A methodological case against over-the-counter marketing of supplements of amino acids

L-tryptophan: a methodological case against over-the-counter marketing of supplements of amino acids

Victor Herbert

This article deals with one of the many recent inappropriate health claims for specific products (as distinguished from appropriate claims for entire diets) which followed the failure of the FDA to prosecute when illegal health claims first appeared. The FDA is now beginning to crack down on these claims, on the theory that “it isn’t the truth if it isn’t the whole truth.”

In 1974, because of substantial safety questions regarding the ingestion of free amino acids, the U.S. Food and Drug Administration (FDA) and Canada’s Food and Drug Directorate both declared all amino acids to be non-GRAS (i.e., not generally recognized as safe), which meant, among other things, that they should not be marketed over-the-counter (OTC). While the U.S. FDA did not enforce the prohibition until the eosinophilia-myalgia syndrome (EMS) epidemic struck in 1989, and then only enforced it against L-tryptophan, Canada vigorously enforced its similar prohibition and thus did not have an epidemic of EMS from OTC tablets of L-tryptophan. As of June 1, 1991, 1543 cases of EMS have been reported to the Centers for Disease Control (CDC) by state health departments, with 10 deaths from New York State alone (JAMA 1991;266:195-6). The CDC indicates the number of cases may be twice that reported (JAMA 1992;267:77-82).

Thus, it seems evident that the FDA should move decisively against the marketing of the other OTC amino acids, instead of waiting for the next tragedy. Moreover, marketing of OTC free amino acids as foods and/or food supplements and/or dietary supplements is fraudulent, with the definition of fraud as “deception for profit.” The deception can be either both by commission or by omission, whether the omission is simply neglecting to tell the whole truth or deliberate fraudulent concealment of adverse facts.

There are no significant amounts of free amino acids in our food nor for the average American, is there any dietary or nutritional need for, or dietary or nutritional value of, eating free amino acids. Thus, since the nutrition efficacy of these free amino acid pills, powders or potions is zero for the average American, and there are known possible harms, the efficacy-to-safety ratio is infinity, which is grossly unacceptable. It was the potential toxicity of large doses of single amino acids, that led the FDA to remove these substances from the agency’s list of those generally recognized as safe (GRAS) in 1974.

The sole legitimate uses of free amino acids are in parenteral alimentation mixtures, since parenteral whole protein is highly allergenic, and as food additives. Under American law, parenterals fall under the drug regulations.

In the L-tryptophan example, a typical side panel on an OTC bottle labeled “NATURAL L-tryptophan 667 mg per tablet” says: “L-tryptophan–As a dietary supplement. DIRECTIONS: 3 tablets after evening meal or before bedtime. The need for L-tryptophan in human nutrition has been established, but the recommended daily allowance has not been determined.” The statement “3 tablets after evening meal or before bedtime” on this alleged supplement is in fact a direction for its use as a drug to induce sleep.

All the L-tryptophan we need from food is supplied by dietary protein, as are all the other amino acids. Free-standing L-tryptophan, like any other free-standing amino acid, is not present in significant quantities in any food we eat, nor has it been shown to be safe to add free-standing L-tryptophan, or any other free-standing amino acid, to food.

The only known reason to eat free-standing L-tryptophan is to produce a selective elevation in blood L-tryptophan so that it will, preferentially to other neutral amino acids, cross the blood-brain barrier, where it is available for the synthesis of the neurotransmitter serotonin. Eating free-standing L-tryptophan produces a relatively high blood level compared to the blood level of other neutral amino acids, thereby increasing its ability to compete with the other neutral amino acids for transport across the blood-brain barrier to form serotonin, which induces sleep and/or has other neurotransmitter effects.

Scientists at MIT, among others, have speculated that Grandma’s injunction to drink some milk with honey at bedtime to induce sleep may actually have worked not by suggestion but because the milk protein supplied the L-tryptophan and other amino acids and the honey supplied the sugar which caused a rise in insulin level. This, in turn, pulled the other neutral amino acids into muscle with the sugar, resulting in a relative elevation in plasma L-tryptophan, which then crossed the blood-brain barrier uninhibited by competition for the barrier pathway by the other neutral amino acids.

