The Office of Dietary Supplements at NIH - Meeting the Needs of a Modern Research Agenda
9 May 2001
by Wyn Snow, Managing Editor

With more than 400,000 published articles of research on dietary supplements, a reasonable person might wonder, "Why do we need more?"

Dr. Paul Coates, director of the federal Office of Dietary Supplements (ODS), replies: "There is a lot of variability in the quality of that research -- just as is true of the literature in many fields. Also, research done as part of a traditional healing system with centuries of experience is appropriate to that use and context. However, that same research may not be sufficient to support claims of effectiveness for a capsule or pill now being marketed for a purpose that wasn't intended in traditional use."

Systematic literature review improves present knowledge and shapes future research

Coates came to the ODS in October 1999 with an agenda of his own. He says, "We need a systematic approach to evaluating literature used to support claims of effectiveness and safety."

Congress agrees. This year's Congressional appropriation encourages ODS -- in consultation with the National Center for Complementary and Alternative Medicine (NCCAM), the Agency for Healthcare Research and Quality (AHRQ), and the Food and Drug Administration (FDA) -- "to review the current scientific evidence on the safety and efficacy of dietary supplements now on the market, which could then form a basis for further research, education of practitioners and consumers, and whether further regulatory requirements are necessary."

Therefore, ODS has embarked on creating a systematic review process. The 2001 budget includes funds to initiate a plan, and they are reaching out to their partner federal agencies to begin this activity. Coates believes the review process will fulfill two central ODS obligations: it will provide solid information to consumers and will help shape the research agendas necessary to support claims of efficacy and safety.

ODS history, mandates, accomplishments and goals

The federal Office of Dietary Supplements (ODS) was created in 1995 as a result of the Dietary Supplement Health and Education Act (DSHEA). Funded with approximately $1 million at its inception, the ODS budget has since expanded to $10 million -- a tiny fraction of the overall NIH appropriation of $20 billion. What has the ODS been able to accomplish with this modest funding, and what are its plans?

DSHEA charged the ODS with two overall mandates:

• "to explore more fully the potential role of dietary supplements as a significant part of the efforts of the United States to improve health care"

• "to promote scientific study of the benefits of dietary supplements in maintaining health and preventing chronic disease and other health-related conditions"

In establishing a long-range plan to meet these two mandates, the ODS defined five major goals:

The first four of these goals are addressed primarily through research, but also through various conferences and workshops. The ODS addresses the fifth goal through a variety of educational activities, including its website, and by developing two databases: IBIDS and CARDS.

Research grants

As the ODS plan points out, research is costly. Basic biological research, animal studies, and small-scale epidemiological studies can range in cost from less than one hundred to several hundred thousand dollars. A large-scale, randomized clinical trial of efficacy and safety can cost millions of dollars.

Despite such challenges, the ODS has co-funded more than a dozen studies in conjunction with the NIH Research Enhancement Awards Program.

• Amino acids and infants with ineffective intestinal metabolic function: Infants with impaired intestinal function are more vulnerable to dietary and bacterial toxins. This study will measure the effect of three amino acids -- glutamate, glycine and cysteine -- on glutatione synthesis. Glutathione may protect against these toxins.

• Antioxidants and cataracts in diabetics: Can antioxidants prevent the production of specific toxic compounds found in the lens of the diabetic eye -- compounds that are thought to contribute to the development of cataracts?

• Calcium and bone density loss with intense exercise: Athletes who exercise intensely can experience decreases in bone density. Can supplemental calcium intake prevent such bone loss?

• Folate and rheumatoid arthritis: Folate can affect the toxicity and/or effectiveness of methotrexate treatment for rheumatoid arthritis. This study in rats will examine the folate/methotrexate interaction and can lead to an improved understanding of the relationship between folate metabolism and the inflammation and tissue injury seen in arthritis.

• L-arginine and cancer: Arginine is an amino acid that influences protein synthesis rates and cell proliferation markers. This study of the benefits and risks of L-arginine supplementation in cancer patients will improve understanding of how arginine may affect tumor stimulation and suppression.

