1 1 MSG: A Review of the Literature and Critique of Industry Sponsored Research January 30, 1991 Revised July 1, 1991 by Adrienne Samuels, Ph.D. Truth in Labeling Campaign P.O. Box 2532, Darien, IL 60561 ABOUT THE AUTHOR Adrienne Samuels, Ph.D., is wife of one, mother of four, experimental psychologist by training, and educational psychologist by degree. She holds a B.S. degree from Northwestern University where she graduated with distinction and departmental honors. She won her Ph.D. degree from the University of Wisconsin, Madison where she studied with Chester Harris and Julian Stanley, both statisticians. While her children were in school, Adrienne worked part time on a variety of research projects (one funded by the Administration on Aging), as a consultant to public school programs of gifted education, and as a private psychometrician and counselor of gifted children and their parents. Among her credits are terms as elementary school PTA president and president of the Illinois Council for The Gifted. In 1981, Adrienne joined her husband in his investment banking firm where she served as chief compliance officer until her husband was forced to retire due to his sensitivity to MSG. In 1988, in an attempt to better understand the etiology of her husband's life-threatening sensitivity to man-made glutamic acid, popularly referred to as monosodium glutamate (MSG), Adrienne undertook an investigation of the literature on MSG toxic reactions in animals and adverse reactions in humans. She has written extensively to the FDA and to various members of the Congress. She has testified before the Advisory Committee on the Food and Drug Administration and submitted testimony to the Federation of American Societies for Experimental Biology, Life Sciences Research Office on the Evaluation of the Safety of Amino Acids and Related Products, and Analysis of Adverse Reactions to Monosodium Glutamate (MSG) FDA Docket No. 92N-0391. She has authored "MSG: A Review of the Literature and Critique of Industry Sponsored Research," "MSG and the FDA: Historical Perspective," "MSG: Food For Thought But Not For Eating," and a number of shorter letters and papers. She has co-authored "MSG: The Truth and Consequences." She is a member of the consumer group NOMSG and secretary of the Truth in Labeling Campaign. August 15, 1995 TABLE OF CONTENTS ABSTRACT 1 INTRODUCTION TO THE PROBLEM 2 RESEARCH: GLUTAMATE AS A DRUG 6 RESEARCH: THE ANIMAL STUDIES 7 Retinal Lesions 7 Hypothalamic Lesions: Non-Primates 7 Hypothalamic Lesions: Sub-Human Primates 8 Neuroendocrine Disorders 8 Focus on Ad Libitum Feeding 9 Focus on Older Animals 10 Focus on Pregnant Females 11 THE ALLEGED PROOF THAT MSG IS SAFE 11 Understanding Statistics 11 Method: How to Obfuscate with Research Design Methodology and Interpretation 12 Animal Studies: Lesions 15 Retinal Lesions 15 Brain Lesions 15 Focus on Subhuman Primates 17 Neuroendocrine Disorders / Ad Libitum Feeding 20 Focus on Pregnant Females 27 THE ANIMAL STUDIES: Putting it All in Perspective 27 The Findings 27 Do the Animal Studies Approximate the Human Condition? What Do We Know? 29 THE HUMAN STUDIES 29 Introduction 29 Evidence of Human Adverse Reactions: The First Case Studies and Research 31 Some Immediate Hypotheses 32 The First Food Industry Reaction 33 Methodology Particular to Human Research 35 The Chronology of the Reports and Studies in the 1970's 37 SUMMARY OF RESEARCH: NEURODEGENERATIVE DISEASE 46 THE JUDGES 47 THE CONCLUSION 47 REFERENCES 51MSG: A Review of the Literature and Critique of Industry Sponsored Research Adrienne Samuels, Ph.D. January 30, 1991 Revised July 1, 1991 Abstract Background In the United States, incidence and severity of human adverse reactions following ingestion of free glutamate (GLU) is increasing at an alarming rate. Yet the scientific community has ignored the literature which reports adverse reactions following ingestion of GLU, has ignored consumer reports of adverse reactions filed with the FDA, has ignored incontrovertible evidence that GLU causes neuronal necrosis in laboratory animals, and has ignored a growing body of evidence which suggests a relationship between elevated brain GLU levels and neurodegenerative disease; and has, instead, given credence to a body of literature produced by industry supported researchers who, 1) using sloppy design combined with misuse of statistics, purport to demonstrate that ingestion of GLU in the form of a food additive poses no hazard to humans, and 2) conclude that use of GLU as a food additive is safe. Method In this paper, we have reviewed, analyzed, and critiqued the industry sponsored literature. In so