Evaluation of the Antihyperlipidemic Properties of Dietary Supplements

Michael F. Caron, Pharm.D., and C. Michael White, Pharm.D.,

Pharmacotherapy. 2001;21(4) 

Abstract and Introduction

We reviewed the published literature regarding the antihyperlipidemic effects of dietary supplements. A search of MEDLINE database, EMBASE Drugs and Pharmacology database, and the Internet was performed, and pertinent studies were identified and evaluated. References from published articles and tertiary references were used to gather additional data. Published trials indicate that red yeast rice, tocotrienols, gugulipid, garlic, and soy protein all have antihypercholesterolemic effects. These supplements, as well as -3 fatty acids, also have antihypertriglyceridemic effects. In clinical trials none of the agents led to a reduction in low-density lipoproteins greater than 25%, suggesting modest efficacy. When recommending these supplements, clinicians should keep in mind that their long-term safety is not established and patients should be monitored closely.

A survey estimated that use of alternative therapy among adults in the United States increased from 33.8% in 1990 to 42.1% in 1997.[1] Consumers showed particular interest in products that may help them reduce the risk of developing heart disease.[2] In a survey of patients with elevated cholesterol levels, 50% indicated that they would like to have an over-the-counter (OTC) antihypercholesterolemic agent available.[2] In patients who are classified as at least somewhat concerned about their cholesterol, more than 60% are interested in taking an OTC 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Therefore, it is increasingly likely that clinicians will encounter patients interested in taking dietary supplements with antihypercholesterolemic effects. The following dietary supplements have been said to have lipid-lowering properties[3,4]: acidophilus, artichoke leaf, bilberry leaf, L-carnitine, chondroitin, copper, dietary fiber, flaxseed oil, -oryzanol, genistein, he shou wu, lecithin, maitake, -3 fatty acids, red yeast rice, silicon dioxide, spirulina, aortic glycosaminoglycans, ashwagandha, calcium, ß-carotene, chromium, creatine, fenugreek, fungal polysaccharides, garlic, gugulipid, indole-3-carbinol, lycopene, niacin, pantethine, saponin, ß-sitosterol and sitostanol, soy protein, and tocotrienols. Of these, only seven have objective clinical trial data to support the claim: red yeast rice, tocotrienols, gugulipid, garlic, soy protein, -3 fatty acids, and niacin. The efficacy and safety of niacin has been reviewed extensively and thus is not discussed here.

Pharmacology and Efficacy

Red yeast rice was used to make rice wine, as a food colorant and preservative, and in Chinese medicine for indigestion and diarrhea, and to improve blood circulation and spleen health.[5,6] It has moderate lipid-lowering properties.[7-9] A double-blind, randomized, placebo-controlled trial evaluated the cholesterol-lowering effects of red yeast rice in 83 men and women with above average low-density lipoprotein (LDL) concentrations (mean 176 ± 29 mg/dl).[10] Subjects were started on a diet similar to the American Heart Association step I diet and were randomly assigned to receive 2.4 g of Cholestin (Pharmanex, Inc., Simi Valley, CA) or rice powder placebo capsules for 12 weeks. Cholestin is a commercially available dietary supplement that is prepared by growing red yeast (Monascus purpureus) on rice to produce a red yeast rice product. It contains nine HMG-CoA reductase inhibitors, sterols (ß-sitosterol, campesterol, stigmasterol, sapogenin), isoflavones and isoflavone glycosides, and monounsaturated fatty acids.[10] It is standardized to 0.4%, by weight, of total HMG-CoA reductase inhibitors. Hence 2.4 g of Cholestin contain approximately 7-8 mg of lovastatin and 2-3 mg of other mevinic acids (HMG-CoA reductase inhibitor compounds).

Total cholesterol concentrations decreased significantly between baseline and 8 weeks in the Cholestin-treated group compared with the placebo-treated group (-42.2 vs -0.8 mg/dl, p<0.001). At 12 weeks, the mean LDL concentrations were -37.9 and -4.7 mg/dl, respectively (p<0.001). Furthermore, mean triglyceride concentrations were 8.9 mg/dl lower and 3.55 mg/dl higher, respectively, at 12 weeks (p=0.05). High-density lipoprotein (HDL) concentrations did not differ significantly within or between groups at baseline or 8 or 12 weeks.

