al. Hepatitis after germander (Teucrium chamaedrys) administration: Another instance of herbal medicine hepatotoxicity. Ann Intern Med 1992;117:129-132.
4. Laliberté L, Villeneuve JP. Hepatitis after the use of germander, a herbal remedy. CMAJ 1996;154: 1689-1692.
5. Roder E, et al. Pyrrolizidines in Echinacea angustifolia DC and Echinacea purpurea M. Arzneim-Forsch 1984;124:2316-2317.
6. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997;54:692-693.
7. Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet 1998;352:36.
8. Gilbert GJ. Ginkgo biloba. Neurology 1997;48:1137.
9. Matthews MK. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 1998;50:1933.
10. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 1997;336:1108.
11. Greenspan EM. Ginseng and vaginal bleeding. JAMA 1983;249:2018.
12. Hopkins MP, et al. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol 1988;159:1121-1122.
13. Slifman NR, et al. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med 1998; 339:806-811.
14. Hobbs C, Foster S. Hawthorn: A literature review. HerbalGram 1990;22:19-33.
15. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. CMAJ 1996;155;293-295.
16. Awang DVC. Siberian ginseng toxicity may be case of mistaken identity. CMAJ 1996;155:1237.
17. Newall CA, et al. Herbal Medicines: A Guide for Health Care Professionals. London: The Pharmaceutical Press; 1996.
18. Almeida JC, Grimsley EW. Coma from the health food store: Interaction between kava and alprazolam. Ann Intern Med 1996;125:940-941.
19. Sotaniemi EA, et al. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 1995;18:1373-1375.May 1999; Volume 1: 44-46
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