REVIEW ARTICLE
An evidence-based review of commonly used dietary supplements John Laird, ND
Integrative medicine combines the most effective therapies from complementary and alternative medicine (CAM) with conventional, evidence-based medical treatments. The concept of integrative medicine was developed by Andrew Weil, MD, who started a fellowship in integrative medicine at the University of Arizona.1 Integrative medicine was further developed with the establishment of the Consortium of Academic Health Centers for Integrative Medicine in 2000 (now called the Academic Consortium for Integrative Medicine and Health). More than 60 centers in the United States and Canada use integrative medicine.2 The consortium defines integrative medicine as “the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals, and disciplines to achieve optimal health and healing.”2 Although integrative medicine has its roots in CAM, it does not indiscriminately accept all CAM therapies. Conversely, although complementary implies a secondary role in therapeutics, integrative implies an equal status between evidence-based CAM and conventional medical therapies. John Laird is an associate professor in the PA program at Chatham University in Pittsburgh, Pa. The author has disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000466643.93467.2a Copyright © 2015 American Academy of Physician Assistants
© TOFINO/ EASYFOTOSTOCK
ABSTRACT Use of complementary and alternative medicine (CAM) is increasing in the United States. Physician assistants need to know about the efficacy of CAM therapies if they practice integrative medicine (which combines CAM and traditional therapies), recommend a CAM therapy occasionally as part of their treatment plan, refer patients to CAM providers, or have patients who self-select CAM therapies. This article describes integrative medicine and reviews the most commonly used dietary supplements. Keywords: integrative medicine, complementary and alternative medicine, dietary supplements, herbal, natural, conventional therapy
A guiding principle of integrative medicine is to first use the least invasive, least toxic, and least costly therapy.1 The National Health Interview Survey found that CAM usage by adults in the United States increased from 36% to 38% between 2002 and 2007.3 According to the National Health and Nutrition Examination Survey, between 1988 and 2006, dietary supplement use increased from 42% to 53% among adults age 20 years and older.4 Nearly 18% of adults took a nonvitamin, nonmineral natural product in 2007.3 The most common dietary supplements were multivitamin minerals, fish and flax oils, glucosamine and chondroitin, echinacea, garlic, ginkgo, ginseng, green tea, melatonin, and coenzyme Q-10.3,4 Out-of-pocket expenditure on CAM products and practitioners totaled $33.9 billion in 2007; $14.8 billion of this was spent on nonvitamin, nonmineral natural products.5 Herbal sales increased by 3.3% in 2010. Black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, soy, and St. John’s wort were the most purchased in the mass market.6 These statistics reveal that CAM is a significant component of US healthcare. The use of CAM is higher among women, those with higher education, and varies by race and ethnicity as follows: Native American (50%), non-Hispanic white (43%), Asian (40%), African American (26%), and Hispanic (24%).3 Knowledge about the efficacy and safety of CAM therapies is clinically useful for providers who practice integrative medicine, recommend a CAM therapy occasionally as part of their treatment plan, refer patients to CAM providers, or have patients who self-select CAM therapies.
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How, though, can physician assistants (PAs) know which therapies are supported by scientific evidence for safety and efficacy? The National Institutes of Health’s National Center for Complementary and Integrative Health (https://nccih.nih.gov) is an excellent resource, rating the quality of the current evidence supporting the use of different CAM treatments. Two subscription-based resources are the Natural Medicines Comprehensive Database (http://naturaldatabase.therapeuticresearch.com/ home.aspx?cs=&s=ND) and the Natural Standard (http:// www.naturalstandard.com). This article identifies which of the top-selling and commonly used CAM products are effective, ineffective, or have insufficient evidence for their therapeutic indication. Efficacy is assessed by well-designed randomized controlled trials using high-quality standardized natural products, or systematic reviews and meta-analyses of such trials. When trials are single, small, or yield conflicting results, the evidence is deemed insufficient to make a recommendation. MIND AND MOOD St. John’s wort (effective) Although St. John’s wort is as effective as standard antidepressants for mild to moderate major depressive disorder, it induces the CYP 3A4 pathway and interacts with about 50% of prescription medications.7 Check for specific drug interactions before recommending St. John’s wort. The best electronic resource is the Natural Medicines Comprehensive Database.8 Kava (effective) This product has been found effective for the treatment of anxiety. Drug monitoring and postmarket surveillance studies of more than 11,000 subjects for 4 to 7 weeks found no cases of liver disorders associated with kava, but long-term studies are needed to assess its risk for hepatotoxicity after kava was implicated in 68 cases in Europe.9 Butterbur (effective) The American Academy of Neurology and the American Headache Society give butterbur (Petasites hybridus) a Level A recommendation, calling it effective for migraine prophylaxis.10 One extract, Petadolex, significantly reduced the frequency of migraines by 48% when dosed at 75 mg twice per day for 4 months.11 Use a formulation that is free of hepatotoxic pyrrolizidine alkaloids. Ginseng (insufficient evidence) According to a systematic review of five randomized controlled trials, ginseng improves working memory, some aspects of learning, calmness, and social relationships in healthy young subjects.12 Larger, well-designed trials are needed to verify these findings. Ginkgo biloba (ineffective) In volunteers age 75 years and older with normal cognition or mild cognitive impairment, ginkgo biloba was no better than placebo in preventing cognitive decline, progression to Alzheimer disease, or allcause dementia.13,14 These trials are particularly strong because they used the most researched formulation of Ginkgo biloba, EGB 761, at an appropriate dosage of 120 mg twice per day, and followed participants for a median of 6.1 years.
