Eosinophilia-Myalgia Syndrome: The 1989 L-Tryptophan Outbreak

In the autumn of 1989, doctors in New Mexico noticed a strange pairing in a few patients: crippling muscle pain and a very high count of one kind of white blood cell. All of them had been taking L-tryptophan, an amino acid then sold over the counter, often for sleep. Within months the United States had counted more than 1,500 cases, and deaths were being reported. Investigators traced most of the illness to tryptophan from one Japanese manufacturer and to trace chemicals in particular lots. More than 35 years later, the chemical responsible has still not been proven.

This page follows the outbreak in order: how it was recognized, how it was traced, what regulators did, what the illness did to the body, how people fared years later, and why the cause is still argued over. For the amino acid itself, see the main Tryptophan page and its shorter History page.

Table of Contents

  1. A Rare Illness of Muscle Pain and Blood Eosinophils
  2. October 1989: The New Mexico Cluster
  3. The Case Definition and the Reported Counts
  4. How the Cases Were Traced to One Manufacturer
  5. Peak E and the Other Trace Contaminants
  6. What Regulators Did and When the Import Restriction Ended
  7. Symptoms and the Skin, Nerve, Lung and Heart Findings
  8. What Long-Term Follow-Up Studies Found
  9. Later Reports Linked to Tryptophan and 5-Hydroxytryptophan
  10. The Unresolved Cause: Contaminant, Tryptophan or Dose
  11. Key Research Papers
  12. Connections
  13. Featured Videos

A Rare Illness of Muscle Pain and Blood Eosinophils

The name describes the two signs that defined the illness. Eosinophils are a type of white blood cell, and "eosinophilia" means too many of them in the blood. A count above 0.5 billion per liter is the usual threshold (Barešić 2014). "Myalgia" means muscle pain. Eosinophilia-myalgia syndrome (EMS) joins the two, with muscle pain severe enough to be called incapacitating or debilitating in the case definitions.

A 2011 report in a rheumatology journal summarizes the usual course as muscle pain and eosinophilia that come on over weeks, followed by long-lasting nerve damage and hardening of the skin (Allen 2011). A 2023 review describes inflammation in several organ systems, including the muscles, skin and lungs (Ko 2023). A 1992 review also lists lung involvement, swelling, rash, nerve damage and possible effects on thinking (Kilbourne 1992).

The illness closely resembles another mass poisoning, Spain's toxic oil syndrome. A 1991 World Health Organization meeting compared the two and noted that both came from consumer products presumed safe, both carried many trace contaminants, and in both the causal chemical remained unidentified. No clinical or laboratory feature was found to be unique to either, and diagnosis rested on the clinical judgment of the treating physician (Philen 1993).

October 1989: The New Mexico Cluster

On October 30, 1989, the New Mexico Health and Environment Department learned of three patients with eosinophilia and severe muscle pain who had been taking L-tryptophan (Eidson 1990). The clinicians who saw them later described the series. All three were women aged 37 to 44, with severe muscle pain, muscle weakness, mouth ulcers and eosinophil counts above 8,000 per cubic millimeter. Fever, abdominal pain, shortness of breath, rash and raised liver and muscle enzymes also appeared. They had been taking 1.2 to 2.4 grams of tryptophan a day, for periods from three weeks to two and a half years. Tests for trichinosis and other parasites, and for allergic and connective-tissue disorders, were negative. Stopping tryptophan and starting glucocorticoid treatment brought improvement, yet all three still had symptoms three to five months later (Hertzman 1990).

Biopsies showed eosinophils in the tissue, along with a toxic eosinophil protein called major basic protein deposited outside the cells. This pointed to eosinophils releasing their contents into organs (Hertzman 1990). The authors wrote that identifying the link in these patients led to the discovery of an epidemic.

