The Evolution of Science and Regulation of Dietary Supplements: Past, Present, and Future.

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 endpoints. New technologies and approaches are being applied to the science of dietary supplements, including nutrigenomics and microbiome analysis, data science, artificial intelligence, 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 paper 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.

Unmet Need: Mechanistic and Translational Studies of Sickle Cell Disease Pain as a Whole-Person Health Challenge.

Sickle cell disease (SCD) is a lifelong monogenic, autosomal-recessive blood disease that predominantly affects individuals of African descent and those who self-identify as Black or Hispanic. Common SCD pathophysiological processes include adhesion, hemolysis, hypoxia, ischemia, oxidative stress, and vaso-occlusion, which often lead to substantial comorbidities and complications. Pain is one of the most common and significant clinical complications for individuals with SCD. Despite advancements in understanding the pathophysiology of SCD, the ways in which SCD pathophysiological processes contribute to nociception and pain signaling, processing, and perception remain largely unclear. Pain management for individuals with SCD is complex and presents unique challenges that must be considered depending on the presenting pain type (eg, acute pain episode vs chronic pain). Racism, stigma (including stigma associated with opioid use), and limited resources present additional challenges. Limited research has been conducted on major clinical features of SCD pain such as its ischemic, inflammatory, and neuropathic components; on its transition from acute to chronic form and across the lifespan; and on factors influencing SCD pain perception. Research on and management of SCD pain requires a whole-person approach, bringing together investigators from multiple disciplines such as hematologists, organ biologists, pain experts, physiologists, neuroscientists, psychologists, geneticists, microbiologists, immunologists, behavioral scientists, and clinicians. Multidisciplinary cross-training, with different platforms for information dissemination and communication, could help promote basic, mechanistic, and translational research to inform the optimization of current treatment strategies and the development of novel therapies for SCD pain. PERSPECTIVE: This review presents the research challenges and negative impact of SCD pain, a grossly understudied condition in a highly underserved population. It also highlights the barriers and opportunities in SCD pain research and could help clinicians better understand current treatment strategies from the whole-person perspective.

Integrated multicomponent interventions to support healthy aging of the whole person.

Healthy aging is an integrated "whole person" process that involves an individual's biology, behavior, and social/physical environment. With the recent development of antiaging drugs, careful consideration of the respective roles of pharmacologic and nonpharmacologic approaches to both health and aging is in order. Recent advances in understanding the cellular and molecular mechanisms of aging are providing new measures that can be used as clinical outcomes in studying the impact of antiaging interventions in humans. This paper outlines the strategic interest of the National Center for Complementary and Integrative Health (NCCIH) in supporting the development, testing, and implementation of effective, scalable, and integrated multicomponent interventions to support healthy aging of the whole person.

NCCIH Priorities for Natural Products Research.

The National Center for Complementary and Integrative Health (NCCIH) is the lead agency within the U. S. federal government for complementary and integrative health research, which includes natural products. Although NCCIH is one of the smaller components of the National Institutes of Health (NIH), NCCIH funds a disproportionately high percentage of natural products research at NIH. This stems from NCCIH being the only NIH grant issuing component that includes natural products as an explicit part of its mission. This perspective provides an overview of the NCCIH mission and summarizes NCCIH funding priorities for natural products research across basic and mechanistic as well as clinical sectors. These priorities are guided by the recently released NCCIH strategic plan. A primary element of this new plan is a focus on whole person health instead of the frequent focus on the treatment of diseases. The NCCIH focus on whole person health includes how natural products and multicomponent therapeutic approaches, which often include natural products, can help move individuals towards health restoration and promotion.

Longitudinal Analysis of Complementary Health Approaches in Adults Aged 25-74 Years from the Midlife in the U.S. Survey Sample.

