The Dietary Supplement Health and Education Act of 1994 (DSHEA) was passed with the unanimous consent of Congress. This statute was enacted amid claims that the Food and Drug Administration (FDA) was distorting the then-existing provisions of the Food, Drug, and Cosmetic Act (FDCA) [1] to try improperly to deprive the public of safe and popular dietary supplement products. The FDA was perceived as engaging in anti-supplement policy and enforcement tactics, provoking a groundswell of legislative criticism. In its official report about the need for DSHEA to curtail excessive regulation of dietary supplements by the FDA, the Senate Committee on Labor and Human Resources charged that the “FDA has been distorting the law in its actions to try to prevent the marketing of safe dietary supplement substances” [2]. The Senate Committee also concluded that the “FDA has attempted to twist the statute (i.e., the provisions of the FDCA, as it then existed) in what the Committee sees as a result-oriented effort to impede the manufacture and sale of dietary supplements” [3].

DSHEA represented a sharp rebuke to the FDA’s regulatory tactics of the time. However, although DSHEA defined “dietary supplements” and “dietary ingredients,” set certain criteria for “new dietary ingredients,” and prevented FDA from overreaching, it did not, as some critics have charged, leave the industry unregulated. The dietary supplement industry is in fact regulated by the FDA as a result of DSHEA. The Center for Food Safety and Applied Nutrition (CFSAN), a branch of the FDA, along with the Office of Dietary Supplements (ODS) assists the FDA in the regulation of dietary supplements. This power ensures the FDA’s authority to provide legitimate protections for the public health. The Federal Trade Commission (FTC) also continues to have jurisdiction over the claims (marketing, from implied to direct claims) that manufacturers make about their products. The FDA and FTC work together to regulate the dietary supplement industry. There is increased sharing of information and overlapping of jurisdiction with regard to marketing and advertising of dietary supplements.

DSHEA regulates dietary supplements more like conventional foods than like drugs. Why? The reasoning is that the ingredients in supplements are inherently safe because they are contained in the foods that humans eat. Unlike drugs, dietary supplements do not require pre-approval from the FDA. Dietary supplements, unlike drugs, cannot be marketed to treat or cure diseases. Accordingly, dietary supplements with claims on the labeling that promote treatment, prevention, or cure for a specific disease or condition would be considered an unapproved—and thus illegal—drug.

How is the FDA authorized to protect the public in the realm of dietary supplements? What if evidence showed that a particular supplement product was causing an acute epidemic of illnesses and fatalities? What could the FDA do about it? The FDA is an Operating Division of the US Department of Health and Human Services (HHS), which is headed by the Secretary of HHS. The Secretary has the power to declare a dangerous supplement to be an “imminent hazard” to public health or safety and immediately suspend sales of the product [4].

The FDA also has the authority to protect consumers from dietary supplements that do not present an imminent hazard to the public but do present certain risks of illness or injury to consumers. The FDCA prohibits introducing adulterated products into interstate commerce [5]. Two important provisions exist by which unsafe dietary supplements can be deemed to be adulterated [6].

The first provision, which applies to all dietary supplements, states that a supplement shall be deemed adulterated if it presents “a significant or unreasonable risk of illness or injury under … conditions of use recommended or suggested in labeling, or … if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use” [7]. The standard does not require proof that consumers have actually been harmed or even that a product will harm anyone. It was under this provision that the FDA concluded that dietary supplements containing ephedra presented an unreasonable risk. The criminal penalties for a first conviction of introducing adulterated supplement products into interstate commerce can include a fine of up to $1,000, imprisonment for up to 1 year, or both [8]. Subsequent convictions, or convictions for offenses committed with the intent to defraud or mislead, can include fines of up to $10,000, imprisonment of up to 3 years, or both [9].

The second provision by which supplements may be deemed adulterated addresses only dietary supplements containing “new dietary ingredients” for which the FDA believes there may be inadequate information to provide a reasonable assurance that the ingredient does not present a significant risk of illness or injury.