INFECTIOUS DISORDERS Zinc (effective) When taken within 48 hours of symptom onset, zinc reduces the duration and severity of the common cold. Its efficacy as zinc sulfate in syrup, and zinc acetate or gluconate in lozenges and tablets may be due to competitive inhibition of the ICAM-1 receptor on the rhinovirus. Adverse reactions such as nausea, bad taste, and abdominal pain are common.15 Echinacea (insufficient evidence) Randomized, placebocontrolled trials of echinacea’s effect on the common cold have a great deal of heterogeneity in design and herbal formulation. Trials that found no effect included ones using standardized tinctures of ethanol and carbon dioxide extracts of Echinacea angustifolia root administered to subjects who were inoculated with rhinovirus, and a nonalcoholic extract of E. purpurea juice administered to children from the onset of cold symptoms.16,17 Two trials found a significant effect for echinacea. The first used a standardized liquid ethanol extract of E. purpurea (Echinilin) administered in 4-mL doses, 10 times on the first day followed by four times per day for 6 days.18 The second trial used an herbal combination tablet (Esberitox) containing fixed amounts of E. purpurea and E. pallida root, Baptisia tinctoria root (wild indigo), and Thuja occidentalis (white cedar) herb administered in a chewable tablet three times per day for 7 to 9 days.19 Cranberry (insufficient evidence) Two meta-analyses of cranberry for the prevention of urinary tract infection (UTI) had opposite conclusions regarding efficacy. A review of 24 clinical trials found cranberry ineffective for the prevention of UTI, but a review of 13 trials found it effective in preventing recurrent UTI in women and children.20,21 The main difference was that the smaller review excluded a large trial in college women because that trial used a threshold of 1,000 colony-forming units (CFU) per mL as the definition of UTI. Clinically, a threshold of 105 CFU per mL is used. Proanthocyanidin compounds in cranberry inhibit P-fimbriated Escherichia coli from adhering to the urogenital epithelium.21 Milk thistle (ineffective) An extract of milk thistle (Silybum marianum) standardized for silymarin has historically been used for liver disorders. A 24-week randomized controlled trial used a high-quality, patented milk thistle extract (Legalon 140) administered at three to five times the normal dose to patients with chronic hepatitis C virus unresponsive to interferon therapy.22 The extract did not significantly reduce serum alanine transferase nor hepatitis C virus RNA serum levels.22 HYPERLIPIDEMIA AND CARDIOVASCULAR DISEASE Fish oil (effective for hyperlipidemia; ineffective for secondary prevention of cardiovascular disease) Fish oil, consisting of 3.25 g of eicosapentaenoic acid (EPA) and/ or docosahexaenoic acid (DHA) per day reduces serum triglycerides by an average of 30 mg/dL over 24 weeks,
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An evidence-based review of commonly used dietary supplements
but has little effect on low-density lipoprotein (LDL) or high-density lipoprotein cholesterol.23 Two meta-analyses of randomized controlled trials using omega-3 fatty acids from fish oil at a mean dose of 1.5 to 1.7 g per day for a mean of 2 years concluded that omega-3 fatty acids are not effective for the secondary prevention of cardiovascular disease including sudden cardiac death, myocardial infarction, and stroke.24,25 Fish oil may not provide added benefit to concurrent lipid-lowering, antiplatelet, antidiabetic, and antihypertensive therapy. Additional trials are needed to determine whether omega-3 fatty acids from fish oil are effective for the primary prevention of cardiovascular disease. Garlic (ineffective) Garlic is purported to lower serum cholesterol; however, a 6-month trial of garlic as a raw clove, powdered supplement standardized for allicin release (Garlicin), or aged extract (Kyolic) did not significantly reduce LDL cholesterol in subjects with baseline levels between 130 and 190 mg/dL.26 Coenzyme Q10 (insufficient evidence) In a randomized controlled trial, patients with hyperlipidemia and myopathic symptoms associated with statins experienced a significant 40% decrease in pain severity after 30 days of supplementation with coenzyme Q10 (100 mg per day).27 BONE AND JOINT Vitamin D (effective) Supplementation at a dose of 800 international units (IU) or more per day reduces the risk of hip fracture by 30% and nonvertebral fractures by 14% in patients age 65 years and older.28 Lower doses are not associated with risk reduction. Glucosamine (insufficient evidence) Two randomized controlled 3-year trials of glucosamine sulfate (Dona) in patients with knee osteoarthritis revealed a significant reduction of pain as assessed by the Western Ontario and McMaster Universities (WOMAC) scale, and a significant preservation of joint space.29,30 A 24-week trial of glucosamine hydrochloride alone or in combination with chondroitin sulfate in patients with knee osteoarthritis was no better than placebo in reducing pain by 20%, although a subgroup with moderate to severe osteoarthritis experienced a significant response.31 CANCER Melatonin (insufficient evidence) A meta-analysis of melatonin as an adjunctive treatment for various solid tumors including metastatic non–small cell lung cancer, glioblastoma, and other advanced cancers found a dose of 20 to 40 mg per day reduced the risk of death at 1 year by 44%.32 A limitation is the lack of blinding in the trials, all of which were performed by the same team of investigators in Italy and Poland. Vitamin D plus calcium (insufficient evidence) Daily supplementation with vitamin D3 (1,100 IU) plus calcium (1,400-1,500 mg) for 4 years in healthy postmenopausal