• Metallothionein and zinc metabolism: Metallothionein is an enzyme that regulates levels of zinc in different tissues throughout the body. This research may offer unique insights into the role of specific gene products and their effect on nutrition and metabolism.

• Supplements and hearing loss with antibiotics: Antibiotic therapy sometimes results in hearing loss. Can supplements either reduce or prevent this loss?

• Supplements, diet, and dental health in relation to cardiovascular disease and stroke: The study will examine dental health, diet, and supplement consumption in more than 50,000 men and 90,000 women currently enrolled in other federally-funded studies. The hypothesis is that tooth loss leads to poor chewing and reduced intake of dietary antioxidants and fiber, which would increase the risk of heart disease.

• St. John's wort and major depression: In this 8-week study, 336 patients with major depression will be given either St. John's wort or a placebo or a selective serotonin reuptake inhibitor (SSRI) that is commonly prescribed for depression. This study has an 18-week extension for people who responded.

• Thiamin and cognitive function: Thiamin deficiency is a frequent complication of alcoholism that can result in brain damage if left untreated. MRI techniques will examine the effects of thiamin deficiency and its treatment on neurochemical markers in the brain of rats.

• Tryptophan and alcoholism: This study will investigate a possible link between low levels of serotonin and increased susceptibility to alcoholism. Low serotonin levels could result from low dietary intakes of the amino acid tryptophan or one of the micronutrients that convert tryptophan to serotonin. This research may help clarify the possible role of dietary tryptophan in preventing alcoholism among high-risk populations.

• Vanadium and diabetes: Vanadium has been used to treat hyperglycemia in animals with diabetes. This study will assess the toxicity and safety concerns of vanadium use in humans.

• Zinc and copper and their effect on the nervous system: Deficiencies or excesses of copper and zinc have been associated with several neuropathologic diseases of aging in humans, such as Alzheimer's disease, epilepsy, and stroke. This study will explore the modulatory actions of these two nutrients and their effect on the nervous system.

The ODS has also co-funded four centers for botanical research over the past two years.

Botanical research centers

The ODS has established a network of four botanical research centers that conduct basic and clinical research on a variety of botanicals. In collaboration with the National Center for Complementary and Alternative Medicine (NCCAM), the Office of Research on Women's Health, and the National Institute of General Medical Sciences, two centers were established in 1999 and another two in 2000.

According to Paul Coates, "We are especially pleased to have this network of centers working together across the country, because they are crucial to our long term mission. One of our goals is for these centers to serve as resources for other organizations -- not just NIH. These centers offer unique collections of expertise, ranging from basic botanical to clinical research, that will be useful for collaboration with other organizations in both public and private sectors, for both regulatory agencies and industry."

UCLA Center for Dietary Supplements Research on Botanicals

• yeast fermented rice: potential mechanisms of action for cholesterol reduction with implications for prevention of heart disease

• green tea extract and soy: for inhibition of tumor growth with implications for treatment of cancer

• St. John's wort: an herb used for relieving mild depression

• several botanicals: levels of bioactive compounds

University of Illinois at Chicago Dietary Supplements Research Center

• ten herbal supplements in relation to women's health issues, including therapies for menopause

• research training in pharmacognosy (the study of natural products, primarily plants)

• information on botanicals for consumers and health professionals, including an interactive website

Purdue Center for Dietary Supplement Research on Botanicals

• health effects of polyphenols in products such as soy, grapes, and green tea: Health-promoting effects of polyphenols are generally attributed to their antioxidant action, but other biological mechanisms may be involved and will be explored. This research agenda has important implications for heart disease, cancer, osteoporosis and cognitive decline.

University of Arizona Center for Dietary Supplement Research on Botanicals

• Ayurvedic medicine: ginger, turmeric and boswellia are widely used in Ayurvedic medicine for the treatment of inflammatory diseases. Researchers will identify the active constituents of these three herbs and study their pharmacological activity. This research will lead to clinical studies of arthritis and other chronic inflammatory conditions including respiratory diseases such as asthma.

