
==== Front
J Nutr
J Nutr
The Journal of Nutrition
0022-3166
1541-6100
American Society for Nutrition

S0022-3166(24)00356-0
10.1016/j.tjnut.2024.06.017
Perspectives
The Evolution of Science and Regulation of Dietary Supplements: Past, Present, and Future
Coates Paul M pmcoates@iu.edu
1⁎
Bailey Regan L 2
Blumberg Jeffrey B 3
El-Sohemy Ahmed 4
Floyd Elizabeth 5
Goldenberg Joshua Z 6
Gould Shunney Aimée 7
Holscher Hannah D 8
Nkrumah-Elie Yasmeen 9
Rai Deshanie 10
Ritz Barry W 11
Weber Wendy J 12
1 Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN, United States
2 Institute for Advancing Health Through Agriculture, Texas A&M University System, College Station, TX, United States
3 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States
4 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
5 McIlhenny Botanical Research Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, United States
6 Helfgott Research Institute, National University of Natural Medicine, Portland, OR, United States
7 Santa Cruz Integrative Medicine, Santa Cruz, CA, United States
8 Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL, United States
9 ChromaDex, Los Angeles, CA, United States
10 OmniActive Health Technologies, Morristown, NJ, United States
11 Nestlé Health Science, Bridgewater, NJ, United States
12 National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD, United States
⁎ Corresponding author. pmcoates@iu.edu
04 7 2024
8 2024
04 7 2024
154 8 23352345
10 4 2024
19 6 2024
26 6 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Dietary supplement use in the United States is widespread and increasing, especially among certain population groups, such as older Americans. The science surrounding dietary supplements has evolved substantially over the last few decades since their formal regulation in 1994. Much has been learned about the mechanisms of action of many dietary supplement ingredients, but the evidence on their health effects is still building. As is true of much nutrition research, there are many studies that point to health effects, but not all are at the level of scientific evidence (e.g., randomized controlled interventions), rigor, or quality needed for definitive statements of efficacy regarding clinical end points. New technologies and approaches are being applied to the science of dietary supplements, including nutrigenomics and microbiome analysis, data science, artificial intelligence (AI), and machine learning—all of which can elevate the science behind dietary supplements. Products can contain an array of bioactive compounds derived from foods as well as from medicinal plants, which creates enormous challenges in data collection and management. Clinical applications, particularly those aimed at providing personalized nutrition options for patients, have become more sophisticated as dietary supplements are incorporated increasingly into clinical practice and self-care. The goals of this article are to provide historical context for the regulation and science of dietary supplements, identify research resources, and suggest some future directions for science in this field.

Keywords

bioactive components
botanical extracts
dietary supplements
gut microbiome
integrative health
micronutrients
nutrigenomics
prebiotics
precision nutrition
recommended nutrient intakes
Abbreviations

CARBON NIH Consortium for Advancing Research on Botanical and Other Natural Products

CDC Centers for Disease Control and Prevention

DRI dietary reference intake

DSHEA Dietary Supplement Health and Education Act

FNB Food and Nutrition Board

MetS metabolic syndrome

NCCIH National Center for Complementary and Integrative Health

ODS Office of Dietary Supplements

PBRC Pennington Botanical Research Center

VDSP Vitamin D Standardization Program
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pmcIntroduction

Dietary supplement use in the United States is widespread and increasing, with surveys showing that half of adults and one-third of children consume these products regularly [1,2]. In the 30 years since Congress passed the Dietary Supplement Health and Education Act (DSHEA) [3], the science behind dietary supplements has evolved considerably; however, there is much that is still not well known. This study attempts to convey what has been learned during that time and what challenges remain, as well as opportunities for future research on dietary supplements, with a goal to provide health care practitioners, public health policy makers, and especially consumers, with the current scientific information that they require to make informed recommendations and decisions about the use of dietary supplements. This article serves to update those conducting research on dietary supplements on needs, gaps, challenges, and lessons learned to help advance science.

Perspectives on the Design, Conduct, Interpretation, and Communication of Dietary Supplement Research

From preventing nutrient deficiency to supporting optimal health

Although James Lind observed the relationship between scurvy and citrus fruit in 1753, modern micronutrient research exploded in the first half of the 20th century (Supplemental Table 1). Over the ensuing 50 y, the notion of “accessory factors” and “vital amines” in food by Frederick Hopkins and Casimir Funk inspired the discovery, isolation, and synthesis of essential micronutrients and their role in deficiency disorders, including beriberi, pellagra, rickets, scurvy, pellagra, goiter, xerophthalmia, and nutritional anemias [4]. These findings led directly to the fortification of selected staple foods—like bread, milk, and salt—which effectively reduced the prevalence of common deficiency diseases [5]. Much of this work coincided with years of widespread fear of food shortages—the Great Depression and World War II—and an emphasis on preventing deficiency diseases. Recommended dietary allowances were first created in 1915 by the UK British Royal Society and followed by guidelines promulgated by the League of Nations and the United States National Nutrition Conference on Defense.

