Have You Heard of the L-Tryptophan Tragedy?

With many biological and physiological effects on human health, the amino acid L-Tryptophan is converted, when obtained from food, to 5-HTP (5-hydroxytryptophan), then to serotonin, melatonin and vitamin B6 (nicotinamide), and serves as a precursor to many other bioactive compounds.

The hormones serotonin and melatonin have many effects on psychology, sleep, body temperature, blood pressure balance, sexuality, immunity and digestion in the human body.

The L-Tryptophan Tragedy

EMS (eosinophilia-myalgia syndrome) first broke out in 1989. EMS is a rare, disabling disease characterized by severe muscle and joint pain, fatigue, swelling of the arms and legs, fever, rash, and an increase in blood eosinophils (a type of white blood cell).

Within 1 year, more than 1,500 EMS cases and twenty-eight deaths were reported to the US Centers for Disease Control and Prevention.

On July 5, 1991, the recorded number of cases was reported to have reached 1543, with a total of 31 deaths.

The EMS outbreak resulted from impure L-Tryptophan produced by Showa Denko K.K., a Japanese wholesaler and the largest supplier to American manufacturers. Documents collected showed that in 1988, Showa Denko realized that its failure to produce pure L-Tryptophan resulted in unidentified and potentially harmful effects, and consequently began using a new bacterial strain. Showa Denko did not inform the US Food and Drug Administration (FDA) either about the production of impure L-Tryptophan or about changes to its manufacturing process. Although the FDA had warned that biotechnologically modified products should be thoroughly tested before marketing, the company began selling the new product without testing it. In brief, Showa Denko could have improved quality by increasing filtration, but this would have reduced the quantity of its product. Instead, it continued production rapidly to meet market demand, and many people were harmed as a result.

Looking back presents a deeply distressing picture. If L-Tryptophan production had been properly supervised, or if its already illegal sale had been stopped, these lives would not have been lost and none of the 1543 patients would have continued living with disabilities. For example, because Sowa Denko skipped filtration steps needed to obtain pure and reliable L-Tryptophan, the product was discolored rather than the "pure white" it should have been. Yet those marketing it in the United States continued without questioning the color difference. These failures harmed many people’s health.

What Regulatory Failures Led to the L-Tryptophan Tragedy?

GMP (Good Manufacturing Practices), known in Turkish as “İyi Üretim Uygulamaları,” is a quality system guiding the conditions under which products directly affecting human health, such as medicines, cosmetics, food and medical devices, should be manufactured in the United States. CMP is often used instead of GMP because the letter c stands for “Current.” This means that GMP is not a set of standards established only once. It is a system of continuous inspection in which deficiencies are adapted to current conditions and corrected. GMP covers both production and distribution and, in brief, every area needed to maintain product quality. It is a set of systems applied from staff training and raw materials to packaging and storage.

How, Despite All These Practices, Did the L-Tryptophan Tragedy Occur in the United States?

How Did L-Tryptophan Reach US Consumers Freely and Without a Prescription?

Under the US Federal Food, Drug, and Cosmetic Act, drugs for humans and animals are defined as:

• Substances that treat, alleviate or prevent disease,
• Substances other than food that alter the body’s structure or function (for example, accelerate weight loss or help hair grow).

According to the FDA, a substance’s intended use determines whether it is a drug. Therefore, food and cosmetic products are also classified as drugs if they have these effects on health.

According to intended use, L-Tryptophan is classified as "FOOD" when used by bodybuilders for muscle development, but as a "DRUG" when used to treat, alleviate or prevent problems such as depression, insomnia and pain in premenstrual syndrome, or to suppress appetite and thereby reduce fat mass and change body structure.

How L-Tryptophan should have been classified could have been determined with the "intended use" test, but the FDA did not apply it. In the 1960s, the FDA placed L-Tryptophan supplements on the "Generally Regarded as Safe" (considered safe) list. Substances on the GRAS list are considered safe by experts and are therefore exempt from tolerance requirements under the Federal Food, Drug, and Cosmetic Act.

