Regulation of Amino Acids and Other Dietary Components Associated with Enhanced Physical Performance1
In the discussions in this volume of research on the use of amino acids and other dietary components to affect physical and mental performance, one question was asked repeatedly: “Is this substance a food or a drug?” Researchers and potential suppliers of these substances are motivated to ask that question because different regulations apply to drugs and foods. These differences include the labeling of the product, requirements for premarketing approval, practices required during manufacturing, the records that must be maintained during production and manufacturing, and the way in which the substance is dispensed. The question also has a profound impact on how the safety of the substance is addressed and what claim can be made for the substance in relation to disease.
The answer to the question depends on answers to a number of other questions, including what the substance is and what it contains, how it is used,
what claims are being made for it, its history of use, its safety under the conditions of use, and how it is administered. The answers to these questions help to classify the substance in accordance with statutory and case law and in implementing regulations.
The Federal Food, Drug, and Cosmetic Act (FD&C Act) defines the term food as articles used for food or drink for humans or animals, chewing gum, and articles used as components of any other such article (United States Code §321[f]). In case law the term food in the first part of this definition has been further defined as articles consumed primarily for their taste, aroma, or nutritive value (Nutrilab, Inc. vs. Schweiker, 1993). The FD&C Act defines the term drug as articles recognized in the official United States Pharmacopeia, the official Homeopathic Pharmacopeia of the United States, the official National Formulary, or supplements to any of them; (United States Code §321[a]), articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or animals; articles (other than food) intended to affect the structure or any function of the bodies of humans or animals; and articles intended for use as components of any articles specified above.
There is some overlap in the definitions of foods and drugs. Therefore, it is not always possible to categorize a substance as either a food or a drug without knowing how it is being used or the claims being made for it. Occasionally, a substance is both a food and a drug. For example, prescribing niacin for an individual to meet his or her nutritional needs is a nutritional function; however, if large amounts are given to lower high blood cholesterol levels, it can be argued that it is not serving as a nutrient but has an effect on a function of the body and therefore is a drug. As Timothy Maher indicated in Chapter 22, an amino acid is generally considered to be a food, but if that amino acid is marketed as a remedy for sleep disorders, depression, premenstrual syndrome, and other medical conditions, then it would be classified as a drug.
Several times during the November 1992 workshop it was suggested that a therapeutic amount of a nutrient was used, therefore, it was a drug and not a food. On one occasion it was stated another way: “The amount needed to show an effect was many times higher than human nutritional requirements and therefore was clearly a drug amount.” In the early 1960s, the U.S. Food and Drug Administration (FDA) decided that the use of vitamins A and D above 150 percent of the U.S. Recommended Dietary Allowance (U.S. RDA) was a drug use. The agency argued that use of amounts of these vitamins above 150 percent of the U.S. RDA clearly had no nutritional value and the vitamins were therefore taken for their pharmacological effects. The FDA was challenged for this regulatory position, and the court ruled that just because a supplement exceeded a nutritional requirement level, there was no legal basis
to declare the product a drug (The National Nutritional Foods Association and Solgar Co., Inc. vs. Food and Drug Administration, 1974).
A long-standing policy of FDA is that the route of administration may determine whether the substance is a drug or a food. According to thispolicy, foods are only consumed enterally (through the digestive tract), whereas drugs are consumed both enterally and parenterally (outside the digestive tract). In a case currently pending, a court is deciding whether the absorption of vitamin B12 through the nasal membranes makes the vitamin a drug. At this time, the FDA considers any substance that is injected or otherwise administered through the skin and that has a metabolic effect to be a drug.
For years, FDA’s policy was to treat any label claim that purported benefits relative to a disease or condition as grounds for automatically subjecting the food to drug regulations. This position was based on the definition of a drug in the FD&C Act. It was also part of the original nutrition labeling regulations published in 1973 (Code of Federal Register, 1973). The Nutrition Labeling and Education Act of 1990 (NLEA) provided the FDA with the authority to publish regulations that would allow manufactures to provide specific health claims on food labels to describe a nutrient-disease relationship but they would not be required to call the product a drug (United States Congress, 1990). However, the provisions of the NLEA establish specific criteria as to when such claims are permitted. In brief, such claims must be based on all publicly available scientific literature, and experts knowledgeable about the relationship must substantially agree that the claim may be permitted.