The state moved quickly. Investigators searched white blood cell counts from nine New Mexico laboratories, for May 1 to October 31, 1989, and interviewed 11 cases and 22 matched controls. All 11 cases had used L-tryptophan products, compared with only 2 of the 22 controls. The authors report that these findings led to a ban on sale in New Mexico, followed by a nationwide recall (Eidson 1990). The Centers for Disease Control published a report on the New Mexico illness on November 17, 1989 (Centers for Disease Control 1989a), and a second one a week later, covering New Mexico, Minnesota, Oregon and New York (Centers for Disease Control 1989b).

The Case Definition and the Reported Counts

The national surveillance system defined a case by two features: debilitating muscle pain and an absolute eosinophil count of at least 1,000 per cubic millimeter (Swygert 1990), with no infection or cancer to explain them (Spitzer 1995). New Mexico's first study used a stricter eosinophil cutoff of 2,000 (Eidson 1990). The definition was built for counting cases, and it had limits. In one South Carolina psychiatrist's practice, where 418 tryptophan users were interviewed, the authors concluded that a strict definition may identify only about half of those affected (Kamb 1992).

Source and dateWhat it reported
National surveillance, to July 10, 1990 (Swygert 1990)1,531 cases and 27 deaths
National surveillance, to August 10, 1991 (Swygert 1993)36 deaths related to the syndrome
Laboratory paper, 1993 (Hill 1993)"Several thousand" cases and 36 deaths
Review of the surveillance file, 1996 (Sullivan 1996a)1,345 people who satisfied the case definition
Food and Drug Administration paper, February 2001More than 1,500 cases and at least 37 deaths; true incidence "thought to be much higher"

In the 1990 national count, 68% of cases were non-Hispanic white women aged 35 or older, and the highest rates were in the western states. Of those reporting, 91% said symptoms began during or after May 1989, and 97% had taken tryptophan first. After the November 1989 recall of over-the-counter tryptophan, new cases fell dramatically (Swygert 1990). Cases were also reported elsewhere. A review of Germany, where tryptophan had drug status and patients were already under medical care, identified 105 patients through May 1992 (Carr 1994).

How the Cases Were Traced to One Manufacturer

The first question was whether tryptophan itself was the problem or something in certain batches. State health departments answered it by following bottles backward through the supply chain.

In Oregon, no common importer, wholesaler, tablet maker, encapsulator or distributor linked the cases. The link appeared one step further back: 45 of 46 cases (98%) had taken a product made by one manufacturer, compared with 3 of 10 telephone-survey controls and 15 of 31 volunteer controls. The lots tied to cases were significantly more likely to have been produced between January and June 1989 (Slutsker 1990). Minnesota found the same pattern: 29 of 30 patients (97%) and 21 of 35 controls (60%) had used tryptophan from a single company, an odds ratio of 19.3 with a wide 95% confidence interval of 2.5 to 844.9 (Belongia 1990). An odds ratio compares how common an exposure was among patients and among controls; 1 means no difference.

New York's study came out the same way. All 113 traceable case-patients and 69 of 95 controls (73%) had used tryptophan from one Japanese manufacturer, and among those users the risk was far greater for product made after December 1, 1988 (odds ratio 25.8) (Back 1993). In Germany, every case was associated with formulators that had used raw material from the implicated source (Carr 1994).

Minnesota's investigators then looked inside the plant's own records. The company made tryptophan by fermentation, using the bacterium Bacillus amyloliquefaciens. Lots used by patients were associated with reduced quantities of powdered carbon in a purification step (odds ratio 9.0, confidence interval 1.1 to 84.6) and with a new bacterial strain called Strain V (odds ratio 6.0, confidence interval 0.8 to 51.8). The two changes were themselves correlated (Belongia 1990). A 2021 neurology review describes the bacteria as genetically engineered (Mathis 2021). A 1994 review concluded that the illness was probably triggered by an impurity formed when manufacturing conditions were modified, and drew the lesson that biotechnology products need close purity monitoring after any significant process change (Mayeno 1994).