The main reason for this decision was that L-Tryptophan also occurs naturally in dietary protein sources. The average person obtains about 1-2 g of L-Tryptophan daily from protein sources, and this natural intake did not harm the body. As a result of this decision, L-Tryptophan products began to be manufactured and sold without FDA approval.

The Changing Understanding of L-Tryptophan Over the Years

The effects of L-Tryptophan on sleep, mood and appetite, and its potential use as a drug, were first discovered in 1970 by a professor of neuroscience and his team at M.I.T and Harvard Medical School. They thought L-Tryptophan could be used as a medicine for sleep regulation, appetite control and pain relief. However, pharmaceutical companies did not want to invest in the safety and efficacy studies needed to market L-Tryptophan as a drug, namely the clinical trials, since L-Tryptophan was already being produced and sold as a dietary supplement.

L-Tryptophan remained on the GRAS list for some time. In the early 1970s, however, animal studies showed adverse health effects from excessive use, prompting the FDA to reevaluate the safety of L-Tryptophan supplementation. In 1972, the FDA published a notice in the Federal Register stating that excessive L-Tryptophan use could potentially harm human health. It also called for all amino acids to be removed from the GRAS list, explaining that supplement makers would need to do more than show an absence of harm: the substances should be marketed as food additives and manufacturers should explain how they were produced and sold. The FDA failed to enforce these rules, however, and L-Tryptophan was not removed from the GRAS list.

In 1977, the FDA again tried to prevent over-the-counter L-Tryptophan sales, but this attempt also failed. Numerous difficulties arose during the court proceedings and the case was dropped. The FDA could not implement its desired regulations and completely failed to prevent supplement makers from selling L-Tryptophan without a prescription. Although selling L-Tryptophan was illegal, the FDA made no further move until EMS (eosinophilia-myalgia syndrome) broke out. The failure to continue the effort accelerated L-Tryptophan marketing. Books, magazine articles and many manufacturers continued promoting L-Tryptophan as beneficial for insomnia, pain, depression, PMS and excess weight, although it had not been shown safe and effective for any of these purposes.

What Is L-Tryptophan, and Which Foods Contain It?

The human body contains a substantial amount of protein. Amino acids, the basic building blocks of proteins, are linked by peptide bonds. The formation of a particular protein depends on the sequence of its amino acids and is regulated by coding. There are 20 amino acids involved in protein production, divided into 2 groups: essential and nonessential. Essential amino acids cannot be synthesized (produced) in the body and must be obtained from the diet. Nonessential amino acids can be synthesized in the body. Since essential amino acids cannot be produced by the body, they must be obtained from food so that vital protein synthesis can continue.

Which Foods Contain L-Tryptophan?

L-Tryptophan is an essential amino acid found most abundantly in eggs, chicken, turkey, red meat, cheese, soy, nuts and legumes.

Can a Balanced Diet Supply All the Essential Amino Acids the Body Needs? Do We Need Protein Supplements?

With a balanced, healthy diet, people can obtain all the essential amino acids their bodies need without any supplements!

Amino acids are the building blocks of proteins. A deficiency of a single, isolated amino acid is not expected. If someone lacks amino acids, this has probably resulted from an unhealthy diet, and taking one amino acid supplement would be pointless. Instead, a healthy, balanced eating plan would provide all the essential amino acids, the building blocks of proteins. For this reason, selling a single amino acid as a supplement and marketing it as beneficial merely misleads consumers.

- Related Topic: Vitamin and Mineral Supplements: What Doctors and Users Should Know

How Did the L-Tryptophan Tragedy End?

Showa Denko realized that it would be responsible not only for the harm suffered by L-Tryptophan victims but also for the costs of legal proceedings against American manufacturers, and agreed to cover all costs. L-Tryptophan victims sued Showa Denko or chose to settle. Many cases were handled with nondisclosure of settlement terms. Although the total amount paid by Showa Denko approached a billion dollars, the news media did not consider the cases newsworthy and the matter received little coverage.

After the FDA banned L-Tryptophan sales, EMS incidence fell rapidly. In 2005, the FDA lifted the L-Tryptophan ban and again allowed products containing L-Tryptophan to be used as dietary supplements. The absence of published new cases since the ban was lifted in 2005 indicates that the tragedy led to more cautious manufacturing and marketing.