doing, we have included an extensive discussion of appropriate/inappropriate research methodology and some detail on the milieu in which the food industry has been able to perpetuate the myth that ingestion of GLU is safe. Results and Conclusion We have unequivocally demonstrated that neither any one study nor any preponderance of literature "proves" that ingestion of GLU in any form is safe. INTRODUCTION TO THE PROBLEM Glutamate (GLU) is an amino acid found in abundance in both plant and animal protein. In humans it is a non-essential amino acid, i.e., the body is capable of producing its own GLU, and is not dependent upon extracting GLU from ingested food. Outside of the body, GLU is produced commercially in food manufacturing and chemical plants. Monosodium glutamate (MSG) is manufactured GLU to which a sodium ion has been attached. Although an extract of seaweed has been used by oriental cultures to enhance food flavor for over 1,000 years, it was not until 1910 that the essential component responsible for the flavor phenome-non was identified as GLU, and industrial production of GLU (and MSG) commenced(256). From 1910 until 1956, the process underlying production of GLU was one of extraction, a slow and costly method. In 1956, the Japanese succeeded in producing GLU by means of fermentation; and after considerable research to identify suitable strains of microorganisms for starting the requisite cultures, large-scale production of GLU through fermen-tation began.(257) According to Schwartz,(258) although considerable effort had been spent to introduce MSG to the USA, little had been accomplished prior to World War II. However, sometime during the war, the use of MSG in Japanese soldiers' rations was noticed. In 1948, a symposium on MSG was held in Chicago, presided over by the Chief Quartermaster of the Armed Forces.(259) The rest is history. Research over the course of the last two decades has demonstrated that in addition to its role as a building block of protein, GLU serves as a neurotransmitter vital to the transmission of nerve impulses in many parts of the central nervous system (CNS)(260). It has also been demonstrated that, under certain circumstances, GLU, along with other acidic amino acids, functions as a neurotoxin, causing neuron degeneration and death and neuroendocrine disorders in a variety of laboratory animals(1,261,262). Since man was created, he has eaten food in the form of protein. We understand a fair amount about human protein digestion and subsequent metabolism at the present time. As part of protein digestion, protein is broken down into its constituent amino acids. In the human body, GLU can be formed from ingest-ed protein. The ingested protein is broken down (hydrolyzed) in the stomach and lower intestines, through the action of hydrochloric acid and enzymes,(263,264)--all produced by the body. In a healthy human, the body controls the amount of GLU converted from protein in this way, and disposes of the "waste." Humans do not store excess GLU as such.(265) The human brain is also capable of synthesizing GLU according to its metabolic needs, from endogenous materials.(1) Ingestion of free amino acids is a relatively new phenomenon. "In naturally occurring food substances, amino acids rarely are free, but rather linked as protein."(1) The free amino acids which are available in the marketplace, either in bulk or in processed foods, are manufactured. Commercially manufactured GLU is produced in food and chemical plants, where protein is broken down (hydrolyzed) through a process which often involves hydrochloric acid and/or enzymes.(266) We know very little about the digestion and subsequent metabolism of free amino acids. We do know that vitamins, minerals, sugars, and some amino acids can be assimilated without digestion.(1,267) It is conceivable, therefore, that GLU introduced as such into the body is not subject, at all, to the processes of digestion, including the processes of elimination of excesses of that which is ingested. To the extent that the process of digestion or absorption of free amino acids differs from the process of digestion of protein, we can only guess how free amino acids are metabolized by the body. Some persons have assumed that ingested free amino acids are digested and metabolized in a manner identical to the manner in which protein is digested and metabolized. The evidence which exists, suggests that this is not true.