In considering the issue of safety, the FD&C Act requires that a food be safe, as judged by the standard that there is reasonable certainty that no harm will be done when the food is consumed as intended. Unlike a drug, no risk-benefit standard is applied for a food. Consequently, a substance that presents some risk of harm and that is used to maintain or improve performance would likely be considered a drug and would be subject to drug regulations. Finally, use of a product that contains measurable amounts of one or more essential nutrients usually implies food status, but other factors such as safety are important overriding considerations.
Under the FD&C Act, several categories of food ingredients have a long history of safe use. In 1958, an amendment to the FD&C Act created two new categories for these food ingredients. One category was based largely on history of use and was referred to in the Act as generally recognized as safe (GRAS) (United States Code, §321[s]). Those substances in use before the passage of the 1958 amendment were automatically given GRAS status. Many, but not all, of these substances have been subjected to an affirmation process to ensure their safety at levels traditionally used in foods. The agency mounted a major effort to affirm the safety of these GRAS substances. Data on use levels were gathered by the Committee on GRAS Substances of the Food and
Nutrition Board, National Academy of Sciences; safety data were assembled by the Special Committee on GRAS Substances, which was established by the Life Sciences Research Office of the Federation of the American Societies for Experimental Biology (FASEB).
Foods not in use before 1958 can gain official GRAS status through a petition process. The petition must demonstrate that the substance is safe at the levels of intended use. For example, rapeseed oil (canola oil) with low erucic acid content was affirmed as GRAS as a result of a petition by the Canadian government (Federal Register, 1984). Regardless of how GRAS status is obtained for a substance, the determination is usually based on specific levels of use. If new uses developed for the substance require higher levels of that substance, then additional assessments must be made to gain official GRAS status for the new levels of use.
Still other substances are claimed to have GRAS status as a result of the manufacturer’s self-determination. Such determinations have been made for substances with no history of use, such as some protein isolates, and new higher levels of use have been made for GRAS substances that were not part of the affirmation process. Examples of the latter are some plant gums and pectin, which are used to increase the fiber content of foods. These products are likely to remain in the marketplace as long as the agency is not confronted with a scientific basis to challenge the safety of the substance. However, any data that raise safety concerns must be addressed by sound scientific arguments; otherwise, there will be a legal basis for removing the substance from the food supply. In addition to a potentially costly recall, a manufacturer would likely be fully responsible for any harm to consumers caused by the use of the substance. A review of the safety data by an independent authoritative scientific body may lower this risk.
New food ingredients that do not fit in any of the GRAS categories are food additives (United States Code §321[s]). Approval to market a food additive is gained by submitting a petition to the FDA with sufficient data to demonstrate reasonable certainty of no harm at the intended levels of use. Regulations for food additives often differ from those for GRAS substances; greater specificity is associated with both levels and conditions of use, and new additional uses for an approved food additive automatically require a separate petition. Procedures for filing a food additive petition are included in FDA regulations. The compositions of both food additive and GRAS substances must be known, and methods must exist for analyzing the substances in foods. Food additives that have harmful contaminants such as natural toxins, heavy metals, and microorganisms will not be approved. Evidence that a food additive is free of such harmful substances must be provided as part of the petition.
Among food products, dietary supplements are subject to certain provisions of the FD&C (United States Code §350). Dietary supplements include vitamins and essential mineral supplements, other essential nutrients such as amino acids, and nonessential substances such as herbal products. In 1978, an amendment to the FD&C Act placed limitations on how the potencies of vitamins and essential mineral supplements can be regulated. This so-called Proxmire Amendment prohibits the agency from using any regulatory authorities in the FD&C except those for food additives for regulating the potencies of vitamins and mineral supplements. Essentially, the only limitations that can be imposed on these products are those associated with safety. Other types of dietary supplements are not covered by the Proxmire Amendment and therefore are subject to other food provisions of the FD&C Act relative to potency. It is important, however, that this category of food has been afforded special status relative to claims for one year under the Dietary Supplement Act of 1992 (United States Congress, 1992), and the agency is required to propose new rules for regulating these substances.