Tocotrienols are naturally occurring analogs of tocopherol (vitamin E) and have lipid-lowering effects in animals and humans.[11-14] They have been isolated from barley, oat, rye, palm oil, and rice, and differ from tocopherols only in three double bonds in the isoprenoid chain, which appears to be essential for inhibition of cholesterogenesis. Tocotrienols exert their pharmacologic activity by posttranscriptional inhibition of HMG-CoA reductase in a dose-dependent fashion.[15-17] It is hypothesized that they increase cellular farnesol, a mevalonate-derived product, which causes downregulation of HMG-CoA reductase activity.[11]

A double-blind, crossover, 8-week study examined the effects of tocotrienols in 25 men and women (mean LDL 246.7 ± 27.5 mg/dl).[12] The study drug was a tocotrienol-enriched fraction (each containing a mixture of -tocopherol and , , and -tocotrienol) of palm oil called Palmvitee supplied by the Palm Oil Research Institute of Malaysia. Subjects were randomly assigned to receive either Palmvitee or corn oil (placebo) for 4 weeks and crossed to the other regimen for another 4 weeks. Palmvitee failed to cause any statistically significant changes in serum lipid levels. However, when three poor responders (serum cholesterol reductions of 4-6%) were excluded from statistical calculations, total cholesterol levels decreased by 58.9 mg/dl in the Palmvitee-treated group and increased by 6.0 mg/dl in the placebo-treated group after 4 weeks (p<0.05). The Palmvitee group had a significant reduction in LDL compared with the placebo group (-62.9 vs +4.1 mg/dl, p<0.05). Serum HDL and triglyceride concentrations showed no significant changes compared with baseline values.

In a substudy, these investigators gave the three poor responders and four new hypercholesterolemic subjects -tocotrienol 200 mg/day for 4 weeks instead of Palmvitee. Compared with placebo, -tocotrienol resulted in a reduction in total cholesterol (-93.4 vs +5.8 mg/dl, p<0.05) and LDL (-67.3 vs -4.3, p<0.05). The additional antihypercholesterolemic effect with g-tocotrienol alone was not unexpected, as -tocopherol attenuates the impact of the tocotrienols on HMG-CoA reductase activity.[17] Therefore, additional dietary supplementation with vitamin E should be avoided since it may augment the antihyperlipidemic effects of tocotrienols.

Gugulipid, also known as guggul or gum guggula, is the gum extract of the mukul myrrh tree (Commiphora mukul), which is native to India.[18] It traditionally is used to reduce weight and treat arthritis and nodulocystic acne.[6] The presumed hypolipidemic constituents are Z- and E-guggulsterones. These constituents may act by decreasing hepatic steroids, which increases compensatory cholesterol biosynthesis and subsequently causes increased plasma LDL particle catabolism.[6,19] Other potential mechanisms are thyroid stimulation and antiinflammatory effects.[6]

Gugulipid had lipid-lowering effects in several trials.[20-22] The most recent was a double-blind, placebo-controlled study in which 61 subjects (mean LDL 136 ± 14 mg/dl) received the agent for 24 weeks.[20] After 12 weeks of consuming a fruit- and vegetable-enriched diet, patients were randomized to either gugulipid (standardized to 100 mg/day of guggulsterones) or placebo, and returned at 12, 24, 36, and 48 weeks for analysis of laboratory data. After 24 weeks of gugulipid treatment, total cholesterol levels decreased by 25.2 mg/dl, compared with a 7.6 mg/dl increase in the placebo group (p<0.01). The LDL was 16.9 mg/dl lower and 4.0 mg/dl higher, respectively (p<0.01). In addition, a significant reduction in triglycerides was seen in the gugulipid-treated arm compared with placebo (-18 vs +5.5 mg/dl, p<0.01). The total cholesterol:HDL ratio in the gugulipid group decreased by 0.5 mg/dl compared with no reduction in the placebo group (p<0.05). Finally, changes in HDL were nonsignificant.

Garlic (Allium savitivum) is proposed as a treatment for asthma, Candida infections, colds, diabetes, and cancer.[6] It has hypotensive, antispasmotic, antibacterial, and antiviral properties, but research focused on its hypolipidemic activity. Three water-soluble, sulfur-containing compounds found in garlic (S-allyl cysteine, s-ethyl-cysteine, S-propyl cysteine) decreased cholesterol production in cultured rat liver cells by 40-50%.[23] The garlic compound ajoene has HMG-CoA-reducing activity as well.[24]

Clinical trials reported varied results regarding garlic's lipid-lowering effects.[25-30] Two meta-analyses of controlled clinical trials assessing varied formulations (dried powder, aqueous extracts, raw, oil) and dosages of garlic showed an approximate 10% reduction in total cholesterol levels.[31,32] Dried powder preparations led to a 13% reduction in serum triglycerides and an insignificant reduction in HDL in one meta-analysis.[31]

