Notes on the Tryptophan Disaster
Stephen Barrett, M.D.
During the closing days of the 1994 Congressional session, a bill was passed to prevent the FDA from banning the sale of several categories of "dietary supplement" products. Passage of this bill capped an aggressive three-year lobbying campaign intended by the health-food industry to cripple FDA regulation of its products. Senator Orrin Hatch (R-UT) championed the bill, an early version of which was described by The New York Times as "The 1993 Snake Oil Protection Act."
The 1994 law, called the Dietary Supplement and Health Education Act, defines dietary supplements to include vitamins, minerals, herbal products, amino acids, other dietary substances, and products derived from any of these substances. Even if a product or ingredient has no practical value in supplementing the diet, the FDA may not object to its sale unless it presents a "significant and unreasonable risk of illness or injury" or poses an imminent safety hazard . Before passage of this Act, the FDA was able to ban many types of worthless "dietary supplements" by designating them "unapproved food additives."
Permitting amino acids to be sold in as "dietary supplements" is a great disservice to consumers. Amino acids are the building blocks of proteins. Individual amino acids are worthless for supplementing an individual's diet because dietary deficiency of single amino acids does not occur. (Most Americans eat considerably more protein than they need. People who are grossly malnourished develop multiple shortages that should be remedied with foods, not individual amino acids.) Moreover, the use of single-or multiple-ingredient amino acid products is based on unsubstantiated beliefs that they are safe and beneficial as drugs or athletic enhancers.
During the early 1970s, Richard J. Wurtman, M.D., professor of neuroscience at M.I.T. and Harvard Medical School, and his colleagues discovered that tryptophan levels normally control the production of serotonin, a brain chemical involved in sleep, mood, and appetite. At the time, he thought that tryptophan might become a legitimate drug that could help people sleep, diminish pain, and control mood and appetite. Pharmaceutical companies were unwilling to invest the money necessary to do safety and efficacy studies to determine whether L-tryptophan was safe and effective enough to be marketed as a drug. But supplement companies began marketing L-tryptophan as a "dietary supplement."
Until 1973, L-tryptophan and other amino acids were included on a list of food substances generally recognized as safe (GRAS) for use as dietary supplements. In 1973, the FDA revoked this GRAS status and stated that amino acids could not be marketed without approval as food additives. Since no approval was sought, the agency initiated seizure actions against two manufacturers of L-tryptophan products. The first case was dismissed because L-tryptophan had accidentally been included on a GRAS list published in 1977. The second case was withdrawn before a verdict was rendered, because the FDA believed that the judge was inclined to favor the manufacturer. The FDA also felt constrained by the Proxmire Amendment, a law passed in 1976 that curbed its ability to regulate vitamin dosage. Although amino acids were not included under this law, the agency took its passage as a signal that Congress did not want supplement products regulated without serious indications of danger to health. Thus, although the marketing of amino acid supplements was illegal, the FDA did nothing further until the EMS outbreak occurred.
Unhampered by the FDA, the health-food industry stepped up its marketing of L-tryptophan. Books, magazine articles, and many manufacturers promoted it with claims that it was useful against insomnia, pain, depression, PMS, and overweight, even though it had not been proven safe and effective for any of these purposes.
In 1989, an outbreak of eosinophilia-myalgia syndrome (EMS) occurred among L-tryptophan users . A hitherto rare disorder, EMS is a debilitating disease characterized by severe muscle and joint pain, weakness, swelling of the arms and legs, fever, skin rash, and an increase of eosinophils (certain white blood cells) in the blood. Over the next year, more than 1,500 cases and twenty-eight deaths were reported to the U.S. Centers for Disease Control and Prevention . The actual toll probably was more than 5,000 people, many of whom suffered for years and are still disabled. Soke of the victims were children. When the link between EMS and L-tryptophan became apparent, the FDA quickly banned its sale [4,5].
The EMS outbreak was traced to the presence of an impurities in the L-tryptophan produced by Showa Denko K.K., a Japanese wholesaler that was the major supplier to American manufacturers [6-8]. Showa Denko realized that it would not only be liable for damages to L-tryptophan victims but would probably be forced to reimburse American manufacturers for the costs of legal actions against them. Rather than working at cross-purposes with the manufacturers, Showa Denko agreed to shoulder all the expenses involved.
