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Statement by
Paul M. Coates, Ph.D.
Director, Office of Dietary Supplements, National Institutes of Health, U.S. Department of Health and Human Services
on
NIH's Role in the Field of Dietary Supplements: Opportunities and Challenges in Developing Good Science
before the
House Committee on Government Reform

July 25, 2002

Mr. Chairman and Members of the Committee,

Thank you for the opportunity to appear before you today representing the Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH). This document describes in some detail the activities of ODS, and it highlights both the opportunities and the challenges associated with developing good science in the field of dietary supplements. At the end of this testimony, I also provide some comments requested by the Committee on the role of diet and lifestyle intervention in the prevention of (or contribution to) chronic diseases.

Health Effects of Dietary Supplement Ingredients

Dietary supplements are widely used by American consumers, often in combination with other lifestyle measures such as diet and physical activity, for their potential benefits in health promotion and disease prevention. Surveys show that 40% or more of American adults use supplements, primarily vitamins and minerals, but herbal and other supplements as well. There are many hopes pinned on dietary supplements to improve health and prevent disease, hopes that have been realized when some of them have been put to a true scientific test. Some examples of these include:

• Folic acid for the prevention of neural tube defects, one of the most common birth defects. As a result of this research, the Centers for Disease Control and Prevention (CDC) and other partners in the National Folic Acid Campaign aim to educate all women of childbearing age to consume 400 micrograms of synthetic folic acid daily from vitamin supplements and/or fortified foods in addition to eating food folate in a healthful diet;
• Calcium to reduce the risk of osteoporosis. The NIH Consensus Development Conference in 1997 concluded that while the preferred source of calcium is through calcium-rich foods, both calcium supplements and calcium-fortified foods are other means by which optimal calcium intake can be reached in those who cannot meet this need by eating conventional foods;
• Iron supplementation during pregnancy to prevent maternal anemia and delivery of premature infants;
• Vitamin B-12 supplementation for those (particularly among the elderly) who cannot readily absorb food-bound B-12;
• Vitamin and antioxidant supplementation to prevent progression of macular degeneration; and
• Supplements promoting antioxidant activity generally to reduce risk of oxidative stress damage from exposure to environmental agents.

By contrast, the positive effects of other products have not yet been proven and need further exploration. A prime example of this is the finding that, instead of reducing cancer risk, beta-carotene may actually increase lung cancer incidence and mortality in a sub-population of cigarette smokers. Furthermore, a recently completed NIH-funded study showed that St. John's wort was no better than a placebo in improving symptoms in patients with major depression of moderate severity.

Many ingredients have yet to be tested in a rigorous, scientifically sound manner. Some are under active investigation at the NIH, including:

• Ginkgo biloba: does it prevent decline of cognitive function in older individuals?
• Dietary phytoestrogens: do they prevent bone loss in postmenopausal women?
• Selenium and vitamin E: alone or in combination, do they prevent prostate cancer?
• Echinacea: does it shorten the duration or lessen the severity of colds in children?
• Glucosamine and chondroitin: alone or in combination, do they diminish the pain associated with knee osteoarthritis?

The Emerging Role of ODS in Dietary Supplement Research

ODS was authorized by the Dietary Supplement Health and Education Act of 1994 (DSHEA) and was formally installed in the Office of the NIH Director in 1995. Its mission, based on a comprehensive strategic planning process, is to "identify and foster research on the health benefits and risks of these substances based on the merit of the underlying scientific evidence, regardless of how they might be currently incorporated into the different categories of commercial products or their regulatory status in the commercial marketplace."