A 12-week randomized, double-blind study compared the effects on serum lipids of dried garlic powder 900 mg/day (Kwai; Lichtwer Pharma GmbH, Berlin, Germany; standardized to provide 1.3% alliin/tablet, equivalent to 2.7 g fresh garlic or 1 clove/day) and placebo.[29] Alliin is the odorless precursor to allicin, a sulfur-containing compound. Subjects were 42 healthy adults (19 men, 23 women) with serum total cholesterol levels of 220 mg/dl or greater. Diets and physical activity were unchanged. The garlic-treated group had a statistically significant reduction in total serum cholesterol of 15 mg/dl, compared with 2 mg/dl reduction in the placebo-treated group after 12 weeks (p<0.01). Also, LDL concentrations in the garlic-treated group were significantly reduced compared with the placebo-treated group after 12 weeks (-20 vs -6 mg/dl, p<0.05). The HDL and triglyceride concentrations were not significantly changed.

In contrast with these positive results, a double-blind, randomized, placebo-controlled trial reported that garlic oil had no influence on serum lipoprotein values.[26] Therefore, oil dosage forms should not be recommended for anti-hyperlipidemic effect. Other clinical trials found 900 mg/day of dried garlic powder (standardized to provide 1.3% alliin/tablet) to be ineffective in lowering cholesterol levels in patients with hypercholesterolemia.[25, 27, 28] In addition, according to a meta-analysis of 13 trials, although garlic reduced total cholesterol levels from baseline (-15.7 mg/dl, 95% confidence interval [CI] -25.6 to -5.7 mg/dl), the size of the effect was modest and the strength of the effect debatable.[33] Thus, overall evidence for garlic's ability to reduce cholesterol concentrations is questionable.

Plasma cholesterol levels decreased when soy protein was substituted for animal protein in the diets of hyperlipidemic individuals.[34,35] This led the Food and Drug Administration to authorize health claims about the role of soy protein in reducing the risk of coronary heart disease on labeling of foods containing the product.[36] Soy commonly is consumed in the U.S. as a cholesterol-free meat and dairy substitute. In addition to its cholesterol-lowering effects, it has been used to prevent cancer (breast, endometrial, prostate); to treat osteoporosis, constipation, and diarrhea; to decrease urinary protein excretion and slow progression of kidney disease; and to relieve menopausal symptoms.[6] Soybeans contain isoflavones (water-soluble chemicals found in many plants), including phytoestrogens genistein and daidzein, that are used in production of soy proteins.[6] Phytoestrogens are compounds that have weak estrogenic effects under certain conditions and antiestrogenic effects under others.[37] The exact mechanism of action is not clear, but isoflavones are considered to be responsible for most of the lipid-lowering effects of soy products; although, it was theorized that the protein and isoflavones have synergistic effects.[38]

Clinical trials examined the effects of soy protein on serum cholesterol with inconsistent results.[38,39,40] Many of these inconsistencies can be attributed to different methodologies among the trials. In a meta-analysis of 38 controlled clinical trials, an average of 47 g/day of soy protein containing various concentrations of isoflavones was administered to 730 subjects with a wide range of baseline cholesterol levels.[34] Ingestion of soy protein was associated with significant reductions in total cholesterol (-23.2 mg/dl, 95% CI -13.5 to -32.9 mg/dl), LDL (-21.7 mg/dl, 95% CI -11.2 to -31.7 mg/dl), and triglycerides (-13.3 mg/dl, 95% CI -0.3 to -25.7 mg/dl) compared with concentrations reached with the control diet. There was a nonsignificant 2.4% increase in HDL concentration. The initial serum cholesterol concentration was the only predictor of change in the value, with significant reductions occurring in patients with moderate (259-333 mg/dl) and severe (> 335 mg/dl) hypercholesterolemia (p<0.001).

-3 Fatty Acids

-3 fatty acids (fish oils, N-3 fatty acids) come from a variety of marine life such as mackerel, herring, tuna, halibut, salmon, cod liver, whale blubber, and seal blubber. They are purported to reduce coronary mortality and treat rheumatoid arthritis.[6, 41] They were first recognized as having antihyperlipidemic effects in the late 1970s when Greenland Inuits (Eskimos) were found to have low serum concentrations of cholesterol, triglycerides, and LDL due to their high intake of fish oils. The exact mechanism of triglyceride-lowering capabilities is not fully understood.

