Wednesday, February 01, 2006

Why tryptophan is bad for people who have chemical imbalances related to histamine and serotonin.

This post is a continuation, with all the fine print, and gory pathological detail, of a post that starts at GMO Pundit as follows:

By a strange twist of fate, GMO Pundit is ideally placed to alert readers to a real hazard - excessive tryptophan intake in the wrong circumstances - that is widely misunderstood in the community, and is a previously falsely diagnosed risk.

The main point of this posting is to help people avoid ill health - that is avoid generalised muscular pains (myalgia, called EMS) - that might be caused by ill-advised self-medication with tryptophan, or excessive intake of foods rich in tryptophan. Such intake is commonly taken because it is perceived to help overcome mental depression caused by chemical imbalances in the brain.

Pundit also wants to get over the message that false information itself can cause harm by the distractions it creates that become red-herrings obscuring which are effective and most important safety precautions to be taken.

go to Tryptophan Risk confusion for the continuation of this story over at GMO Pundit.
go to 1.20—High Doses of Tryptophan Cause EMS at Academics Review for a readable short update on how this issue has been mis-used by Jeffrey M Smith  (March 2010)

While over at GMO Pundit, when you get to a link that brings you back here for further details, just click it.

The following are extensive quotations of relevant biological science, starting with the recent major medical review article by Smith and Garrett that explains how there has been a paradigm shift on concepts telated to EMS and similar diseases.

Some points that falsify the conjecture thay GM technology causes EMS are coded in Red. Point supporting other factors cause EMS are in Blue. Further points are obtainable in the original paper and in the extra quotes at GMO Pundit

At the end is an extensive literature citation list on the topic.

A heretofore undisclosed crux of Eosinophilia-Myalgia Syndrome [EMS] : compromised histamine degradation.

M. J. Smith1 and R. H. Garrett2 Infl ammation Research 54 (2005) 435–450
1 Division of Natural Products, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway,
College Park, Maryland 20740-3835, USA, Fax: ++ 301 436 2644, e-mail:
2 Department of Biology, University of Virginia, Charlottesville, Virginia, 22904-4328, USA, Fax: ++ 434 982 5626, e-mail:

In contrast to early epidemiological evidence offering links between eosinophilia-myalgia syndrome (EMS) and microimpurities of L-tryptophan-containing dietary supplements (LTCDS), this account shows why reliance on a finite impurity from one manufacturer is both unnecessary and insufficient to explain the etiology of EMS. Excessive histamine activity has induced blood eosinophilia and myalgia (Greek:mys, muscle + algos, pain). Termination of the multiple actions of histamine is dependent on particular amine oxidases and histamine-N-methyltransferase. Histamine metabolism is rapid when these degradative reactions are operative. The latent effects of incurred histamine can be potentiated and aggravating when these mechanisms are impaired. Overloads of tryptophan supplements cause – among other relevant side-effects – an increased formation of formate and indolyl metabolites, several of which inhibit the degradation of histamine. Moreover, (non-EMS) subjects with hypothalamic-pituitary-adrenal (HPA) axis dysregulation have also manifested greatly increased sensitivities to incurred tryptophan and histamine. A final common pathway for syndromes characterized by eosinophilia with myalgia is now evident.

A scientific tenet is undermined when the manifestations of a malady or outbreak are attributed – without ascertainable evidence – to a singular cause. Because a wide variety of agents and conditions can induce metabolic aberrations inextricably linked to compromised histamine degradation, reliance on a finite impurity as “the etiologic agent” [11, 34–36] is both unnecessary and insufficient to account for the key features of EMS.
At a minimum, over 20,000 consumers were seriously afflicted by eosinophilia with myalgia in the 1980s, and nearly 400 direct deaths have been recorded [2, 317].41 Above all, a wide spectrum of primary data converges at the etiologic junction where compromised histamine degradation, abnormal eosinophil counts and myopathy overlap — whereby histamine disequilibrium appears to be a final common pathway for syndromes characterized by eosinophilia with myalgia. Sattler and Lorenz [318] have outlined a “histaminosis” model of disease susceptibility based on histamine and incurred inhibitors of SSAO.
Processes that bring hazards, maladies and outbreaks to professional and public attention can create misperceptions about their root causes and true incidences. Misdiagnosis of histamine intoxication is common [118] and compromised histamine degradation is even less perceptible. Apprehensions that EMS-like disorders will continue to surface among unsuspected subpopulations are well-founded in light of several mechanisms (disclosed above) that greatly increase a subject’s sensitivities to incurred tryptophan and histamine.

