Use of Dietary Supplements by Military Personnel (2008)

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7 Research Needs The committee was requested to select a limited number of dietary supplements to review and then determine whether further examination and integrative evaluation or research on each is warranted. There are numerous research questions about the safety and efficacy of the selected dietary supplements. A first step in developing a research agenda, however, is to set priorities to deliver answers to the questions most critical to the military with the most efficient use of resources. In a complex institution like the military, whose subpopulations within the various services might have different tasks, the coordination of efforts to prioritize research needs is key to the success of this endeavor. Consequently, the committee did not attempt to provide an exhaustive listing of research needs for any dietary supplement; instead, the committee presents an approach for the military to use to prioritize research needs. For example, research might focus on supplements with anticoagulant effects as a potential critical concern, re- gardless of the potential benefit for which they are marketed. Box 7-1 lists examples of research needs for the supplements reviewed in this report. Future studies on dietary supplement use in the military should be ap- proached from an etiological or mechanistic perspective, focusing on areas of particular concern or potential benefit for health, performance, and survivability (e.g., fitness level, hydration; gastrointestinal tract, hepatic, and cardiovascular function; and cognitive and neurobehavioral function). In agreement with the committee’s recommendation that both risks and benefits be considered in management decisions about dietary supplements, studies that focus on answering questions about potential safety concerns and putative benefits may need to be prioritized separately according to the 368 

RESEARCH NEEDS 369 BOX 7-1 Examples of Potential Research Questions on the Dietary Supplements Selected for Committee Evaluation Of the supplements selected for review, the committee found no compelling reason for the military to make research on the following dietary supplements a high priority at this time: chromium, dehydroepiandrosterone, garlic, ephedra, ginseng, melatonin, valerian, and Ginkgo biloba. For the remaining dietary supple- ments reviewed by the committee, further investigation into the following specific questions may be warranted: • What is the range of consumption of caffeine in the military population? What are the sources and amounts of total intake? To what extent are patterns of consumption approaching the limits for operationally effective doses of caffeine? • What are the beneficial or adverse effects of long-term use of tyrosine? Of creatine? • Are there tolerance or withdrawal effects from using creatine, caffeine, or other dietary supplements? • Given that β-Hydroxy-β-methylbutyrate (HMB) appears to improve muscle function or mass in physically untrained subjects or those in a catabolic state, what are the effects of HMB in new recruits or those with hypocaloric intake? • What are the effects of varying the protein content (amount and composition of amino acids) in sports bars or drinks and the timing of their consumption on recovery from strenuous activity (e.g., on reduction of immune suppression after exercise, hydration, or reduction of muscle soreness)? • Are there any dietary supplements (e.g., quercetin) that help reduce post- stress health effects such as respiratory infections? special needs of military subpopulations. The military has unusual access to its members’ medical records, and its population is in better general health and includes fewer individuals at risk for certain diseases and drug interac- tions, all of which should facilitate the identification of potential concerns and possible benefits associated with the use of dietary supplements by service members. KEY CONSIDERATIONS FOR CONDUCTING MILITARY NUTRITION RESEARCH Study Designs In conducting research of interest to the military, it is critical that the efficacy and safety of dietary supplements be tested with representative subjects engaged in training that is similar to combat and in specific military 

370 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL conditions (e.g., in situations of sleep deprivation, extreme environments, moderate physical activity of long duration). Study designs should continue to include human models that mimic some of the physical stresses and en- vironments that accompany military missions and training programs. For example, a human model could consist of individuals exercising on a pre- defined, outdoor running and obstacle course or a specific physical activity in an environmentally controlled laboratory setting. The selection of study subjects should take into consideration physi- ological differences (e.g., blood pressure, body mass index) that reflect demographic factors (i.e., gender, age, or ethnicities) of the military popula- tion that might result in differential effects of dietary supplements. Research populations should represent the current targeted population participating in garrison training, serving in combat, or both. Animal Models Although the military can conduct studies of the effects of dietary supplements on subjects undergoing the physical stresses of training or con- ditions simulating combat, using human models for the simulation of severe mental and emotional stress presents practical and ethical limitations. Like- wise, some procedures (e.g., multiple liver biopsies) would be difficult to justify on humans. The military should therefore continue the development of animal model systems that mimic the stresses of garrison training and combat to allow screening for the physiological effects of dietary supple- ments under extreme conditions. Screening with well-designed and ethical animal studies could be followed with more focused and better-designed human studies. These models would not only provide preliminary informa- tion about the effects of dietary supplements but could also be applied to obtaining preliminary information about the effects of other interventions in preventing and treating diseases and injuries under conditions of garrison training and combat. To maximize and coordinate efforts in this area, col- laboration with civilian researchers is of vital importance. The following paragraphs describe key elements of an animal model research program. Animal–Human Transposition This committee recommends that the military support and conduct experiments to understand animal–human transpositions. It is increasingly apparent that it is not possible to directly extrapolate data obtained in ani- mal studies to humans (IOM, 2006; NRC, 2005, 2007). Not only are there differences in biological regulation between species, but the premises for most safety studies might also be inappropriate. For example, feeding test animals with multiples of expected exposure levels to increase the sensitivity of a test may yield inaccurate results as substances may act metabolically 