Recognizing that new and untested dietary supplement products may pose unknown health issues, DSHEA distinguishes between products containing dietary ingredients that were already on the market and products containing new dietary ingredients that were not marketed prior to the enactment of the law [10]. A “new dietary ingredient” (NDI) is defined as a dietary ingredient that was not marketed in the United States before October 15, 1994 [11]. DSHEA grants the FDA greater control over supplements containing new dietary ingredients. A new dietary ingredient is deemed adulterated and subject to FDA enforcement sanctions unless it meets one of the two exemption criteria: either (1) the supplement in question contains “only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered,” or (2) there is a “history of use or other evidence of safety” provided by the manufacturer or distributor to the FDA at least 75 days before introducing the product into interstate commerce [12]. The first criterion is silent as to how and by whom presence in the food supply as food articles without chemical alteration is to be established. The second criterion—applicable only to new dietary ingredients that have not been present in the food supply—requires manufacturers and distributors of the product to take certain actions. Those actions include submitting, at least 75 days before the product is introduced into interstate commerce, information that is the basis on which a product containing the new dietary ingredient is “reasonably be expected to be safe” [13]. That information would include (1) the name of the new dietary ingredient and, if it is an herb or botanical, the Latin binomial name and (2) a description of the dietary supplement that contains the new dietary ingredient, including (a) the level of the new dietary ingredient in the product; (b) conditions of use of the product stated in the labeling or, if no conditions of use are stated, the ordinary conditions of use; and (c) a history of use or other evidence of safety establishing that the dietary ingredient, when used under the conditions recommended or suggested in the labeling of the dietary supplement, is reasonably expected to be safe. For most of DSHEA’s existence, there was no guidance as to what evidence might be required to establish a reasonable expectation of safety. In fact, the FDA specifically stated that the person submitting the application is responsible for determining what information provides the basis for the conclusion that the product is reasonably expected to be safe. The only hint given was that the FDA expects the applicant to “consider the evidence of safety found in the scientific literature, including an examination of adverse effects associated with the use of the substance” [14].

In July 2011, the FDA released a Draft Guidance for Industry, entitled “Dietary Supplements: New Dietary Ingredient Notifications and Related Issues” [15]. While a guidance does not carry the authority or the enforceability of a law or regulation, the FDA’s NDI draft guidance represented the agency’s current thinking on the topic:

The purpose of this guidance is to give manufacturers and distributors of these products information and recommendations to help them decide when a NDI notification is necessary and to improve the quality and quantity of NDI notifications. There are an estimated 55,600 dietary supplement products on the market, and FDA has received approximately 700 NDI notifications since we began reviewing NDI notifications approximately 16 years ago. Additionally, the Institute of Medicine has estimated that 1,000 new dietary supplements are introduced to the market each year These figures, coupled with recent concern by both the agency and industry regarding the presence of undeclared active ingredients in products marketed as dietary supplements, highlight the necessity for marketers of dietary supplements to submit NDI notifications as an important preventive control to ensure that the consumer is not exposed to potential unnecessary public health risks in the form of new ingredients with unknown safety profiles. [16]

The controversial draft guidance was met by staunch criticism from the supplement industry. Senators Orrin Hatch (R-UT) and Tom Harkin (D-Iowa), who were the principal authors of DSHEA, asked the FDA Commissioner to withdraw the guidance and replace it with a new draft that “will provide needed clarification on what constitutes an NDI, but does not undermine the balance Congress struck in DSHEA to provide consumers with access to safe, affordable dietary supplement products” [17]. Other members of Congress and various industry trade groups have asked the FDA to clarify its positions, including the subject of identity information for NDI notifications. Other questions surround whether NDI notifications should be submitted when a firm changes its manufacturing process or the ratio of ingredients and what would cause an ingredient to be “chemically altered.” Given the many uncertainties surrounding the draft guidance, the FDA eventually agreed (after initially refusing) to withdraw the document. As of this writing, the FDA has not issued further NDI guidance documents.