Minneapolis attorney Roger P. Brosnahan, who chaired the steering committee for all plaintiffs who brought cases in federal court, estimates that about 2,000 L-tryptophan victims (or their survivors) filed lawsuits or entered negotiations without suing. Most cases have generated little publicity because they were settled out of court with an agreement not to disclose the settlement terms. Even though the total amount paid by Showa Denko approximated one billion dollars, the general news media have not considered the outcome of the lawsuits newsworthy.
GNC Denies Responsibility
Since General Nutrition Corporation (GNC) was named as a codefendant in many of the lawsuits, Brosnahan's steering committee investigated its marketing practices. In August 1992, his partner David L. Suggs deposed GNC board chairman Jerry D. Horn . After asking Horn about 25 government enforcement actions that had been taken against the company between 1969 and 1989, Suggs queried:
- Q. Is it your testimony that . . . it's perfectly okay for
GNC to put products on its shelves, to sell pills to people if
those pills have no benefit? . . .
A. We make the assumption that they make the decision based on some perceived benefit.
Q. Isn't it a fact that . . . whether or not it is going to benefit your body is a question of science and a question of fact?
A. Limited science.
Q. Don't you think that GNC, before it sells pills for people to take, ought to make some evaluation of the science and the facts to . . . determine whether there is in fact some benefit in people taking those pills into their bodies?
A. No. I would say no, we should not. We are not compelled to do that.
Q. So far as you're concerned, and . . . speaking as the chairman of the board of GNC, it's perfectly all right for GNC to sell people pills to take even if those pills have no benefit whatsoever, there's no scientific benefit. Is that correct?
A. That's not what I said.
Q. Well, are you saying, then, that there should be a benefit?
A. The benefit to them is from their perception, their need, their diet, how they're trying to supplement. We don't know each individual's supplement needs to their diet, if any.
Q. So in other words, it's OK for GNC to sell pills for people to take them into their bodies . . . as long as some customer is under the belief or perception that they're going to get some benefit? . . .
- A. I'm telling you that it's up to the individual. . . . They make the decision how they want to supplement their diet.
* * *
- Q. Would you agree that your company has an obligation to test . . . products before they're sold for human consumption to determine whether they are in fact beneficial?
A. No more than a grocery store does foods coming in. We're a retailer.
Q. You also manufacture products, don't you?
A. We manufacture a portion of our line.
Q. Well, with respect to the products that you manufacture, would you agree that GNC has an obligation to test those products to make sure they are in fact beneficial?
A. You can't test whether an apple a day really keeps the doctor away. There's no way to test that I know of.
* * *
- Q. Have you ever heard of things like safety studies or toxicology studies or . . . clinical studies? . . .
Q. And what do those terms relate to?
A. I believe to the drug industry. . . . We're not in the drug business, we're in the food business as defined by the FDA.
More Mischief Revealed
Showa Denko also maintained that its L-tryptophan had been marketed as a "dietary supplement." However, company documents gathered by Brosnahan and his colleagues indicate otherwise:
- A 1984 memo stated: "If you take a look at each company which constitute the [nutritional supplement] market, they are positioned ambiguously in between medical and food manufactures/distributors. They get around the restrictions on 'Drugs' and sell 'food supplements.'"
- An undated internal memo (shown opposite) contained a long list of other reasons why "semi-healthy people" and "the sick" might purchase L-tryptophan products.
- An undated brochure stated that L-tryptophan "has antistress function and minor tranquilizer effect" and had pharmaceutical application as a "sleep inducer" and "antidepressant." 
Other documents revealed that in 1988, Showa Denko became aware that its L--tryptophan contained impurities that were unidentified and therefore potentially harmful. The company then began using a new strain of bacteria modified from previous strains by means of biotechnology. (Bacteria were used to synthesize the L-tryptophan.) Showa Denko did not notify the FDA about the impurities or its modification of the manufacturing process. Nor did the company test the newly made product for safety in humans, even though the FDA had previously cautioned that biotechnologically modified products should be thoroughly tested before public distribution. In fact, instead of increasing filtration to remove the impurities, which would decrease the amount of L-tryptophan produced, Showa Denko continued full-speed production to meet high market demand .
After the outbreak occurred, I sent the FDA a package of ads and product literature that contained therapeutic (drug) claims for L-tryptophan. FDA attorney Mary Pendergast, who compiled a 21-page analysis of this material, concluded that at least 26 companies had made illegal claims and that many "amino acids" were still sold as dietary supplements in violation of FDA food additive and drug regulations. She also concluded that the occurrence of EMS in children might be related to the marketing of the products advertised for use in sedating children .