Objectives: Complementary health approaches include herbal products and mind-body practices. Several studies have identified predictors for complementary health approach use, yet there are two gaps: (1) How does use change? (2) Do factors associated with use influence this change over time? Using the Midlife in the United States (MIDUS), we examined how sociodemographic factors affected use longitudinally, and whether these associations differed between new and continued/discontinued use of herbal products, meditation, chiropractic, and massage therapy. Design: MIDUS is a national probability sample of adults aged 25 or older that has collected more than 20 years of longitudinal data, including the use of complementary health approaches. We employed the Andersen Model as a framework to identify predisposing, enabling, and health need factors associated with complementary health approach use based on previously identified and hypothesized factors. We ran Chi-square analyses to first test bivariate associations between our independent variables and four modalities to further guide logistic regression models. Results: Each of the four approaches examined saw substantial increases in prevalent use. However, only about 25% to 38% of individuals continued use from one wave to the next, whereas only 2%-9% of individuals who did not use a given approach in a wave reported use in the subsequent wave. Age, spiritual importance, and previous wave one use were all significantly associated with new use across all four modalities. Previous wave one use was associated with continued/discontinued use for all modalities. Age and education were significantly associated with discontinued use of chiropractic. Conclusion: We present the first longitudinal analysis of complementary health approaches in a nationally representative sample. These data distinguish between new and continued/discontinued use of complementary health approaches over time and provide insights into the interpretation of complementary health approach prevalence data, as well as important predictors of use.

National Center for Complementary and Integrative Health Perspectives on Clinical Research Involving Natural Products.

The sales of dietary supplements continue to increase year after year. Despite their use by a large percentage of Americans, there is little evidence for the vast majority of products regarding their safety or efficacy. National Center for Complementary and Integrative Health supports a broad range of research on dietary supplements, including clinical trials. Our experience with these trials has shaped our current policies and priorities for clinical research. This perspective outlines those policies and priorities that are shaping our investments going forward. SIGNIFICANCE STATEMENT: The sales of dietary supplements continue to increase year after year. Despite their use by a large percentage of Americans, there is little evidence for the vast majority of products regarding their safety or efficacy. National Center for Complementary and Integrative Health supports a broad range of research on dietary supplements, including clinical trials. Our experience with these trials has shaped our current policies and priorities for clinical research. This perspective outlines those policies and priorities that are shaping our investments going forward.

Pragmatic clinical trials offer unique opportunities for disseminating, implementing, and sustaining evidence-based practices into clinical care: Proceedings of a workshop.

The National Institutes of Health (NIH) Health Care Systems (HCS) Research Collaboratory hosted a workshop to explore challenges and strategies for the dissemination, implementation, and sustainability of findings from pragmatic clinical trials (PCTs) embedded in HCS. PCTs are designed to assess the impact of interventions delivered in usual or real-world conditions and leverage existing infrastructure to answer important clinical questions. The goal of the workshop was to discuss strategies for conducting impactful future PCTs that bridge the gap between evidence, practice, and policy. This paper summarizes presentations about how to design and conduct PCTs embedded in HCS and use dissemination and implementation strategies during the planning and conduct of projects, emphasizing the ever-changing world of care delivery and the need for pragmatic trial operations to adapt at various levels of operation.

The NIH Science of Behavior Change Program: Transforming the science through a focus on mechanisms of change.

The goal of the NIH Science of Behavior Change (SOBC) Common Fund Program is to provide the basis for an experimental medicine approach to behavior change that focuses on identifying and measuring the mechanisms that underlie behavioral patterns we are trying to change. This paper frames the development of the program within a discussion of the substantial disease burden in the U.S. attributable to behavioral factors, and details our strategies for breaking down the disease- and condition-focused silos in the behavior change field to accelerate discovery and translation. These principles serve as the foundation for our vision for a unified science of behavior change at the NIH and in the broader research community.

Evidence-Based Evaluation of Complementary Health Approaches for Pain Management in the United States.

Although most pain is acute and resolves within a few days or weeks, millions of Americans have persistent or recurring pain that may become chronic and debilitating. Medications may provide only partial relief from this chronic pain and can be associated with unwanted effects. As a result, many individuals turn to complementary health approaches as part of their pain management strategy. This article examines the clinical trial evidence for the efficacy and safety of several specific approaches-acupuncture, manipulation, massage therapy, relaxation techniques including meditation, selected natural product supplements (chondroitin, glucosamine, methylsulfonylmethane, S-adenosylmethionine), tai chi, and yoga-as used to manage chronic pain and related disability associated with back pain, fibromyalgia, osteoarthritis, neck pain, and severe headaches or migraines.

Building an evidence base in complementary and integrative healthcare for child and adolescent psychiatry.

Complementary and integrative strategies are widely used by families with children who have mental health diagnoses. The therapies used by these children include herbs, dietary supplements, massage, acupuncture, meditation, and naturopathy. The literature on efficacy of complementary and alternative approaches is of limited value, and studies are needed to test efficacy and safety. Interpretation of complementary and integrative health care studies for symptomatic management of mental health conditions is hampered by study design and methodological limitations. Well-designed, adequately powered, and suitably controlled clinical trials on promising complementary and integrative modalities are needed for children and adolescents with psychiatric conditions.