(268,269) The Food and Drug Administration (FDA)(270,271) distinguishes between two classes of commercially manufactured GLU, when GLU is to be used as a food additive. When hydrolyzed protein is refined to approximately 99% GLU, the FDA requires that the GLU be identified on food labels as "monosodium glutamate," ("MSG".)272 When the refinement of hydrolyzed protein results in a product which is less than 99% GLU, the product is called "hydrolyzed protein products" ("HPP"). The "HPP" include (but are not limited to) products called "calcium caseinate," "sodium caseinate," "autolyzed yeast," "hydrolyzed protein," "hydrolyzed vegetable protein," "hydrolyzed animal protein," "yeast extract," and "textured vegetable protein." All of these invariably contain commercially manufactured GLU. The only factor which distinguished them from "MSG" is that the per cent of GLU in the "HPP" can not, by definition, exceed 98%. Depending on the degree to which the "HPP" have been hydrolyzed, "HPP" contain GLU along with other free amino acids and possibly small peptides and even some protein. A third class of commercially manufactured GLU is created by adding protease enzymes to a product during processing. Under certain conditions, if a product contains protein, the addition of protease enzymes during processing, will produce GLU in the end product of the food being packaged or manufactured. The creation of GLU in this way does not require disclosure. The FDA does not address this third type of production of commercially manufactured GLU. GLU is also to be found in the end product of a relatively new class of materials known to the food industry as "reaction flavoring." The status of "reaction" substances is unclear. Olney and others(273,274) have demonstrated that "HPP," like "MSG," cause GLU type hypothalamic lesions and neuroendocrine disorders. "HPP" contain not only GLU but other amino acids, including aspartic acid and L-cysteine, which are known to exert the same or similar neurotoxic effects as GLU.(1,1) Humans who suffer adverse reactions to the ingestion of "MSG," also suffer adverse reactions to ingestion of "HPP",(1) and to the GLU products of such things as the protease enzymes. FDA regulations require that products which contain GLU in its "MSG" form must be labeled with the words, "monosodium glutamate." However, the FDA does not require, and has refused to require, that the GLU, in products which contain any source of GLU other than "MSG," be identified. The rationale given by the FDA for this refusal is that FDA code does not require that constituents of an ingredient be disclosed to the consumer. The GLU in hydrolyzed vegetable protein, autolyzed yeast, sodium caseinate, etc., is considered, by the FDA, to be a constituent, and therefore does not need to be disclosed. Thus, very often, nothing on the label of a product containing GLU reveals that the product contains GLU. The FDA goes even farther in allowing GLU to be "hidden," even more surreptitiously, in food. When sugar is added to a spice package, the addition of the sugar must be disclosed. But when "HPP" (which invariably contains GLU) is added to "flavoring," or "natural flavor-ing," or "bouillon," or "broth," not even the "HPP" has to be disclosed. Finally, the FDA allows the inclusion of GLU produced during the process of manufacture to be totally undisclosed. Thus, the FDA allows a substance which is potentially harmful to be included in food without identification. The importance of this will be demonstrated in the body of this paper. We will reference research which shows that: 1) there is undeniable evidence that the neurotransmitter and neurotoxic substance, GLU, causes neuron degeneration and death, and neuroendocrine disorders in a variety of laboratory animals; 2) there is evidence, denied only by the food industry and the FDA, that some people suffer adverse reactions to commercially manufactured (free) GLU, regardless of the source; and 3) there are links between increased levels of GLU in the body and incidence of a number of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Yet it is maintained by both the food industry and the FDA that ingestion of GLU poses no human health hazards. In this paper, we will demonstrate that there are no studies which "prove" that "MSG" and "HPP" are safe. Simply stated, the statistical models used by food industry researchers to "prove" that GLU is safe, have been used inappropriately. Industry researchers say that their statistics prove that GLU is safe; but those who understand the limitations of the statistical models used, also understand that this can not be true. Given the way in which hypotheses have been set up for testing, and the nature of the statistics used, it is not possible to "prove" that GLU is safe.