By Dr. Greg Sperber
My research about applying evidence-based medical levels to drug-herb interactions has led me to the conclusion that there aren't very many interactions that are above the lowest level of evidence. In fact, out of approximately1,000 drug-herb interactions, I only found 56 that were above "D" level (the lowest level) evidence. A little over a third of these involved Ma Huang (herba ephedra). Only two were "A" level, 18 were "B" level, and the rest were "C" level. Obviously, these numbers are not static and there is always new research, but these at least give us a good feel for what may be an important drug-herb interaction.
As may be inferred from the previous paragraph, there are many levels of evidence according to the Oxford Centre for Evidence-based Medicine (Phillips, et al., 2001). First, each individual research paper is given a level from 1 to 5. Then as an aggregate, based on these individual papers, an overall evidence level is given to the interaction from a grade of "A," the highest level, to "D," the lowest level. The other issue is that just because an interaction exists does not mean it is particularly bad. Some interactions enhance the effects of the constituents.
This article will look at four herbs that may cause interactions according to these evidence levels. This does not mean these are the only drug herb interactions or even the worst interactions. It simply means these are the interactions with the most evidence. There are many potential interactions that have not been investigated and may or may not be more serious than what appears here.
Ma Huang (Ephedra) has been shown in numerous studies to cause interactions and harmful effects. This led to this herb being banned by the Food and Drug Administration in any prepared form. While this was probably an overreaction to political pressure, there are some well established dangers in the literature. Ephedrine, a chief component of ma huang, increases the incidence of side effects, such as agitation, tremors, insomnia, blood pressure, heart rate, and in higher doses, plasma glucose, insulin, and C-peptide when combined with caffeine (Astrup, et al., 1991, level 2c evidence). Another study confirmed these effects, but noted the transient nature of the side effects (Astrup & Toubro 1993, level 2c evidence). A well constructed, randomly controlled trial showed that these negative effects were transient and equaled placebo levels after eight weeks (Astrup, Breum, Toubro, Hein, Quaade, 1992, level 1b evidence). So while these interactions are fairly well established, they seem to be for only for a short while.
When combined with methylxanthines, such as theophylline or caffeine, ephedra may increase thermogenesis, an increase in the body's ability to generate heat, and weight loss. This may be considered a positive interaction except in patients who may not tolerate the increase in the sympathetic system. These patients include those with cardiovascular conditions. This interaction has been shown in many mice (Dulloo & Miller, 1986a, level 5 evidence), and human studies (Dulloo & Miller, 1986b, level 2b evidence), (Malchow- Moller, Larsen, Hey, Stokholm, Juhl, Quaade, 1981, level 2b evidence), (Boozer, Daly, Homel, Solomon, Blanchard, Nasser, et. al. 2002, level 1b evidence), (Greenway, de Jonge, Blanchard, Frisard, Smith, 2004, level 2b evidence), (Astrup, Breum, Toubro, Hein, Quaade, 1992, level 1b evidence). Theophylline was one of the first drugs to treat asthma. It has largely been replaced by safer agents, but is still rarely used when other agents are not tolerated.
Monoamine oxidase inhibitors (MAOIs) are primarily antidepressants but some are used in treating symptoms of Parkinson's disease. They include isocarboxazid, phenelzine, rasagiline, selegiline and tranylcypromine. Based on the ephedrine content, ma huang may cause hypertension when combined with MAOIs according to an expert opinion (Blumenthal, 1998, level 5 evidence). One case report described a patient who stopped a MAOI, phenelzine, and ingested a combination pill of ephedrine, caffeine, and theophylline 24 hours later. She developed encephalopathy, a problem with the brain, neuromuscular irritability, tachycardia, a rapid heart rate, hypotension, rhabdomyolysis (a life threatening condition of muscle breakdown), and hyperthermia, a raised body temperature (Dawson, Earnshaw, Graham, 1995, level 4 evidence). Other possible effects include arrhythmias, an irregular heart beat, chest pain, hyperpyrexia (fever), and death (Gruenwald, Brendler, & Jaenicke, 2004, p. 535). One human study showed an increase in cardiovascular symptoms (Dingemanse, 1993, level 2c evidence). Ma huang should be avoided for at least 2 weeks after stopping MAOIs (Brinker, 2001, p. 89).
