Advancing supplement science: challenges and solutions

Pills, powders, and elixirs sold to improve health and enhance performance have never been as widely accessible as they are today. A global market of prescription medications flourishes online, thousands of medications are available over-the-counter, and illicit markets for performance-enhancing drugs exist worldwide. The extensive access to pharmacologically active substances sold to enhance health poses tremendous challenges to scientists, regulators, and consumers attempting to understand the safety and efficacy of these myriad products. One of the most controversial and challenging categories is known as ‘dietary supplements’ in the United States (USA) and ‘food supplements’ in the European Union (EU). Supplements may include vitamins, minerals, amino acids, protein powders, botanical extracts, and many other ingredients. They are often sold as medicines but regulated as food. From a regulatory perspective, supplements are assumed to be safe and evidence of efficacy is not required. Supplements may be advertised as having beneficial health effects, even when convincing data from high quality clinical studies are not available. Furthermore, the accuracy of supplement labels with respect to ingredients and health claims is not ensured by governmental agencies. This liberal regulatory framework has allowed for a boom in supplement sales. In the USA alone, an estimated 85 000 brands of supplements are sold for more than $34 billion a year.1 Since the inception of Drug Testing and Analysis, the science of doping, including the identification of doping substances in sports supplements, has been a cornerstone of the journal's remit.2-8 This issue of Drug Testing and Analysis expands the discussion with contributions designed to encourage debate and reflection on our current understanding of supplement quality and safety. We turn to a wide range of international experts in the field to understand how the current regulatory framework in the US” as follows came about, the challenges it created, and the potential solutions. We begin with John Swann's comprehensive review of the historical factors that created the environment in which the US law, known as the Dietary Supplement Health and Education Act of 1994 (DSHEA), was enacted. Swann, a US Food and Drug Administration (FDA) historian, reviews the attempts throughout the twentieth century to regulate vitamins. He describes how the FDA's attempt to create a more rigorous regulatory framework for vitamins ‘triggered a paroxysm of public backlash unseen in agency history’.9 These protests eventually led to the passage of DSHEA, a law which protects not only vitamins and minerals from additional governmental scrutiny but also thousands of botanical ingredients.9 Many new companies entered the lightly regulated industry and introduced a wide variety of supplements including those to improve sports performance and help lose weight, improve sexual function, and other human enhancers.10 By permitting these marketing claims, the law appears to have created an incentive for manufacturers to design supplements with pharmacological activity comparable to licensed medicines.11 A common approach to providing a pharmacological effect in sports and weight loss supplements, initially, was to combine ephedra and caffeine. Eventually, the health risks linked to ephedra, including heart attacks and sudden death, led the FDA to ban it in 2004. Rasmussen and Keizers provide a historical perspective on the search to find a replacement for ephedra in supplements. The authors note a striking similarity with efforts to find a replacement pharmaceutical drug for amphetamine in the early twentieth century.12 The extent of harm to public health from these next-generation stimulants and other supplement ingredients requires further investigation10, 13 but significant developments are underway. In a landmark study published in late 2015 in the New England Journal of Medicine, investigators estimated that supplements are responsible for 23 000 emergency department visits each year in the USA alone.14 This study likely underestimates the extent of harm from supplements because it surveyed mainly civilian hospitals. US troops can purchase supplements directly on military bases around the world,15 but we lack accurate estimates of the risks that supplements pose to the military. To address this gap in knowledge, a study of 4400 US troops, published in this issue by Austin et al., found that 69% of military personnel used supplements and that 17% of them reported adverse effects.16 Keeping in mind the limitations of data obtained from self-reports, the authors highlight the potential for using this approach to detect novel adverse effects. In another article, Deuster and Lieberman explain how the US Department of Defense tackles the health challenges posed by supplements and educates troops about the health risks involved.17 Expanding on this work to educate consumers, Eichner and Tygart, from the US Anti-Doping Agency, warn of the risks that supplements pose to the health and careers of young athletes and share approaches to educating athletes about these risks.18 What supplements might be responsible for the harms identified by these recent studies? In this issue, this question is explored by an in vitro study, case reports, an epidemiological investigation, and analytical studies. An investigation of the pharmacological effect of a number of phenethylamine-based substances is provided by FDA investigators Liu and Santillo who examined 27 stimulant drugs, including aliphatic amines and phenethylamines, using human recombinant CYP2D6 and CYP3A4 inhibition assays.19 Case reports can begin to shed light on the health effects of novel supplement ingredients.20-22 In this issue, van Hunsel et al. and Venhuis et al. provide case reports of the potential health risks from sibutramine in purportedly ‘natural’ weight loss supplements and monacolin K (lovastatin) in red yeast rice supplements.23, 24 Such case reports are an important first step, but epidemiological studies are needed to quantify the risks. In one of the most important epidemiologic studies