Peak E and the Other Trace Contaminants

A laboratory method called high-performance liquid chromatography separates a mixture into a series of peaks on a chart. Run on this company's tryptophan, it showed one peak, labeled "peak E", in 9 of 12 retail lots used by patients (75%) and 3 of 11 lots used by controls (27%), an odds ratio of 8.0 with a confidence interval of 0.9 to 76.6. The authors wrote that peak E might contribute to the illness or might only be a stand-in for another chemical (Belongia 1990).

Later that year, chemists identified peak E as 1,1'-ethylidenebis[tryptophan], essentially two tryptophan molecules joined together. They again left both possibilities open: the cause, or a marker of a still unidentified cause (Mayeno 1990).

The list of suspects then grew:

Peak E's standing weakened on closer analysis. In a study of 101 lots, once lots were grouped by time of manufacture, higher peak E levels were still associated with case lots, but no longer significantly (odds ratio 1.56, confidence interval 0.758 to 3.23, p = 0.120). The authors wrote that other contaminants might modify its effect or that the true cause might be a different compound entirely (Philen 1993b).

Laboratory work has pointed in more than one direction:

What Regulators Did and When the Import Restriction Ended

The sequence, as the sources record it:

The word "ban" in those accounts is looser than the agency's own wording. The 2001 paper states that its safety concern "does not mean that FDA prohibits the marketing" of supplements containing L-tryptophan. Under the Dietary Supplement Health and Education Act of 1994, it explains, a firm is responsible for its product's safety and needs no premarket approval. The same paper states the agency's safety position at that time: it "cannot determine that oral dosage forms of L-tryptophan and related compounds such as L-5-hydroxytryptophan can be safely used as dietary supplements" (Food and Drug Administration 2001).

Symptoms and the Skin, Nerve, Lung and Heart Findings

The national count gives the broad picture. Beyond the defining muscle pain, the most frequent features were joint pain (73%), rash (60%), cough or shortness of breath (59%), swelling of the limbs (59%), a raised muscle enzyme called aldolase (46%) and abnormal liver tests (43%). Nerve damage or inflammation appeared in 27%, in some cases leading to paralysis and death, and 21% of those tested had abnormal chest X-rays (Swygert 1990). An Oregon follow-up describes the timing: severe muscle pain, fatigue, weakness, swelling and rash tended to start in the first three months, while tingling, cramps, limb weakness and hair loss tended to come later (Hedberg 1992).

Skin and fascia

In a report on 10 patients, skin changes fell into three groups: patches of hardening resembling morphea, hive-like and bumpy lesions, and widespread hardening. Under the microscope they looked strikingly similar, with inflammation around blood vessels, mucin deposits and inflamed fascia. An average of 24 months after stopping tryptophan, 30% still had severe, disabling disease (Oursler 1992). Fascia is the sheet of connective tissue surrounding muscles. Some patients developed eosinophilic fasciitis, a thickening and inflammation of that layer (Martin 1990). Reports often call the hardening scleroderma-like, after the skin disease of systemic sclerosis. A 2011 study of a later case found activated transforming growth factor beta and interleukin-4 signaling in the affected skin (Allen 2011).

Nerves and brain

One series described 10 patients whose peripheral neuropathy was prominent or the only presenting feature. Two needed mechanical ventilation and one died, and severity appeared to rise with the total tryptophan dose (Smith 1990). A smaller series described three patients with mostly motor nerve damage in the legs: two used wheelchairs and one was ventilator-dependent and bedridden. Nerve biopsies showed axon degeneration in all three, and quinolinic acid, a nerve-toxic breakdown product of tryptophan, was raised in the spinal fluid of the two tested (Heiman-Patterson 1990). A study of 23 patients and 18 controls found specific deficits in complex visual memory, shifting between concepts, and attention. Eight of 12 brain scans showed white matter abnormalities (Armstrong 1997).