This strategic planning process helped considerably in guiding ODS activities by identifying the research and education goals that ODS would meet. ODS has been able to embark on a number of important activities, including:

• Co-funding of dietary supplement research grants with other Institutes and Centers (ICs) at NIH;
• Sponsoring conferences and workshops, again most often in collaboration with other ICs;
• Developing a series of fact sheets on vitamins and minerals, in collaboration with the Clinical Center at NIH; and
• Initiating two important database efforts: the International Bibliographic Information on Dietary Supplements (IBIDS), developed jointly with the National Agricultural Library of the US Department of Agriculture (USDA) and citing more than 600,000 references to the world's literature; Computer Access to Research on Dietary Supplements (CARDS) to track the Federal investment in dietary supplement research; the current data set describes the FY 1999 NIH investment as 354 grants, totaling $206 million.

I became Director of ODS towards the end of 1999. By that time, ODS started the development of a program of comprehensive Dietary Supplement Research Centers around the country. By the end of 2000, the program had four of these multidisciplinary Centers. The Centers are jointly funded with the National Center for Complementary and Alternative Medicine (NCCAM) and are administered by NCCAM. The National Institute of General Medical Sciences (NIGMS) and the Office of Research on Women's Health (ORWH) also participate in funding these Centers. The National Institute of Environmental Health Sciences (NIEHS) supports the activities of another related Center.

Let me pause for a moment to stress a theme that runs through all of the activities that I have just mentioned. All of them have been developed in collaboration with other agencies, both within and outside the NIH. They could not have been accomplished otherwise. To me, this is the strength of forging partnerships and exploring common research goals. Our position in the Office of the Director, NIH, has permitted us to do just that.

More recently, the budget for ODS has grown, from approximately $3.5 million in FY 1999 to $17 million in FY 2002. This has permitted expansion of our research agenda into new and important areas:

• Evidence-based reviews of dietary supplement efficacy and safety;
• The development of an ephedra research agenda;
• Surveys of dietary supplement use, e.g., the National Health and Nutrition Examination Survey (NHANES) directed by the CDC;
• Training and career development;
• Participation in international research efforts; and
• Development, validation, and dissemination of analytical methods and reference materials for dietary supplements.

In partnership with other Institutes and Centers at NIH, ODS funds research grants in areas such as:

• The role of B-vitamins in atherosclerosis;
• The interaction between St. John's wort and drug metabolizing systems in men and women;
• Clinical study of the effect of chromium on insulin action;
• Isolation, identification, and quantification of phenolic compounds in botanicals;
• Zinc therapy in HIV-positive drug users;
• Homocysteine lowering in renal transplant patients;
• Conjugated linoleic acid effects on lipid synthesis;
• Folate receptors in craniofacial malformations;
• Dietary supplement use by participants in the International Population Study of Macronutrients and Blood Pressure (INTERMAP) study;
• Dietary supplement knowledge and use in youth; and
• The role of St. John's wort in the management of minor depression.

• The Role of S-Adenosylmethionine (SAMe) in Treatment of Alcoholic Liver Disease. This led to issuing a Request for Applications (RFA) earlier this year with the National Institute on Alcohol Abuse and Alcoholism and NCCAM; applications submitted in response to this RFA are currently being reviewed;
• The Role of Antioxidants in the Prevention of Diabetic Complications. This led to a Program Announcement (PA) jointly sponsored with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke;
• Diet, DNA Methylation Processes and Health, sponsored by the National Cancer Institute (NCI) with participation by ODS, NIEHS, NIDDK, the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Child Health and Human Development (NICHD), and the Food and Drug Administration (FDA). This is expected to lead to a substantial research initiative;
• Chromium as Adjuvant Therapy for Type 2 Diabetes and Impaired Glucose Tolerance. This led to a PA jointly sponsored with NIDDK and NCCAM;
• Metals in Medicine. This led to a PA jointly sponsored with NIGMS, NIEHS and NIDDK;
• Two conferences on Dietary Supplement Use in Children and in Women (with NICHD, NCCAM, ORWH and others); and
• Science and Policy of Performance-Enhancing Products (with the Council for Responsible Nutrition).

