Natural Foods Merchandiser

Year-end research review

New health claims are made for dietary supplements all the time, and it can be difficult to separate the wheat from the chaff when trying to evaluate new information. Are new health claims based on well-controlled clinical studies? What?s the mechanism of action behind proven benefits? Here?s a snapshot of recent research on some of today?s hottest-selling dietary supplements. The studies show possible health benefits that may be news to your consumers.

Debate has raged for years over whether glucosamine sulfate or chondroitin sulfate is better at lessening the pain of osteoarthritis—not to mention the many debates over which is better at building up the joint synovial fluid and actually repairing the problem. Now a major new clinical study provides strong evidence that supplementing with a combination of glucosamine sulfate and chondroitin sulfate is the most effective in relieving osteoarthritis knee pain and improving function.1 The multicenter study, known as the Glucosamine/Chondroitin Arthritis Intervention Trial, was conducted according to rigorous standards under the auspices of the National Center for Complementary and Alternative Medicine, a division of the National Institutes of Health.

The study involved 1,583 people who were diagnosed with OA of the knee and had experienced knee pain for at least six months. The participants were randomized to receive one of five different treatments for 24 weeks, with each treatment given three times per day except celecoxib (a standard pharmaceutical treatment marketed under the trade name Celebrex). The treatments included glucosamine HCl alone (500 mg/dose), sodium chondroitin sulfate alone (400 mg/dose), glucosamine HCl (500 mg/dose) plus chondroitin sulfate (400 mg/dose), celecoxib (200 mg/day) or placebo. The primary outcome measurement was a 20 percent improvement in pain and function over baseline measurements at the end of the study. Patient responses were assessed according to pain severity.

All treatments were significantly more effective than placebo in reducing pain and improving function. In patients with more severe pain, however, pain reduction for those taking the glucosamine HCl and chondroitin sulfate combination was significantly better than placebo (79.2 percent versus 54.3 percent; a high placebo response rate is not uncommon in OA trials). Glucosamine HCl alone and chondroitin sulfate alone produced response rates of 65.7 percent and 61.4 percent, respectively, and a response rate of 69.4 percent was reported for those who took celecoxib. The glucosamine HCl and chondroitin sulfate utilized in this study were described as meeting pharmaceutical standards, and the researchers noted that GAIT was conducted under an Investigational New Drug application.1

MSM, officially known as methylsulfonylmethane, is another supplement popular for promoting joint health, but few clinical trials have actually tested its effects against OA pain. Recently, a pilot study conducted at the Southwest College of Naturopathic Medicine in Tempe, Ariz., showed that MSM was also significantly more effective than placebo in relieving pain and improving function for people with OA of the knee. The study, which involved 50 men and women between the ages of 40 and 76, utilized a dosage regimen of 3 g MSM twice daily for 12 weeks.2

Heart health
Heart disease remains a significant problem for American consumers, and supplements that aim to improve heart health continue to top the best-seller lists. Lycopene, a carotenoid compound with potent antioxidant effects, has been widely touted for its potential to lower risks for a variety of cancers, including prostate, lung and digestive tract cancers. Less well known is that lycopene?s antioxidant power may also help protect against arteriosclerosis (commonly known as ?hardening of the arteries?), thus lowering risks of heart attack and stroke.3 Studies also suggest that lycopene may be useful for controlling high blood pressure (hypertension).3 Good natural sources of lycopene include tomatoes (with the highest amounts in cooked tomatoes) and many other red and pink fruits, including pink guava, watermelon and pink grapefruit. (For more information on lycopene, see ?A tomato a day? in the March 2005 issue of NFM).

A new study published earlier this year in the American Journal of Hypertension provides more evidence that a standardized tomato extract can help lower high blood pressure.4 The double-blind, placebo-controlled, crossover study involved 60 adults with moderately elevated blood pressure who were already taking one or two antihypertensive medications. In addition to these regular medications, participants were randomly assigned to take either the standardized tomato extract or a placebo for six weeks; after a washout period during which they received no treatment, the two groups were switched for another six weeks. After treatment with the standardized tomato extract, results demonstrated higher blood levels of lycopene along with significant decreases in both systolic and diastolic blood pressure measurements, and beneficial increases in plasma nitrate (a measure of blood vessel function). Treatment with tomato extract reduced mean systolic blood pressure from a baseline measurement of 144mmHg to 135 mmHg (an average reduction of 9 mmHg) and reduced diastolic blood pressure from a baseline mean of 91 to 84mmHg (an average reduction of 7 mmHg). The standardized tomato extract delivered a daily dose of 15 mg lycopene, along with beta-carotene, vitamin E, phytoene and phytofluene.4