(275,276,277) Given that "proof" is unobtainable, the secondary considerations pertaining to research design, methodology and interpretation are of little importance. However, as we move through our review of research, we shall demonstrate that food industry sponsored researchers have organized both animal studies and human studies in a purposeful effort to appear to fail to reproduce findings of neurotoxicity and neuroendocrine dysfunction associated with administration of GLU, when, in fact, what they have failed to reproduce is the research. Industry sponsored research will be discussed in some detail in order to describe the various approaches to design, methodology, and interpretation used in research which alleges to "prove" that GLU is safe. We will point out a number of research reports in which there exists a marked disparity between the body of the research (including the results) and what is said in the discussion, conclusions, and abstract or summary. We will also comment on what might be termed false or misleading "advertising" (ambiguous use of terms, omission of pertinent detail, etc.), associated with the promotion of GLU. Within this same general scheme lies a strategy that would have the researcher focus on, and thoroughly investigate, a variable or variables which have little or nothing to do with human sensitivity to GLU. The research may be appropriately executed and in many ways, be quite complete. Yet it will focus on irrelevant variables and/or on subjects who are not sensitive to GLU. It is irrelevant to the research reported here, yet in order to understand why this research has been so badly used in the marketplace, mention must be made of the "judges" appointed by the FDA to review the data of safety of GLU over the years. In every case, judges have been biased individuals, with close ties to, or directly supported by the food industry; or judges have been persons with limited knowledge of the scientific disciplines involved, or even the issue at hand, who were provided with a preponderance of biased research and with-held not only published data, but information on such things as case studies of human adverse reactions, on file with the FDA. For example, the Food and Agriculture Organization of the United Nations World Health Organization (FAO/WHO) Expert Committee on Food Additives that reported on GLU in 1987(278,279) did not consider all of the available published data on GLU toxicity and/or adverse reactions; and that data which it did consider had a strong food industry bias. Moreover, never has a qualified neuroscientist sat on an FDA or WHO committee evaluating brain damage caused by the ingestion or administration of GLU. RESEARCH: GLUTAMATE AS A DRUG The toxic action of GLU was first reported by Lucas and Newhouse in 1957(280). Prior to that time, and throughout the 1960's, a consider-able body of research had focused on potential positive or curative effects of various forms of GLU used as a drug. During this period, "side effects" of GLU were noted. But no one considered that these "side effects" might be toxic reactions to GLU. In 1955, Himwich et al.,(281) tracing the use of GLU as far back as 1926, noted that results were, indeed, controversial. In 1960, Astin and Ross(282) reviewed 33 studies which used GLU therapy as a means of improving intellectual functioning in mental defectives, and concluded that careful analysis of the studies caused them to question if there were beneficial effects to the use of GLU. In 1970, Nutrition Reviews(283) provided a review of the history of GLU and its use as a drug which might improve the function of the central nervous system (CNS). They suggested that recent (1969-1970) reports of adverse effects of GLU should be cautiously evaluated in light of the contradictory reports surrounding the earlier reports of beneficial effects. Research included studies which examined the effects of GLU on human intelligence and mental deficiency(284,285,286); behavior problems and memory defects in aged patients(287); nausea and vomiting(288,289,290); the intravenous use of protein and protein hydrolysates(1,291); hypoglycemia (292,293); seizures (294,295,296,297); and hepatic coma.(298,299) Results of these and other studies were generally either negative or mixed and inconclusive. In general, the methodology left a great deal to be desired. Astin and Ross(1) for example, noted that positive studies using control groups had serious methodo- logical flaws, and that positive studies without method-ological flaws had no control groups. Adverse reactions to "very large" doses of GLU were reported by Astin and Ross.