women living in rural Nebraska was associated with a 77% reduction in the incidence of any cancer when the analysis was limited to those cancers that were diagnosed after the first 12 months of the trial.33 Green tea (insufficient evidence) A meta-analysis of mostly case control and prospective cohort studies found insufficient evidence for green tea consumption as a prevention for cancer of the gastrointestinal tract, pancreas, breast, prostate, lung, or bladder.34 MEN’S HEALTH Vitamin E and selenium (ineffective) Daily supplementation with selenium as 200 mcg of selenomethionine and vitamin E as 400 IU of dl-alpha tocopherol acetate either singly or in combination did not reduce the incidence of prostate cancer in more than 26,000 men during a median follow-up of 5.46 years.35 An additional 3-year follow-up revealed that vitamin E supplementation significantly increased the risk of developing prostate cancer by 17%; selenium alone or in combination with vitamin E had no significant effect.36 Vitamin C (ineffective) In the Physicians’ Health Study II, supplementation with vitamin E as 400 IU of dl-alpha tocopherol every other day or vitamin C as 500 mg of ascorbic acid daily for a mean of 8 years did not reduce the incidence of prostate, lung, colorectal, bladder, or pancreatic cancer.37 Saw palmetto (ineffective) Compared with placebo, saw palmetto did not reduce American Urological Association Symptom Index (AUASI) scores, prostate size, or residual urine volume after voiding.38 The product was given as a standardized carbon dioxide extract of 160 mg twice per day for 1 year in men with moderate to severe symptoms of benign prostatic hyperplasia (BPH).38 Doubling and tripling the dosage of saw palmetto to 960 mg per day of a standardized ethanol extract over 72 weeks had no effect on lower urinary tract symptoms in men with baseline AUASI scores between 8 and 24.39 WOMEN’S HEALTH Soy isoflavones (effective) Administered at an average dose of 54 mg per day for 12 weeks or longer, soy isoflavones containing at least 19 mg of genistein significantly reduced the frequency and severity of hot flashes.40 A prospective cohort study of breast cancer survivors in China found that soy food reduced the recurrence of breast cancer. The daily isoflavone intake for maximum benefit was 40 mg per day.41 Soy food consumption appears to pose no risk of breast cancer recurrence in breast cancer survivors; however, the effects of high-dose isoflavone supplements are unknown. Black cohosh (insufficient evidence) The heterogeneity of trial design and formulations contributes to mixed findings for black cohosh. A standardized isopropanolic extract of black cohosh containing 1 mg of triterpene
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glycosides per 20 mg tablet (Remifemin) significantly reduced hot flashes and other menopausal symptoms when administered twice per day for 12 weeks.42 However, a 1-year trial of an ethanol extract of black cohosh providing 4 mg of triterpene glycosides daily was no more effective than placebo in reducing the frequency and severity of vasomotor symptoms in peri- and postmenopausal women.43 Recent investigation into the mechanism of action of the isopropanolic extract of black cohosh have ruled out direct endocrine effects, and have identified effects on central mu-opioid receptor binding affinity that may account for the observed vasomotor responses.44 Black cohosh appears safe for women with a higher risk for hormone-dependent cancers. GASTROINTESTINAL HEALTH Lactobacillus rhamnosus and Saccharomyces boulardii (effective) When taken concurrently with antibiotics, probiotics containing Lactobacillus rhamnosus or Saccharomyces boulardii at a dose of greater than 5 billion CFUs are effective in preventing antibiotic-associated diarrhea in children.45 Bifidobacterium infantis (effective) The probiotic Bifidobacterium infantis 35624 (Align) dosed at 10 billion CFUs per day significantly reduces abdominal pain, bloating, and bowel movement difficulty in patients with irritable bowel syndrome.46 Lactobacillus GG (effective) This probiotic was administered as 20 billion CFUs per day to mothers with a family history of atopy 2 to 4 weeks before delivery, and subsequently to their infants for 6 months.47,48 Lactobacillus GG (Culturelle) reduced the incidence of atopic eczema by 50% in these children at age 2 years and 43% at age 4 years.47,48 According to the hygiene hypothesis, early exposure to probiotics modulates the immune system and prevents the development of atopy. MULTIPLE CONDITIONS Multivitamin mineral (insufficient evidence) Although 40% of adults in the United States take a multivitamin mineral supplement, most epidemiologic evidence does not support its efficacy in preventing disease or decreasing mortality.4 Multivitamin mineral use did not reduce or increase mortality from all causes, cardiovascular disease, or cancer in 182,099 adults in Hawaii and California, nor in 67,150 postmenopausal women who participated in the Women’s Health Initiative.49,50 Among women older than age 61 years participating in the Iowa Women’s Health Study, multivitamin use since 1986 was associated with an absolute increased risk of mortality by 2.4%, although shorter period analyses were not significant.51 A recent randomized controlled trial of a daily multivitamin mineral administered to 14,641 male physicians for an average of 11 years was associated with a significant 8% decrease in total cancer, but insignificant