The development of other new areas of investigation relies on forging strategic partnerships with other agencies as well. A few current examples include Interagency Agreements with:

• The National Center for Health Statistics at CDC to support improvements in the ability of NHANES to more accurately assess dietary supplement intake in the US;
• The Agency for Healthcare Research and Quality (AHRQ) to develop evidence reports of dietary supplement efficacy and safety. The first of these, on ephedra efficacy and safety in weight management and athletic performance enhancement is currently under review in draft form and is planned for release in final form later this year. ODS, NCCAM, and other agencies will use this report as the basis for further discussion about an appropriate research agenda;
• The FDA to support the development and validation of analytical methods, beginning with validation of analytical methods for ephedra by the Association of Official Analytical Chemists (AOAC) International; and
• The National Institute of Standards and Technology (NIST) in the Department of Commerce to support botanical reference standard development, also beginning with ephedra.

We have worked with partners in the private sector in a number of areas:

• Publication of an annual bibliography of outstanding research in dietary supplements with the Consumer Healthcare Products Association;
• Co-sponsorship of a conference on the science and policy of performance-enhancing products with the Council for Responsible Nutrition; a summary of this conference is in press in the journal, Medicine and Science in Sports and Exercise; and
• Engaging with industry � as well as other federal agencies, non-governmental organizations and academia � to develop, validate, and disseminate analytical methods and reference materials for dietary supplements.

In my view, these collaborations � within and outside the NIH � are crucial to the advancement of science in the area of dietary supplements. Further details of these and other interactions can be found on the ODS website ods.od.nih.gov.

Development of a Research Agenda for Ephedra

I noted earlier that ODS and NCCAM jointly funded an evidence report on the efficacy and safety of ephedra-containing dietary supplement products for weight loss and for athletic performance. This report, still in draft form and under review by content experts, has been developed by the RAND/Southern California Evidence-Based Practice Center, one of a network of such Centers supported by AHRQ. This is the first step for us in determining whether � and what � further research is necessary to understand the potential health benefits and risks of ephedra.

Among the studies to be included in the RAND report is a recently published clinical trial (Boozer CN et al, International Journal of Obesity 26:593-604, 2002) of a product containing ephedra and kola (a source of caffeine). The authors concluded that it was both effective and safe for weight loss over a 6-month period in a population of well-characterized, carefully monitored subjects. This is important information, but it must be remembered that this is a single study conducted under careful medical supervision and it is not yet clear whether a similar profile of benefit and safety would be seen in more typical settings with more prolonged use.

CANTOX Health Sciences International conducted a risk assessment study of ephedra under contract to the Council for Responsible Nutrition ("Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra"). Its approach and conclusions will be considered in the RAND report as well. We will await the results of the full evidence report before determining what future clinical research strategies are necessary.

In the meantime, ODS has begun to develop other components of a research agenda for ephedra. We have funded the validation of several methods for the analysis of ephedra and the development of standard reference materials for ephedra. We initiated an evaluation of potential ephedra toxicity by the National Toxicology Program of the NIEHS.

Dietary Interventions to Prevent Chronic Disease

You have asked me to address some issues related to the role of dietary interventions that may be involved in the prevention of, or contribution to, chronic diseases. While this is somewhat outside the purview of ODS, I did have the benefit of comments from colleagues in some of the NIH ICs, which I present below.