(1) They cited flushing(300); nausea and vomiting(301); and distractibility and non-cooperativeness of children, insom-nia, and occasional gastric distress.(302) Similarly, Weil-Malherbe(1) reported hyper-tension, tachycardia, and hyperglycemia following GLU administration to hypoglycemic coma patients. Although these authors mentioned "side effects" of GLU admin- istration, no one, prior to Lucas and Newhouse,(1) suggested that GLU might have the capability of producing severe toxic reactions. RESEARCH: THE ANIMAL STUDIES Retinal Lesions In 1957, Lucas and Newhouse(1) first noticed that severe retinal lesions could be produced in suckling mice (and to some extent in adult mice) by a single injection of GLU. Studies confirming their findings using neonatal rodents (303,304, 305,306) and adult rabbits(307) followed shortly thereafter, with others being reported from time to time (308 309,310, 311,312). These studies concerned themselves not only with the confirmation of GLU induced retinal lesions, but with the formulation and testing of hypotheses to explain the phenomenon. Hypothalamic Lesions: Non-Primates In the late 60's, Olney(313) became suspicious that obesity in mice, which was observed after neonatal mice were treated with GLU for purposes of inducing and studying retinal pathology, might be associ-ated with hypothalamic lesions caused by GLU treatment; and in 1969 he first reported that GLU treatment did indeed cause brain lesions, particularly acute neuronal necrosis in several regions of the developing brain of neonatal mice, and acute lesions in the brains of adult mice given 5 to 7 mg/g of GLU subcutaneously.(1) Research which followed confirmed that GLU, which is usually given as the sodium salt, MSG, induces hypothalamic damage when given to immature animals after either subcutaneous (314,315,316, 317,318, 319,320, 321,322, 323,324, 325,326, 327,328, 329,330, 331, 332,333,334,335) or oral(1,1,1, 1,336,337,338, 339, 340) doses. Work by Lemkey-Johnston and Reynolds(1) published in 1974 included an extensive review of the data on brain lesions in mice. They confirmed the phenomenon of GLU induced neuro-toxicity; described the sequence of the lesions; and emphasized the critical aspects of species variation, developmental age, route of administration, time of examination of brain material after insult, and thorough- ness of tissue sampling methods. A review of GLU induced neurotoxicity, published by Olney in 1976,(341) mentioned species (immature mice, rats, rabbits, guinea pigs, chicks, and rhesus monkeys) demonstrating GLU induced neurotoxicity, and efficiency of both oral and subcutaneous administration of GLU in producing acute neuronal necrosis; discussed the nature and extent of the damage done by GLU administration and the impact of GLU administration to GLU levels in both brain and blood; and discussed the similar neurotoxic effects of a variety of acidic structural analogues. Hypothalamic Lesions: Sub-Human Primates Studies of sub-human primates (1,1) were felt to be particularly meaningful to the study of GLU toxicity, particularly because GLU toxicity found in laboratory animals might be relevant to humans. As early as 1969,(1) Olney had suggested that GLU could be involved in the unexplained brain damage syndromes occurring in the course of human ontogenesis. Olney(1) demonstrated that the infant rhesus monkey (Macaca mulatta) is susceptible to GLU- induced brain damage when administered a high dose (2.7g GLU/kg of body weight) subcutaneously. Olney et al.(1) expanded Olney's earlier work(1) with a study of eight additional infant rhesus monkeys and, using light microsco-py and the electron microscope, reconfirmed Olney's earlier findings(1) of hypothalamic lesions, and discussed the findings of both Abraham et al.(1) and Reynolds et al.(342) who had questioned his work. (See THE ALLEGED PROOF THAT MSG IS SAFE, page 11, herein.) Olney found his data to be entirely consistent with studies done previously by his own and other laboratories on all species of animals tested. Neuroendocrine Disorders Olney(1) found not only hypothalamic lesions in 1969, but described stunted skeletal development, obesity, and female sterility, as well as a spate of observed pathological changes found in several brain regions associated with endocrine function in maturing mice which had been given GLU as neonates. Longitudinal studies in which neonatal/infant animals were given doses of GLU and then observed over a period of time before being sacrificed for brain examination, repeatedly support-ed Olney's(1) early findings of abnormal development, behavioral aberration, and neuroendocrine disorder. Developmental dysfunction or abnormalities in growth and behavior have been noted in numbers of animal studies. Animals treated with GLU as neonates or in the first 12 days of life suffer neuroendocrine disturbances including obesity and stunting, abnormalities of the reproductive system, and underdevelopment of certain endocrine glands (1,1, 1,1, 343,344, 345,346, 347,348, 349, 350, 351,352, 353,354, 355,356, 357,358, 359, 360) and possible learning deficits either immediately or in later life (1,1, 1,361, 362,363, 364,365, 366, 367). In addition, Bhagavan and others have reported behavioral reac- tions including somnolence and seizures (368, 369, 370, 371, 372, 373, 374,375); tail automutilation (1,1); and learned taste aversion.