Regardless of the category to which a new substance belongs, safety data are necessary before the substance can be legally marketed. Research conducted on animals usually provides much of the data on which safety assessments are based; however, clinical data are increasingly important in situations in which a substance is intended to have an effect on body structure or function. Clinical studies conducted on an unapproved substance that will be marketed as a drug require an Investigational New Drug application (IND). An IND provides a useful mechanism for obtaining the authority to conduct tests on substances that affect body structure or function but that will eventually be marketed as a food. Obtaining an IND for such testing provides some measure of protection if problems are incurred during the research. Clearly, the sponsor will still be responsible for any harm caused by the use of the product, but acquisition of an approved IND will demonstrate an effort to comply with the law and perform such tests in a safe manner. The requirements for obtaining an IND are not complicated, especially for small clinical studies involving 50 or fewer subjects. The following must be provided: (1) data on the toxicology of the product (usually obtained from animal studies), (2) chemical data indicating the purity of the test substance, (3) procedures for obtaining informed consent for the study, (4) evidence of approval of an institutional review board, and (5) the study protocol. The FD&C Act gives FDA the authority to grant permission for clinical testing of unapproved food additives; however, no regulations have been created to implement this provision of the act.
With regard to the regulatory status of amino acids and other dietary components associated with enhanced physical performance, the agency first addressed the addition of amino acids to foods in 1945 (Food and Drug
Administration, 1945). In a Trade Correspondence, the agency indicated that such a food was considered to be a food for special dietary use and would have to be labeled to conform to applicable regulations. The agency also indicated that amino acid preparations for oral use may in some cases also be subject to the drug provisions of the act. Amino acids were listed on the original GRAS list under “nutrients and/or dietary supplements” in 1961 (Federal Register, 1961). In 1972, the agency proposed that the GRAS status of all amino acids for nutritive purposes be revoked (Federal Register, 1972). A food additive regulation was proposed, setting out the conditions under which amino acids used as food additives may be safely added to intact, protein-containing foods that were considered significant sources of dietary protein. The proposal stated that this action did not include amino acids in foods that did not contain intact protein in their original form. The FDA finalized the regulations in 1973 (Federal Register, 1973). In so doing, the agency stated that it wanted to prevent the random addition of amino acids to foods and limited the approved use of amino acids as additives to foods in which intact protein primarily occurred naturally. From 1973 to 1977, all amino acids were listed as “not GRAS” as a nutrient and/or dietary supplement and were subject to the food additive regulation. However, in 1977 the Code of Federal Regulations involving foods was recodified, and by error, L-tryptophan was listed as GRAS. At the same time, the agency seized two quantities of L-tryptophan being sold as dietary supplements on the grounds that the L-tryptophan in these supplements was an unapproved food additive. The court ruled that the claimant was entitled to rely on the GRAS list as published (Federal Register, 1993). The agency corrected the error but took no action because of other priorities. The industry maintains that those amino acids that were in the marketplace are safe and are GRAS on the basis of self-determination. The FDA’s position is that amino acids cannot be GRAS because there was a determination through public rule making that supported the agency’s assessment that free amino acids are not GRAS.
In 1991, the agency removed L-tryptophan supplements from the market after it was discovered that they were associated with the eosinophilia myalgia syndrome (EMS), which reportedly caused the deaths of at least 38 individuals and serious illness in more than 1,500 others (Varga, et al., 1992). Following this serious incident, the agency contracted with the Life Sciences Research Office (LSRO) of FASEB to review the existing data on the safety of all amino acids. The FASEB report that was discussed by Timothy Maher in Chapter 22 the result of that effort (LSRD, 1992) (FASEB, 1992). The FDA is reviewing the report and is considering appropriate action. Clearly, many individuals consumed L-tryptophan supplements without apparent harm. There is significant evidence that EMS may have been caused, or at least made worse, by a contaminant in the L-tryptophan supplements. Until there is clear
evidence that such a contaminant was the cause of EMS, however, it would be unlawful to market L-tryptophan as a food except in accordance with the food additive regulation (Code of Federal Regulations, 1993). In light of the events surrounding amino acids, the commissioner of FDA has created a task force to develop options for regulating all dietary supplements. The report of that task force will soon be released for public comment as part of the agency’s process of reviewing current policy for regulating these products (Food and Drug Administration, 1992).