The Dietary Guidelines for Americans issued by the Departments of Agriculture and Health and Human Services in 2000 recommend a diet low in saturated fat and cholesterol and moderate in total fat as part of an overall healthy eating pattern. There is strong evidence that saturated fat raises blood cholesterol levels and increases the risk of heart disease. Clinical trials have shown that blood cholesterol lowering reduces the risk of heart disease, and the composite results of the diet trials are entirely consistent with drug trials that have shown comparable blood cholesterol reductions. The critical importance of maintaining a healthy weight and a physically active lifestyle is emphasized in the 2000 Guidelines. Balancing dietary intake with energy expenditure to maintain a healthy weight and avoid weight gain during adult life was given increased attention because of the concern for the rising epidemic of obesity and the increase in sedentary lifestyles in the US. The 2000 Guidelines emphasize that a healthy eating pattern consists of a variety of foods, with several recommendations related to eating a variety of grains, fruits and vegetable, including whole grain foods and eating at least 5 servings of fruits and vegetables a day. Other aspects of a healthy eating pattern consist of eating a variety of other foods including lean meat, fish, poultry, low-fat dairy products, and foods rich in unsaturated fats (such as olive oil and canola oil). Fresh fruits and vegetables, which are low in saturated fat and rich in folic acid and other vitamins, antioxidants, and fiber, are encouraged because in population studies their consumption is associated with a reduction in heart disease and its risk factors.

A large body of evidence on the adverse effect of overweight, obesity and adult weight gain and physical inactivity has been recently summarized in a February 2002 International Agency for Research on Cancer (IARC) report on Weight Control and Physical Activity. This research indicates that avoiding overweight, obesity and adult weight gain is linked with reduced risk of colon, postmenopausal breast, endometrial cancer, adenocarcinoma of the esophagus, and renal cell cancer. In addition, increasing physical activity is linked with reduced risk for colon and breast cancer. The evidence is also strong to support weight control by increasing physical activity and decreasing caloric intake for reducing the risk for heart disease, hypertension, and type 2 diabetes mellitus.

There is limited research on the specific effect of weight control diets, including plant-based diets, on cancer outcomes. Recent meta-analyses of cohort studies and randomized controlled trials on the effect of fruits and vegetables on selected cancers, such as colon cancer, have not found strong protective effects of such diets on colon cancer incidence. Therefore, these new data are inconsistent with prior research on the protective effect of high intakes of fruits and vegetables on colon cancer incidence. Extensive research is ongoing on the effects of specific dietary components, including individual nutrients such as calcium, folate, and various carotenoids, as well on types of fatty acids and how these are influenced by the genetic characteristics of the individual. In addition, research is ongoing on the effect of specific food groups and dietary patterns on cancer outcomes.

At the present time, there are not major clinical trials directly investigating the specific comparative effects of plant-based versus animal-based or high protein diets in the prevention of chronic diseases, such as cancer, diabetes, and heart disease. With careful attention and good diet design, either of these approaches can contribute to the prevention of chronic disease, but in general, a variety of food choices are suggested. Advantages of plant-based foods include their low levels of saturated fat and lack of cholesterol and their high content of folic acid and other vitamins, beneficial antioxidants, and fiber. As has been described in the literature and lay media, a vegetarian diet can be considered healthful; however, individuals choosing a vegetarian diet must be careful of their selections in order to obtain adequate amounts of all nutrients (i.e., vitamin B-12 and iron). Animal-based diets, comprising most high-protein diets, tend to be high in saturated fat and cholesterol; on the other hand, they are excellent sources of many micronutrients and trace elements.

Currently, the Department of Health and Human Services and the US Department of Agriculture, along with the Canadian government, have contracted with the Food and Nutrition Board of the Institute of Medicine to prepare a report on Dietary Reference Intakes with a focus on macronutrients (carbohydrates, proteins, and fats). This report is being prepared by a committee of experts and, after undertaking a review of all available scientific studies in this area, is to make recommendations related to various macronutrient intakes to the health of the public. It is anticipated that recommendations will be made related to adequate levels of intake, levels that may exert positive health benefit, and levels that may be associated with adverse health events. The committee has also been requested to identify research needs and opportunities related to this topic. The report is due to be released within the next several weeks.

Closing Remarks

Mr. Chairman and Members of the Committee, I thank you again for inviting me to review the accomplishments of the Office of Dietary Supplements at NIH, and to highlight some of its ongoing research opportunities and challenges. I would be happy to answer questions from the Committee.