If a supplement manufacturer seeks to market an ingredient to the public that was not previously sold on the US market (prior to October 15, 1994), a dossier of animal and human safety data and/or proof of historical use as a food must be compiled. Unless the ingredient has been present in the food supply as an article used for food in a form in which the food has not been chemically altered, the history of use or other evidence of safety must be presented to the FDA/CFSAN at least 75 days before introducing the product into interstate commerce. What sort of information should be presented? By what process would the FDA evaluate the data to determine if the ingredient should be allowed on the market? Let us take an example.

Excluding discussions of whether animal safety studies have utility as related to efficacy outcome-oriented research in humans, let us assume that the product of interest was found to be of acceptable safety margins when used in human doses. This means that the animal studies found the ingredient to be noncarcinogenic, to have a high LD₅₀ (median lethal dose), and not to be organotoxic. In addition, let us assume that the human studies also found the product not to have an effect on blood pressure or heart rate or on markers of safety as denoted by specific blood tests (e.g., liver, kidney). Based on the compilation of animal and brief human studies, we can believe that the product is nontoxic, although further and more invasive safety data are warranted.

For example, the dietary supplement popularly known as 7-Keto®, also known as 3-acetyl-7-oxo dehydroepiandrosterone, was “approved” by the FDA via the NDI premarket notification process. Prior to marketing 7-Keto as a dietary supplement, it was submitted for a review of safety to the FDA in the form of an NDI premarket notification. This document, which can be viewed at the FDA website, received no comments or concerns expressed from the FDA. Subsequent to this initial filing, another NDI premarket notification has been filed specific to the use of 7-Keto for weight loss in adults at the prescribed dosage. This notification also has received no comments or concerns expressed from the FDA.

The FDA has a searchable database of submitted NDIs that the public can view, located online [18]. In addition to 7-Keto, other popular dietary supplements (e.g., creatine ethyl ester, vinpocetine, Diosmin 95) have successfully undergone the NDI process. Some applications to the FDA fail to meet the bar of demonstrating relative safety, usefulness, and other criteria requested by the FDA in the application, and thus the rejection or failure rate for NDI applications is thought to be about 65–70 % of the applications submitted.

In February 2004, the FDA issued a final rule prohibiting the sale of dietary supplements containing ephedrine alkaloids, reasoning that this category of supplements presented an unreasonable risk of illness or injury (based on a risk-to-benefit evaluation) [19]. The rule took effect on April 12, 2004, 60 days from the date of publication, at which time companies that continued to sell supplements containing ephedra alkaloids found themselves subject to a variety of enforcement possibilities, including seizure of the product, injunction against the manufacturers and distributors of such products, and criminal prosecution of violators. Three months after the rule was announced, Utah-based Nutraceutical Corp. filed suit challenging the ban, specifically the FDA’s risk-to-benefit analysis, arguing that the FDA had not shown ephedra supplements to present an undue risk at low doses.

In April 2005, a federal court in Salt Lake City (US District Court for the District of Utah, Central Division) issued its decision on a legal challenge to the FDA’s 2004 Final Rule banning all ephedrine-alkaloid dietary supplements. Judge Tena Campbell’s decision made two key points:

The FDA filed a notice of appeal in the 10th Circuit Court of Appeals.

On August 17, 2006, the US Circuit Court of Appeals in Denver reversed and remanded the Utah ruling that challenged the FDA ban on products containing ephedra. The federal appeals court overturned Judge Campbell’s decision, ruling that the FDA was correct in its 2004 analysis of ephedrine products, concluding that the FDA had properly examined the facts when it ruled, in 2004, that dietary supplements containing ephedrine alkaloids present an “unreasonable risk of illness or injury” and that there is no acceptable dose of the ingredient. Pursuant to this, the government has since seized numerous products containing the herbal ingredient.

Further appeals/petitions were filed by Nutraceutical, followed by a petition for a writ of certiorari to the US Supreme Court. The US Supreme Court denied Nutraceutical’s petition for certiorari on May 14, 2007, refusing to consider their appeal, establishing a precedent for the applicable legal standards, and confirming the FDA’s regulatory authority over the issues.