The scientific basis underlying the development of dietary supplements has evolved in parallel with, and dependent upon, that of nutrition science. This is particularly true for the conceptual and research approaches used to establish the requirements and safety of micronutrients and other dietary components, as well as their application to guidance from regulatory agencies. The United States Recommended Dietary Allowances, now part of the Dietary Reference Intake (DRI) values, were created in 1943 by a committee chaired by Dr. Lydia Roberts to develop a table of the best available evidence on the amounts of the various nutrients and other food substances (e.g., energy) desirable to include in practical diets. In 1974, the Food and Nutrition Board (FNB) of the National Academy of Sciences defined specific research approaches as an evidentiary basis for recommended target values, including balance studies, nutrient depletion/repletion studies, observations of deficient populations corrected by dietary improvement, and biochemical measurements assessing the degree of tissue saturation or adequacy of molecular function. In the 1980s, the United States Surgeon General and FNB incorporated key elements of the Bradford Hill criteria for causation in their reports on diet, nutrition, and health [6]. In 1989, the DRIs were updated to reflect a set of target values that could be used at the individual and group levels for determining adequacy, preventing potential excess, and using in meal planning. In addition, reflecting a hierarchy of scientific evidence for grading health care recommendations developed in the 1990s, systematic reviews were instituted to identify and tabulate the available literature to answer defined questions put forth by the FNB to advance public health nutrition.

Recent advances in diverse scientific fields now provide new and more types of information to determine causal relationships between diet and health. Large datasets allow for inferring causation from quasi-randomized observations between exposed and nonexposed groups. Pairing AI and machine learning to analyze data from multiomic and microbiome studies together with relevant information collected from the real-world exposome are now informing tailored dietary recommendations to population subgroups (i.e., precision nutrition) and specific advice at the individual level (i.e., personalized nutrition).

The rationale for these policies evolved from starvation relief to health maintenance to chronic disease risk reduction, and hence, the research evidence base required to support these goals has substantially evolved. Nonetheless, these historical events have established a precedent for nutrition research that continues to focus on single nutrients linked to a specific function or disease. Some key dates in the evolution of dietary supplement science and regulation are given in Supplemental Table 1.

Dietary supplement science and communication from the 1990s to today: the role of the NIH

When DSHEA was passed in 1994, establishing a framework for the regulation of dietary supplements in the United States, its ending paragraph [3] required that the NIH create a science-based office to be called the Office of Dietary Supplements (ODS). It was formally established within the Office of the NIH Director in 1995.

DSHEA defined the purpose and responsibilities of ODS as follows:• 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;

• To conduct and coordinate scientific research within NIH relating to dietary supplements;

• To collect and compile the results of scientific research relating to dietary supplements, including scientific data from foreign sources; and

• To serve as the principal advisor to the Secretary and to the Assistant Secretary for Health and provide advice to the Director of NIH, the Director of the Centers for Disease Control and Prevention (CDC), and the Commissioner of the Food and Drug Administration (FDA) on issues relating to dietary supplements.

ODS is one of many entities—institutes, centers, and offices—at the NIH. The annual budget for ODS was ∼$1 million for the first several years and then grew rapidly until it reached a plateau at around $25 million beginning in 2005. Successive strategic plans for ODS were published, beginning in 1998, to lay out its goals and how they would be implemented [7]. In 1999, when the first author of this review became its director, 2 major issues loomed large among the many that the dietary supplement field presented: the strength of evidence for benefits and risks of products and matters related to the quality and integrity of products.

For its part, ODS confronted the strength of evidence issue by creating an Evidence-Based Review Program, which used systematic review methodology to evaluate the science of dietary supplement efficacy and safety. In fact, the first systematic review was conducted to evaluate the efficacy and safety of ephedra-containing products [8]. This program subsequently addressed efficacy and safety issues related to ingredients in dietary supplement products, including ω-3 (n–3) fatty acids, B-vitamins, vitamin D, and calcium. As the program evolved, its work helped to inform the evidence-based approach that was successfully applied to the development of DRI values, dietary guidelines, and clinical practice [[9], [10], [11], [12]].