(1) Irritability to touch was interpreted as conspicuous emotional change by Nemeroff.(1) Lynch(1) reported hyperglycemia along with growth suppression. He noted that hyperglycemia did not occur when subjects were given intact protein containing a large amount of GLU. Olney et al. (376,377,378) have written a number of review articles which summarize the data on neuroendocrine dysfunction following GLU treatment. Nemeroff (379) has provided another. Focus on Ad Libitum Feeding Findings of neurotoxicity and neuroendocrine dysfunction in laboratory animals, following GLU administration, raised questions about the effects which GLU might have on humans. One such possible effect was GLU involvement with as yet unexplained brain damage syndromes. Since it would be unthinkable to administer doses of GLU to humans which might produce the same sorts of neurotoxicity and neuroendocrine dysfunction as found in laboratory animals, researchers had no alternative but to make decisions based on the best of the animal studies. "Best," in this case, would be studies which would most closely parallel the true human condition. A seemingly logical first step would be to study the effects of GLU on sub-human primates380; and, as already noted, hypothalamic lesions were demonstrated in monkeys as early as 1969.(1) A seemingly logical second step would be to study what might be considered "normal" ingestion of GLU as opposed to some kind of forced feeding. It was felt by many that ad libitum feeding of laboratory animals parallels the human situation more closely than either subcutaneous or gavage administration of GLU, and that ad libitum feeding studies were, therefore, the vehicle of choice. Others tended to disagree, feeling that the ad libitum feeding studies were, by and large, studies which had the greatest potential for minimizing the amount of GLU actually ingested while registering the irrelevant amount of GLU available. These studies were largely initiated and designed to "prove" that ad libitum feeding of GLU to laboratory animals did not result in the brain lesions and or neuroendocrine disorders found using other routes of administration. Only two studies which demonstrate neurotoxic reactions after ad libitum feeding of GLU are reported here. Actually, one would expect few positive studies, because those who are employed by the food industry rarely, if ever, publish them, and no one else appeared to be interested in "proving" that GLU is, or is not, safe. In a 1979 study by Vorhees(1), done as part of a project designed to evaluate a developmental test battery for neuro-behavioral toxici-ty in rats, in which rats were exposed to GLU and other food additives mixed with ground Purina rat chow, beginning five days after arrival at the laboratory, it was demonstrated that high doses of dietary GLU produce behavioral variations. GLU was mixed with food as opposed to being administered subcutane-ously or by gavage. Positive effects were found. A year later, dietary studies reported by Olney(381) demon-strated that weanling mice will voluntarily ingest GLU (and/or aspartate) and that such voluntary ingestion results in readily detectable brain damage. Focus on Older Animals Most studies demonstrating retinal necrosis, brain lesions and/or neuroendocrine dysfunction, focused on neonatal or infant animals. The reason for this focus is simple. Researchers were primarily interested in producing lesions in order to expand their knowledge of brain function; and the lesions were most easily produced in the young. It was, however, also of scientific interest to understand the relationship of age of animal to type and severity of lesion or dysfunction. Thus, older animals were studied, but not to the same extent as the young. Hypothalamic lesions have been produced in adult animals using considerably greater doses of GLU than those required to produce lesions in younger animals. Nemeroff(1) reports that the least effective dose for a ten day old mouse, given orally, is .5g/kg of body weight, and given subcutaneously is .35g/kg of body weight. According to Olney(382) the dose required to damage the adult rodent brain is given as 1.5-2 mg/g of body weight as compared to 0.3-0.5mg/g required to damage the brain of an infant rodent. Only minimal damage is induced unless very high doses (4-8 mg/g) are used.