U. S. Food and Drug Administration
Office of Health Affairs
September 3, 1992

"Dear Colleague" letter regarding the
Research on Eosinophilia-Myalgia Syndrome and
Current Regulatory Status of L-Tryptophan

Dear Colleague:

We are writing to update you regarding the research on "eosinophilia-myalgia syndrome" (EMS) and the current regulatory status of L-tryptophan (LT). EMS was originally described in 1989 as a symptom complex associated with the ingestion of LT. Although the majority of the individuals originally described developed significant eosinophilia (>1000/mm ) and debilitating muscle pain, it is now recognized that the syndrome may encompass a wide range of symptoms that may change over time. Early symptoms may include myalgias, arthralgias (in the absence of arthritis), weakness or fatigue, dyspnea or cough, rash, headache, fever and paresthesias. While not all patients may exhibit eosinophilia, many patients go on to experience peripheral edema -- both pitting and nonpitting, as well as features of peripheral neuropathy, myocarditis, pneumonitis, fasciitis, or a scleroderma-like syndrome. As of August 1, 1992, the Centers for Disease Control (CDC) had received 1,511 reports of EMS from 52 state and territorial health departments, including 38 deaths from neurologic, cardiac, and pulmonary complications, as well as secondary infections.

LT Recall and Import Alert

Our first letter regarding this subject, dated January 17, 1990, identified the association between LT consumption and EMS and advised you of the recall of capsules and tablets providing 100 milligrams of LT or greater. On February 2, 1990, FDA notified you regarding an expansion of the recall to include all dietary supplements containing "manufactured, added" LT.

On March 22, 1990, FDA also imposed an Important Alert prohibiting the importation of manufactured LT, which included all forms in bulk, and LT as a single ingredient or major ingredient of tablets, capsules, caplets, liquids or powders into the United States without prior FDA approval. An exception is provided for LT used for special dietary purposes (see page 4).

Because all of the LT sold in the U.S. was produced elsewhere, the net effect of the recall and Import Alert has been a ban on most oral dosage forms of LT. Health professionals should be aware that although LT is not on the U.S. market, FDA and CDC have confirmed reports within the past year of persons who have become ill after consuming LT obtained through illegal means.

LT as a Component of "Health Foods"

FDA has received numerous reports from consumers concerned that LT is still on the market in the form of "sports" formulas, weight gain products and protein supplements. Many of these products display the amino acid content on the label in an amino acid profile. FDA has investigated these reports and invariably found the source of LT, as well as other amino acids, to be intact animal or plant proteins which may or may not be hydrolyzed to free amino acids. LT typically comprises about 1.6% of the total weight of amino acids in these products. No case of EMS has definitively been associated with any of these products, although several are under investigation.

EMS Patients May Have Gone Undiagnosed

The number of new cases of EMS has declined sharply since the implementation of the recall and Import Alert. However, the agency is concerned that may individuals may still be undiagnosed and untreated. Of the cases that meet the CDC surveillance case-definition criteria, the CDC suggests that only half have been reported. The CDC also estimates that another 3,000 individuals who have consumed LT are now exhibiting symptoms compatible with EMS, but do not fully meet the surveillance criteria for EMS (e.g., typical symptoms without eosinophilia or debilitating myalgias).

The CDC emphasizes that the published case-definition for surveillance was not intended to be used as diagnostic criteria, ant that each case should be judged on its own merits. Health professionals experiencing difficultly evaluating individuals with EMS-like symptoms are encouraged to consult academic medical centers with clinical experience in evaluating typical and atypical symptoms of EMS.

Since EMS has been so recently described, relatively little is known about the later manifestations of the disease, which may include chronic fasciitis, myopathy, neuropathy, and/or pulmonary disease. Health professionals following EMS patients should be aware of the potential for remissions as well as exacerbations of this illness. Recently patients with EMS have complained of alterations in mentation and memory, as well as gynecologic symptoms that may be a result of EMS. Although not identical to EMS, Toxic Oil Syndrome and scleroderma which produce symptoms similar to those of EMS, may be useful in predicting later phases of EMS. Therefore, any new symptom or condition observed in EMS patients should be evaluated for potential relationship to the progression of EMS.

Since EMS has been so recently described, relatively little is known about the later manifestations of the disease, which may include chronic fasciitis, myopathy, neuropathy, and/or pulmonary disease. Health professionals following EMS patients should be aware of the potential for emissions as well as exacerbations of this illness. Recently patients with EMS have complained of alterations in mentation and memory, as well as gynecologic symptoms that may be a result of EMS. Although not identical to EMS, Toxic Oil Syndrome and scleroderma which produce symptoms similar to those of EMS, may be useful in predicting later phases of EMS. Therefore, any new symptom or condition observed in EMS patients should be evaluated for potential relationship to the progression of EMS.

Etiology of EMS

In multiple epidemiologic studies, more than 95 percent of the cases of EMS were traced to LT supplied by one company, Showa Denko K.K. (Japan). Although no other company's product has been definitely linked to EMS, in some instances the source of LT could not be fully ascertained. However, several observations have caused FDA not to eliminate other brands of LT, or LT itself, as causal or contributing to the development of EMS:

1. Three to five percent of the EMS cases have not been definitively linked to Showa Denko's product.

2. At least eight cases with EMS-like symptoms have been associated with 5-hydroxytryptophan, a compound related to LT, but produced from botanical sources.