The product quality issue was confronted by creating an Analytical Methods and Reference Materials Program [13] aimed initially at providing laboratory tools to measure the contents of products. It was subsequently built as a broad collaboration among the NIH and other government agencies, such as FDA, CDC, USDA, and the National Institute of Standards and Technology; nongovernmental organizations, such as US Pharmacopeia and AOAC International; academic institutions; contract laboratories; and dietary supplement industry scientists. The program promoted the development and dissemination of laboratory tools, such as validated analytical methods and certified reference materials, and developed proficiency testing opportunities. As it evolved over the years, it became very much involved in the measurement of biomarkers of nutritional status, such as vitamin D and folate.

The work of ODS evolved over the years, guided by a framework for setting priorities. The guidelines have been the following:• What is the public health issue?—Safety? Health promotion? Reducing risk of disease?

• How is nutritional status measured? Are the measures reliable?

• What is the evidence for health effects of dietary supplements? At what levels?

• How should ODS and the research community fill the gaps in knowledge?

• How should ODS translate the results of research for policymakers, clinicians, and especially the public?

Many programs were created by ODS, including a robust grant co-funding program operated in conjunction with other parts of the NIH; the development of research databases in collaboration with CDC and USDA; creation of a population studies program; and initiatives aimed at particular nutrients (vitamin D, ω-3 fatty acids, and iodine).

Perhaps, the most influential efforts were those directed at vitamin D [14]. As part of its vitamin D Initiative, ODS established the Vitamin D Standardization Program (VDSP) in 2010 and coordinated its efforts until 2018. VDSP is an international collaborative effort to standardize the laboratory measurement of vitamin D status. The VDSP goal has been to improve the detection, evaluation, and treatment of vitamin D deficiency and insufficiency by promoting the standardized laboratory measurement of serum total 25-hydroxyvitamin D, thereby making it accurate and comparable over time, location, and laboratory procedure. The VDSP involved the coordinated efforts of many organizations: ODS; National Institute of Standards and Technology; CDC; the Vitamin D External Quality Assessment Scheme; the College of American Pathologists; the American Association for Clinical Chemistry; the International Federation of Clinical Chemistry and Laboratory Medicine; the Laboratory for Analytical Chemistry; Faculty of Pharmaceutical Sciences; Ghent University, Ghent, Belgium; plus, national surveys and collaborators around the world. Since the inception of VDSP, ODS enlisted the participation of national health surveys from Australia, Canada, Germany, Ireland, Mexico, South Korea, the United Kingdom, and the United States.

ODS, in conjunction with USDA, developed a Dietary Supplement Ingredient Database, a tool that compares the amount of nutrients or other supplement ingredients to analytically derived values. This database is available at https://dsid.od.nih.gov/ and is described elsewhere [15]. It has been used to report the measured content of multivitamin–mineral products [16,17], with substantial overages noted for certain micronutrients [18].

ODS leadership identified that the major contribution the office could make was to provide science-based, reliable, and up-to-date information for policymakers, clinicians, and, ultimately, the public. To that end, ODS established a robust communications program [19] that fielded questions from consumers, practitioners, and the media. It also wrote and published a series of fact sheets for the ODS website, which feature information about commonly consumed dietary supplement ingredients (vitamins, minerals, ω-3 fatty acids, soy, herbs, and other botanicals, and more). These are available for both health professionals and consumers and are provided in English and Spanish. The fact sheet page of the website also points to monographs written by other federal government agencies. Other sources of information on dietary supplements from Federal entities are summarized elsewhere [20].

For all these efforts, it was important for ODS to collaborate with other entities at NIH. The closest partner for many of them was—and continues to be—the National Center for Complementary and Integrative Health (NCCIH). It was established by Congress as the Office of Alternative Medicine in 1993, then authorized to become an independent Center at NIH called the National Center for Complementary and Alternative Medicine in 1999. In 2014, Congress renamed the Center to NCCIH to better align with the increasing trend toward combining complementary and integrative and conventional therapies as integrative health care.

Early in its history, NCCIH funded several large clinical trials to evaluate the efficacy of commonly used botanicals and dietary supplements, including Echinacea, St. John’s wort, Ginkgo biloba, and glucosamine. For all of these, previously published studies had suggested benefits, but the large NCCIH-funded trials failed to replicate the hypothesized clinical effects [[21], [22], [23], [24], [25]]. The results of these trials raised questions after publication about the dose or formulation of the product used in the trial [26,27]. These concerns led to NCCIH reappraising its investment in research on dietary supplements.