The cardiovascular benefits of fish oil, solidly established in clinical studies, are attributed at least in part to the anti-inflammatory activities of the oil?s omega-3 fatty acids.5,6 Inflammatory processes are known to play a role in the development of many degenerative diseases, including heart disease. Recently, researchers identified a family of bioactive lipids (fats) produced by the body during resolution of inflammation that they believe may help explain such anti-inflammatory benefits.7 They named these compounds resolution-phase interaction products, or resolvins. Resolvins appear to be potent inflammatory mediators.7 According to research, the presence of aspirin triggers the body to convert eicosapentaenoic acid (found in abundance in fish oil) into resolvins at the site of inflammation. This is an important discovery that is likely to change scientists? understanding of anti-inflammatory mechanisms. However, additional research is needed to determine if the body produces resolvins in the absence of aspirin—and whether or not fish oil alone would produce them. In addition, research is needed to determine if a combination of fish oil and aspirin may be a useful clinical treatment for inflammatory conditions.8

Immune system support
The immune system plays a vital role in defending against everything from the common cold to cancer, and supplements that promise to enhance this fundamental function continue to proliferate. More than 200 studies document the myriad health benefits of probiotics, often described as ?friendly? bacteria, which help promote a favorable balance of intestinal flora in the gut. The most commonly used probiotic organisms are members of two particular genera of bacteria, Lactobacillus and Bifidobacterium. They have been widely used to improve digestive function and treat infections, and there is compelling evidence that their benefits stem at least in part from their effects on the immune system.9 A number of studies have demonstrated that probiotics may be effective in treating conditions with an immune component, including allergies.9,10,11

Results of a recent controlled study involving babies with allergic eczema poses an interesting possibility as to how probiotics may work to stimulate the function of the immune system.12 Earlier clinical research indicated that treatment with Lactobacillus rhamnosus GG (the best-studied probiotic) was effective in alleviating symptoms of atopic eczema?dermatitis syndrome and boosting immune responses in affected infants.13 The new study involved 230 infants with AEDS and a suspected cow?s milk allergy. The infants were randomly assigned to take Lactobacillus GG (5 capsules containing 109 colony-forming units), placebo or a mixture of four different probiotic strains, mixed with food, twice daily for four weeks. The researchers tested the infants? plasma to find out whether their eczema was associated with immunoglobulin E, an antibody responsible for allergic reactions. After treatment with probiotics, the infants with IgE-associated AEDS who were treated with Lactobacillus GG had higher serum levels of C-reactive protein, a marker of inflammation, indicating a low-grade inflammatory response.12 Based on their results, as well as earlier research that correlates increased levels of CRP with enhanced immune system activity, the researchers propose that the low-grade inflammation was induced by Lactobacillus, which in turn contributed to clinical benefits in infant AEDS. Obviously, more research is needed before such a cause-and-effect relationship can be established. For now, it remains a theory that may someday help explain the clinical benefits of probiotics in childhood allergic eczema.

Prebiotics are indigestible carbohydrate substances (such as oligosaccharides, inulin and fructans) that selectively stimulate the growth of beneficial probiotic organisms in the gut. One recent study suggests that prebiotics have promise in the treatment of Crohn?s disease, a serious inflammatory bowel disease believed to have an autoimmune component.14 In a small, open-label study, 10 people with moderately active Crohn?s disease took 15 g fructo-oligosaccharide each day for three weeks. The researchers reported that FOS treatment significantly increased concentrations of beneficial bifidobacteria, improved function of intestinal immune cells and significantly reduced disease activity in study participants. The researchers call for larger, better-controlled studies to confirm these results.

Medicinal mushrooms have been well studied for their beneficial effects on immune function and have been used as supportive therapy for people undergoing cancer chemotherapy. Active hexose correlated compound is an extract derived from several hybrids of basidiomycete-type mushrooms. According to research, AHCC enhances the activity of natural killer cells in the immune system, which may help explain its supportive effects in cancer.15 Another supplement under study for its supportive effects during cancer treatment is fermented wheat germ extract. Some small, open-label clinical studies suggest that fermented wheat germ extract may be useful as supportive therapy for people undergoing cancer chemotherapy, but larger, controlled studies are needed to clarify its effects.16,17

Weight loss
Citrus aurantium extract, derived from bitter orange, has become a popular ingredient in ephedra-free supplements promoted to enhance weight loss. Some researchers have expressed concern about the safety of C. aurantium because of its content of synephrine alkaloids, some of which may have the potential to raise blood pressure.18 However, one recent study demonstrated that a proprietary C. aurantium product had no effect on blood pressure, even when given at doses eight-fold higher than recommended.19 Differences in pharmacologic effects may be due to the type of synephrine alkaloid contained in individual extracts. The isomer p-synephrine is stable and does not raise blood pressure, while m-synephrine may pose more problems. However, it can be difficult to determine whether a C. aurantium supplement contains p-synephrine, m-synephrine or both.18 Independent testing of individual products is probably the only way to determine actual synephrine content.