A well-known prescription use of L-tryptophan “supplements” was as a putative sleep aid. In the late 1980s, they were widely promoted as sleep aids for insomnia sufferers, and many psychiatrists also prescribed them to treat depression. Then in 1989, there came a rash of reports of a rare muscle disorder, eosinophilia-myalgia syndrome. By early 1990, several thousand cases of EMS had been identified and some 20 deaths. As of this writing, it is not known whether the eosinophilia was caused by tryptophan, a contaminant introduced in manufacturing the supplements or both. The Food and Drug Administration barred further sales; Canada did so years ago and had no EMS problem.

The label designation “NATURAL L-tryptophan” (or NATURAL any other amino acid) can be construed as fraudulent, because freestanding L-tryptophan and other amino acids are not naturally present in significant quantity in food. What is in OTC bottles of amino acids labeled “NATURAL” is not natural, but rather a synthetic product of laboratory chemistry, microbial fermentation or some other manufacturing process. The amino acids are only present in food in significant quantity as part of intact large protein molecules. Because free amino acids are not naturally present in food in significant quantity, they cannot be extracted from food without first chemically breaking food protein in the laboratory into its constituent amino acids.

The OTC label panel statement, “Natural L-tryptophan is an essential amino acid. The need for L-tryptophan in human nutrition has been established, but the recommended daily allowance has not been determined,” is, in my opinion, fraudulently and deliberately misleading. This is so because inherent in the label representation that “the recommended daily allowance has not been determined” for an amino acid is the implication that the Food and Nutrition Board are simply waiting for more data so that they may finally state the specific RDA quantity for the particular free amino acid. This is a blatant deception because, in fact, the establishment of an RDA for amino acids has not been needed, contemplated or suggested in any of the most recent RDA reports, since there is no value in a dietary RDA for any isolated amino acid in the diet of the average American.

The proper use of the phrase “but the recommended daily allowance has not been determined” is as used in the RDAs in relation to vitamins and essential minerals whose need in human nutrition has been established but whose recommended daily allowance has not yet been determined. Using that wording for an amino acid fraudulently represents that amino acid to be a vitamin or mineral, or at least one of “other substances in food” discussed in RDAs.

The OTC label statement “L-tryptophan–As a dietary supplement. DIRECTIONS: 3 tablets after evening meal or before bedtime” indicates that the seller knows he is selling the product for a drug purpose–to induce drowsiness.

This is unequivocally a drug use direction and not a food use direction. If it were a food use direction, it would specify “take one with each meal or after each meal”, rather than “take all three tablets after evening meal or before bedtime.” There is no basis in the logic or wisdom of nutrition science, for which a basic rule is moderation, for taking any food supplement tablet, each one of which contains twice the total daily absorbed need, as all three before bedtime. This can magnify only the drug and not food action, by throwing three pills, i.e., three times the dose of one pill, against the gut wall. This large dose could interfere with the absorption of other nutrients and would sharply raise the blood level peak over that reached by one tablet 3 times a day, to produce a pharmacologic effect that could be undesirable. For example, if 2000 Mg of L-tryptophan eaten all at once did induce drowsiness, it could have caused a school bus driver who took it in the morning to fall asleep at the wheel, resulting in injuries and fatalities in his passengers. We will never know if falling asleep at the wheel after eating L-tryptophan tablets has already happened, or how many times it has happened, because the sellers do not do any studies to find out, and any cases that might have been reported to them would most probably be quietly settled without notifying the FDA. (Since the promoters contend that free-standing amino acids are not drugs, they do not report adverse drug reactions from them to the FDA.) This is classic behavior by “health food” entrepreneurs.