NCCIH has continued to provide funding for basic, mechanistic, translational, and clinical research on dietary supplements. This area of research fits into the new NCCIH Strategic Plan [28], which now includes the concept of Whole Person Health. This concept embraces new areas of emphasis for NCCIH on health restoration, resilience, and disease prevention. NCCIH’s thinking about natural product clinical trials has evolved considerably since its early years, and the Center now requires more extensive preliminary data to justify efficacy trials [29]. For example, investigators must provide preliminary data to demonstrate that the product being studied impacts a biological signature or demonstrates target engagement and that the impact is reproducible with the formulation and dose to be used in the efficacy trial [30]. NCCIH also requires information on the product characterization along with confirmation of the key markers or compounds from an independent laboratory [31].

Together with other partners at the NIH, ODS and NCCIH collaborate to support additional resources for investigators, including:• the Natural Product Drug Interaction Research Program;

• the NIH Consortium for Advancing Research on Botanical and Other Natural Products (CARBON) Program; and

• the NIH Common Fund Nutrition for Precision Health Powered by All of Us Program.

Finally, additional resources are available from NIH that may be helpful to those conducting research on natural products: available funding opportunities [32]; where to find validated health measures such as PROMIS, Neuro-QoL, ASCQ-Me, and NIH ToolBox [33]; and the PhenX Toolkit of consensus measures for phenotypes and exposures to facilitate collaboration and data sharing [34,35]; and databases of dietary supplement labels and composition [36].

Dietary Supplement Research: The Next 20 Y

The following section provides examples of evolving areas of scientific research on dietary supplements. They are not intended to be all-inclusive but rather to illustrate some of the types of research that are emerging.

Micronutrient exposure and status: from populations to individuals

Decades of fundamental and human participant nutrition research have taken a reductionist approach to understanding the biochemistry and physiology of micronutrients and their functional roles in biological pathways. The reductionist approach has greatly advanced the field of nutritional biochemistry, including characterizing the mechanisms of action of nutrients that are common across individuals and populations. However, this strategy fails to account for the interactions among essential and nonessential bioactive nutrients within physiologic systems that connect the intake of food and dietary supplements to health outcomes. Furthermore, this approach does not address the antagonistic and synergistic interactions among these dietary components that are critical to understand bioavailability and function in vivo. More simply stated, humans do not consume nutrients in isolation. Adding to this complexity, individuals and population subgroups respond differently to similar dietary exposures when deficiency is not the end point of interest [37]. Little is known about the pleiotropic biological effects related to human health that micronutrients from all sources exhibit because they are consumed in various combinations of doses, forms, and frequency. Micronutrient exposures from dietary supplements differ from those of micronutrients from foods. Unlike foods and beverages, the amount of nutrients from supplements is not bound by calorie/energy intakes under homeostatic control [38]. Similarly, supplements can contribute a very large amount of nutrients in a discrete bolus form, unlike many foods and beverages. Additionally, when nutrients are provided in isolation, their utilization and metabolism may be different than when they are provided in foods with multiple, naturally occurring bioactive ingredients [39]. As we move toward precision nutrition, it is critical to identify the optimal combinations, amounts, and forms of micronutrients that are required to promote human health. To this end, tools and technologies that accurately and reliably reflect the black box between complex dietary exposures and health outcomes are critical. Three primary areas of research are key in terms of where this field currently stands, as well as the next steps that are needed in order to address the significant gaps: 1) improving dietary assessment methods [[40], [41], [42]]; 2) the need for validated surrogate or other markers that connect dietary exposures to metabolic and physiologic responses; and 3) leveraging advanced technologies, including multiomic approaches and computational/data science [43,44].

Recent advances in diverse scientific fields now provide new and more types of information to determine causal relationships among nutrients, diet, and health. Large datasets allow for inferring causation from quasi-randomized observations between exposed and nonexposed groups.

Together, these developments in the field will aid in creating comprehensive dietary guidance aimed at reducing risk of diet-related chronic disease, currently experienced by most Americans [37]. The field of precision nutrition research has shifted from preventing deficiency disorders to promoting human health [42,45]. This is evidenced by the development of the DRI value called Chronic Disease and Risk Reduction [45] within the DRI framework (see Table 1 of reference 45). At the same time, micronutrient deficiency remains a global problem [46].

Diet–microbiota connections to health

Decades of research have linked dietary intake and food-related behaviors to health outcomes. For example, adequate intake of dietary fiber is reported, with varying degrees of data, to reduce risks of developing obesity, cardiovascular disease, diabetes, and colorectal cancer [47]. Over the past 10 y, the boom in molecular and computations approaches have allowed us to better study the composition and function of the gastrointestinal microbiota, a collection of trillions of microorganisms that reside within the gastrointestinal tract.