The situation is perhaps different for other nutrients that are on the GRAS list as nutrient supplements, dietary supplements, or other functions. One could argue that a nutrient found to be effective for some function could be declared GRAS by a manufacturer or a distributor. As indicated earlier, such a position is not without risk. On the other hand, if the FDA has affirmed the substance as GRAS or has approved it as a food additive for one or more intended uses, there is assurance that the agency will not take action against the product. Furthermore, it stands to reason that an approval based on an independent review of the safety data will increase the chances of no harm.
A more interesting question will be whether the substance is a drug on the basis of its stated function. For example, if the function is described as preventing drowsiness or fatigue, then clearly the product is a drug. On the other hand, if the claim is that a substance maintains performance, alertness, or effectiveness, is it a drug claim? Perhaps an argument could be made that these are food claims, but the final determination may actually depend on other factors. Another important question is whether there is some element of risk of harm. If so, then the substance may fall in the category of a drug, which allows for some risk-benefit consideration. How will the product be administered? If the answer is by injection, then clearly the substance is a drug. Finally, what is the history of use? If the substance was consumed before 1958 as a food at the level found to satisfy some nutritional function and the manufacturer does not make drug claims, then it is likely a food.
In summary, the regulation of amino acids and other dietary components associated with maintaining or enhancing physical performance is dependent on the substance, the safety of the substance at the level of use, the way in which it is administered, its history of use, and the claims made for it. Approval for the use of a substance either as a drug or as a food will require data on its composition, toxicity, and function. In addition, drug approval requires data on effectiveness but allows for approval on the basis of a risk-benefit analysis, whereas food use does not. Self-declaration of GRAS
status by a producer or a supplier, although practiced for some dietary supplements, places both the researcher and the subject at increased risk. Research conducted under an IND lowers the risk to the subject and the investigator and provides an atmosphere of trust.
Code of Federal Regulations 1973 Food: Nutrition Labeling, 21CFR 38(49), 6959–6961.
Code of Federal Regulations. 1993 Amino Acids 21CFR 172.320, 38–40.
Federal Register. 1984 Rapeseed Oil. 49(31):5613.
Federal Register. 1961 Substances Generally Recognized as Safe. 26:1444.
Federal Register. 1972 Amino Acids in Food for Human Consumption. 37(67):6938–6940.
Federal Register. 1973 Amino Acids in Food for Human Comsumption. 38(143):20036–20057.
Federal Register 1993 Amino Acids. 58(116):33696.
Federation of the American Societies for Experimental Biology, Life Sciences Research Office 1992 Safety of amino acids used as dietary supplements. Center for Food Safety and Applied Nutrition. FDA Contract No. 223–88–2124, Task No. 8.
Food and Drug Administration. 1945 Statement Relating to the Use of Amino Acids in Foods and Drugs, FD&C Act Trade Correspondence. TC 2-A.
Food and Drug Administration. 1992 Task Force of Dietary Supplements, Final Report. FDA. The National Nutritional Foods Association and Solgar Co., Inc. vs. Food and Drug
1974 Administration, 491 F. 2d 1141 (2nd Cir.).
Nutriab, Inc. vs. Schweiker, 731 F. 2nd 335 (7th Cir.).
United States Code §321(f). 21 U.S.C. The Food, Drug, and Cosmetic Act of 1938 as amended. See §201(f).
United States Code §321(g). 21 U.S.C. The Food, Drug, and Cosmetic Act of 1938 as amended. See §201(g).
United States Code §321(s). 21 U.S.C. The Food, Drug, and Cosmetic Act of 1938 as amended. See §201(s).
United States Code §350. 21 U.S.C. The Food, Drug, and Cosmetic Act of 1938 as amended. See §411.
United States Congress. 1990 (Public Law 101–535) Nutrition Labeling and Education Act of 1990 104 STAT. 2353–2367.
United States Congress 1992 (Public Law 102–571). Dietary Supplement Act of 1992.
Varga, J., J.Uilto, and S.Jimenez. 1992 The Cause and Phaogenesis of Eosinophilia-Myalgia Syndrome. Annals of Internal Medicine 116:140–147.