A meta-analysis reviewed 36 crossover and 29 parallel design studies to evaluate the effects of less than 7 g/day of N-3 fatty acids with treatment periods of 2 weeks in more than 2800 subjects.[42] In crossover studies total cholesterol concentrations were unaffected by N-3 fatty acids. Triglyceride concentrations decreased by 25% in subjects with normal triglyceride concentrations (< 177 mg/dl) and by 34% in those with elevated concentrations (> 177 mg/dl). The LDL was slightly increased by 4.5% and 10.8% in patients with normal and elevated triglyceride concentrations, respectively. The HDL was essentially unchanged. Parallel studies reported similar effects. The authors concluded that N-3 fatty acids have a significant and probably clinically important effect on serum triglycerides, especially in hypertriglyceridemic patients. However, similar to fibric acid derivatives, as very low-density lipoprotein (VLDL) concentrations decrease, LDL may rise to a small extent. Table 1 summarizes the comparative, cholesterol-modifying potential of these agents.

Safety

Although all of these products were well tolerated during clinical trials and side effects are uncommon when the agents are taken in recommended dosages, it is not known whether prolonged use or increased dosages could result in toxicity. Because herbal products are classified as dietary supplements, they are exempt from legislation requiring postmarketing surveillance of safety. Furthermore, it is important to examine the potential for contraindications and drug interactions when the products are concomitantly administered in patients with other disease states or taking prescribed drugs. A survey found that individuals using herbal remedies also reported taking significantly more prescription drugs than nonusers.[43] Table 2 summarizes key safety data for the six supplements discussed.

Other safety concerns include, but are not limited to, inability to identify active ingredients, various amounts of active ingredients, potential for adulterated or misbranded products, and different methodologies of clinical trials. Despite these issues, consumers continue to purchase dietary supplements at an untoward rate. For these reasons, clinicians should take an active role in caring for these patients, including monitoring for adverse events and ensuring that appropriate outcomes are met.

Summary

Limited evidence shows the effectiveness of red yeast rice, tocotrienols, gugulipid, garlic, and soy protein as antihyperlipidemic agents. These products and -3 fatty acids all have anti-hypertriglyceridemic effects. Of the agents reviewed, red yeast rice resulted in the greatest reduction in LDL, but none lowered LDL more than 25%. The most potent agent for reducing triglycerides is -3 fatty acid, but it does not reduce LDL and if fact may increase it to a small extent.

The supplements appeared to be generally well tolerated in clinical trials, but their long-term safety is not established. Clinicians should not recommend them as substitutes for conventional antihyperlipidemic and hypertriglyceridemic drugs. However, they may be adjunctive therapy when proven agents reach maximum dosages or are intolerable, or as preventive therapy in patients with mild hyperlipidemia or hypertriglyceridemia. Because of safety issues, sound clinical judgment makes us interpret clinical trial results with caution. Clinicians should be aware of the risk of unexpected effects that may be influenced by a patient's age, gender, concurrent disease states, and other concomitant nonprescription and prescription drugs.

References

  1. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997. JAMA 1998;280:1569-75.

  2. Johnson & Johnson Merck Consumer Pharmaceuticals. Data on file. New Brunswick, NJ; 1999.

  3. Natural Pharmacist. High cholesterol. Available from http://www.tnp.com/topic.asp?ID=181. Accessed August 7, 2000.

  4. Wang HX, Ng TB. Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic, and antithrombotic activities. Life Sci 1999;65(25):2663-77.

  5. Robbers JE, Tyler VE, eds. Tyler's herbs of choice: the therapeutic use of phytomedicinals. Binghamton, NY: Haworth Press, 1999:138-40.

  6. Jellin JM, Batz F, Hitchens K. Pharmacist's letter/prescriber's letter natural medicines comprehensive database. Stockton, CA: Therapeutic Research Faculty, 1999.

  7. Zhu Y, Li CL, Wang YY. Effects of xuezhikang on blood lipids and lipoprotein concentrations of rabbits and quails with hyperlipidemia. Chin J Pharmacol 1995;30:4-8.

  8. Zhu Y, Li CL, Wang YY, Zhu JS, Chang J, Kritchevsky D. Monascus purpureus (red yeast): a natural product that lowers blood cholesterol in animal models of hypercholesterolemia. Nutr Res 1998;18:71-81.

  9. Wang J, Su M, Lu Z, et al. Clinical trial of extract of Monascus purpureus (red yeast) in the treatment of hyperlipidemia. Chin J Exp Ther Prep Chin Med 1995;12:1-5.

  10. Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VLW. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999;69:231-6.