In 2012, the FDA again targeted a fat-loss ingredient. This time, it was a stimulant called DMAA, also known as 1,3-dimethylamylamine, methylhexanamine, or geranium extract. Citing evidence that DMAA, especially in combination with other ingredients such as caffeine, can pose health risks to consumers, FDA issued warning letters to companies notifying them that DMAA products were adulterated and needed to be taken off the market [20]. One company resisted, defending its marketing of the substance as legal, until FDA took administrative detention actions. In July 2013, the remaining stock of the products, estimated to have been worth more than $8 million at the retail level, was voluntarily destroyed by the firm [21].

The ban on androstenedione is another example of the authority of the FDA to prohibit the marketing of ingredients the agency believes are adulterated. On March 11, 2004, the FDA pronounced that dietary supplement products containing androstenedione were adulterated new dietary ingredients under DSHEA. For the second time in as many months, the FDA took regulatory action against the sports nutrition industry. There was no evidence of an imminent health hazard posed by androstenedione. However, instead of the formal administrative procedure of issuing a proposed rule and inviting public comment, the FDA took unilateral action, issued a press release, held a news conference, and sent warning letters to 23 companies that had manufactured, marketed, or distributed the products containing androstenedione. In its warning letters, the FDA threatened possible enforcement actions for noncompliance. The effect was to cause retailers, manufacturers, and distributors alike to cease selling products containing androstenedione. No meaningful dialogue between the FDA and industry occurred prior to the FDA taking this action.

Supplements containing androstenedione were introduced during the mid-1990s and were promoted as a natural way to help increase strength and muscle mass as well as to combat the effects of the aging process in older men, much of which is attributed to declining testosterone levels. Like dehydroepiandrosterone (DHEA), androstenedione is a naturally derived precursor to testosterone. Androstenedione converts directly to testosterone in the metabolic pathway. The fact that it is naturally derived and, as described below, present in the food supply is important in relation to the action taken by the FDA. In its press release [22] and warning letters, the FDA declared androstenedione to be an adulterated new dietary ingredient based on its position that no evidence demonstrates “that androstenedione was lawfully marketed as a dietary ingredient in the United States before October 15, 1994” [23]. It seems to be correct that androstenedione was not marketed before 1994, given that the first commercial marketing of products containing androstenedione appears to have been in 1996. Furthermore, a review of the FDA’s electronic database indicates no submission of an application for a new dietary ingredient involving androstenedione [24]. Interestingly, however, the FDA went beyond the explicit words of the statute and used the term “lawfully marketed” in their letters instead of simply “marketed.” The implication was that to receive “grandfathered” status into DSHEA as a pre-1994 supplement ingredient, the product must not only have been marketed but must have met the additional requirement of having been lawfully marketed. At least one commentator has interpreted this language to impose a burden on industry to prove the product was generally recognized as safe (GRAS) pre-1994—an impossible standard for any product that was not explicitly affirmed as such by the FDA prior to the enactment of DSHEA [25]. Assuming that androstenedione is indeed a new dietary ingredient, the FDA could determine that products containing androstenedione are adulterated under DSHEA unless they meet either of the two exemption criteria stated above.

Accordingly, it appears that the question of exemption turns on (1) whether androstenedione is present in the food supply as an article used for food without chemical alteration and (2), if not, whether the product could satisfy the requirement of reasonable expectation of safety. With respect to the first exemption, according to scientific journals, androstenedione is indeed present in the food supply without chemical alteration [26]. Had there been open communication between the FDA and industry, the scientific evidence that androstenedione is present in the foods we eat could have been presented and discussed. Moreover, until 1998, which is the date for the most recent information, there were no reports of adverse events reported on the FDA’s database [27]. Adverse events comprise one of the few specific pieces of information that the FDA sets forth in their “information” about what safety data they require [28]. The FDA’s requirements to show safety have never been fully articulated; arguably, the FDA’s policy creates a nearly impossible procedure to demonstrate safety. Unlike the situation regarding ephedra supplements, industry did not formally challenge the FDA’s regulatory action regarding androstenedione, and sales of androstenedione ceased.