An unreported case in point of a “health food” entrepreneur is one that involved a professor of nutrition who ate a high-fiber “health food” bar while driving his car on a California freeway, developed an acute anaphylactic reaction to the point that he could not breathe and luckily was able to get off the freeway quickly to a hospital emergency room for a life-saving shot of epinephrine. It turned out there was cotton fiber, to which he was allergic, in the health food bar. He reported it to the health food company, which laconically told him they knew of other cases, happily paid his medical expenses since he did not want to make an issue of it by suing, which would have protected others. Thus, it was kept quiet, as was the case of a California lawyer who had the same experience. That particular company was finally put out of business, not by the FDA which should have done so, but by state attorneys stimulated by Fred Stare of Harvard.

The food and drug laws of the United States state that making a specific disorder prevention, mitigation or treatment claim (i.e., a pharmacologic claim) for a substance automatically makes the substance a drug and triggers operation of the drug laws. The same laws also state that no drug may be sold to the public until the seller has submitted to the FDA acceptable evidence that it is effective and safe for the proposed drug use and has provided to the FDA (and all customers) adequate directions for use to achieve the desired effect and adequate warnings about potential harms.

The OTC L-tryptophan label representation that people need 3 x 667 mg = 2000 mg/day of the freestanding chemical L-tryptophan in their diet is blatantly false, What people need in their diet is high-quality whole protein or a mixture of several complementary proteins, in which are bound all the amino acids essential for humans. This is why there is an RDA for protein but not for individual amino acids.

The RDAs are a product of the Food and Nutrition Board (FNB) of the National Academy of Sciences/ National Research Council. The U.S. RDAs used for labeling purposes are an FDA derivative of the FNB RDAs.

The deceptive phraseology on OTC L-tryptophan labels that “the need for L-tryptophan in human nutrition has been established” deliberately conceals the fact that there is no need for or nutritional value of (and indeed, possible harms from), free L-tryptophan or other amino acids in average American diets.

The essential amino acids are building blocks, which when bound together form protein molecules. They are not meant to be eaten freestanding, dissociated from intact protein, since this would unbalance the relationships of amino acids to each other in the amino acid pool. Put in the logic favored by natural food enthusiasts, “If God meant us to eat free amino acids, they would grow on trees.”

The human machinery is constructed to make human proteins from dietary proteins. The digestive tract enzymes hydrolyze ingested proteins into their constituent amino acids, When our bodies absorb the amino acid components, they are transported via the bloodstream to our livers, which take them up and bind them together in the correct sequence to synthesize human proteins. Some L-tryptophan is delivered from the bloodstream across the blood-brain barrier to be converted into serotonin. The estimated upper range of the daily requirement for each essential amino acid is almost invariably far exceeded by the amount we absorb from the protein we eat.

As stated in the 10th edition of the RDAs, “Average diets in the United States for women ages 19 to 50 supply 700 mg of tryptophan daily, and for men 19 to 50, 1100 mg.” The claim that average American adults on average American diets can profit nutritionally from dietary supplements of L-tryptophan is thus clearly fraudulent, since a 220-pound (100-kg) adult needs to absorb only a daily upper range of about 350 mg of L-tryptophan and doubles that from the protein s/he eats. Similar conclusive arguments can be made against dietary supplements of each of the other amino acids.

POTENTIAL HARMS FROM EATING PURE USP L-TRYPTOPHAN (AND OTHER FREE AMINO ACIDS)

Potential Harm 1. There may already be harms reported in the literature but overlooked. For example, the first case similar to EMS in a patient taking a type of tryptophan tablet (5-hydroxy-L-tryptophan) to increase brain serotonin was seen in 1978 in Montreal. Thus, sellers of free L-tryptophan tablets have been on notice since 1980 of an EMS-like syndrome from eating an L-tryptophan analog, chemically almost identical to L-tryptophan, and capable of being made from L-tryptophan almost molecule for molecule in the human body. If you are going to sell to the public an OTC something which is not GRAS, you have an obligation to comb the literature thoroughly for potential harm before you put it on sale.