J Neural Transm Suppl. 1990;32:291-314.
Intestinal diamine oxidases and enteral-induced histaminosis: studies on three prognostic variables in an epidemiological model.Sattler J, Lorenz W.
The danger of luminal histamine administered orally or formed in the intestinal fluid by bacteria has long been neglected. However, the demonstration of blocking intestinal diamine oxidase (DAO) by a variety of common drugs has revived the discussion and has created a new disease concept: enteral-induced histaminosis. In an animal model the three central prognostic variables of this disease concept (large amounts of histamine in food to make the individual ill, blocking of DAO by commonly used drugs, and the relationship between increased plasma histamine levels and disease manifestation by exogenous histamine application) were tested with randomized trials in vivo and biochemical tests in vitro using semipurified enzymes from pig and man. In the first trials authentic histamine in quantities similar to that in normal amounts of food or cheese bought from a supermarket produced life-threatening reactions if the DAO was inhibited by pretreatment with aminoguanidine. In the second series of experiments in vitro a numerous commonly used drugs was shown to inhibit both the porcine and human enzyme. Some of the inhibitors were really strong, such as dihydralazine, chloroquine, pentamidine, cycloserine, clavulanic acid, dobutamine, pancuronium and others. The type of inhibition was sometimes competitive as in the case of dihydralazine and pancuronium, sometimes non competitive (e.g. pentamidine) which may be important for long-term treatment.
In the third group of experiments a relationship between the dose of i.v. injected histamine and the elevation in plasma histamine levels and clinical symptoms in pigs was demonstrated. Hence, elevated plasma histamine in pigs acts as a pathogenetic factor for the disease manifestation. It is concluded that after modelling enteral-induced histaminosis in an animal the trias of variables shown in this study should be consequently investigated in man.

According to certain epidemiologists, “the available evidence provides a strong basis for concluding consumption of products containing tryptophan manufactured by Showa Denko caused the 1989 epidemic of EMS in the United States” [12]. Some medical dictionaries [13], websites2 and many investigators have favored such hypotheses, e. g., “Conclusions. The outbreak of EMS in 1989 resulted from the ingestion of a chemical constituent that was associated with specific tryptophan-manufacturing conditions at one company” [14]. With respect to studies offering links between EMS and tryptophan-manufacturing conditions at Showa Denko K.K., one epidemiological study emphasized: “the company used a fermentation process involving Bacillus amyloliquefaciens to manufacture tryptophan. In December 1988, the company introduced a new strain of B. amyloliquefaciens that increased the synthesis of serine and 5-phosphoribosyl-1-pyrophosphate, which are intermediates in the biosynthesis of tryptophan. This new strain (Strain V) was used for the manufacture of tryptophan after December 25, 1988” [14].

Innumerable investigations worldwide have attempted to resolve the precise cause(s) of eosinophilia with myalgia.3 As yet, few molecular breakthroughs have emerged. Pervasive hypothesis, two alleged (and partially interrelated) cofactors – namely, genetic engineering and a microimpurity/ies of dietary supplements [15] – are both unnecessary and insufficient explanations of enigmatic (multifactorial)4 chains of causality underlying a majority of official EMS cases.
Numerous etiologic incongruities [16–19]

[16] Blauvelt A, Falanga V. Idiopathic and L-tryptophan-associated eosinophilic fasciitis before and after L-tryptophan contamination. Arch Dermatol 1991; 127: 1159–66.
[17] Spry CJF. Eosinophils: A Comprehensive Review, and Guide to the Scientifi c and Medical Literature. Oxford, U.K.: Oxford University Press, 1988: 1–484.
[18] Goronzy JJ, Weyand CM. Eosinophilia, myopathy, and neuropathy in a patient with repeated use of L-tryptophan. Klin Wochenschr 1990; 68: 735–8.
[19] Kaufman LD. Neuromuscular manifestations of the L-tryptophanassociated eosinophilia-myalgia syndrome. Curr Opin Rheumatol 1990; 2: 896–900.

– including two reports of L-tryptophan-induced eosinophilia with myalgia in 1986 [20–22] – underscore why a paradigm shift was advisable.

[20] Strongwater SL, Woda BA, Yood RA, Rybak ME, Sargent J, De-
Girolami U et al. Eosinophilia-myalgia syndrome associated with L-tryptophan ingestion. Analysis of four patients and implications for differential diagnosis and pathogenesis. Arch Intern Med 1990; 150: 2178–86.