effects on prostate and colon cancer, myocardial infarction, and stroke.52,53 CONCLUSION Integrative medicine advances the practice of CAM in the context of conventional medicine with its emphasis on evidence-based treatment. Randomized controlled trials of commonly used dietary supplements have contributed to an understanding of their efficacy or lack thereof. PAs can review excellent online databases, systematic reviews, and textbooks to educate patients about the appropriate use of CAM products and therapies. JAAPA REFERENCES 1. Rakel D, Weil A. Philosophy of integrative medicine. In: Rakel D, ed. Integrative Medicine. 3rd ed. Elsevier Saunders: Philadelphia, PA; 2012:2-11. 2. Academic Consortium for Integrative Medicine and Health. https://www.imconsortium.org. Accessed April 15, 2015. 3. Barnes PM, Bloom B, Nahin R. CDC National health statistics report No. 12. Complementary and alternative medicine use among adults and children: United States, 2007. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. http://nccam. nih.gov/sites/nccam.nih.gov/files/news/nhsr12.pdf. Accessed April 15, 2015. 4. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among US adults has increased since NHANES III (1988–1994). National Center for Health Statistics data brief No. 61. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. April 2011:1-8. http://www.cdc.gov/nchs/data/databriefs/db61. pdf. Accessed April 15, 2015. 5. Nahin RL, Barnes PM, Stussman BJ, Bloom B. Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States, 2007. National health statistics report No. 18. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. http://nccam. nih.gov/sites/nccam.nih.gov/files/nhsrn18.pdf. Accessed April 15, 2015. 6. Blumenthal M, Lindstrom A, Lynch ME, et al. Herb sales continue growth—up 3.3% in 2010. HerbalGram. 2011;90:64-67. http://cms.herbalgram.org/herbalgram/issue90/MarketReport. html. Accessed April 15, 2015. 7. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448. 8. Clauson KA, Polen HH, Peak AS, et al. Clinical decision support tools: personal digital assistant versus online dietary supplement databases. Ann Pharmacother. 2008;42)(11):1592-1599. 9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD003383. 10. Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353. 11. Lipton RB, Göbel H, Einhäupl KM, et al. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244. 12. Geng J, Dong J, Ni H, et al. Ginseng for cognition. Cochrane Database Syst Rev. 2010;(12):CD007769. 13. Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. 2009;302(24):2663-2670.
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An evidence-based review of commonly used dietary supplements 14. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300(19):2253-2262. 15. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2011;(2):CD001364. 16. Turner RB, Bauer R, Woelkart K, et al. An evaluation of echinacea angustifolia in experimental rhinovirus Infections. N Engl J Med. 2005;353(4):341-348. 17. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract Infections in children: a randomized controlled trial. JAMA. 2003;290(21): 2824-2830. 18. Goel V, Lovlin R, Barton R, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2004;29(1):75-83. 19. Henneicke-von Zepelin H, Hentschel C, Schnitker J, et al. Efficacy and safety of a fixed combination phytomedicine in the treatment of the common cold (acute viral respiratory tract infection): results of a randomised, double blind, placebo controlled, multicentre study. Curr Med Res Opin. 1999;15(3):214-227. 20. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2012;(10): CD001321. 21. Wang CH, Fang CC, Chen NC, et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(13): 988-996. 22. Fried MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA. 2012;308(3):274-282. 23. Eslick GD, Howe PR, Smith C, et al. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and metaanalysis. Int J Cardiol. 2009;136(1):4-16. 24. Kwak SM, Myung SK, Lee YJ, et al. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694. 25. Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033. 26. Gardner CD, Lawson LD, Block E, et al. Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med. 2007;167(4):346-353. 27. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99(10):1409-1412. 28. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367(1):40-49. 29. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357 (9252):251-256. 30. Pavelká K, Gatterová J, Olejarová M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162(18):2113-2123. 31. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8):795-808. 32. Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39(4):360-366.
33. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586-1591. 34. Boehm K, Borrelli F, Ernst E, et al. Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst Rev. 2009; (3):CD005004. 35. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39-51. 36. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556. 37. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2009;301(1):52-62. 38. Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med. 2006;354(6):557-566. 39. Barry MJ, Meleth S, Lee JY, et al. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA. 2011;306(12):1344-1351. 40. Taku K, Melby MK, Kronenberg F, et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause. 2012;19(7):776-790. 41. Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302(22):2437-2443. 42. Osmers R, Friede M, Liske E, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005;105(5 Pt 1):1074-1083. 43. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006;145(12):869-879. 44. Reame NE, Lukacs JL, Padmanabhan V, et al. Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause. 2008;15(5):832-840. 45. Johnston BC, Supina AL, Ospina M, Vohra S. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2007;(2):CD004827. 46. O’Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-551. 47. Kalliomäki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebocontrolled trial. Lancet. 2001;357(9262):1076-1079. 48. Kalliomäki M, Salminen S, Poussa T, et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet. 2003;361(9372):1869-1871. 49. Park SY, Murphy SP, Wilkens LR, et al. Multivitamin use and the risk of mortality and cancer incidence: The Multiethnic Cohort Study. Am J Epidemiol. 2011;173(8):906-914. 50. Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women’s Health Initiative cohorts. Arch Intern Med. 2009;169 (3):294-304. 51. Mursu J, Robien K, Harnack LJ, et al. Dietary supplements and mortality rate in older women: the Iowa Women’s Health Study. Arch Intern Med. 2011;171(18):1625-1633. 52. Gaziano JM, Sesso HD, Christen WG, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308(18):1871-1880. 53. Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308 (17):1751-1760.
