Food Components to Enhance Performance: An Evaluation of Potential Performance-Enhancing Food Components for Operational Rations (1994)

Timothy J.Maher¹

In the late summer and fall of 1989 there suddenly appeared a number of individuals who developed eosinophilia-myalgia syndrome (EMS) associated with the use of supplemental L-tryptophan (Hertzman et al., 1990; Kamb et al., 1992). This amino acid, which has been used for many years for its pharmacological properties (e.g., as a sedative-hypnotic, analgesic, and anorexiant), was available to consumers under the guise of a “dietary supplement” in health food stores, pharmacies and grocery or department stores (Young, 1986). More than 30 individuals died and many thousands were severely injured in the United States alone as a result of exposure to what is now believed to have been a contaminant in one manufacturer’s L-tryptophan. This contaminant, 1,1’-ethylene-bis (tryptophan), commonly referred to as “Peak 97” or “Peak E,” was produced during the manufacture of this amino acid (Mayeno et al., 1990). A number of other impurities have since been detected in implicated

lots of L-tryptophan, the concentrations of which varied significantly over time as the manufacturer presumably modified synthesis and/or purification conditions during its quest to produce this amino acid more efficiently.

Largely as a result of the tragic EMS epidemic that resulted from the use of L-tryptophan, the U.S. Food and Drug Administration (FDA) contracted with the Life Sciences Research Office (LSRO) of the Federation of the American Societies for Experimental Biology (FASEB) to perform an extensive review of the scientific literature to determine the safety of amino acids used as dietary supplements (Federation of the American Societies for Experimental Biology, Life Sciences Research Office, 1992). Not only was L-tryptophan use to be assessed for safety, but in addition, all the available amino acids were to be evaluated, since prolonged daily ingestion of large quantities of these compounds as dietary supplements is known to occur.

In the fall of 1990, LSRO initiated the study by first searching the extant scientific literature for reports that related to the safety of amino acids. During February 1991, LSRO sponsored an open meeting where interested parties could present information and views related to this issue (U.S. Food and Drug Administration, 1990). Eight individuals made oral presentations, and 30 individuals or organizations later submitted written materials for consideration by LSRO. Following these activities, an ad hoc expert panel consisting of nine scientists was assembled. The panel met on four occasions during the subsequent year to advise LSRO on the adequacy of the available materials and to prepare a final report. In addition to assessing safety on the basis of information in the present literature, the report also contained suggested guidelines for future safety evaluations. This report was made available in the summer of 1992 (Anderson and Raiten, 1992).

The use of amino acids as dietary supplements created a serious dilemma in the evaluation of safety, since these substances are used primarily by consumers for presumed pharmacological purposes or for the enhancement of physiological function rather than for any nutritional purposes. There was no evidence available in the literature indicating that a normal, healthy individual would benefit nutritionally in any way from supplementation of the diet with a single amino acid. Even in those individuals with a less than ideal diet, the practice of supplementing the diet with single amino acids was considered potentially dangerous. Additionally, the literature was replete with studies

demonstrating “antinutritional” effects (i.e., depressed growth and other adverse effects) associated with the intake of imbalanced amino acid diets (Benevenga and Steele, 1984).

Products in the marketplace that were surveyed were characterized by a wide diversity of label information and generally failed to provide the required information regarding chemical composition, isomeric identification, purity, shelf-life and contraindications to use. For instance, although some labels of products containing L-phenylalanine warned patients with phenylketonuria, others failed to do so. The potential for adverse effects associated with the ingestion of this amino acid in patients with this inherited metabolic abnormality are well documented (Lenke and Levy, 1980; Matalon et al., 1991).

Although manufacturers carefully avoid legal drug claim language on labels and advertising, many product labels and advertisments clearly suggested that such products provided pharmacological rather than nutritional benefit. No reliable information was available to accurately assess the patterns of consumption of these supplements in the U.S. population. The expert panel was aware of the use of D-amino acids as dietary supplements and concluded that such a practice was clearly inappropriate because these enantiomerically related amino acids have generally been shown to provide no nutritional support for humans and, in many cases, are potent toxicants (Friedman, 1991). Concern was also expressed regarding the interaction between amino acids used as dietary supplements and over-the-counter and prescription drugs, as this constitutes an area not adequately investigated to date. There are numerous examples in the literature detailing observed or potential interactions between these amino acids and monoamine oxidase inhibitors, many antidepressants, sympathomimetic amines, and opioids (Glassman and Platman, 1969; Hull and Maher, 1990).

As part of the scope of work associated with the FASEB/LSRO investigation, some estimate of the safe upper level of intake for each individual amino acid was requested. The expert panel was unable to identify a safe upper level for any of the amino acids considered, beyond that normally found in typical proteins. Additionally, the only safe form of amino acid ingestion was considered to be via protein in the diet.