Microorganisms within the gastrointestinal tract have unique capabilities to metabolize nondigestible dietary components, including prebiotic compounds and fiber [48]. Microbial metabolism of dietary fiber can result in increased production of short-chain fatty acids [49] and may result in health effects [50]. Dietary fatty acids also affect the intestinal microbiota. Primary bile acids can be converted to secondary bile acids by certain microorganisms within the intestinal tract, and a growing body of evidence indicates that bile acids affect not only gastrointestinal health but also metabolic health [51].

However, it is important to also look beyond the nutrients listed on the food label and consider factors related to food science, in addition to nutritional sciences. Food is not just a combination of nutrients; the food matrix plays an important role in the health effects of dietary intake [52,53]. For example, processing almonds affects nutrient bioaccessibility and, subsequently, the human intestinal microbiota. Whole natural, whole roasted, and roasted chopped almonds have ∼20% less metabolizable energy than predicted by Atwater factors and they enrich microbes such as Roseburia, while the metabolizable energy of almond butter aligns with predicted values and results in few detectable differences in the microbiota [54]. Evolving research at the intersection of food science and nutrition will continue to impact our understanding of how the microbiota interacts with the nutrients in the lumen and subsequently impacts human health.

Personalized nutrition is increasingly relevant in diet–microbiota–health connections. Personalized nutrition uses individual-specific information, founded in evidence-based science, to promote dietary behavior change that results in measurable health benefits [55]. Humans differ from one another and can respond differently to dietary exposures based on an array of features: health status, dietary habits, eating patterns, genetics, epigenetics, and the microbiome. Both host [56] and microbial [57] phenotypes are predictive of health responses to dietary intake. Using microbiome features in modeling increases the accuracy of predicting glycemic responses to meal challenges [58,59]. Other studies have reported that the Bacteroides/Prevotella ratio is predictive of weight loss [[60], [61], [62], [63], [64]].

There is a large body of evidence on the health benefits of prebiotics [65] and probiotics [66], but the research on synbiotics [67] is more limited. Expansion of microbe and microbe-derived preparations, such as next-generation probiotics and postbiotics, and microbial substrates, such as polyphenols and fatty acids [68,69], can be expected. Moreover, to move this research area forward, new innovations in food formulations that provide biotics should be considered to support the microbiota and enhance human health [70]. It will be necessary, however, to ensure that recommendations focused on the microbiome align with the current state of the science; for example, there is no currently accepted definition of a “healthy” microbiome [71], nor are their clinically valid tests to assess it [72]. Personalized nutrition approaches that use advanced analytics to integrate the multiomics data with clinical, lifestyle, and dietary data will help us to provide more targeted recommendations to groups and individuals. At this time, however, such data are limited.

Interdisciplinary teams are necessary to continue to move research forward in the diet–microbiota–health space. Preclinical studies using computational approaches and model systems will allow for pipelines for discovery and testing, while high-quality clinical trials will remain integral to translate results and demonstrate causal relationships among diet, the microbiota, and health.

Harnessing botanical bioactives to promote human health

Since its establishment in 1999 by ODS and NCCIH, the CARBON Program [73] has supported a wide range of studies exploring the health effects of botanical dietary supplements. The increasing use of dietary supplements to improve health has sparked renewed interest in plants as a rich source of potentially health-promoting compounds.

The work of current CARBON Centers is given elsewhere [73]. The type of work that has been conducted at these Centers is illustrated by the Pennington Botanical Research Center (PBRC) which, for many years, has pursued characterizing botanical-derived extracts that promote resilience to metabolic syndrome (MetS), a set of risk factors that predict the development of type 2 diabetes mellitus [74]. Although plant-based extracts have considerable untapped potential to prevent or alleviate MetS risk factors, their complexity introduces unique challenges to development as dietary supplement products [75]. Good manufacturing practices are required but will not ensure a consistent mixture of compounds in the botanical extract or efficacy of a plant-based dietary supplement [76]. To address these challenges, the PBRC has collaborated with experts from a wide range of scientific disciplines to screen hundreds of crude botanical extracts, with the goal of generating well-characterized botanical extracts with a defined mixture of compounds that have biological activity related to insulin’s action. The resulting extracts are investigated for their potential to promote insulin responsiveness in preclinical models of obesity-induced insulin resistance, a primary risk factor for MetS [77]. When coupled with recent advances in analytic techniques to dissect the role of each compound in a botanical extract [78], this approach offers the possibility of developing botanical-based dietary supplements based on a designed combination of phytochemicals with predictable safety and efficacy.