ELDON ASKEW: Let me get to the heart of the issue: Say we take some applesauce, put some tyrosine in it, and give it to a soldier with instructions on the outside saying, “Take when exposed to cold or high-altitude stress.” What problems are we running into there?
JOHN VANDERVEEN: If you want it to be recognized as a food, I would prefer you did not say “stress.” I would prefer that you say, “This will maintain your performance,” and then I can say it is a food. When you say “stress,” I think that you are in a situation in which you may be making a drug claim. If it is a drug claim, FDA is going to ask you for an IND and will you have to go through that process. Not that I think that is a bad thing to do. If you are going to do research in this area, you may want to be in the IND category. Let me just say that you are taking a risk, by saying that applesauce with tyrosine was going to maintain performance without new safety data, you take the risk of the FDA determining that this was an unapproved use for tyrosine, and that should be made abundantly clear. Futhermore, if you look at the billions of dollars of lawsuits against the manufacturers and suppliers of L-tryptophan at the moment, it becomes evident that there is financial risk too. Even FDA becomes vulnerable by not providing consumer protection. It is a very serious situation. I do not know the answer to that.
DAVID SCHNAKENBERG: Who, in essence, when we talk about a scientist within a federal laboratory, is taking the risk: the individual scientist or the FDA? I presume it is the FDA.
JOHN VANDERVEEN: Some of that has changed, and you have to be very careful. Individuals now, at least civilians, can be sued along with the FDA. I do not know the real answers to that. I think you have to be very cautious and really ask your Inspector General (IG) where you are in that situation. I think that is very clear.
DAVID SCHNAKENBERG: Do you have the same thing with tyrosine? What if we had the same thing with glucose, which we used to enhance performance, and someone got hurt?
JOHN VANDERVEEN: I think you have more protection, because glucose is an approved food additive at any level. It is a carbohydrate, and we do not have a limit on the use of carbohydrates.
IRWIN TAUB: It becomes a semantics problem, and we have to deal with those semantics. You have clearly stated that as long as we are approving structured function of the body, we can use such ingredients. I am not going to say “amino acids”; I will say “ingredients.” Furthermore, basically, if you also said in your definition that a food is used to support life (that is somehow included in the reply), part of life is to perform work. You determine your nutrients on the basis of what you have to do, and that becomes the required daily allowance, so we are saying here that performance of the kind of work that a soldier or anyone else has to do is simply going to require certain levels of ingredients, and again, I will use the word ingredients. As long as we stick to that and avoid words like stress, for example, I will say that under all conditions, we do not have to spell out what those conditions are; there is no longer a special case.
Just one last point about this, which is, we do not necessarily have to use the pure amino acid. We can use some natural ingredient that converts to those amino acids. There are many amino acids in soy protein and hydrolyzed vegetable protein. We use them for flavor and maybe we can use them for performance, as long as the distribution is right. By your definition, is it not true that we could be safe under the law?
JOHN VANDERVEEN: Approved ingredients can be used in it; there is no question there. The difficulty with amino acids, as Timothy Maher pointed out, is the fact that the FDA made a conscious decision in 1973 that they were not safe to be used individually. What data was used to arrive at this decision is not entirely clear. I tried to look back over the record, but unfortunately, the total record is no longer available. It has apparently been destroyed.
What we do have is what has been published in the Federal Register, and you can see that. We had a number of consultants. We had Dr. Alfred Harper and others who were knowledgeable about the metabolism of amino acids, and FDA decided that it was not appropriate to leave them on the GRAS list, so we took them off. And then FDA said that they could be used for a number of things but in very trivial amounts. Small amounts could be used for technological purposes, and then FDA said that larger amounts could be used to improve protein quality.
That is the difficulty we are in on the amino acids. On other things, of course, if you wanted to increase your omega-3 fatty acid level, you could buy an oil that has omega-3 fatty acid in it. As you say, you may even be able to
get hydrolyzed vegetable protein, which is an ingredient that can be and is used.
One thing I did not say, of course, is that Good Manufacturing Practice is always implied in good manufacturing practices, and so as a consequence, you have to keep that in the general context. I think you are right, however, I think you could approach it in that manner, but you have to be cautious. It is a semantics problem.
ROBERT NESHEIM: How about a real simple one like caffeine? Two hundred milligrams in a tablet is a drug, and 600 milligrams in four or five cups of coffee would be a food.