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An evidence-based review of commonly used dietary supplements John Laird, ND
Integrative medicine combines the most effective therapies from complementary and alternative medicine (CAM) with conventional, evidence-based medical treatments. The concept of integrative medicine was developed by Andrew Weil, MD, who started a fellowship in integrative medicine at the University of Arizona.1 Integrative medicine was further developed with the establishment of the Consortium of Academic Health Centers for Integrative Medicine in 2000 (now called the Academic Consortium for Integrative Medicine and Health). More than 60 centers in the United States and Canada use integrative medicine.2 The consortium defines integrative medicine as “the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals, and disciplines to achieve optimal health and healing.”2 Although integrative medicine has its roots in CAM, it does not indiscriminately accept all CAM therapies. Conversely, although complementary implies a secondary role in therapeutics, integrative implies an equal status between evidence-based CAM and conventional medical therapies. John Laird is an associate professor in the PA program at Chatham University in Pittsburgh, Pa. The author has disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000466643.93467.2a Copyright © 2015 American Academy of Physician Assistants
© TOFINO/ EASYFOTOSTOCK
ABSTRACT Use of complementary and alternative medicine (CAM) is increasing in the United States. Physician assistants need to know about the efficacy of CAM therapies if they practice integrative medicine (which combines CAM and traditional therapies), recommend a CAM therapy occasionally as part of their treatment plan, refer patients to CAM providers, or have patients who self-select CAM therapies. This article describes integrative medicine and reviews the most commonly used dietary supplements. Keywords: integrative medicine, complementary and alternative medicine, dietary supplements, herbal, natural, conventional therapy
A guiding principle of integrative medicine is to first use the least invasive, least toxic, and least costly therapy.1 The National Health Interview Survey found that CAM usage by adults in the United States increased from 36% to 38% between 2002 and 2007.3 According to the National Health and Nutrition Examination Survey, between 1988 and 2006, dietary supplement use increased from 42% to 53% among adults age 20 years and older.4 Nearly 18% of adults took a nonvitamin, nonmineral natural product in 2007.3 The most common dietary supplements were multivitamin minerals, fish and flax oils, glucosamine and chondroitin, echinacea, garlic, ginkgo, ginseng, green tea, melatonin, and coenzyme Q-10.3,4 Out-of-pocket expenditure on CAM products and practitioners totaled $33.9 billion in 2007; $14.8 billion of this was spent on nonvitamin, nonmineral natural products.5 Herbal sales increased by 3.3% in 2010. Black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, soy, and St. John’s wort were the most purchased in the mass market.6 These statistics reveal that CAM is a significant component of US healthcare. The use of CAM is higher among women, those with higher education, and varies by race and ethnicity as follows: Native American (50%), non-Hispanic white (43%), Asian (40%), African American (26%), and Hispanic (24%).3 Knowledge about the efficacy and safety of CAM therapies is clinically useful for providers who practice integrative medicine, recommend a CAM therapy occasionally as part of their treatment plan, refer patients to CAM providers, or have patients who self-select CAM therapies.
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How, though, can physician assistants (PAs) know which therapies are supported by scientific evidence for safety and efficacy? The National Institutes of Health’s National Center for Complementary and Integrative Health (https://nccih.nih.gov) is an excellent resource, rating the quality of the current evidence supporting the use of different CAM treatments. Two subscription-based resources are the Natural Medicines Comprehensive Database (http://naturaldatabase.therapeuticresearch.com/ home.aspx?cs=&s=ND) and the Natural Standard (http:// www.naturalstandard.com). This article identifies which of the top-selling and commonly used CAM products are effective, ineffective, or have insufficient evidence for their therapeutic indication. Efficacy is assessed by well-designed randomized controlled trials using high-quality standardized natural products, or systematic reviews and meta-analyses of such trials. When trials are single, small, or yield conflicting results, the evidence is deemed insufficient to make a recommendation. MIND AND MOOD St. John’s wort (effective) Although St. John’s wort is as effective as standard antidepressants for mild to moderate major depressive disorder, it induces the CYP 3A4 pathway and interacts with about 50% of prescription medications.7 Check for specific drug interactions before recommending St. John’s wort. The best electronic resource is the Natural Medicines Comprehensive Database.8 Kava (effective) This product has been found effective for the treatment of anxiety. Drug monitoring and postmarket surveillance studies of more than 11,000 subjects for 4 to 7 weeks found no cases of liver disorders associated with kava, but long-term studies are needed to assess its risk for hepatotoxicity after kava was implicated in 68 cases in Europe.9 Butterbur (effective) The American Academy of Neurology and the American Headache Society give butterbur (Petasites hybridus) a Level A recommendation, calling it effective for migraine prophylaxis.10 One extract, Petadolex, significantly reduced the frequency of migraines by 48% when dosed at 75 mg twice per day for 4 months.11 Use a formulation that is free of hepatotoxic pyrrolizidine alkaloids. Ginseng (insufficient evidence) According to a systematic review of five randomized controlled trials, ginseng improves working memory, some aspects of learning, calmness, and social relationships in healthy young subjects.12 Larger, well-designed trials are needed to verify these findings. Ginkgo biloba (ineffective) In volunteers age 75 years and older with normal cognition or mild cognitive impairment, ginkgo biloba was no better than placebo in preventing cognitive decline, progression to Alzheimer disease, or allcause dementia.13,14 These trials are particularly strong because they used the most researched formulation of Ginkgo biloba, EGB 761, at an appropriate dosage of 120 mg twice per day, and followed participants for a median of 6.1 years.