Tolerability of curcumin in pediatric inflammatory bowel disease: a forced-dose titration study.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation in the absence of a recognized etiology. The primary therapies are medications that possess anti-inflammatory or immunosuppressive effects. Given the high use of complementary alternative medicines in pediatric IBD, a prospective tolerability study of curcumin, an herbal therapy with known anti-inflammatory effects, was conducted to assess possible dosage in children with IBD. METHODS: Prospectively, patients with Crohn disease or ulcerative colitis in remission or with mild disease (Pediatric Crohn's Disease Activity Index [PCDAI] <30 or Pediatric Ulcerative Colitis Activity Index [PUCAI] score <34) were enrolled in a tolerability study. All patients received curcumin in addition to their standard therapy. Patients initially received 500 mg twice per day for 3 weeks. Using the forced-dose titration design, doses were increased up to 1 g twice per day at week 3 for a total of 3 weeks and then titrated again to 2 g twice per day at week 6 for 3 weeks. Validated measures of disease activity, using the PUCAI and PCDAI, and the Monitoring of Side Effect System score were obtained at weeks 3, 6, and 9. RESULTS: All patients tolerated curcumin well, with the only symptom that was consistently reported during all 3 visits being an increase in gassiness, which occurred in only 2 patients. Three patients saw improvement in PUCAI/PCDAI score. CONCLUSIONS: This pilot study suggests that curcumin may be used as an adjunctive therapy for individuals seeking a combination of conventional medicine and alternative medicine.

DoD-NCCAM/NIH workshop on acupuncture for treatment of acute pain.

The Department of Defense (DoD) and the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) cosponsored a workshop that explored the possible benefits of acupuncture treatment for acute pain. One goal of the workshop was to establish a roadmap to building an evidence base on that would indicate whether acupuncture is helpful for treating active-duty military personnel experiencing acute pain. The workshop highlighted brief presentations on the most current research on acupuncture and acute pain mechanisms. The impact of various modifiers (stress, genetics, population, phenotypes, etc.) on acute pain pathways and response to acupuncture treatment was discussed. Additional presentations focused on common neural mechanisms, an overview of real-world experience with using acupuncture to treat traumatic acute pain, and best tools and methods specific for acupuncture studies. Three breakout groups addressed the gaps, opportunities, and barriers to acupuncture use for acute pain in military and trauma settings. Different models of effectiveness research and optimal research designs for conducting trials in acute traumatic pain were also discussed.

Detoxification in naturopathic medicine: a survey.

OBJECTIVES: This study sought to assess the use of clinical detoxification therapies used by licensed naturopathic doctors (NDs) in the United States. DESIGN: This was a qualitative, descriptive, online survey of a convenience sample of NDs. METHODS: An online survey was conducted of NDs who were licensed in the United States. Responses were analyzed descriptively regarding the use of clinical detoxification therapies. Respondents were recruited from a membership list provided by the American Association of Naturopathic Physicians, and from alumni e-mail lists of Council of Naturopathic Medical Education accredited naturopathic medical schools. RESULTS: Surveys were sent out to 1442 e-mail addresses (261 were returned to sender); a total of 196 respondents completed the survey (16.6%). Ninety-two percent (92%) of respondents reported using clinical detoxification therapies. Over 75% of respondents utilized detoxification therapies primarily to treat patients for environmental exposures, general cleansing/preventive medicine, gastrointestinal disorders, and autoimmune disease. Regarding methods used, >75% reported using dietary measures, reducing environmental exposures, and using botanicals as detoxification therapies. Eighty-three percent (83%) of NDs surveyed reported using follow-up measurements to determine efficacy of detoxification therapies. The most common were patient symptom questionnaires (66%), patient medical histories (54%), and urinary provocative challenge testing (53%). CONCLUSIONS: The majority of NDs responding to this survey reported routine use of clinical detoxification therapies to treat a range of medical conditions utilizing multiple therapeutic approaches. Although the majority of NDs reported using some follow-up measurements after detoxification therapy, few of these are an objective means to determine treatment efficacy. Further research is needed in the field of complementary and alternative medicine clinical detoxification to determine the safety and efficacy of these approaches.