For example, an ethanolic extract of Russian tarragon (termed PMI5011) is one of the primary botanical extracts studied at the PBRC as part of the CARBON Program. In a series of experiments using a range of preclinical models of obesity-induced insulin resistance, a set of bioaccessible bioactive compounds in PMI5011 was identified that reproducibly improves insulin responsiveness and lower blood glucose concentrations [[79], [80], [81], [82], [83]]. In collaboration with experts in natural products analytical chemistry, PBRC investigators have begun to understand the mechanism of action of individual compounds in PMI5011 [84,85]. These studies are laying the foundation to develop a defined set of phytochemicals in PMI5011 with known mechanisms of action that is suitable for formulating a dietary supplement to promote insulin responsiveness and improve glucose homeostasis.

Realizing this goal requires expanding the expertise needed to include computational biology and bioinformatics [86,87]. The advances in computing capabilities in machine or deep learning to examine large datasets will enable researchers to understand how the complex mixture of bioactive compounds found in botanicals impacts health as a reliable and safe dietary supplement. A machine learning approach is equally applicable to exploring the complexities of how micronutrients and macronutrients contribute to the potential health benefits of other dietary supplements.

Applying nutrigenomics and precision nutrition to dietary supplementation

Whether assessing the potential health effects of micronutrients, fiber, probiotics, or botanical extracts, there is increasing awareness among researchers, educators, health care professionals, and consumers that a 1-size-fits-all, population-based approach to nutritional guidance is inefficient and sometimes ineffective [88]. Innate genetic—as well as microbial—variations impact an individual’s nutritional needs and responses to various foods, beverages, and supplements by altering the rate of nutrient absorption, distribution, metabolism, cellular uptake, and excretion [89]. These genetic differences impact how much of a nutrient or food bioactive reaches the target cell. Genetic variation in certain targets, such as nuclear receptors, enzymes, transporters, or ion channels, can also alter the nutrients’ biological effects, and explain some of the individual differences in response to dietary factors. Some randomized controlled clinical trials demonstrate that giving DNA-based dietary advice to individuals can be superior to population-based recommendations for improving compliance [90,91]. With increasing consumer awareness and demand for genetic testing for personalized nutrition, there is a need for health care professionals to have sufficient knowledge to understand the science behind these tests and determine the benefits and limitations of both the science and the testing [92]. Moreover, there is an opportunity for nutrition and dietary supplement companies to establish a leadership position in the field of precision supplementation by partnering on research projects to expand the science or with precision nutrition companies to develop companion tests that can be used to optimize nutritional status and, ultimately, health, performance, and longevity.

Related to this in the exploration of precision nutrition is whether there is actionable evidence from evaluating subgroups in clinical studies. This concept is attractive because secondary analysis of subgroups [93] has suggested that some subpopulations benefit more than others from interventions such as ω-3 fatty acids. Understanding how to identify responsive subgroups will advance our understanding in this regard. To that end, more precise measures of dietary intakes, how those exposures impact various biological systems, and how collectively those relate to human health are the goals. This concept, however, remains controversial and not universally accepted [94]. Using multiomic technologies and wearable devices paired with data science approaches may be an actionable step in addressing subgroup responses. However, subgroup exploration should proceed cautiously using rigorously developed tools (e.g., ICEMAN) [95] and statistical techniques to decipher the most credible evidence of effect modification.

The Role of Industry and Clinical Practice in Research on Dietary Supplements

Integrative medicine research needs industry partnerships to expand the nascent evidence base for dietary supplements. Nonetheless, research resulting from such collaborations presents unique challenges that require consideration. An issue that is not unique to dietary supplement research is that industry-funded trials tend to show treatments to be more efficacious and less harmful than non–industry-funded trials [96]. One issue arises with masked studies of herbal and other botanical dietary supplements. Despite starting off as double blind, the strong taste and aroma of some herbal dietary supplements often make it challenging to keep the blinding intact. Consequently, it is relatively easy for the blinding to be unmasked; readers scrutinizing this type of literature should take this into account, regardless of the claims of the article [97]. To address this issue when designing research, both researchers and their industry partners can consider using active controls and objective measures (such as laboratory values) to mitigate the impact of bias resulting from unmasking.