INFECTIOUS DISORDERS Zinc (effective) When taken within 48 hours of symptom onset, zinc reduces the duration and severity of the common cold. Its efficacy as zinc sulfate in syrup, and zinc acetate or gluconate in lozenges and tablets may be due to competitive inhibition of the ICAM-1 receptor on the rhinovirus. Adverse reactions such as nausea, bad taste, and abdominal pain are common.15 Echinacea (insufficient evidence) Randomized, placebocontrolled trials of echinacea’s effect on the common cold have a great deal of heterogeneity in design and herbal formulation. Trials that found no effect included ones using standardized tinctures of ethanol and carbon dioxide extracts of Echinacea angustifolia root administered to subjects who were inoculated with rhinovirus, and a nonalcoholic extract of E. purpurea juice administered to children from the onset of cold symptoms.16,17 Two trials found a significant effect for echinacea. The first used a standardized liquid ethanol extract of E. purpurea (Echinilin) administered in 4-mL doses, 10 times on the first day followed by four times per day for 6 days.18 The second trial used an herbal combination tablet (Esberitox) containing fixed amounts of E. purpurea and E. pallida root, Baptisia tinctoria root (wild indigo), and Thuja occidentalis (white cedar) herb administered in a chewable tablet three times per day for 7 to 9 days.19 Cranberry (insufficient evidence) Two meta-analyses of cranberry for the prevention of urinary tract infection (UTI) had opposite conclusions regarding efficacy. A review of 24 clinical trials found cranberry ineffective for the prevention of UTI, but a review of 13 trials found it effective in preventing recurrent UTI in women and children.20,21 The main difference was that the smaller review excluded a large trial in college women because that trial used a threshold of 1,000 colony-forming units (CFU) per mL as the definition of UTI. Clinically, a threshold of 105 CFU per mL is used. Proanthocyanidin compounds in cranberry inhibit P-fimbriated Escherichia coli from adhering to the urogenital epithelium.21 Milk thistle (ineffective) An extract of milk thistle (Silybum marianum) standardized for silymarin has historically been used for liver disorders. A 24-week randomized controlled trial used a high-quality, patented milk thistle extract (Legalon 140) administered at three to five times the normal dose to patients with chronic hepatitis C virus unresponsive to interferon therapy.22 The extract did not significantly reduce serum alanine transferase nor hepatitis C virus RNA serum levels.22 HYPERLIPIDEMIA AND CARDIOVASCULAR DISEASE Fish oil (effective for hyperlipidemia; ineffective for secondary prevention of cardiovascular disease) Fish oil, consisting of 3.25 g of eicosapentaenoic acid (EPA) and/ or docosahexaenoic acid (DHA) per day reduces serum triglycerides by an average of 30 mg/dL over 24 weeks,
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An evidence-based review of commonly used dietary supplements
but has little effect on low-density lipoprotein (LDL) or high-density lipoprotein cholesterol.23 Two meta-analyses of randomized controlled trials using omega-3 fatty acids from fish oil at a mean dose of 1.5 to 1.7 g per day for a mean of 2 years concluded that omega-3 fatty acids are not effective for the secondary prevention of cardiovascular disease including sudden cardiac death, myocardial infarction, and stroke.24,25 Fish oil may not provide added benefit to concurrent lipid-lowering, antiplatelet, antidiabetic, and antihypertensive therapy. Additional trials are needed to determine whether omega-3 fatty acids from fish oil are effective for the primary prevention of cardiovascular disease. Garlic (ineffective) Garlic is purported to lower serum cholesterol; however, a 6-month trial of garlic as a raw clove, powdered supplement standardized for allicin release (Garlicin), or aged extract (Kyolic) did not significantly reduce LDL cholesterol in subjects with baseline levels between 130 and 190 mg/dL.26 Coenzyme Q10 (insufficient evidence) In a randomized controlled trial, patients with hyperlipidemia and myopathic symptoms associated with statins experienced a significant 40% decrease in pain severity after 30 days of supplementation with coenzyme Q10 (100 mg per day).27 BONE AND JOINT Vitamin D (effective) Supplementation at a dose of 800 international units (IU) or more per day reduces the risk of hip fracture by 30% and nonvertebral fractures by 14% in patients age 65 years and older.28 Lower doses are not associated with risk reduction. Glucosamine (insufficient evidence) Two randomized controlled 3-year trials of glucosamine sulfate (Dona) in patients with knee osteoarthritis revealed a significant reduction of pain as assessed by the Western Ontario and McMaster Universities (WOMAC) scale, and a significant preservation of joint space.29,30 A 24-week trial of glucosamine hydrochloride alone or in combination with chondroitin sulfate in patients with knee osteoarthritis was no better than placebo in reducing pain by 20%, although a subgroup with moderate to severe osteoarthritis experienced a significant response.31 CANCER Melatonin (insufficient evidence) A meta-analysis of melatonin as an adjunctive treatment for various solid tumors including metastatic non–small cell lung cancer, glioblastoma, and other advanced cancers found a dose of 20 to 40 mg per day reduced the risk of death at 1 year by 44%.32 A limitation is the lack of blinding in the trials, all of which were performed by the same team of investigators in Italy and Poland. Vitamin D plus calcium (insufficient evidence) Daily supplementation with vitamin D3 (1,100 IU) plus calcium (1,400-1,500 mg) for 4 years in healthy postmenopausal