JOHN VANDERVEEN: Caffeine is an approved food additive. It was obviously used in soft drink beverages.
ROBERT NESHEIM: But if we took it in a tablet like No-Doz, is that classified as a drug?
JOHN VANDERVEEN: Again, it depends on what you are taking it for.
ROBERT NESHEIM: It depends on the claim.
JOHN VANDERVEEN: The claim that it is being used for. Are you taking it to avoid drowsiness? That may be considered a drug.
HARRIS LIEBERMAN: How about what you said to maintain alertness?
UNIDENTIFIED SPEAKER: I have a question that relates to liability. If we made a product that, let’s say, had peanuts in it and this individual was allergic to peanuts and died, can we be sued for that?
JOHN VANDERVEEN: Well, peanuts are clearly permitted in the food supply, and that is a food that has been around for a long time. By history of use, I doubt seriously if you could be considered liable. But now, you see, as part of the Nutrition Labeling and Education Act of 1990, you have to include all ingredients, regardless of the product, even if it is one ingredient. You have to tell the person that there is peanuts in it.
UNIDENTIFIED SPEAKER: I guess what I was driving at is the genetic variation that you see, that you mentioned, that somebody is going to be invariably susceptible to these products. How are you going to find out who is going to be susceptible, or are you liable?
JOANNA DWYER: Just one question, John. I am from a family of lawyers so I am familiar with weasel words. You know, every meal is something of semantics, but the thing I wonder about, you must forgive my ignorance, if the group here in the Army feeds soldiers substances, am I to understand that if it is considered a drug, that there has to be an IND? If I fed choline or something at New England Medical Center, is it pretty much the same situation?
JOHN VANDERVEEN: Actually, that is another point. The Army can do whatever it pleases because it is not subject to the Food, Drug, and Cosmetic Act per se. The problem they get into, as I understand it, is that their IG said, look, we are not going to take that risk; you are only going to use substances that are approved for use, and I think that is basically the philosophy that is now prevailing. But for years, when I was with DOD I ate irradiated food when it was not approved by the FDA. I was working for the Air Force and when the National Aeronautics and Space Administration (NASA) decided to use these same products for space flight. When they had the recent problem in NASA with the Challenger, their IG came out and said, you were feeding irradiated food and it was not approved by the FDA. As a result, the FDA got a letter from Richard Truly, the NASA administrator saying, wouldn’t you approve the use of the irradiated food for use on board the shuttle, and we said “sure,” and that took care of it.
DAVID SCHNAKENBERG: A related thing could come down the road: We could have a product intended for use just for military populations on the Meal Ready-to-Eat (MRE). However, when MREs get to the soldiers, it is now common practice through our Defense Personnel Subsistence Agency for those products to end up in the marketplace. They are given food relief; sometimes it is the Kurds, sometimes it is the Somali children, other times it is homeless people, and sometimes it is advertently or inadvertently resold, and then there we come into an issue.
JOHN VANDERVEEN: I do not think that this is an insurmountable problem. I think that you can go ahead and do what you want and need to do; it is just that you probably have to ask and get the agency to focus on your problem. We (FDA, CFSAN) have been reorganized as of last Monday and now there is an Office of Pre-Market Approval, which should help things to move smoothly.
FREDERICK MANNING: I was going to bring up by suggesting we really need to interact with the agency, but I was sort of taking off on your comment by the IG. I think we have to recognize as hard as we are working to be inside
the law here that the military, at least in the eyes of the media, if not the general public, is somewhat suspect and that is why the IG says down here, if you are exempt or if you are not covered by the law, I want you to do it anyway. We have numerous examples here coming out of the Gulf. So that I think we need to think very carefully about whether we want to be ahead of the mainstream on this one. Even if it is legal, we may want to think about possible public relations disasters from pushing the envelope.
ELDON ASKEW: I tend to agree with John Vanderveen that the problem is not insurmountable with regard to the issue that David Schnakenberg raised. People do not go into the Army-Navy Surplus Store to buy a BD boost and then turn around and sue the Army because they get frozen toes. There is a precedent for that sort of thing, so I do not think we are getting in real deep trouble there, although it is certainly something to think about.