Educational activities

The ODS has organized or co-hosted several conferences and a wide variety of workshops, both to promote the exchange of information and also to identify the most pressing research needs. Conferences and workshops enable scientists to get together and share what they know.

Conferences

• Bioavailability of nutrients and other bioactive components of dietary supplements: defining the research agenda.
• Diabesity[tm] - cosponsored with Shape Up America!
• Dietary supplements of potential benefit to patients with sickle cell disease
• Dietary supplement use in children - cosponsored with National Institute of Child Health and Human Development
• Efficacy and safety of medicinal herbs
• Metals in medicine - targets, diagnostics, and therapeutics
• Nutritional and health benefits of inulin and oligofructose
• Phospholipids in health and disease
• Zinc: What role might supplements play

Workshops

• Two ODS workshops focused on melatonin -- in regard to aging and helping people sleep.
• Much of the research done overseas on botanicals has been criticized as faulty in various ways; another workshop evaluated research needs on the use and safety of medicinal herbs.
• Antioxidants are thought to be important in reducing the risk of contracting many serious chronic diseases -- especially heart disease, cancer and diabetes; this workshop looked at frontiers in antioxidant research.
• Another workshop examined copper needs across the lifespan.
• Drug abuse and HIV/AIDS are difficult and challenging health problems; one ODS workshop explored metabolic, endocrine and gastrointestinal disorders in these conditions.
• Another workshop focused on treatment of mental disorders with essential fatty acids.
• Another looked at safety issues in supplementing with lutein and zeaxanthin -- two chemical compounds in plants that have shown promise in preventing or slowing the development of macular degeneration, one of the two major causes of blindness in America.

Databases

International Bibliographic Information on Dietary Supplements (IBIDS)

The IBIDS database has gathered more than 400,000 citations of research on dietary supplements that has been published throughout the world. IBIDS can be searched by title, author and keywords. Every citation provides author name(s), title, and publication data. Approximately two-thirds of the entries include an abstract; when an entry does not, either an English translation of the abstract was not available or there were copyright issues.

Computer Access to Research on Dietary Supplements (CARDS)

The CARDS database will provide information on all federally funded research about dietary supplements. Current plans are to begin with NIH-funded research. Fiscal 1999 records are now being entered into the database.

Organizing a database and making its information accessible on the Web is always a challenging process. However, Coates is hopeful that CARDS will be operational before the fall, and is himself looking forward to finding out about the depth and breadth of dietary supplement research funded by NIH.

Once the process of entering NIH research into the CARDS database is going smoothly, they will expand the pipeline to include information from other federal agencies that fund research on dietary supplements. While agencies such as the Food and Drug Administration (FDA), US Department of Agriculture (USDA), Centers for Disease Control & Prevention (CDC) and others may provide some funding, Coates believes the NIH proportion of the total research budget will be the highest.

Training and career development

Last but certainly not least, the ODS also encourages training and career development for scientists in areas relevant to dietary supplements. According to Coates, "This is a major area for us. We want to encourage young scientists to understand that this field of research has plenty of promise."

Looking to the future

Coates sees several significant trends for ODS on the horizon. One is to support training and career development. Coates administered such programs on the university level and at NIH, and believes it is vital to work with young investigators when they are looking at career options. Another is to capitalize on the systematic literature review to develop research agendas. Coates also anticipates that recent conferences and workshops will lead to useful research opportunities.

For example, the conference on dietary supplement use in children led to three especially useful insights.

Coates says, "There are some perfectly good reasons for thinking that some supplements may be important for some children. If you look at calcium, post-pubertal boys have more than adequate intakes, but many post-pubertal girls fall short of meeting daily needs. Boys eat everything in sight, but girls who have body image problems shy away from certain kinds of foods. Also, children may have particular needs that are different from adults, although we don't know yet which nutrients or how much. However, other supplements may or may not be of value, or might even be detrimental to children. These questions have not been adequately studied. For example, is there a benefit or harm to exposing kids to androgenic supplements such as DHEA? We simply don't know."