women living in rural Nebraska was associated with a 77% reduction in the incidence of any cancer when the analysis was limited to those cancers that were diagnosed after the first 12 months of the trial.33 Green tea (insufficient evidence) A meta-analysis of mostly case control and prospective cohort studies found insufficient evidence for green tea consumption as a prevention for cancer of the gastrointestinal tract, pancreas, breast, prostate, lung, or bladder.34 MEN’S HEALTH Vitamin E and selenium (ineffective) Daily supplementation with selenium as 200 mcg of selenomethionine and vitamin E as 400 IU of dl-alpha tocopherol acetate either singly or in combination did not reduce the incidence of prostate cancer in more than 26,000 men during a median follow-up of 5.46 years.35 An additional 3-year follow-up revealed that vitamin E supplementation significantly increased the risk of developing prostate cancer by 17%; selenium alone or in combination with vitamin E had no significant effect.36 Vitamin C (ineffective) In the Physicians’ Health Study II, supplementation with vitamin E as 400 IU of dl-alpha tocopherol every other day or vitamin C as 500 mg of ascorbic acid daily for a mean of 8 years did not reduce the incidence of prostate, lung, colorectal, bladder, or pancreatic cancer.37 Saw palmetto (ineffective) Compared with placebo, saw palmetto did not reduce American Urological Association Symptom Index (AUASI) scores, prostate size, or residual urine volume after voiding.38 The product was given as a standardized carbon dioxide extract of 160 mg twice per day for 1 year in men with moderate to severe symptoms of benign prostatic hyperplasia (BPH).38 Doubling and tripling the dosage of saw palmetto to 960 mg per day of a standardized ethanol extract over 72 weeks had no effect on lower urinary tract symptoms in men with baseline AUASI scores between 8 and 24.39 WOMEN’S HEALTH Soy isoflavones (effective) Administered at an average dose of 54 mg per day for 12 weeks or longer, soy isoflavones containing at least 19 mg of genistein significantly reduced the frequency and severity of hot flashes.40 A prospective cohort study of breast cancer survivors in China found that soy food reduced the recurrence of breast cancer. The daily isoflavone intake for maximum benefit was 40 mg per day.41 Soy food consumption appears to pose no risk of breast cancer recurrence in breast cancer survivors; however, the effects of high-dose isoflavone supplements are unknown. Black cohosh (insufficient evidence) The heterogeneity of trial design and formulations contributes to mixed findings for black cohosh. A standardized isopropanolic extract of black cohosh containing 1 mg of triterpene
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glycosides per 20 mg tablet (Remifemin) significantly reduced hot flashes and other menopausal symptoms when administered twice per day for 12 weeks.42 However, a 1-year trial of an ethanol extract of black cohosh providing 4 mg of triterpene glycosides daily was no more effective than placebo in reducing the frequency and severity of vasomotor symptoms in peri- and postmenopausal women.43 Recent investigation into the mechanism of action of the isopropanolic extract of black cohosh have ruled out direct endocrine effects, and have identified effects on central mu-opioid receptor binding affinity that may account for the observed vasomotor responses.44 Black cohosh appears safe for women with a higher risk for hormone-dependent cancers. GASTROINTESTINAL HEALTH Lactobacillus rhamnosus and Saccharomyces boulardii (effective) When taken concurrently with antibiotics, probiotics containing Lactobacillus rhamnosus or Saccharomyces boulardii at a dose of greater than 5 billion CFUs are effective in preventing antibiotic-associated diarrhea in children.45 Bifidobacterium infantis (effective) The probiotic Bifidobacterium infantis 35624 (Align) dosed at 10 billion CFUs per day significantly reduces abdominal pain, bloating, and bowel movement difficulty in patients with irritable bowel syndrome.46 Lactobacillus GG (effective) This probiotic was administered as 20 billion CFUs per day to mothers with a family history of atopy 2 to 4 weeks before delivery, and subsequently to their infants for 6 months.47,48 Lactobacillus GG (Culturelle) reduced the incidence of atopic eczema by 50% in these children at age 2 years and 43% at age 4 years.47,48 According to the hygiene hypothesis, early exposure to probiotics modulates the immune system and prevents the development of atopy. MULTIPLE CONDITIONS Multivitamin mineral (insufficient evidence) Although 40% of adults in the United States take a multivitamin mineral supplement, most epidemiologic evidence does not support its efficacy in preventing disease or decreasing mortality.4 Multivitamin mineral use did not reduce or increase mortality from all causes, cardiovascular disease, or cancer in 182,099 adults in Hawaii and California, nor in 67,150 postmenopausal women who participated in the Women’s Health Initiative.49,50 Among women older than age 61 years participating in the Iowa Women’s Health Study, multivitamin use since 1986 was associated with an absolute increased risk of mortality by 2.4%, although shorter period analyses were not significant.51 A recent randomized controlled trial of a daily multivitamin mineral administered to 14,641 male physicians for an average of 11 years was associated with a significant 8% decrease in total cancer, but insignificant