[21] Lakhanpal S, Duffy J, Engel AG. Eosinophilia associated with perimyositis and pneumonitis. Mayo Clin Proc 1988; 63: 37–41.
[22] Martin RW, Duffy J, Engel AG, Lie JT, Bowles CA, Moyer TP et al. The clinical spectrum of the eosinophilia-myalgia syndrome associated with L-tryptophan ingestion. Clinical features in 20 patients and aspects of pathophysiology. Ann Intern Med 1990; 113:124–34

According to several analytical surveys, incriminated tryptophan met Pharmacopeia criteria (DAB 9) for products intended for medicinal purposes in Germany [23]. LTCDS [Diet with tryptophan supplement] incriminated in the U.S. were Pharmacopoeia grade also [11]; aside from one internally incongruent outlier about inorganic impurities [24], no known data undercut widespread evidence that other incriminated case lots had ananalytical purity of 98.5%5 or higher [5, 7, 25–27]. Analysis of other incriminated case lots disclosed purities of 99.6%, which meet Japanese Pharmacopoeia specifications [28–30].
Thus, the quantities of adulterants in incriminated LTCDS remained exceedingly low – 650 ppm for the most prevalent (confirmed) impurity [31] – according to virtually all ascertainable evidence.

Additional counterevidence from Waller, Wood, Breckenridge and Rawlins, (published by the London Department of Health and Social Security) disclosed at least 3 official6 EMS cases in the United Kingdom that were associated with a Merck pharmaceutical product containing L-tryptophan (Optimax)7 [32]. An analogous survey in Ireland disclosed 5 cases of eosinophilia linked to Optimax [33]. These little known landmarks do not comport with hypotheses that “the etiologic agent” [11, 34–36] of L-tryptophan-induced EMS is a finite microimpurity/ies of LTCDS manufactured by Showa Denko K.K.

As the proceedings of a symposium devoted to EMS amply illustrate (J Rheumatol 1996; 23 (Suppl 46): 1–110), epidemiological data implicating finite microimpurities from one manufacturer are controversial and understandably so. One should be mindful of six incontestable facts that collectively undercut unifactorial explanations of an epidemiologic spike [37, 38] in recorded cases of eosinophilia with myalgia in the late 1980s: the stringent surveillance criteria devised for case-control studies were never meant to be employed as diagnostic criteria [11]; a U.S. Food and Drug Administration (FDA) nationwide recall and import alert in November 1989 for LTCDS in which L-tryptophan is the sole or major component [39]; a preceding “sharp upturn” [40] in nationwide consumption of L-tryptophan supplements [41, 42]; an inconsistent incidence among subjects who consumed L-tryptophan from common bottles [43]; a relatively low yet telling apparent incidence (vis-à-vis stringent criteria compounded by host susceptibility; see the penultimate Section) [44]; and lastly, analytical determinations of blood cell counts remain unmonitored in most medical checkups.

Aust N Z J Psychiatry. 1988 Mar;22(1):83-97. L-tryptophan: a rational anti-depressant and a natural hypnotic? Boman B.
L-tryptophan is an essential amino acid which is the metabolic precursor of serotonin. Because of the evidence that serotonin deficiency may be an aetiological factor in some sorts of affective disorder and that serotonin is important in the biochemistry of sleep, L-tryptophan has been suggested as a "rational" anti-depressant and as a "natural" hypnotic. This paper reviews the
biochemistry and pharmacology of L-tryptophan as well as the literature of the clinical trials that have been conducted with it and suggests that, by itself, L-tryptophan may be useful in mild cases of depression accompanied by endogenous features and cases of bipolar disorder resistant to standard treatments. It also potentiates the monoamine oxidase inhibitors and possibly the serotonergic tricyclic drugs. L-tryptophan may improve the depressed mood of Parkinsonian patients and has a clinically useful hypnotic action. There is evidence it may be useful in organic mental disorders induced by levodopa. Dosage schedules, contraindications and complications are discussed.

primarily because of implied benefits that might be accrued if certain indoleamines were to be augmented; cf. the serotonin hypothesis of affective disorders [102].

Dis Nerv Syst. 1977 Aug;38(8):646-53. The indoleamine hypothesis of depression: an overview and pilot study. Zarcone VP Jr, Berger PA, Brodie KH, Sack R, Barchas JD.