As a result of the paucity of available information bearing upon the safety of amino acids used as dietary supplements, the ad hoc expert panel concluded that a systematic approach to safety testing was needed. The proposed testing should involve studies in both animals and humans and should employ a two-tiered approach. In the first tier, studies with animals should investigate the

effects of acute and chronic ingestion of amino acids. Such studies would include the determination of weight changes, food intake, neurological and behavioral changes, liver function, routine blood chemistry and hematological parameters, hormonal changes, and pharmacokinetic profiles following oral administration of the amino acid with and without food in both sexes. Multiple observation points would be used throughout the studies, and various doses would be employed. The expert panel suggested doses of 3, 10, 30, and 100 times the nutritional requirements for indispensable amino acids and 3, 10, 30 and 100 times the levels permitted for protein fortification for the dispensible amino acids (21 CFR 172.320). Teratologic and developmental effects would also be ascertained simultaneously during this preliminary testing phase. On the basis of the findings of those studies and the existing literature, specialized studies would then be performed during the second tier. The second-tier studies would include functional assessment and gross pathological examinations.

Following studies in animals, acute and chronic testing in humans would be required to satisfy additional safety concerns. Growth, neurological and behavioral function, hematological parameters, pharmacokinetic profiles, and hormonal changes would be monitored following exposure to various doses of the selected amino acids. Although initial studies should be carried out in normal healthy adult volunteers, additional studies should use selected groups of individuals who might be expected to use the particular amino acid, e.g., athletes and bodybuilders. Since certain subsets of the population, e.g., infants, children, adolescents, pregnant and lactating women, and elderly individuals, might be expected to be at greater risk of adverse effects from ingestion of particular amino acids, they should be excluded from such studies. Additionally, persons with specific diseases or conditions, e.g., diabetes mellitus, endocrine disorders, hepatic disease, or other conditions, should similarly be excluded from this phase of investigation. Special precautions would be required to address safety concerns in these subgroups, and studies in these subgroups should be performed only after a reasonable degree of safety has been established.

The FASEB/LSRO report on the safety of amino acids as dietary supplements concluded the following:

• There is no nutritional rationale to the use of amino acids as dietary supplements, and such a practice can be dangerous.

• Supplemental amino acids are used for pharmacological rather than nutritional purposes.

• Currently available labeling fails to supply the required information on a routine basis.

• The extant scientific literature fails to support a safe upper limit for supplementation with any amino acid beyond that found in protein.

• There are several subsets of the population that are likely to be more sensitive to the adverse effects of amino acid supplementation.

• Systematic testing in animals and humans is required before the safety of supplemental amino acids can be adequately assessed.

It is therefore recommended by this author that any approach to the fortification of military rations with supplemental amino acids beyond those levels found in protein should be considered a pharmacological intervention and not merely a nutritional manipulation, and thus should be initiated with appropriate caution to safeguard the welfare of those who consume military rations.

Anderson, S.A., and O.J.Raiten (eds.) 1992 Safety of amino acids used as dietary supplements. Bethesda, MD: FASEB.

Benevenga, N.J., and R.D.Steele 1984 Adverse effects of excessive consumption of amino acids. Annu. Rev. Nutr. 4:157–181.

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 1990 Evaluation of the safety of amino acids and related products; announcement of study; request for scientific data and information; announcement of open meeting. Fed. Regist. 55:49141–49142.

Friedman, M. 1991 Formation, nutritional value, and safety of D-amino acids. Pp. 447–481 in Nutritional and Toxicological Consequences of Food Processing. New York: Plenum Press.

Glassman, A.H., and S.R.Platman 1969 Potentiation of a monoamine oxidase inhibitor by tryptophan. J. Psychiatric Res. 7:83–88.

Hertzman, P.A., W.L.Blevins, J.Mayer, B.Greenfield, M.Ting, and G.J.Gleich 1990 Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N. Engl. J. Med. 322:869–873.

Hull, K.M., and T.J.Maher 1990 L-Tyrosine potentiates the anorexia induced by mixed-acting sympathomimetic drugs in hyperphagic rats. J. Pharmacol. Exp. Ther. 255:403–409.

Kamb, M.L., J.J.Murphy, J.L.Jones, J.C.Caston, K.Nederlof, L.F.Horney, L.A.Swygert, H.Falk, and E.M.Kilbourne 1992 Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients. J. Am. Med. Assoc. 267:77–82.

Lenke, R.R., and H.L.Levy 1980 Maternal phenylketonuria and hyperphenylalaninemia: An international survey of the outcome of untreated and treated pregnancies. N. Engl. J. Med. 303:1202–1208.

Matalon, R., K.Michals, C.Azen, E.G.Friedman, R.Koch, E.Wenz, H.Levy, F.Rohr, B. Rouse, L.Castiglioni, W.Hanley, V.Austin, and F.de la Cruz 1991 Maternal PKU collaborative study: The effect of nutrient intake on pregnancy outcome. J. Inherit. Metab. Dis. 14:371–374.

Mayeno, A.N., F.Lin, C.S.Foote, D.A.Loegering, M.M.Ames, C.W.Hedberg, and G.J.Gleich 1990 Characterization of “Peak E,” a novel amino acid associated with eosinophilia-myalgia syndrome. Science 250:1707–1708.

Young, S.N. 1986 The clinical psychopharmacology of tryptophan. Pp. 49–88 In Nutrition and the Brain, R.J.Wurtmen and J.J.Wurtman, eds. Vol. 7. New York: Raven Press.