A recent double-blind, placebo-controlled pilot trial adds strength to other studies showing that chromium picolinate may be useful in weight loss. A recent study found the supplement helped to control appetite increase and carbohydrate cravings commonly found in people with atypical depression.20 Atypical depression is often associated with increases in appetite and weight gain, among other distinctive symptoms. (The study authors note that in spite of the term atypical, 22 percent to 83 percent of patients with major depressive disorder may have such symptoms.) For the multicenter study, which involved 113 adults diagnosed with atypical depression, participants were randomized in a 2:1 ratio to take either chromium picolinate (providing 600 mcg elemental chromium/day) or placebo for eight weeks. The researchers assessed the results using the 29-item Hamilton Depression Rating Scale and the Clinical Global Impressions Improvement Scale, both standard measurements of responses to antidepressant treatment. At the end of the study, those who took chromium picolinate showed significant improvements in four main measurements: increased appetite, increased eating, carbohydrate cravings and daily mood swings compared with placebo. This does not prove that chromium picolinate is a good treatment for depression, but according to the researchers, their findings with regard to appetite disturbances may be especially significant in light of a proven link between depression and decreased insulin sensitivity.20 Decreased insulin sensitivity is linked to diabetes, and popular theory suggests it may contribute to carbohydrate cravings and therefore weight gain.

Direction for future research
It?s important to note that many of the studies described here have limitations, including inadequate numbers of subjects and lack of controls. Thus, in spite of their promise, the results cannot be interpreted as conclusive. However, they point the way for future research that may result in better treatments for many common health conditions.

Evelyn Leigh is a freelance writer and natural products industry consultant based in Boulder, Colo.

1. Clegg DO, et al. The efficacy of glucosamine and chondroitin sulfate in patients with painful knee osteoarthritis: the glucosamine/chondroitin arthritis intervention trial. American College of Rheumatology annual meeting, November 15, 2005, San Diego, Calif.
2. Kim L, et al. Efficacy of methylsulfonylmethane in osteoarthritis pain: a pilot clinical trial. Arth Rheum 2005;52:S256.
3. Omoni AO and Aluko RE. The anticarcinogenic and antiatherogenic effects of lycopene: a review. Trends Food Sci Technol 2005;16:344?50.
4. Paran E, et al. Effect of standardized tomato extract on blood pressure, endothelial function and plasma lycopene levels in treated hypertensive patients. AJH 2005;18(5):213A.
5. Ismail HM. The role of omega-3 fatty acids in cardiac protection: an overview. Front Biosci 2005;10:1079?88.
6. Mori TA and Beilin LJ. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep 2004;6(6):461?7.
7. Arita M, et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. JEM 2005;201(5):713?22.
8. Flower RJ and Perretti M. Controlling inflammation: a fat chance? JEM 2005;210:671?4.
9. Schrezenmeir J and De Vrese M. Probiotics, prebiotics, and synbiotics?approaching a definition. Am J Clin Nutr 2001;73(2):361S?364S
10. Macfarlane GT and Cummings JH. Probiotics, infection and immunity. Curr Opin Infect Disease 2002;15(5):501?6.
11. Gorbach SL. Probiotics in the third millennium. Dig Liv Dis 2002;34 (suppl 2):S2?7.
12. Viljanen M, et al. Induction of inflammation as a possible mechanism of probiotic effect in atopic eczema?dermatitis syndrome. J Allergy Clin Immunol 2005;115(6):1255?9.
13. Viljanen M et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double blind placebo controlled trial. Allergy 2005;60:494?500.
14. Lindsay JO, et al. The clinical, microbiological and immunological effects of fructo-oligosaccharide in patients with Crohn?s disease. Gut 2005; September 14. [Published online ahead of print:]
15. Ghoeum M, et al. Immunomodulatory and anticancer effects of active hemicellulose compound (AHCC). Int J Immunotherapy 1995;11(1):23?28.
16. Garami M, et al. Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients. J Pediatr Hemtol Oncol 2004;26(10):631?5.
17. Jakab F, et al. A medical nutriment has supportive value in the treatment of colorectal cancer. Br J Cancer 2003;89(3):465?9.
18. Allison DB, et al. Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain? Int J Obes 2005;29:443?6.
19. Haller CA. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med 2005;118:998?1003.
20. Docherty JP, et al. A double-blind, placebo-controlled, exploratory trial of chromium picolinate in atypical depression: effect on carbohydrate craving. J Psychiatr Pract 2005;11(5):302?14.

Dosages used in recent clinical studies



Dosage Regimen

Active hexose correlated compound

Immune support during cancer treatment

3 g/day for 2 weeks15

Chromium picolinate

Atypical depression/carbohydrate cravings

600 mcg/day for 8 weeks20


Crohn?s disease

15 g/day for 3 weeks14

Glucosamine/ chondroitin sulfate


1500 mg glucosamine and 1200 mg chondroitin sulfate/day for 24 weeks1

Lactobacillus GG

Childhood atopic eczema

10 capsules (109 cfu)/day for 4 weeks13



6 g/day for 12 weeks2

Tomato extract (standardized to lycopene)


15 mg/day lycopene for 6 weeks4

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