RESEARCH NEEDS 371 quite differently at low levels than they do at high levels. The development of animal models allowing animal–human transposition will require better understanding of fundamental biology. For example, better understanding of the molecular and genetic regulatory bases of physiological responses to extreme environments will permit more credible qualitative and quantita- tive comparisons of animal and human outcomes, and hence more precise predictions of adverse effects in humans. Methods to Quantify Stress There are many stressors experienced by deployed service members and the corresponding stress responses can be perceived in the short or long term. Stress frequently results from military situations that include ther- moregulatory challenges, physical exertion, inadequate sleep and rest, and psychological stressors such as confronting unknown, high-risk situations and the threat of death. Because of the multidimensional nature of stress, its measurement will continue to be difficult. The military should support or conduct studies on improving the methods to quantify stress. APPROACHES TO IDENTIFYING AND SELECTING RESEARCH NEEDS Coordinating Efforts Among Military Services To identify dietary supplement research topics of interest to the mili- tary, a clear coordinating process needs to be implemented between all services. Ideally, this process will include input from all the services and will evaluate the potential topics as well as the feasibility and implementation of the research methods. The highest-priority research should be performed or sponsored by the military and should occur in conjunction with monitoring the results of research conducted in the civilian population for potential military im- plications. As with other aspects of dietary supplement management, rec- ommending research to be conducted or sponsored by the military should be a task for the designated oversight committee (see Chapter 6). Specific criteria for priorities or concerns might be set by the individual services and submitted to the Dietary Supplement Oversight Committee. Identification of Research Needs for Specific Dietary Supplements This committee recommends that gaps in data or information be iden- tified based on the following elements of the recommended approach to manage dietary supplement use: (1) the results of the surveillance system evaluating the use of dietary supplements within the military (Chapter 2); 

372 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL (2) gaps identified in the reviews conducted for specific dietary supplements, especially those issues relevant to military performance and survivability (Chapter 5); and (3) the occurrence of adverse events of military impor- tance associated with the use of specific dietary supplements (Chapter 6). As the committee evaluated dietary supplements (Chapters 3 and 4) using the framework, it identified examples of potential research questions for the selected dietary supplements (Box 7-1). Safety Following the framework illustrated in Figure 5-1, the military should develop a list of adverse effects of particular concern for service members (e.g., interference with blood clotting). One potential response for the mili- tary would be to generate requests for proposals for methods to evaluate safety in these areas or to identify any particular classes of compounds that could be expected to cause such safety concerns. Benefit There is a long history of use of botanicals (e.g., Chinese traditional medicines) with putative beneficial effects that could be the subject of re- search by the military. The committee recommends that the military narrow its research questions to those traditional botanicals that are believed to affect physical and mental functions; one approach to focus their searches might be consultation with expert ethnobotanists and pharmacognocists. In addition, the military should consider conducting research to de- velop a framework approach to determine the efficacy of dietary supple- ments. Such an approach should consist of a mechanism to determine the level of benefit to service members under specific environmental conditions and for specific military tasks; it should include elements such as recom- mendations for appropriate research designs, for conducting literature re- views, and for identifying research gaps. Concomitantly, the military could take a similar approach as that suggested for safety, that is, to make requests for proposals that address methods for evaluation of efficacy, any particular class of compound that might be expected to confer these benefits, or both. POTENTIAL RESEARCH AREAS OF INTEREST Research on Adverse Effects from Supplements Relevant to the Military As mentioned above, the military should determine the adverse effects of dietary supplements in the context of specific military environments and 

RESEARCH NEEDS 373 tasks. Broad research areas that would shed light on the safety of dietary supplements are described below. As with benefits, for all areas of research described, it is necessary to determine the dosage and duration of use of the dietary supplement leading to adverse effects and to consider the impact of unique military environments on these effects. Frequency and Severity of Adverse Events Before prioritizing research on adverse effects or taking management action, it is important to determine the frequency and severity of adverse events of interest to the military; one way to acquire this information is the use of well-designed surveys (Chapter 2). Another approach recommended by the committee is the implementation of an adverse-event monitoring system for the military (Chapter 6). Identification of Ingredients Associated with Adverse Events The concomitant analytical evaluation of the identity and integrity of the supplement products associated with reported adverse events is a key element in managing the use of dietary supplements. One potential strategy to conduct these analyses would be to contract with appropriate research facilities that are equipped for and experienced in chemical analysis of natural products. Interactions with Other Compounds When designing surveys and studies and interpreting their results, re- searchers should be mindful of the large number of dietary supplements available, which are often consumed in combination and whose composi- tion is often changed or is unknown. Intake of multiple supplements could lead to interactions having either synergistic or antagonistic effects. Like- wise, dietary supplements could interact with other food components or medications. Speculation on the impact of the interactions is possible based on mechanisms of action or other factors, but there is minimal research in this area. Tolerance and Withdrawal Effects Research should assess the development of tolerance and/or withdrawal effects following chronic use of those dietary supplements frequently con- sumed by the military (e.g., caffeine, creatine, tyrosine). 