effects on prostate and colon cancer, myocardial infarction, and stroke.52,53 CONCLUSION Integrative medicine advances the practice of CAM in the context of conventional medicine with its emphasis on evidence-based treatment. Randomized controlled trials of commonly used dietary supplements have contributed to an understanding of their efficacy or lack thereof. PAs can review excellent online databases, systematic reviews, and textbooks to educate patients about the appropriate use of CAM products and therapies. JAAPA REFERENCES 1. Rakel D, Weil A. Philosophy of integrative medicine. In: Rakel D, ed. Integrative Medicine. 3rd ed. Elsevier Saunders: Philadelphia, PA; 2012:2-11. 2. Academic Consortium for Integrative Medicine and Health. https://www.imconsortium.org. Accessed April 15, 2015. 3. Barnes PM, Bloom B, Nahin R. CDC National health statistics report No. 12. Complementary and alternative medicine use among adults and children: United States, 2007. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. http://nccam. nih.gov/sites/nccam.nih.gov/files/news/nhsr12.pdf. Accessed April 15, 2015. 4. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among US adults has increased since NHANES III (1988–1994). National Center for Health Statistics data brief No. 61. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. April 2011:1-8. http://www.cdc.gov/nchs/data/databriefs/db61. pdf. Accessed April 15, 2015. 5. Nahin RL, Barnes PM, Stussman BJ, Bloom B. Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States, 2007. National health statistics report No. 18. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. http://nccam. nih.gov/sites/nccam.nih.gov/files/nhsrn18.pdf. Accessed April 15, 2015. 6. Blumenthal M, Lindstrom A, Lynch ME, et al. Herb sales continue growth—up 3.3% in 2010. HerbalGram. 2011;90:64-67. http://cms.herbalgram.org/herbalgram/issue90/MarketReport. html. Accessed April 15, 2015. 7. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448. 8. Clauson KA, Polen HH, Peak AS, et al. Clinical decision support tools: personal digital assistant versus online dietary supplement databases. Ann Pharmacother. 2008;42)(11):1592-1599. 9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD003383. 10. Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353. 11. Lipton RB, Göbel H, Einhäupl KM, et al. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244. 12. Geng J, Dong J, Ni H, et al. Ginseng for cognition. Cochrane Database Syst Rev. 2010;(12):CD007769. 13. Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. 2009;302(24):2663-2670.
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An evidence-based review of commonly used dietary supplements 14. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300(19):2253-2262. 15. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2011;(2):CD001364. 16. Turner RB, Bauer R, Woelkart K, et al. An evaluation of echinacea angustifolia in experimental rhinovirus Infections. N Engl J Med. 2005;353(4):341-348. 17. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract Infections in children: a randomized controlled trial. JAMA. 2003;290(21): 2824-2830. 18. Goel V, Lovlin R, Barton R, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2004;29(1):75-83. 19. Henneicke-von Zepelin H, Hentschel C, Schnitker J, et al. Efficacy and safety of a fixed combination phytomedicine in the treatment of the common cold (acute viral respiratory tract infection): results of a randomised, double blind, placebo controlled, multicentre study. Curr Med Res Opin. 1999;15(3):214-227. 20. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2012;(10): CD001321. 21. Wang CH, Fang CC, Chen NC, et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(13): 988-996. 22. Fried MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA. 2012;308(3):274-282. 23. Eslick GD, Howe PR, Smith C, et al. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and metaanalysis. Int J Cardiol. 2009;136(1):4-16. 24. Kwak SM, Myung SK, Lee YJ, et al. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694. 25. Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033. 26. Gardner CD, Lawson LD, Block E, et al. Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med. 2007;167(4):346-353. 27. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99(10):1409-1412. 28. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367(1):40-49. 29. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357 (9252):251-256. 30. Pavelká K, Gatterová J, Olejarová M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162(18):2113-2123. 31. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8):795-808. 32. Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39(4):360-366.
33. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586-1591. 34. Boehm K, Borrelli F, Ernst E, et al. Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst Rev. 2009; (3):CD005004. 35. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39-51. 36. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556. 37. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2009;301(1):52-62. 38. Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med. 2006;354(6):557-566. 39. Barry MJ, Meleth S, Lee JY, et al. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA. 2011;306(12):1344-1351. 40. Taku K, Melby MK, Kronenberg F, et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause. 2012;19(7):776-790. 41. Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302(22):2437-2443. 42. Osmers R, Friede M, Liske E, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005;105(5 Pt 1):1074-1083. 43. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006;145(12):869-879. 44. Reame NE, Lukacs JL, Padmanabhan V, et al. Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause. 2008;15(5):832-840. 45. Johnston BC, Supina AL, Ospina M, Vohra S. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2007;(2):CD004827. 46. O’Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-551. 47. Kalliomäki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebocontrolled trial. Lancet. 2001;357(9262):1076-1079. 48. Kalliomäki M, Salminen S, Poussa T, et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet. 2003;361(9372):1869-1871. 49. Park SY, Murphy SP, Wilkens LR, et al. Multivitamin use and the risk of mortality and cancer incidence: The Multiethnic Cohort Study. Am J Epidemiol. 2011;173(8):906-914. 50. Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women’s Health Initiative cohorts. Arch Intern Med. 2009;169 (3):294-304. 51. Mursu J, Robien K, Harnack LJ, et al. Dietary supplements and mortality rate in older women: the Iowa Women’s Health Study. Arch Intern Med. 2011;171(18):1625-1633. 52. Gaziano JM, Sesso HD, Christen WG, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308(18):1871-1880. 53. Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308 (17):1751-1760.
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