3. Surveillance for EMS has demonstrated that "non-epidemic" cases were occurring prior to the epidemic in 1989-90.

The FDA, CDC, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Mental Health are continuing collaborative research efforts to determine the etiology of EMS. A number of independent studies by academic scientists in the U.S. and at the National Institute for Hygienic Sciences of Japan are also underway. Numerous trace level impurities have been identified in the LT implicated in many of the EMS cases. Based on the epidemiologic data, several of these impurities, including 1,1'-ethylidenebis[L-tryptophan] ("EBT"), have been associated with EMS. However, the role of these impurities is unclear. Animal studies in the Lewis rat showed that EBT caused some, but not all, of the pathologic effects associated with EMS. In addition, these studies showed that significant myofascial thickening and pancreatic fibrosis occurred in rats treated with LT products other than EBT. These findings raise serious questions regarding the safety of high dose levels of "uncontaminated" LT. EBT and the other impurities epidemiologically associated with the EMS epidemic cases may only be markers for a yet unidentified substance(s) which trigger(s) EMS. Some literature reports also have attributed EMS-like symptoms to other components of dietary supplements; however, the evidence has been inconclusive.

Because of the causal mechanism is still not understood and the precise contaminant(s) have not been definitely identified, prevention of EMS with future products cannot be assured until the causal mechanism from past products has been ascertained. Factors, such as individual host susceptibilities, including differences in LT metabolism, may play a significant role. Despite the efforts of researchers in government and academia, these questions remain unanswered.

L-tryptophan for Special Dietary Purposes

FDA has provided for and will continue to permit the use of manufactured LT for special dietary purposes. Manufactured LT is a lawful and essential component of foods, such as infant formulas, enteral products and approved parenteral drug products, in compliance with Title 21, Code of Federal Regulation 172.320. Although LT produced by Showa Denko is not used in any of these products, under the above regulations free amino acids, such as LT, may be added to foods to improve the biological quality of an intact protein, if they are not used in concentrations above those specified in the regulations. LT as an amino acid may also be added as a nutrient to special dietary foods which are intended for use under medical supervision.

Future Regulatory Status of L-tryptophan

The agency does not wish to interfere with the conduct of legitimate research on the medical uses of LT, but rather encourages such investigation. Sponsors may apply for an Investigational New Drug (IND) application to carry out clinical investigations for medical indications. Protocols designed for the study of LT should include well-controlled clinical trials for defined indications. Due to the serious nature of the adverse effects associated with LT, investigators should consider that informal use of LT in uncontrolled studies is inappropriate. This policy is intended to balance the importance of conducting research and the need for scientific information, with the obligation to protect participants in clinical studies.

Contacts

Douglas Archer, Ph.D. (202) 205-4057 or Lori Love, M.D., Ph.D. (202) 205-4583 of FDA's Center for Food Safety and Applied Nutrition may be contacted for questions concerning LT for non-drug use. Questions regarding the distribution of LT as a dietary supplement should be direct to Crystal Willis, Ph.D. (202) 205-4726.

Mr. Patrick Savino (301) 295-8012 of FDA's Center for Drug Evaluation and Research may be contacted for questions regarding drug use of LT and investigational new drug (IND) applications.

For additional information on EMS, please contact Rossanne M. Philen, M.D. or Elizabeth Sullivan, M.D. of the Centers for Disease Control at (404) 488-7350.

Should you have questions regarding this letter, please contact Freddie Ann Hoffman, M.D. of my office at (30l) 443-5470.

We hope this information will be useful to you.

Sincerely yours,

/S/

Stuart L. Nightingale, M.D.
Associate Commissioner For Health Affairs

Suggestions for Further Reading:

Belongia, E. A.; A.N. Mayeno; and M. T. Osterholm: The eosinophilia-myalgia syndrome and tryptophan. Annual Reviews of Nutrition 12:235-256 (1992).

Duffy, J.: The lessons of eosinophilia-myalgia syndrome. Hospital Practice (Office edition) 27:65-90 (1992).

Hertzman, P. A.; H. Falk; E. M. Kilbourne; S. Page; and L. E. Shulman: The eosinophilia myalgia syndrome: The Los Alamos Conference. Journal of Rheumatology 10:867-873 (1901).

Kaufman, L. D. and R. J. Seidman: L-tryptophan-associated eosinophilia-myalgia syndrome: perspective of a new illness. Rheumatic Disease Clinics of North America 17:427-441 (1991).

Swygert, L. A.; E. F. Maes; L. E. Sewell; L. Miller: H. Falk; and E. M. Kilbourne: Eosinophilia-myalgia syndrome and results of national surveillance. Journal of the American Medical Association 264:1698-1703 (1990).

Varga, J.; J. Uitto; and S. A. Jimenez. The cause and pathogenesis of the eosinophilia-myalgia syndrome. Annals of Internal Medicine 116:140-147 (1992).

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