Because of ephedra's potential for raising blood pressure, it, theoretically, should not be combined with agents that lower blood pressure (Mills & Bone, 2000). Ephedrine and pseudoephedrine toxicity may result from combining this herb with antacids (Brater, et. al., 1980). Dang Gui (Angelica Sinensis). It has been suggested that gan cao may have phytoestrogen content (Miller, 1998, level 5 evidence), however, the jury is still out on whether dang gui has estrogenic activity. One rat study (Circosta, De Pasquale, Palumbo, Samperi, Occhiuto, 2006, level 5 evidence) showed significant estrogen changes. While in vitro (in humans) research showed little or no estrogen activity (Zava, Dollbaum, Blen, 1998, level 5 evidence). Finally, a double blinded randomly controlled trial showed no estrogen-like effects in postmenopausal women (Hirata, Small, Swiersz, Ettinger, Zell, 1997, level 1b evidence). While there is some controversy, the preponderance of evidence suggests that there is no estrogen-like activity, at least in postmenopausal women. The evidence is still out on whether it may have these effects in other patients.
Dang Gui has been shown in a small human study to potentiate warfarin and caution should be used in combining these two (Page& Lawrence, 1999). Gan Cao (Licorice) and oral contraceptive pills may increase blood pressure and fluid retention as shown in two case studies (de Klerk, Nieuwenhuis, Beutler, 1997, level 4 evidence), and an uncontrolled human study (Bernardi, D'Intino, Trevisani, Cantelli-Forti, Raggi, Turchetto, et al., 1994, level 2c evidence).
Gan cao has quite a reputation in the medical literature for increasing blood pressure. However, this is based on its western herbal use as a single herb, and these effects may be mitigated by Chinese medicine's use of formulas. Because of this tendency, gan cao should not be combined with drugs that reduce blood pressure (Gruenwald, Brendler, & Jaenicke, 2004, p. 514). It may also cause potassium loss when combined with diuretics.
Guan Ye Lian Qiao (St. John's wort) affects a liver enzyme, cytochrome P450, which has led to being implicated in numerous drug herb interactions. It was found to decrease the effectiveness of indinavir in a small human study (Piscitelli, Burstein, Chaitt, Alfaro, Falloon, 2000, level 2c evidence). Indinavir is an antiretroviral agent used in treating the human immunovirus (HIV) and acquired immune deficiency syndrome (AIDS). Any reduction in its effectiveness could allow advancement of the disease and can be life threatening.
B- level evidence showed a significant interference between Guan Ye Lian Qiao and digoxin (Johne, Brockmöller, Bauer, Maurer, Langheinrich, Roots, 1999). Guan Ye Lian Qiao is also considered to act like selective serotonin reuptake inhibitors, anti depressants, and should not be combined with any type of antidepressants.
While these are not the only herbs that should be carefully administered with drugs, they are among the most researched and accepted. Of course, combining drugs with these herbs can be dangerous, only a very few case studies have shown them to be. In other words, be cautious, but not paranoid. Use a step-by-step approach to combining drugs with these herbs and there is little to fear.
Dr. Greg Sperber is author of Integrated Pharmacology, Combining Modern Pharmacology with Chinese Medicine. He received a Masters and Doctor of Acupuncture and Oriental medicine from Pacific College of Oriental Medicine, San Diego and a medical degree from Flinders University of South Australia. Currently he teaches at PCOM, is president of the California State Oriental Medical Association, and a practitioner at New Life Health Partners in San Diego.
Four Worrisome Chinese Herbs Sources
Astrup, A., Breum, L., Toubro, S., Hein, P., Quaade, F. (1992). The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int. J. Obesity. 16(4):269-277.
Astrup, A. & Toubro, S. (1993). Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. Int. J. Obes. Relat. Metab. Disord. 17(Suppl 1):S41-3.
Astrup, A., Toubro, S., Cannon, S., Hein, P., Madsen, J. (1991, Mar). Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double-blind, placebocontrolled study. Metabolism. 40(3):323-9.