This paper reviews the evidence for a specific indoleamine deficiency in depression and the attempts to correct this suspected deficiency with serotonin precursors. It also presents the clinical and biochemical data on six patients with depression treated with L-5-HTP in a nonrandom, double-blind protocol. The oral administration of L5-HTP was associated with a rise in CSF5-HIAA, but only two of six patients studied had any decrease in depression ratings. 5-HTP was also shown to decrease urinary excretion of 17 hydroxycorticosteroids in twodepressed patients and three normal controls suggesting an interrelationship between serotonin metabolism and the pituitary adrenal system. This leads to the suggestion that in a postulated subgroup of depressed patients with pituitary adrenal hyperactivity and evidence of serotonin deficiency, L5-HTP deserves a further trial as an experimental treatment.

According to several epidemiologists, host susceptibility bias (among other little-known shortcomings) [46, 264, 303, 311–316] undercut the few case-control studies on EMS performed; hence, statistical (epidemiological) underpinnings purportedly supporting a contaminant theory’s primacy as well.

[46] Shapiro S. Epidemiologic studies of the association of L-tryptophan with the eosinophilia-myalgia syndrome: a critique. JRheumatol Suppl 1996; 46: 44–58; discussion 58–9.
In 1989 and 1990, 2 reports of a new disease labeled the eosinophilia-myalgia syndrome (EMS) and attributed to L-tryptophan (LT) were published. In subsequent studies a putative contaminant was implicated. In this review the following studies are considered: the initial 2 reports of the overall association, one report of an association between LT and eosinophilic fasciitis, and one report describing the scale of the apparent epidemic of LT induced EMS. Of the 2 initial studies, one included previously reported exposed cases, failed to rule out the possibility that early symptoms of EMS could have caused LT use rather than the reverse, and failed to adhere to the methods, as published. The 2nd study has not been published in a peer reviewed journal. The study of eosinophilic fasciitis was subject to information bias and misclassification of the timing of LT use. The apparent epidemic could have been an artefact of waxing and waning enthusiasm for reporting exposed cases to an EMS registry, corresponding with the timing and the amount of publicity given to the topic. The questionable validity of these studies considerably weakens the claim that LT or a contaminant caused EMS.

[264] Daniels SR, Hudson JI, Horwitz RI. Epidemiology of potential association between L-tryptophan ingestion and eosinophilia-myalgia syndrome. J Clin Epidemiol 1995; 48: 1413–27; discussion 1429–40.

This article examines the methodology of the epidemiological studies of the association between L-tryptophan and eosinophilia-myalgia syndrome (EMS) and evaluates the validity of the conclusions from these studies. In the initial case-control studies of L-tryptophantryptophan and EMS there were a variety of methodological problems, including different sources and different exclusion criteria for cases and controls, which could have resulted in selection bias, as well as problems with information bias and confounding. The studies of manufacturer and brand also had similar potential for bias. The L-tryptophan-EMS association is based on two small studies that had important methodological inadequacies. Subsequent studies of brand of L-tryptophan also contained errors in design, which may have produced biased results and call the conclusions into question. The cause of eosinophilia-myalgia syndrome remains unknown.

[303] Shapiro S. L-tryptophan and eosinophilia-myalgia syndrome.Lancet 1994; 344: 817–9.

[311] Spitzer WO, Haggerty JL, Berkson L, Davis W, Palmer W, Tamblyn R et al. Continuing occurrence of eosinophilia myalgia syndrome in Canada. Br J Rheumatol 1995; 34: 246–51.

Eosinophilia myalgia syndrome (EMS), was defined by the Centers for Disease Control (CDC) as eosinophilia > 1000 mm3 and incapacitating myalgia without infection or neoplasm. Studies suggested that use of L-tryptophan (L-T), was a risk factor. We conducted a pharmacoepidemiological survey in Canada where access to L-T is limited. Using the active surveillance method, a 100% sample of potentially involved specialists and a 15% sample of family physicians from Ontario and Quebec were surveyed regarding treatment of patients with severe myalgia within the past year. Follow-up amplified clinical and laboratory information. Overall response rates were 61.4%. Thirty-eight per cent of respondents reported at least one patient. Of 6423 patients assessed, 19 'definite' and 25 'possible' EMS cases were identified. Information from physicians did not suggest use of L-T in patients with definite or possible EMS. It was considered that the cases found an underestimate of the incidence of EMS. Its continuing occurrence in Canada brings causal interpretations of earlier studies into question.

[312] Spitzer WO, Haggerty JL, Berkson L, Davis W, Palmer W, Tamblyn R et al. Analysis of Centers for Disease Control and Prevention criteria for the eosinophilia-myalgia syndrome in a geographically defi ned population. J Rheumatol Suppl 1996; 46: 73–9; discussion 79–80. 1: J Rheumatol Suppl. 1996 Oct;46:73-9; discussion 79-80.