Lungs

Of 18 patients with chest X-rays, nine were normal. The other nine showed fine linear shadows in the lungs, fluid around the lungs, or both, with denser shadows in some (Williamson 1991). In two autopsied patients, the lung findings included damage to the lining of blood vessels, inflammation inside arteries and veins, and interstitial pneumonitis with scarring (Herrick 1991). Long-term complications listed at the 1991 World Health Organization meeting included pulmonary hypertension, peripheral nerve damage and joint contractures (Philen 1993).

Heart

In three fatal cases, the small arteries, nerves and conduction system of the heart were abnormal, and within the heart's natural pacemaker, areas of dense scar had replaced the nodal tissue. The authors wrote that this could underlie electrical instability and sudden death (James 1991). One 46-year-old woman developed restrictive cardiomyopathy, with dense scarring of the heart's inner lining, two years after stopping tryptophan (Berger 1994).

How people died

A review of 36 reported deaths found that all involved several organ systems: 33 had nerve and muscle complications, 29 lung complications and 23 heart involvement. Progressive nerve and muscle disease, ending in pneumonia, sepsis or respiratory failure, was the most common route (24 of 36). Heart muscle disease was the underlying cause in 4, primary lung disease in 3, sudden death attributed to arrhythmia in 2, stroke in 2, and septic complications of therapy in 1. Patients who died were older and had higher white cell and eosinophil counts (Swygert 1993).

What Long-Term Follow-Up Studies Found

Follow-up studies agree that this was rarely a short illness, but they differ in how much recovery they found. Their patients came from different sources, and a 1996 summary cautions that patient selection and missing information on health before the illness limit even the largest of them (Pincus 1996).

The treatment evidence in these reports comes from observation. Prednisone was reported as helpful in 79% of those who received it in the acute phase, and no other treatment was reported to be consistently beneficial (Hertzman 1995). In Washington state, long-term duration and severity did not differ significantly between patients who did and did not receive prednisone (Culpepper 1991). The university clinic reported that early corticosteroids did not seem to prevent chronic problems (Kaufman 1991). The 1991 World Health Organization meeting recorded symptomatic relief without a change in clinical course or long-term outcome, and cumulative mortality of about 2.5% in the first two years (Philen 1993).

Later Reports Linked to Tryptophan and 5-Hydroxytryptophan

Before the epidemic

The illness may not have begun in 1989. Among 45 patients with eosinophilic fasciitis diagnosed before 1988, nine (20%) recalled taking L-tryptophan beforehand, compared with none of 126 polymyositis patients used as controls (Hibbs 1992). In the national surveillance file, 191 of 1,345 cases (14%) reported illness starting before July 1, 1989, and 26 (2%) reported no tryptophan use at all. Those non-users were younger and more likely to have started before the epidemic, but otherwise looked similar (Sullivan 1996a).

After the recall

A survey of doctors in Ontario and Quebec, where access to tryptophan was limited, identified 19 definite and 25 possible cases among 6,423 patients assessed, and the physicians' information did not suggest tryptophan use. The authors wrote that this brought causal interpretations of earlier studies into question (Spitzer 1995). In 2011, a United States group reported a new case associated with L-tryptophan, writing that none had been described since 2005 (Allen 2011). In 2014, one report described a 59-year-old woman with this diagnosis after a weight-loss diet heavy in cashew nuts. They attributed it to extreme tryptophan intake from the nuts, and she improved after stopping them and taking steroids. This is a single case report, and the attribution is its authors' own (Barešić 2014).

5-Hydroxytryptophan

5-hydroxytryptophan (5-HTP) is the next step after tryptophan on the way to serotonin. Its supplement story runs alongside this one, and the 5-HTP page covers it in general. The reports here are few and disputed:

A related laboratory finding involves melatonin. In three commercial preparations, chemists found seven contaminants, six of which were analogues of impurities in the contaminated tryptophan. The same paper notes that no major outbreak has followed melatonin use (Williamson 1998).