The FDA’s action on androstenedione marked the start of a heightened enforcement policy against what the agency deems to be adulterated new dietary ingredients. In August 2010, the FDA took actions with respect to piracetam and 1,4,6-etioallocholan-dione (also known as 3,17-keto-etiochol-triene and more commonly referred to as ATD). The FDA sent a letter to a dietary supplement firm indicating that the agency did not believe that piracetam and ATD are dietary ingredients, and when combined with claims that the products affect the structure or function of the body, these substances are “new drugs,” not supplements [29]. Significantly, in a footnote to the letter, the FDA referenced a 2003 NDI notification filed by the firm for piracetam and a 2004 reply by CFSAN, stating FDA’s position that piracetam is “not a dietary ingredient.” Although the company apparently complied with the 75-day premarket NDI notification requirement, the FDA failed to respond to the company’s notification within the 75-day waiting period (the response was more than 90 days after the notification had been filed). The warning letter was not issued until 6 years after the notification was filed and after the products had been discontinued.

Due to the long-after-the-fact timing of these particular enforcement actions, little substantive debate or review of the NDI regulations was generated. The FDA actions do, however, reinforce the need for clarification and guidance with respect to NDI notifications. These actions should also serve as notice to the dietary supplement industry as a whole that FDA is shifting its focus toward NDIs and that we can likely expect more enforcement actions in the near future.

If a new dietary ingredient is exempted from adulterated status because it is present in the food supply as an article used for food in a form in which the food has not been chemically altered, it is prudent for supplement companies to document that information prior to marketing the product or even to communicate that information to the FDA. If a new dietary ingredient is not exempted from adulterated status based on the food-supply exemption, premarket notification of history of use or other evidence of safety establishing that the dietary ingredient, when used under the conditions recommended or suggested in the labeling of the dietary supplement, is reasonably expected to be safe must be provided to the FDA at least 75 days before the product is introduced into interstate commerce.

Research conducted by the United States Olympic Committee in 2004 found that 90 % of athletes use some form of dietary supplements. To ensure a “level playing field” and protect the health of athletes, sports bodies are free to create their own lists of banned ingredients. Athletes are generally held under a standard of “strict liability” by their respective sport bodies and are therefore held responsible for everything they put into their bodies.

Highly publicized cases, however, have shown that when athletes fail drug tests, tainted dietary supplements may be blamed, and expensive litigation may follow. Such lawsuits may seek not only compensation for the athlete’s lost potential income during the ever-lengthening suspensions from athletic bodies and the tarnishing of the athlete’s name in the publicity that follows a positive test but also punitive damages in the tens of millions. One of the most well-known lawsuits against a dietary supplement company involved world-class swimmer Kicker Vencill, who tested positive for the anabolic steroid nandrolone. He blamed it on contaminated dietary supplements—vitamin capsules. When he received a 2-year suspension from competition, he sued the sports nutrition company Ultimate Nutrition and received a nearly $600,000 verdict, which was later appealed. The case was later settled for an undisclosed amount with no direct admission of guilt by the manufacturer.

The National Football League (NFL) running back Mike Cloud, a Boston College graduate playing for the Patriots, tested positive for norandrostenedione and androstenediol (two nandrolone metabolites). He claimed that a tainted whey protein powder (Nitro-Tech™) caused his positive test and consequent four-game suspension, while the supplement’s Canadian manufacturer, MuscleTech, countersued, maintaining that the allegations were false and amounted to trade libel. Pavle Jovanovic, a US bobsledder, tested positive for 19-norandrosterone (also a nandrolone metabolite) in 2001. He was suspended for 2 years and disqualified from the Salt Lake City Olympics in 2002. He blamed his troubles on MuscleTech’s whey protein, saying it was cross-contaminated by one of its prohormone products. Jovanovic also filed suit, and MuscleTech countersued. Both Cloud and Jovanovic submitted tests showing containers of the product contained nandrolone metabolites not listed on the label (these results were also televised nationally on Bryant Gumbel’s HBO Inside Sports show).