How Tryptophan Went From a 1901 Paper to the 1989 Recall
Hopkins and Cole described a new product of protein digestion in 1901. In 1989, an outbreak of eosinophilia-myalgia syndrome was traced to a chemical constituent tied to one maker's tryptophan process. CDC and NEJM records tie the outbreak to that manufacturing process.
The 1989 tryptophan outbreak was traced to a chemical constituent linked to one manufacturer's process, which makes it a manufacturing story as much as a nutrition story. In the Belongia case-control study, 29 of 30 case patients (97 percent) had taken tryptophan from one company, against 21 of 35 controls (60 percent). [According to PubMed](https://pubmed.ncbi.nlm.nih.gov/2370887/), the study then tied those lots to specific manufacturing conditions ([DOI](https://doi.org/10.1056/NEJM199008093230601)). The study was built to answer a basic question: whether the cause was tryptophan itself or a chemical introduced during manufacturing. The Belongia team combined three pieces: surveillance for the syndrome in Minnesota, a community survey of tryptophan use in the Minneapolis-St. Paul area, and a case-control study that compared case patients with controls on the products they had used. They also ran high-performance liquid chromatography on the tryptophan samples to look for other chemical constituents. ## A 1901 paper on a product of digestion F. Gowland Hopkins and Sydney W. Cole published a preliminary study of "a hitherto undescribed product of tryptic digestion" in the *Journal of Physiology* in 1901. The reprint held by Wellcome Collection carries that title, and its catalogue files the work under tryptophan. We could not confirm from a primary or institutional record which protein they digested, so this post does not name one. ## One company's process sat at the center The study found that the one company's tryptophan came from a fermentation using *Bacillus amyloliquefaciens*. Lots used by case patients had less powdered carbon in a purification step (odds ratio 9.0, with a wide confidence interval) and more often came from a new bacterial strain (odds ratio 6.0). A chromatography peak called peak E showed up in 9 of 12 case-linked retail lots and 3 of 11 control lots. The authors wrote that the outbreak resulted from a chemical constituent tied to manufacturing conditions at one company, and they left open whether that constituent caused the illness or stood in for another chemical. Tryptophan use had also risen from 1980 to 1989, and it was highest among women. ## CDC counted cases as they came in The syndrome was first reported from New Mexico. CDC contacted state health departments on November 9, 1989, and set up a standardized national surveillance system. By December 6, 730 cases had been reported from 48 states, the District of Columbia and Puerto Rico, and four deaths had been reported among patients who met the surveillance definition and had used L-tryptophan ([CDC MMWR, 8 December 1989](https://www.cdc.gov/mmwr/preview/mmwrhtml/00001514.htm)). Among 64 cases with completed forms from 21 states, 63 (98 percent) had taken L-tryptophan. Ages ran from 14 to 73, with a median of 44, and 95 percent of the patients were non-Hispanic white. Doses ran from 500 to 5,000 mg a day, with a median of 1,500 mg, 81 percent of the cases were women, and 33 percent had been hospitalized. By August 24, 1990, the count reached 1,536 cases from all 50 states, the District of Columbia and Puerto Rico, with 27 deaths among patients who met the surveillance definition and had used L-tryptophan-containing products. Of the 1,117 patients with completed report forms, 930 (83 percent) were women, and 360 (32 percent) had been hospitalized. CDC also warned that its case definition, which required severe, debilitating myalgias and an eosinophil count of at least 1,000 per cubic millimeter, may be too narrow for clinical use, since milder forms of the syndrome may exist ([CDC MMWR, 31 August 1990](https://www.cdc.gov/MMWR/preview/mmwrhtml/00001738.htm)). ## FDA moved from supplements to nearly all products On November 17, 1989, the FDA recalled all dietary supplements that provided 100 mg or more of L-tryptophan a day. By March 22, 1990, the recall covered all L-tryptophan-containing products at any dose, except some protein supplements, infant formulas, special dietary foods and certain fortification solutions. CDC's editorial note says the eight cases with onset on or after February 1, 1990 appear to have come mainly from continued use after the recall. One patient started on March 20, 1990, and became ill a month later ([CDC MMWR, 31 August 1990](https://www.cdc.gov/MMWR/preview/mmwrhtml/00001738.htm)). ## Later quality work set limits on contaminants A 1999 market survey examined 22 tryptophan lots from six manufacturers and identified EBT, 1,1'-ethylidenebis-(L-tryptophan), as a marker for EMS-suspicious tryptophan. Its abstract notes that European authorities limit EBT to under 10 mg per kg of tryptophan, and the sum of UV-detectable contaminants to under 400 mg per kg ([DOI](https://doi.org/10.1007/978-1-4615-4709-9_59)). Non-EMS-correlated contaminants also showed up in raw materials, at levels up to 13,500 mg per kg. A companion 1999 paper describes a seven-step synthesis of one case-associated contaminant, 2-(3'-indolylmethyl)-indole, so it could serve as a reference substance ([DOI](https://doi.org/10.1007/978-1-4615-4709-9_60)). That paper reports the contaminant as a major one in two case-associated samples. ## Tryptophan still feeds the niacin story Tryptophan matters to nutrition for another reason. The NIH Office of Dietary Supplements says that tryptophan, when present beyond what protein synthesis needs, can be converted to NAD, mainly in the liver, and it counts 60 mg of tryptophan as 1 mg of niacin ([NIH ODS](https://ods.od.nih.gov/factsheets/Niacin-HealthProfessional/)). The same fact sheet says people who do not get enough riboflavin, vitamin B6 or iron convert less tryptophan to niacin, because the enzymes in that pathway depend on those nutrients. A rare inherited condition, Hartnup disease, affects how the body transports several amino acids, tryptophan among them. Our [NAD longevity guide](/health/nad-longevity-complete-guide) covers the NAD side, and our [tryptophan-to-niacin research article](/research/can-diet-raise-nad-tryptophan-niacin) covers whether diet can raise NAD this way. Niacin's flush is a separate question, covered in [does NR cause niacin flush](/health/nad-longevity-complete-guide/does-nr-cause-niacin-flush). The detail to keep from the CDC record is small: eight people fell ill on or after February 1, 1990, and most of them appear to have kept taking the product after the FDA recall. **Next reads** - [NAD longevity complete guide](/health/nad-longevity-complete-guide): the pillar behind the NAD and niacin context here. - [Tryptophan, niacin and whether diet raises NAD](/research/can-diet-raise-nad-tryptophan-niacin): the diet question in more detail. ### Related reading - [how a pineal gland hormone became a supplement](/blog/history/history-of-melatonin-from-pineal-gland-to-sleep-supplement) - [how pellagra became a lesson in diet](/blog/history/history-of-niacin-b3-from-pellagra-to-flush) - [how rat skin studies led to P5P](/blog/history/history-of-vitamin-b6-from-pyridoxine-to-p5p)