  11. Theriault A, Chao J, Wang Q, Gapor A, Adeli K. Tocotrienol: a review of its therapeutic potential. Clin Biochem 1999; 32(5):309-19.

  12. Qureshi AA, Qureshi N, Wright JJK, et al. Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienol (Palmvitee). Am J Clin Nutr 1991;53:1021S-6.

  13. Tan DTS, Khor HT, Low WHS, Ali A, Gapor A. Effect of palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans. Am J Clin Nutr 1991;53:1027S-30.

  14. Qureshi AA, Qureshi N, Hasler-Rapacz JO, et al. Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias. Am J Clin Nutr 1991;53:1042S-6.

  15. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 1993;268(15):11230-8.

  16. Pearce BC, Parker RA, Deason ME, et al. Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and anti-oxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols. J Med Chem 1994;37(4):526-41.

  17. Qureshi AA, Pearce BC, Nor RM, Gapor A, Peterson DM, Elson CE. Dietary alph -tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J Nutr 1996;126(2):389-94.
  18. Center for Science in the Public Interest. Cholesterol-lowering supplements. Available from http://www.cspinet.org/ nah/novnah.htm. Accessed August 8, 2000.

  19. Anonymous. Guggul. In: DerMarderosian A, ed. The review of natural products by Facts and Comparison. St. Louis: Wolters Kluwer, 1999:1-2.

  20. Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of Commiphoro mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994;8:659-64.

  21. Ararwal RC, Singh SP, Saran RK, et al. Clinical trial of gugulipid -- a new hypolipidemic agent of plant origin in primary hyperlipidemia. Indian J Med Res 1986;84:626-34.

  22. Verma SK, Bordia A. Effect of commiphora mukul (gum guggula) in patients of hyperlipidemia with special reference to HDL-cholesterol. Indian J Med Res 1988;87:356-60.

  23. Alternative Health News. Cholesterol inhibitors in garlic named. Available from http://www.altmedicine.com/app/registeruser.cfm. Accessed August 8, 2000.

  24. Gebhardt R, Beck H, Wagner KG. Inhibition of cholesterol biosynthesis by allicin and ajoene in rat hepatocytes and HepG2 cells. Biochim Biophys Acta 1994;1213:57-62.

  25. Isaacsohn JL, Moser M, Stein EA, et al. Garlic powder and plasma lipids and lipoproteins, a multicenter, randomized, placebo-controlled trial. Arch Intern Med 1998;158: 1189-94.

  26. Berthold HK, Sudhop T, von Bergmann K. Effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism. JAMA 1998;279 (23):1900-2.

  27. Superko HR, Krauss RM. Garlic powder, effect on plasma lipids, postprandial lipemia, low-density lipoprotein particle size, high-density lipoprotein subclass distribution and lipoprotein (a). J Am Coll Cardiol 2000;35:321-6.

  28. Neil HA, Silagy CA, Lancaster T, et al. Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysis. J R Coll Physicians Lond 1996;30(4):329-34.

  29. Jain AK, Vargas R, Gotzkowsky S, McMahon FG. Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med 1993;94:632-5.

  30. Steiner M, Khan AH, Holbert D, I-San Lin R. A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr 1996;64:866-70.

  31. Silagy C, Neil A. Garlic as a lipid lowering agent -- a meta-analysis. J R Coll Physicians Lond 1994;28:39-45.

  32. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med 1993;119:599-605.

  33. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. Ann Intern Med 2000;133:420-9.

  34. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333:276-82.

  35. Carroll KK. Review of clinical studies on cholesterol-lowering response to soy protein. J Am Diet Assoc 1991;91:820-7.

  36. Food and Drug Administration. FDA talk paper. FDA home page. Available from http://www.fda.gov/bbs/topics/ANSWERS/ ANS00980.html.

  37. Cassidy A, Biongham S, Setchell KD. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:333-40.

  38. Crouse JR, Morgan T, Terry JG, Ellis J, Vitolins M, Burke GL. A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch Intern Med 1999;159:2070-6.

  39. Baum JA, Teng H, Erdman JW Jr, et al. Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women. Am J Clin Nutr 1998;68:545-51.

  40. Simons LA, von Konigsmark M, Simons J, Celermajer DS. Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. Am J Cardiol 2000;85 (11):1297-301.

  41. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995;274:1363-7.

  42. Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65(suppl):1645S-54.

  43. Klepser TB, Doucette WR, Horton MR, et al. Assessment of patients' perceptions and beliefs regarding herbal therapies. Pharmacotherapy 2000;20 (1):83-7.

  44. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-11.