374 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Multi-Ingredient Dietary Supplement Products Multi-ingredient dietary supplements, which are frequently reformu- lated and for which safety data are limited, will continue to be available and used by military service members. It is critical to identify concerns (or potential benefits) associated with these products. Use of the framework developed by the committee is recommended to identify concerns associ- ated with the use of multi-ingredient dietary supplements; the same criteria for initiating a review (i.e., frequency of use and adverse event reporting) should be followed. A high prevalence (or significant increase) of use indi- cated by the surveillance system, adverse event reports suggesting a poten- tial for concern, or a known hazardous component in a multi-ingredient dietary supplement constitute signals calling for review and possibly man- agement action. If literature reviews fail to reveal any safety data, then the military should consider conducting safety evaluation studies of the product or significant ingredients and potential effects of ingredient interactions (see above). The development of methodologies to evaluate multi-ingredient products, including potential interactions, is an area of reasearch that should be supported by the military. Research on Beneficial Effects from Supplements Relevant to the Military When prioritizing research on potentially beneficial dietary supple- ments, the military might consider the general topics described below. For all topics, determining the dosage and length of exposure necessary to ob- serve benefits and the impact of the military’s tasks and extreme operational environments on those effects are crucial research questions. (The reader is referred to the World Health Organization monographs, a series of four volumes published by the Traditional Medicines Programme in Geneva, Switzerland; the German E monographs; or the United States Pharmacopeia monographs.) In all cases, these putative benefits of dietary supplements need to be proven scientifically and compared to those provided by alterna- tive compounds (drugs) currently used as the standard of care. Mitigation of the Adverse Effects of Stressors on Service Member Performance One important category of research is determining which dietary sup- plements would be useful in alleviating physiological fatigue resulting from sleep deprivation, shift work, and transmeridian travel. An existing example of military interest in these types of supplements is the addition of caffeinated chewing gum to some military rations. Aside from research assessing the effects of caffeine on fatigue, few studies have been conducted 

RESEARCH NEEDS 375 to evaluate the actions of other naturally occuring stimulants, despite their worldwide use. Another category of research that might be addressed is the use of dietary supplements to moderate physiological responses to extreme en- vironments, such as hypoxia and altitude sickness. Indigenous peoples in the Himalayan and Andes Mountains tolerate high altitude and cold with a hardiness for which no genetic link has been scientifically proven (Wu and Kayser, 2006). These groups use various herbs and other nutrients to maintain their strength and prevent altitude sickness, and these may be of interest to the military. Other stressors regularly encountered by military personnel that might be mitigated by dietary supplements are dehydration, radiation from explo- sive sources, physiological and psychological stress, and exhaustion. Prevention or Treatment of Injuries In addition to promoting recovery from the previously mentioned stressors, dietary supplements might also facilitate wound healing, a pro- cess frequently encountered in a military setting. Many plants have been used worldwide for wound healing and related concerns (e.g., sunburn relief). Some in vitro and in vivo data suggest the beneficial effects of these plants; however, there are few experimental studies on their value in human populations. Surveys on Dietary Supplement Use Analysis of surveys to determine the pattern and extent of dietary sup- plement use is a critical element of a dietary supplement research agenda. This need has been amply discussed in Chapter 2. Briefly, the committee recommends continuing the collection of usage data by expanding the De- partment of Defense Health Related Behaviors Survey; it also recommends that more comprehensive surveys be conducted at select military sites where service members are likely to face higher risks due to the intensity of their training or exposure to extreme environments. As described in Chapter 5, adequate surveillance systems will help alert the military to potential concerns. Validation of the Recommended Approach to Manage Dietary Supplements Validation of the approach laid out by this committee is strongly rec- ommended, especially for these elements of the approach: the surveillance system; the adverse event report monitoring system; and the framework for 

376 USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL safety, including the recommendation to integrate consideration of risks and benefits as the basis for taking action. The efficacy of this overall approach will best be determined by an annual status report and a five-year review of results from the surveillance, the adverse-event report monitoring system, and the effectiveness of command recommendations to allow or restrict the use of specific supplements. The designated oversight committee should decide on a timeline and specific criteria to validate this approach as well as to review the results. Research on Education Methods Research should be conducted to identify the effectiveness of various methods of communication and outreach to educate service members, com- manders, health care personnel, and physical training and fitness centers staff on the use of dietary supplements. Information should be obtained on the awareness of use and knowledge about supplements among military personnel, commanders, and military physicians. REFERENCES IOM (Institute of Medicine). 2006. Dietary reference intakes research synthesis: Workshop summary. Washington, DC: The National Academies Press. NRC (National Research Council). 2005. Application of toxicogenomics to cross-species ex- trapolation: A report of a workshop. Washington, DC: The National Academies Press. NRC. 2007. Toxicity testing in the 21st century: A vision and a strategy. Washington, DC: The National Academies Press. Wu, T., and B. Kayser. 2006. High altitude adaptation in Tibetans. High Alt Med Biol 7(3):193-208.