Creating a modern research agenda

Coates believes that systematic literature reviews will be even more valuable than workshops and conferences for developing a research agenda that addresses the ways in which dietary supplements are used today.

"Ephedra is an excellent example," Coates says. "The Senate appropriation for ODS specifically encourages us to support research on ephedra. Their language gives the ODS latitude to establish priorities -- 'by engaging in a systematic review of current literature on ephedra safety and efficacy for its currently used purposes of weight management, energy enhancement and performance enhancement.' So we will be looking at the current state of published evidence that relates to ephedra use in those areas. What are the gaps in the knowledge that we can fill with a well constructed agenda for research?"

According to Coates, "Ephedra is a very appropriate example, because it serves as a model for how we want to approach supplement ingredients in current use. We felt invigorated by the Congressional language that told us about doing an evaluation of evidence on one hand and developing a research agenda on ephedra on the other hand. The experience we glean from ephedra will serve as a excellent model for all of our research endeavors."

Settling the controversies surrounding supplement safety and effectiveness

Ephedra is an especially controversial supplement. An impartial review of the literature on its safety and efficacy is urgently needed. Such a review can guide an appropriate research agenda leading to scientific consensus -- and thereby settle the public debate, not to mention provide evidence for a few lawsuits.

However, controversy surrounds many other supplements as well. As we noted recently on this website, three of the recommended dietary allowances (RDAs) set by the national Institute of Medicine will be publicly debated by experimental biologists. Even vitamin C is not free of controversy: Does it prevent colds or ease their symptoms? Is 2000 mg an appropriate "safe upper level"?

Ultimately, scientific investigation is the best means of determining whether a specific nutrient or supplement is both safe and effective -- and systematic review of current literature is the best method of assessing "what we know now" and evaluating "what we need next."

Such reviews need to be as impartial and unbiased as possible, conducted by people with a range of viewpoints and perspectives. Even though all government agencies are, by definition, political in nature, the Office of Dietary Supplements has brought a science-based point of view to the question of what kinds of research to support and seems well suited to lead the debate on what kinds of research to encourage next.

Sources

Paul M. Coates, PhD, Director of the Office of Dietary Supplements. Personal communication, 25 and 27 April 2001.

Office of Dietary Supplements. "New NIH Office of Dietary Supplements announces first research awards." Office of Dietary Supplements, NIH, Washington DC, press release, 17 December 1996. ods.od.nih.gov/news/releases/reap_rel96.html.

Office of Dietary Supplements. "NIH Office of Dietary Supplements expands research support." Office of Dietary Supplements, NIH, Washington DC, press release, 25 September 1997. ods.od.nih.gov/news/releases/reap_rel97.html.

Office of Dietary Supplements. "The National Institute of Mental Health/National Center for Complementary and Alternative Medicine/ODS clinical trial on St. John's wort." Office of Dietary Supplements, NIH, Washington DC, web document, 1 October 1997. ods.od.nih.gov/index.aspx.

Office of Dietary Supplements. "NIH Office of Dietary Supplements expands research support." Office of Dietary Supplements, NIH, Washington DC, press release, 1 October 1998. ods.od.nih.gov/news/releases/reap_rel98.html.

Office of Dietary Supplements. "NIH Office of Dietary Supplements to examine the role of zinc in health." Office of Dietary Supplements, NIH, Washington DC, press release, 30 October 1998. ods.od.nih.gov/news/releases/zinc.html.

Office of Dietary Supplements. "NIH Office of Dietary Supplements announces funding of dietary supplements research centers." Office of Dietary Supplements, NIH, Washington DC, press release, 6 October 1999. ods.od.nih.gov/news/releases/funding_rel99.html.

Office of Dietary Supplements. "NIH announces two additional centers for dietary supplement research." Office of Dietary Supplements, NIH, Washington DC, press release, 20 September 2000. ods.od.nih.gov/news/releases/funding_rel00.html.

Office of Dietary Supplements. Status Report: The First Years of the Office of Dietary Supplements, 1995-1998. Office of Dietary Supplements, NIH, Washington DC, January 1999. ods.od.nih.gov/index.aspx.