Potential Harm 2. There is strong evidence that eating purified amino acids apart from food promotes osteoporosis: “Purified amino acids may cause a negative calcium balance, with increased loss of calcium through the urine and feces, but studies have shown that this does not happen with whole protein such as that found in foods.” The studies over a decade ago of Linksweiler and others suggest the reason is that in the absence of phosphorus (present in whole food containing whole animal protein) most of the calcium absorbed attached to amino acids pours right out in the urine and never gets laid down in bone.

Potential Harm 3. The high urine loss also relates to another amino acid tablet scam: “chelated mineral” tablets to “enhance mineral absorption.” The chelation is to amino acids, and the seller tells the customer that chelating a mineral to an amino acid enhances the mineral’s absorption. The seller deceives the customer by omitting the fact that after absorption the mineral goes right on out through the kidneys with the amino acid, only putting an added load on the kidneys and not improving body mineral content more than unchelated minerals. The average American already eats much more protein than needed, putting a burden on the kidneys to get rid of the nitrogenous waste. Adding still more protein, or amino acid building blocks for protein, puts a still greater unnecessary burden on the kidneys. Since we fill most of our cell protein receptors with amino acids from food each day, the large bulk of amino acid supplements has nowhere to go but out in the urine via the kidneys.

Potential Harm 4. Amino acid tablets may cause urinary loss not only of calcium but also of some other minerals. While whole animal protein with its “animal protein factor” (which could be an amino acid released from protein in the intestine) enhances inorganic iron absorption from plant products, addition of extra amino acids to diets already rich in animal protein has not been shown to be of added value in this regard. If it was, then free amino acids should not be eaten by anyone who has not had his/her serum ferritin determined, since 10% of Americans are heterozygous for hemochromatosis and 1 in 250 is homozygous and can only be harmed by anything which increased iron absorption and thereby iron-loading.

Potential Harm 5. The amount (667 mg x 3 = 2000 Mg) of L-tryptophan eaten per day is 6 times the need of a 220-pound adult (350 mg) and could produce an imbalance in blood levels of L-tryptophan, as compared to other neutral amino acids, thereby driving excess L-tryptophan into the brain, producing excess serotonin, and drowsiness and sleepiness when undesirable (e.g., when driving a car home after an evening meal followed by 3 tablets adding up to 2000 mg of L-tryptophan).

Potential Harm 6. It has been known for decades that large doses of tryptophan will block gluconeogenesis.

Potential Harm 7. Excess free L-tryptophan may promote cancer (Hayashi et al., 1980).

SUMMARY

In summary, tryptophan is an essential amino acid in human biochemistry. Twice as much as we need is supplied by the amount of animal protein in the American diet. Even vegans can get adequate tryptophan by mixing plant sources of protein. Not only is there no need for free tryptophan in the diet, but free tryptophan is not recognized as safe by the Food and Drug Administration. It is a drug whose only use is as a drug or food additive (in infant formulas, medical foods, and as an additive to tryptophan-poor protein of plant origin).

SELECTED READINGS

Centers for Disease Control. Eosinophilia Myalgia syndrome: follow-up survey of patients, New York, 1990-91. JAMA 199 1;226:195-6. Fahey J. Toxicity and blood ammonia rise resulting from intravenous amino acid administration in man. J Clin Invest 1958;30:1647-1655. Hayashi A, Ishimura Y, Kido R, eds. Biochemical and medical aspects of tryptophan metabolism. New York: Elsevier-North Holland, 1980. Kamb ML, et al. Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients. JAMA 1992; 267:77-82. Silver R, et al. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 1990;322:874-81. Wurtman RJ, Wurtman JJ. Carbohydrates and depression. Sci Am Jan 1989:68-75. Wurtman R, Wurtman J. Nutrition and the brain. New York: Raven Press, 1990, Vol. 8.

Dr. Herbert is a Professor of Medicine and Chairman of the Committee to Strengthen Nutrition at Mount Sinai School of Medicine and Chief of the Hematology and Nutrition Research Laboratory at the Bronx VA Medical Center, Bronx, New York.

COPYRIGHT 1992 Lippincott/Williams & Wilkins

COPYRIGHT 2004 Gale Group