Another area of importance is researcher affiliation. Standard conflict of interest statements and funding disclosures may not be independently verified by journal editors. Therefore, integrative clinicians critically evaluating an article should do basic due diligence on the authors to investigate potential conflict with industry. Meta-epidemiologic research has suggested biased effect sizes when studies are funded by industry. The mechanisms through which such funding may influence results are actively debated and may include spin, straw man comparators, selective outcome reporting, and p-hacking. However, recent research has revealed a more nuanced picture. Studies that receive industry funding without influence on study design, data collection, analysis, or publication decisions do not demonstrate significant differences in effect estimates compared to research without industry funding [98]. Therefore, industry partners exploring research on their products may benefit from partnering with academic or nonindustry affiliated researchers and forgoing input on methods, analysis, and publication to maximize confidence in the published article. Indeed, there is a growing and evolving recognition of the need for conflict-of-interest guidance by the food and nutrition industry. In 2009, the International Life Sciences Institute North America Working Group on Guiding Principles published 8 principles that were meant as “ground rules” for industry-sponsored research [99]. These were updated in 2022 [100] and include a robust list of principles, such as “control of the study design, the research itself, and the interpretation of findings [will] remain with scientific investigators,” full and transparent disclosure of financial and non-financial conflicts,” and “guarantee[d] accessibility to all data.”

Industry partnerships can play a vital role in advancing research in integrative medicine. Although there is an inherent risk of bias, clinicians can have confidence in studies conducted in collaboration with industry if they adhere to practical measures aimed at increasing transparency and reducing industry influence on study design and reported outcomes.

Concluding Remarks

The last 25 y of dietary supplement research have been marked by an increased understanding of the mechanisms by which these ingredients exert their effects, how they are consumed by the American public, and how they might contribute to health maintenance and disease risk reduction. There remain many questions, however, driven in part by the fact that dietary supplements are often complex mixtures of individual ingredients. In the case of botanical and food-based supplements, only some of these ingredients are well characterized. We have learned many lessons from these past scientific advances:a. Nutritional status is a key determinant of possible health effects of dietary supplements. As this field progresses, more precise measures of dietary intake and status must be developed. Emerging technologies, such as AI, hold promise in meeting this need.

b. Most dietary guidance (e.g., DRIs and Dietary Guidelines for Americans) is provided at the population level. As we move into the era of personalized and precision nutrition, it is hoped that this guidance will evolve accordingly.

c. Although significant strides have been made in understanding how dietary supplements can affect human health outcomes, there are still gaps in the areas of phytochemistry, pharmacognosy, safety, toxicology, and standardization of the active ingredients, particularly for botanical dietary supplements [101]. For these products, there is also the additional complexity of horticulture in terms of sustainability and managing issues related to biodiversity loss, as well as variation in the quality of the active compounds of interest. Over the next decade, research will likely focus on using emerging technologies such as AI to help bring safe, effective, and sustainably sourced botanical ingredients into the supplement category [102].

d. Government, particularly the NIH, contributes the bulk of funds for dietary supplement research in the United States. This is heartening, but it does have its challenges. Clinical endpoints often used in these studies, such as disease occurrence, cannot be used by companies in making label claims. NIH-funded studies tend to be all-inclusive, which means that effect sizes are likely to be small overall and do not always allow for the characterization of health effects in vulnerable or sensitive subgroups. Because nutritional interventions tend to be cumulative over time, these types of studies may not be reasonable, given the 3–5-y funding cycles for most NIH-funded grants.

e. Larger investments in nutrition by industry and trade organizations might correct some of these problems. However, there is a need to educate academic researchers about the challenges companies face in conducting and supporting research or interpreting research findings.

f. There is a need to accurately and transparently communicate the results of dietary supplement research by all stakeholders. This includes research scientists, the media, policymakers, clinicians, and those with commercial interests.

Increasingly, consumers are taking greater charge of their own care. The consumer self-care dynamic has changed considerably over the last decade, impacting reliance on health care providers and other resources for information about dietary supplements. There is an increasing shift by consumers to seek alternative strategies to support their health and well-being. These include the use of dietary supplements, including herbal and other plant-based products Pharmaceutical and dietary supplement companies are increasingly investing in innovative technologies to safely incorporate botanical products as part of the consumer self-care regimen [103].

Personalized or precision nutrition has resonated with consumers over the past 5–10 y, especially given the rise of commercial genetic services. The goal of this study was to tailor nutritional therapies that are specific to an individual based on their individual characteristics using data collected through genomics, proteomics, and metabolomics, in addition to wearable technologies that monitor sleep, dietary intakes, physical activity, blood glucose concentrations, and heart rate. AI-based chatbots, or virtual assistants, may be useful in influencing such parameters, and AI-based image capture to assess food intake is at least at parity with human calculations, showing promise for both research and personalized daily applications [104,105].

Although this may appear to be the future of dietary supplement research over the next coming decade, all stakeholders—including regulatory authorities, academic scientists, and industry—must work together to address some of the key challenges and opportunities around emerging technologies for precision nutrition. These efforts will likely be guided by integrating and harmonizing datasets collected through different personalized nutrition services, such as direct-to-consumer genetic and/or microbiome testing. The accuracy of the data in most cases still must be verified, including the ability to predict emergent behaviors for the whole-body system through relevant and validated biomarkers. There are also ethical issues regarding who owns the data [106].