Building bridges: qualitative assessment of a clinical faculty exchange between a naturopathic and an allopathic medical training program.

RESEARCH QUESTION: What are the perceived benefits of a clinical exchange experience designed as part of a program to promote acceptance and use of evidence-based medicine (EBM) in naturopathic clinical practice? METHODS: Nine faculty members participated in a focus group (n = 6) or a structured interview (n = 3) to assess experience in the program. Investigators independently analyzed transcribed notes for common experience themes. ANALYSIS AND INTERPRETATION: Six major themes emerged: integrating EBM into naturopathic clinical teaching, strengthening of professional relationships, exposure to clinical experiences outside the usual naturopathic scope, reaffirmation of naturopathic training and profession, observation of clinical and administrative resources and practices, and recommendations for future clinical exchanges. MAIN RESULTS: A clinical exchange experience was viewed as a favorable way to promote EBM appreciation within the complementary and alternative medicine educational community and to foster improved clinical experiences for faculty and their students and patients.

Development of a symptom score for clinical studies to identify children with a documented viral upper respiratory tract infection.

The objective of this study was to develop a symptom scoring system for use in clinical studies that differentiates children with cold symptoms who have an identifiable viral etiology for their upper respiratory tract infection (URI) from those in whom no virus is detected. Nasal swabs for PCR testing for identification of respiratory viruses were obtained on children aged 2-11 y at baseline and when parents thought their child was developing a cold. Parental-recorded severity of specific symptoms in children with and without a documented viral URI were compared. Nasal swabs were obtained on 108 children whose parents reported their child was developing a cold. A viral etiology was identified in 62 of 108 (57.4%) samples. Symptom measures that best differentiated children with a viral etiology from those without were significant runny nose and significant cough on days 1-4 of the illness. A URI symptom score was developed based on these symptoms, with a sensitivity of 81.4%, specificity of 61.9%, and accuracy of 73.3%. Parental impression is only a moderately accurate predictor of viral URI in children. Our URI symptom score provided a more accurate method for identifying children with viral URIs for clinical studies.

Research on integrative healthcare: context and priorities.

It is important that integrative healthcare research be conducted to optimize the effectiveness, safety, costs, and social and economic impact of prospective, personalized, patient-centered, comprehensive, and holistic healthcare that focuses on well-being as well as disease management, and that the research itself be well understood. The scope of this research extends beyond evaluation of specific therapies, to include evaluations of multimodality whole system intervention, practitioner-patient relationships, patient goals and priorities, promoting self-care and resilience, personalized diagnostic and therapeutic measures, practitioner well-being, the comparative effectiveness of different educational and outreach strategies in improving health and healthcare, and the environmental/social causes and consequence of health and healthcare. In this paper, we describe the state of the science of research on integrative healthcare, research needs, and opportunities offered by cutting-edge research tools. We propose a framework for setting priorities in integrative health research, list areas for discussion, and pose a few questions on a future research agenda.

Complementary and alternative medicine use and quality of life in pediatric diabetes.

OBJECTIVES: The objectives of this study were to explore the association between complementary and alternative medicine (CAM) use as reported by youth, and parents' and children's reported quality of life in youth with diabetes. DESIGN: The study design was a cross-sectional survey. SETTING: Youth in Washington State participated in the SEARCH for Diabetes in Youth study, a national, multisite epidemiological study designed to assess the prevalence and incidence of diabetes in U.S. youth. Surveys assessing CAM utilization were mailed in January and April 2006. PARTICIPANTS: One thousand four hundred and thirty-nine (1439) youth were mailed a CAM survey. The final sample consisted of 467 youth with both CAM survey results and quality-of-life data. OUTCOME MEASURES: Difference in mean scores on Pediatric Quality of Life Inventory (PedsQL) between CAM users and nonusers overall, and specific CAM therapies were the outcome measures. RESULTS: Of the 1439 participants approached, 587 (40.8%) returned the CAM survey. In adjusted analyses, children reported any CAM use as associated with more barriers to treatment (difference in mean scores -3.48, 95% confidence interval [CI] -6.65, -0.31). Children following a CAM diet reported higher quality of life (PedsQL Core Total difference 4.01, 95% CI [0.10-7.91]; Core Psychosocial difference was 6.45, 95% CI [1.95 to 10.95]), but those using stress-reduction activities reported poorer quality of life (Diabetes Total difference -4.19, 95% CI [-8.35 to -0.04]). Parent-reported quality of life was lower for children who used "other supplements" (Core Total difference -6.26, 95% CI [-11.29 to -1.24]; Core Psychosocial difference was -5.92, 95% CI [-11.65 to -0.19]). CONCLUSIONS: CAM diets were associated with increased quality of life in youth with diabetes, whereas supplement use and stress-reduction activities were associated with decreased quality of life. The temporal sequence between CAM use and quality of life requires further study.