At the same hearing, Dr. Wurtman stated:
Tryptophan in a bottle is not a nutritional supplement. In protein, it comes with 21 other amino acids, and you need all of them in order to utilize them and make protein. Pure tryptophan in pills or in a bottle is not natural. . . . The body cannot use it to make its own protein. There is not a single person in America who is tryptophan-deficient. Isolated amino acid deficiencies do not occur. People who have low blood tryptophan levels also have low blood levels of other essential amino acids as well, because these people are protein-deficient. Giving one amino acid to a protein-deficient person can make matters worse .
Dr. Wurtman noted that since manufacturers did not want to invite FDA regulatory action by openly marketing tryptophan as a drug, they did not list appropriate use, dosage, or contraindications on their labels. "Tryptophan was, in every sense, an accident waiting to happen," he added. He also described hazards associated with other amino acids that are still marketed in health food stores. He believes that isolated amino acids should not be marketable unless they can meet regulatory standards for prescription drugs.
In response to the EMS epidemic, the FDA commissioned the Federation of American Societies for Experimental Biology (FASEB) to study the safety of amino acids used as dietary supplements. FASEB concluded:
- Single- or multiple-ingredient capsules, tablets, and liquid products are used primarily for pharmacological purposes or enhancement of physiological functions rather than for nutritional purposes;
- Little scientific literature exists on most amino acids ingested for these purposes
- No scientific rationale has been presented to justify the taking of amino acid supplements by healthy individuals.
- Safety levels for amino acid supplement use cannot be established at this time.
- Systematic approach to safety testing is needed .
The tryptophan tragedy would not have occurred if the FDA had been able to ban these products or prosecute manufacturers who marketed them improperly. But passage of the Dietary Supplement Health and Education Act has given the health-food industry more freedom instead of less .
In 1998, FDA scientists confirmed the presence of impurities in some 5-hydroxy-L-tryptophan (5HTP) products currently marketed as "dietary supplements" for insomnia, depression, obesity, and in children with attention deficit disorder. One impurity, known as "peak X," was identified in one case of EMS associated with a 5HTP product in 1991, and similar impurities were found in L-tryptophan products associated with the 1989 EMS epidemic.. About ten other cases pf EMS associated with 5HT use have been reported. The body synthesizes 5HTP from L-tryphophan. The significance of finding "peak X" and other impurities in products containing 5-HTP is unknown .
- Barrett S. How the Dietary Supplement Health and Education Act weakened the FDA. Quackwatch June 8, 2000.
- Kamb MI and others. Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients JAMA 267:77-82, 1992.
- Update: Update: Eosinophilia-myalgia syndrome associated with ingestion of L-Tryptophan —United States, through August 24, 1990. Morbidity and Mortality Weekly Report 39:587-589 1990.
- "Dear colleague" letter on L-tryptophan and eosinophilia-myalgia syndrome. FDA Center for Food Safety Applied Nutrition, Jan 17, 1990.
- Williamson BL and others. On-line HPLC-tandem mass spectrometry analysis of contaminants of L-tryptophan associated with the onset of the eosinophilia-myalgia syndrome. Toxicology Letter 92:139-148, 1997.
- Information paper on L-tryptophan and 5-hydroxy-L-tryptophan: Background on L-tryptophan and 5-hydroxy L-tryptophan and the eosinophilia myalgia syndrome. FDA Center for Food Safety Applied Nutrition, Feb 2001.
- Task Group on Public Perceptions of Biotechnology. The tryptophan incident. Fact sheet. European Federation of Technology, July 2000.
- Deposition of Jerry D. Horn. Re: Tryptophan litigation, MDL Docket No 865. U.S. District Court, District of South Carolia, Columbia Division, Aug 11, 1992.
- Barrett S. Herbert V. The Vitamin Pushers: How the "Health Food Industry" Is Selling America a Bill of Goods. Amherst, NY: Prometheus Books, 1994.
- FDA's Regulation of the Dietary Supplement L-Tryptophan. Hearing held by the Human Resources and Intergovernmental Relations Subcommittee of the House of Representatives' Committee on Government Operations, July 18, 1991. [ISBN 0-16-03830-9]
- Anderson RA, Ralten DJ, editors. Safety of Amino Acids Used in Dietary Supplements. Washington, DC: Federation of Societies for Experimental Biology, July 1992.
- Impurities confirmed in dietary supplement 5-hydroxy-L-tryptophan. FDA talk paper 98-48, Aug 31, 1998.
This article was revised on Dvcember 22, 2001.