One critical aspect to note as dietary supplement research evolves is that we must ensure inclusivity and representativeness of the demographics of our society. This is especially true in building algorithms for AI and personalized nutrition services. Genomic, proteomic, and metabolic heterogeneity can be influenced by more than not only just variations in genetics but also epigenetics, lifestyle, dietary intakes, environmental exposures, socioeconomic status, and access, among various other factors. These inputs are best addressed when diverse populations are included in research and consumer studies and will hence better guide our ability to drive dietary supplement research that resonates with all.

Author contributions

The authors’ responsibilities were as follows – PMC: wrote the initial draft of the manuscript based upon presentations made by the speakers and session moderators at the symposium and had primary responsibility for the final version; and all authors: provided input on, edited, revised the manuscript, and read and approved the final manuscript.

Conflict of interest

PMC reports consulting on grant application writing for Indiana University and, previously, for Purdue University; serving as an expert consultant in the past to US Pharmacopeia, AARP, Tilia Holdings, and Mars Symboscience; serving on the American Society for Nutrition Foundation Board of Trustees. RLB reports serving as a member of the CRN Science Advisory Team; consulting in the past to the NIH Office of Dietary Supplements, Nestlé, the General Mills Bell Institute, Research Triangle Institute (RTI) International, Think Healthy Group, and Nutrition Impact; trustee of the International Food Information Council; and former board member of the International Life Sciences Institute North America and the American Society for Nutrition; and receiving travel support to present her research on dietary supplements; member of the Journal of Nutrition editorial board. JBB reports serving on scientific advisory boards for Advocare, Bragg Live Food Products, Blueshift Nutrition, California Prune Board, Cranberry Institute, Good Pharma, Guiding Stars Licensing, Haleon, Inside Tracker/Segterra, January.ai, and Vital Technologies, all outside the submitted work. AE-S holds shares in Nutrigenomix, which provides genetic testing for personalized nutrition. ZEF reports no conflicts.

JZG reports consulting in legal matters involving traumatic brain injury and is the owner of physician education company; co-owner of forensic research contract organization; and owner of naturopathic medical clinic focusing on gastroenterology. AGS reports being on scientific advisory boards for Winged Women’s Wellness and Happy Mammoth. HDH reports speaking honoraria from Abbott Nutrition, Beneo, Global Prebiotic Association, DSM, and Dairy Management and consulting fees from Bobbie. YN-E reports being an employee of ChromaDex, a publicly-traded company and serving as a member of CRN’s Senior Scientific Advisory Council. DR reports being an employee of OmniActive Health Technologies and serving as Chair of the CRN’s Senior Scientific Advisory Council and CRN Board Member. BWR reports being an employee of Nestlé Health Science and serving as past Chair, CRN Board of Directors. WJW reports no conflicts.

Funding

All speakers, except for YN-E, DR, BWR, and WJW, received travel support and honoraria from CRN to participate in the symposium. PMC received financial support from CRN to write and organize the publication of this manuscript. RLB is supported by 2R01CA215834-05A1. JBB receives support from the Food is Medicine Institute, Friedman School of Nutrition Science and Policy, Tufts University. AE-S has held grants from the Canadian Institutes of Health Research, the Advanced Foods and Materials Network Center of Excellence, the Allen Foundation, and the Canadian Foundation for Dietetic Research for projects on personalized nutrition. ZEF is supported by NIH grant P50AT002776. JZG is supported by NIH grants R25DK130848 and R90AT008924. AGS did not receive additional funding from any agency in the public, commercial, or not-for-profit sectors for this work. HDH has received grant funding from the Almond Board of California, Bio-Cat, Danone Research, General Mills, Hass Avocado Board, Tate & Lyle, National Honey Board, and USDA. DR received travel support from OmniActive Health Technologies. WJW reports no sources of support.

Disclaimers

The article is based on information presented and discussed at the Council for Responsible Nutrition (CRN) Science in Session symposium entitled “The Evolution of Science on Dietary Supplements: Past, Present, and Future” held in October 2023. The event was organized and supported by CRN, www.crnusa.org, a trade association representing dietary supplement and functional food manufacturers and ingredient suppliers. CRN receives support primarily from its industry membership.

Appendix A Supplementary data

The following is the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Acknowledgments

We thank the CRN Science Advisory Council and CRN staff for their invaluable assistance in organizing the symposium that led to this article.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.tjnut.2024.06.017.
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