A survey of complementary and alternative medicine (CAM) awareness among neurosurgeons in Washington State.

OBJECTIVES: Use of complementary and alternative medicine (CAM) by the U.S. population increased significantly in the past 2 decades. To maximize a patient's recovery from a neurosurgical procedure, it is critical that neurosurgeons be aware of the benefits and potential adverse complications of CAM therapies. The survey's purpose was to assess the current patterns of CAM utilization by neurosurgery patients and neurosurgeon knowledge of CAM therapies among Washington State Association of Neurological Surgeons (WSANS) members. METHODS: Members of the WSANS were surveyed in 2005. The survey was sent via e-mail and the data were anonymously collected using an online survey tool, Catalyst WebQ. RESULTS: The majority of responses (79%) stated that their neurosurgery practice was > or =75% adults. Acupuncture, herbs, massage therapy, prayer, and yoga were the most common CAM treatments patients used or discussed with their neurosurgeon. Fifty percent (50%) of neurosurgeons discussed the use of acupuncture among their colleagues. Concerning prayer and spirituality, 38% of the surveyed neurosurgeons stated that > or =25% of their patients have disclosed that they pray for their health; 42% stated that spirituality and prayer may affect neurosurgery outcome; and 38% stated that they pray for their patients. Overall, 63% of surveyed neurosurgeons stated that CAM treatments have a role in neurosurgery. CONCLUSIONS: The use of CAM may influence neurosurgical care; and the role of spirituality and prayer should be further explored. Because CAM utilization is ubiquitous, open discussion and familiarity with CAM treatments are becoming increasingly important in the field of neurosurgery.

Hypericum perforatum (St John's wort) for attention-deficit/hyperactivity disorder in children and adolescents: a randomized controlled trial.

CONTEXT: Stimulant medication can effectively treat 60% to 70% of youth with attention-deficit/hyperactivity disorder (ADHD). Yet many parents seek alternative therapies, and Hypericum perforatum (St John's wort) is 1 of the top 3 botanicals used. OBJECTIVE: To determine the efficacy and safety of H. perforatum for the treatment of ADHD in children. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted between March 2005 and August 2006 at Bastyr University, Kenmore, Washington, among a volunteer sample of 54 children aged 6 to 17 years who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for ADHD by structured interview. INTERVENTION: After a placebo run-in phase of 1 week, participants were randomly assigned to receive 300 mg of H. perforatum standardized to 0.3% hypericin (n = 27) or a matched placebo (n = 27) 3 times daily for 8 weeks. Other medications for ADHD were not allowed during the trial. MAIN OUTCOME MEASURES: Performance on the ADHD Rating Scale-IV (range, 0-54) and Clinical Global Impression Improvement Scale (range, 0-7), and adverse events. RESULTS: One patient in the placebo group withdrew because of an adverse event. No significant difference was found in the change in ADHD Rating Scale-IV scores from baseline to week 8 between the treatment and placebo groups: inattentiveness improved 2.6 points (95% confidence interval [CI], -4.6 to -0.6 points) with H. perforatum vs 3.2 points (95% CI, -5.7 to -0.8 points) with placebo (P = .68) and hyperactivity improved 1.8 points (95% CI, -3.7 to 0.1 points) with H. perforatum vs 2.0 points (95% CI, -4.1 to 0.1 points) with placebo (P = .89). There was also no significant difference between the 2 groups in the percentage of participants who met criteria for improvement (score < or = 2) on the Clinical Global Impression Improvement Scale (H. perforatum, 44.4%; 95% CI, 25.5%-64.7% vs placebo, 51.9%; 95% CI, 31.9%-71.3%; P = .59). No difference between groups was found in the number of participants who experienced adverse effects during the study period (H. perforatum, 40.7%; 95% CI, 22.4%-61.2% vs placebo, 44.4%; 95% CI, 25.5%-64.7%; P = .78). CONCLUSION: In this study, use of H. perforatum for treatment of ADHD over the course of 8 weeks did not improve symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00100295.