Bernardi, M., D'Intino, P. E., Trevisani, F., Cantelli-Forti, G., Raggi, M. A., Turchetto, E., Gasbarrini, G. (1994). Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci. 55(11):863-72.
Blumenthal, M. (ed.). (1998). The Complete German Commission E Monographs. Integrative Medicine Communications. Boston: Mass.
Boozer, C. N., Daly, P. A., Homel, P., Solomon, J. L., Blanchard, D., Nasser, J. A., Strauss, R., Meredith, T. (2002). Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. International Journal of Obesity. 26, 593-604.
Brater, D. C., Kaojarern, S., Benet, L. Z., Lin, E. T., Lockwood, T., Morris, R. C., McSherry, E. J., Melmon, K. L. (1980). Renal excretion of pseudoephedrine. Clin Pharmacol Ther. Nov; 28(5):690-4.
Brinker, F. (2001). Herb contraindications & drug interactions (3rd ed.). Sandy, OR: Eclectic Medical Publications. Circosta, C., De Pasquale, R., Palumbo, D. R., \Samperi, S., Occhiuto, F. (2006). Estrogenic activity of standardized extract of Angelica
sinensis. Phytotherapy Research. 20(8):665-9.
Dawson, J. K., Earnshaw, S. M., Graham, C. S. (1995). Dangerous monoamine oxidase inhibitor interactions are still occurring in the 1990s. Journal of Accident and Emergency Medicine. 12(1): 49-51.
de Klerk, G. J., Nieuwenhuis ,M. G., Beutler J. J. (1997). Hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ. 314:731
Dulloo, A. G. & Miller, D. S. (1986a). The thermogenic properties of ephedrine/methylxanthine mixtures: animal studies. Am. J. Clin. Nutr. 43:388-94.
Dulloo, A. G. & Miller, D. S. (1986b). The thermogenic properties of ephedrine/methylxanthine mixtures: human studies. Int J Obes. 10(6):467-81.
Greenway, F. L., de Jonge, L., Blanchard, D.,
Frisard, M., Smith, S. R. (2004, July). Effect of a dietary herbal supplement containing caffeine and ephedra on weight, metabolic rate, and body composition. Obesity Research. 12(7):1152-7.
Gruenwald, J., Brendler, T., Jaenicke, C. Eds. (2004). PDR for herbal medicines (3rd ed.). Montvale, NJ: Thomson PDR. Hirata, J. D., Small, R., Swiersz, L. M., Ettinger,
B., Zell, B. (1997, Dec). Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fert. Steril. 68(6):981-86.
Johne, A., Brockmöller, J., Bauer, S., Maurer, A., Langheinrich, M., Roots, I. (1999, Oct). Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther.
Malchow-Moller, A., Larsen, S., Hey, H., Stokholm, K. H., Juhl, E., Quaade, F. (1981). Ephedrine as an anorectic: the story of the ‘Elsinore pill'. Internat. J. Obesity. 5:183-7.
Miller, L. G. (1998). Herbal medicinals - selected clinical considerations focusing on known or potential drug-herb interactions. Arch. Intern. Med. 158(20):2200-11.
Mills, S. & Bone, K. (2000). Principles and Practice of Phytotherapy. Churchill Livingstone:
Edinburg. Page, R. L. & Lawrence, J.D. (1999, Jul). Potentiation of warfarin by dong quai. Pharmacotherapy.19(7):870-6.
Phillips, B., Ball, C., Sackett, D., Badenoch, D., Straus, S., Haynes, B., Dawes, M. (2001). Levels of evidence and grades of recommendation. Centre for Evidence-Based Medicine. Retrieved May 10, 2006, from http://www.cebm.net/levels_of_evidence.asp.
Piscitelli, S. C., Burstein, A. H., Chaitt, D., Alfaro R. M., Falloon, J. (2000, Feb 12). Indinavir concentrations and St John's wort. The Lancet. 355(9203):547-8.
Zava, D. T., Dollbaum, C. M., Blen, M. (1998, Mar). Estrogen and Progestin Bioactivity of Foods, Herbs, and Spices. Proc. Soc. Exp. Biol. Med. 217(3):369-78.