of supplements of the last decade, experts from the Center for Disease Control and Prevention (CDC) and the Hawaiian Department of Public Health report their findings from an investigation into a statewide outbreak of supplement-induced hepatitis. The investigators traced the origin of the outbreak in Hawaii to one weight-loss product, OxyELITE Pro™.25 The authors found that this one supplement brand was responsible for 38 cases of hepatitis, including two requiring liver transplants and one resulting in death. Continued monitoring for cases led to the identification of an additional 8 cases of hepatitis. In total, one product was found to have caused 44 cases of hepatitis in one state.25 Future research will be required to determine how many consumers were harmed throughout the continental USA. In the meantime, this meticulous study provides a model for future epidemiological investigations of supplement-induced outbreaks. Research in this issue is also dedicated to identifying high-risk supplements based on detecting pharmacologically active substances, particularly if these substances have received little scientific scrutiny or pose known risks. In this issue, Cohen et al. identified β-methylphenylethylamine (BMPEA) in supplements labelled to contain Acacia rigidula extracts21 and Avula et al. found vinpocetine sold as a constituent of lesser periwinkle.26 In a separate investigation, Brown et al. confirmed the presence of BMPEA and its N-methyl derivative, the positional isomers of amphetamine and methamphetamine respectively, in a number of supplements.27 Avula et al. found picamilon (N-nicotinoyl-γ-aminobutyric acid), a prescription drug used in Russia, in multiple supplement brands.26 Zeng et al. analyzed 447 seized weight loss supplements and found adulterants in 119, including sibutramine, phenolphthalein, bisacodyl, fluoxetine, and furosemide.28 Investigators also raise concerns that high doses of bioactive phytochemicals may pose health risks. Venhuis et al.24 found pharmacologically active doses of lovastatin in red yeast rice supplements, and Cohen et al.29 report that yohimbe supplements often contain pharmaceutical quantities of yohimbine. Analytical methods used to examine supplements are equally relevant to detecting counterfeit products. Rebiere et al. showed that the two-step implementation of near infrared (NIR) spectroscopy and Raman chemical imaging helped detect counterfeit tablets labelled as methandienone.30 Further studies of counterfeit products are offered by Custers et al. and Dégardin and Roggo. In the first case, the authors studied the use of physical profiling and NIR/mid-range infrared spectroscopy for the discrimination between genuine and counterfeit samples of Viagra® and Cialis®.31 In the second case, Degardin and Roggo provide an industry perspective on the steps involved in the analysis of counterfeit preparations and highlight the value of information provided by forensic intelligence.32 Although not specifically mentioned in their article, the product in question appears to be Herceptin®. Venhuis et al. describe Operation Resistance, an initiative of the Dutch National Institute for Public Health in collaboration with a variety of European partners that removed falsified antibiotics and biopharmaceutical injectables from the market. During the week-long operation, products were seized in 12 European countries including approximately 21 000 units of falsified antibiotics.33 The detection of potentially harmful products either before or after the reporting of adverse events serves only as an initial step. In a series of opinion pieces in this issue, a variety of experts argue that supplement safety will not be ensured without regulatory reform. Looking beyond the FDA's regulation of supplements, Ranjani Starr argues that state and local governments have an important role to play in regulating supplements.34 Tonya Dodge reviews studies of consumer understanding of supplement labels and proposes eliminating manufacturers’ ability to advertise health benefits without FDA approval.35 Donald Marcus argues that there is no legitimate distinction between botanical supplements and pharmaceutical drugs.36 He recommends that the FDA evaluate efficacy and safety prior to the sale of all botanical supplements. In an effort to bridge the large gap that often exists between experts in the field and the supplement industry, Joshua Sharfstein, former Principal Deputy Commissioner of the FDA, and co-author Akshay Kapoor propose a new regulatory paradigm for supplements that they call ‘access with safety’.37 The authors propose several commonsense reforms that can be accomplished in the short-term, including: registering all supplements with the FDA; enhancing the quality of disclaimers on supplement labels; standardizing manufacturing methods – exemplified by work by the US National Institute of Health and US Pharmacopeial Convention described in separate articles in this issue1, 38; and developing more effective surveillance systems to detect dangerous supplements.37 In the meantime, research published online from this issue of Drug Testing and Analysis has already led to important regulatory developments. Following the publication of research confirming the presence of the synthetic stimulant BMPEA in supplements,21 the FDA declared BMPEA an illegal ingredient and sent warning letters to companies selling BMPEA supplements.39 The research finding picamilon in supplements26 has spurred the FDA to declare picamilon an illegal ingredient and to send warning letters to manufacturers to cease sales of picamilon-containing supplements.40 This issue of Drug Testing and Analysis provides scientists, clinicians, regulators, and industry experts with important contributions in the field of dietary supplements. While it contributes to a better understanding of the challenges and opportunities, the hard work of translating these findings into effective policy to ensure the safety of supplements worldwide has just begun. The editors express their gratitude to the authors and reviewers for their contributions. We also appreciate the support of Dr Mario Thevis, Paul Trevorrow, and the production team.