The Unresolved Cause: Contaminant, Tryptophan or Dose

Most of the epidemiology points at something in one manufacturer's product, yet no single chemical has been proven responsible. Several positions remain in the published record.

The contaminant view

The tight link to one source, to specific production months and to changes in the plant's process supports this position, and the same pattern held in Oregon, Minnesota, New York and Germany. A 2012 nutrition review states that the cause was shown to be a contaminant in certain production batches and not tryptophan (Fernstrom 2012). A 2022 review of amino acid impurities makes a similar general point: it reports no adverse effects from amino acid overdosing and names impurities in low-quality amino acids as causes of several health hazard events (Karakawa 2022). The two 2018 chemistry papers open by treating the manufacturer's product as the cause, while identifying which compounds were in it (Klarskov 2018a; Klarskov 2018b).

The unproven-culprit view

Others stop short of naming any chemical. The Food and Drug Administration's 2001 paper says the role of the impurities "is unclear", that they may be only markers, and that it cannot determine with certainty whether illness comes from the tryptophan, an impurity or a combination with unknown outside factors. It also cites rat studies in which myofascial thickening and pancreatic scarring occurred with control tryptophan that lacked peak E, and says these raise "serious questions regarding the safety of high dose levels" of uncontaminated L-tryptophan. It also records that many people who took the implicated product stayed well (Food and Drug Administration 2001). The 2023 review reaches a similar place: many laboratory and animal studies have tested the suspect impurities, and "no clear and convincing conclusions have been drawn so far" (Ko 2023). Four of that review's six authors declared employment at a company in South Korea (Ko 2023).

The challenge to the original studies

A few authors questioned the association itself. A 1995 methods review argued that the first case-control studies had selection bias, information bias and confounding, and that the studies of brand had similar problems, concluding that the cause remained unknown (Daniels 1995). A 1997 article noted that the early tryptophan studies included only 23 patients and that case reports were inconsistent. It also found that clinicians shown a case were much more likely to diagnose the syndrome when tryptophan use was mentioned (Blackburn 1997). Those arguments sit beside the Canadian survey above, and beside one early series of 20 patients in which no relation to dose or duration was apparent and chromatography and mass spectrometry identified no organic contaminants (Martin 1990).

Dose and the person taking it

Dose has been measured repeatedly, and most studies found a link. In the South Carolina practice, among 157 users of one retail brand, 29% developed definite illness and 23% possible illness, and risk rose with dose: of 38 people using more than 4,000 milligrams a day, 50% developed definite illness and 84% definite or possible illness. The authors called the dose of presumably contaminated tryptophan the most important predictor (Kamb 1992). New York found higher risk with higher dose, older age and use as a sleep aid (Back 1993). The German review found no apparent correlation with dose or duration (Carr 1994). A dose link cannot separate more tryptophan from more contaminant, since in these products the two rose together; the Oregon authors made this point when they suggested that varying contaminant amounts may explain part of the severity (Hedberg 1992).

Personal biology may also play a part. In 94 white subjects with documented tryptophan use, higher dose, age over 45 and certain immune-gene types (HLA-DRB1*03, DRB1*04 and DQA1*0601) were risk factors, while DRB1*07 and DQA1*0501 appeared protective (Okada 2009).

Modern direct safety data on tryptophan alone remain small. One randomized, double-blind, placebo-controlled crossover trial gave 17 healthy Japanese women aged 18 to 26 placebo or 1 to 5 grams of L-tryptophan a day, for 21 days at each level, and reported no effect on the general blood and urine markers measured, food intake, body weight or mood (Hiratsuka 2013). Each dose ran for three weeks in those 17 women. The 2012 review describes the wider safety literature as small and largely anecdotal, and says a thorough, dose-related assessment of side effects remains to be conducted (Fernstrom 2012).

Key Research Papers

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