OBJECTIVE: To test whether individuals can be identified in a geographically defined population who would meet criteria for the eosinophilia-myalgia syndrome (EMS) established by the US Centers for Disease Control and Prevention (CDC), i.e, (1) eosinophil count > 1 x 10(9)/l, (2) myalgia severe enough to limit usual activities of daily living, and (3) no evidence of infection or neoplasm that could explain the first 2 findings. METHODS: To discover the number of individuals who would meet CDC criteria, the population was exhaustively searched using methods adapted from active pharmacoepidemiologic surveillance.
Medical consultants and primary care practitioners were questioned as many as 5 times in a search for patients with severe myalgia. A predetermined protocol was used to screen those patients who appeared to meet CDC criteria for EMS using active surveillance methods. The study population was limited to Quebec and Ontario (combined population 18,980,000) with special attention to the period July 1, 1992, to June 30, 1993. RESULTS: The prevalence of severe incapacitating myalgia was 43 per 100,000 persons, including 19 individuals with eosinophilia > 1 x 10(9)/l, who met CDC criteria for EMS. None of these individuals were reported to have taken L-tryptophan (LT). CONCLUSION: The CDC criteria for EMS are met by individuals in the general population who have never been exposed to LT.

[313] Hudson JI, Pope HG Jr, Daniels SR, Horwitz RI. Eosinophiliamyalgia
syndrome or fibromyalgia with eosinophilia? JAMA
1993; 269: 3108–9.

[314] Shapiro S. Comment. J Rheumatol Suppl 1996; 23: 89–91.

[315] Shapiro S. L-tryptophan and eosinophilia-myalgia syndrome.
Lancet 1994; 343: 1035–7.
[316] Horwitz RI, Daniels SR. Bias or biology: evaluating the epidemiologic
studies of L-tryptophan and the eosinophilia-myalgia
syndrome. J Rheumatol Suppl 1996; 46: 60–72.

Department of Medicine and Epidemiology, Yale University School of Medicine, New
Haven, Connecticut 06520-8056, USA.

When investigating the cause of a chronic disease, epidemiologists are forced to substitute observational, nonexperimental methods such as cohort or case-control studies for the scientifically preferred "gold standard," the randomized controlled trial. Because neither cohort nor case-control studies are done under experimental conditions, the results may not accurately reflect those that would be found in a randomized experiment. Before the results of epidemiologic research can be used for inference regarding a cause of disease, it is necessary to examine the design and conduct of such studies to ensure their results could not have been distorted by potential sources of bias. We evaluate the epidemiologic studies of the relationship between intake of L-tryptophan (LT) and the occurrence of eosinophilia-myalgia syndrome (EMS) from information provided in the published reports and underlying data and documentation of the studies obtained from the US Centers for Disease Control and state health departments. We reviewed separately the initial 2 studies that examined the link between LT and the risk for EMS and the subsequent studies that focused on the specific manufacturing process or chemical constitutents of LT that might have been responsible for EMS. The 2 initial studies compared cases of EMS with controls who were asymptomatic. The investigators concluded that ingestion of LT was associated with the occurrence of EMS. However, these studies contained methodologic problems, including diagnostic bias, publicity, recall and reporting bias, bias in the inclusion and exclusion of cases and controls, inequalities between cases and controls in the indications for the use of LT, and failure to ensure that the exposure to LT preceded the onset of symptoms of EMS. These potential biases make it difficult to use the data derived from these investigations to justify a causal inference. Subsequent studies were conducted under the assumption that there was a valid association between ingestion of LT and the occurrence of EMS. These studies focused on tracing back LT to the manufacturer. These studies also had a variety of methodologic shortcomings, including problems in the assembly of study subjects leading to the selected samples of cases and controls, the lack of information on the brand and lot of LT for many subjects, multiple brand use, differences in the timing of exposure between cases and controls, the difficulty of the process of tracing LT products to the appropriate manufacturer, inconsistent classification of symptoms depending on brand of LT used, and inconsistencies in the traceback procedures between cases and controls. In light of these analyses, it appears that the cause of EMS has not been definitively identified. The search for the cause of EMS should continue without the underlying assumption that LT or some contaminant is responsible.

( Many thanks to R Roush, A. Apel, and A. Avery for the original reference heads-up)

The Full Monty on tryptophan EMS references
A heretofore undisclosed crux of Eosinophilia-Myalgia Syndrome: compromised histamine degradation
M. J. Smith and R. H. Garrett Inflamm. res. 54 (2005) 435–450

Collected other references (from above review) provide the Full Monty on tryptophan and EMS:

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