(1) Although advances in technology have facilitated the observation of brain lesions to some extent, it is still true today, as it was in the 1960's, that simple light microscopes are adequate to identifying GLU induced lesions if one looks in the right (sensitive) locations within 4-5 hours of GLU administration. By 24 hours after insult, lesions will be filled in ("healed") with cells, but the cells will be cells other than neurons. Thus the "hole" is filled in, but the lost neurons are not replaced. The damage will have been done, but will be virtually impossible to see. Although it is now possible, under optimal circumstances, to count neurons in well defined areas, the arcuate nucleus of the hypothalamus383 is not a well defined area, and lesions in that area will defy detection after as little as 24 hours after GLU administration. One could not, therefore, ascertain whether or not an adult animal given GLU as an infant, had suffered a lesion in the arcuate nucleus. Focus on Pregnant Females There has been considerable interest in possible transplacental neurotoxicity of GLU, particularly on the part of food technologists who have attempted to demonstrate that GLU fed to a pregnant rodent has no adverse effects on its offspring. We have made no attempt to do a comprehensive review of the literature, but cite here only one study(384) which demonstrates that pregnant rats administered subcutaneous doses of GLU develop acute necrosis of the acetylcholinesterase-positive neurons in the area postrema. The same effect was obtained in the area postrema of fetal rats. THE ALLEGED PROOF THAT GLU IS SAFE Understanding Statistics We shall demonstrate, as we move through our review of the research which purports to "prove" that GLU is safe for human consumption, that food industry researchers have generated animal studies in a purposeful effort to fail to reproduce findings of neurotoxicity and neuroendocrine dysfunction associated with administration of GLU to laboratory animals. We start with a simple truth. The use of statistics is based on a mathematical model which requires, before a conclusion can be drawn, that the researcher first sets up an hypothesis which says that there is no difference between two (or more) conditions, and then rejects the hypothesis of no difference with a certain degree of confidence (confidence that the results of the experiment have not occurred by chance, and, therefore, would be reproduced if the experiment were replicated at another time.) Rejection of the "null" hypothesis is always associated with a value which specifies the probability with which the conclusion, that the difference did not occur by "chance," could be in error. Given two groups, where one is given a test material and one a placebo, if the two groups perform differently enough, we reject the hypothesis of no difference and conclude (at a particular level of confidence) that the difference in performance was not due to chance. We say that there is a significant difference between the two groups, and we state our level of confidence. The model allows us to conclude that there is a difference. The model, however, does not allow us to accept the null hypothesis and conclude that there is no difference. "...Evidence that is consistent with a hypothesis can almost never be taken as conclusive grounds for accepting it, whereas evidence that is inconsistent with a hypothesis does provide grounds for rejecting it....The reason for not necessarily accepting consistent evidence is that a finding that is consistent with a hypothesis would be consistent with other hypotheses too, and thus does not necessarily demonstrate the truth of the given hypothesis as opposed to these other alternatives....An experimenter accordingly always sets up his experiment so that by rejecting his hypothesis he will prove what he has wished to prove. To accept a hypothesis is to conclude that it may be true, but to reject it is to conclude that it is, without doubt, false."(1) Given the statistical model, rigorous demonstration of the truth of the null hypothesis is a logical impossibility.(1) Failure to find a statistically significant difference between groups may provide useful information for planning one's next experiment, but it "proves" nothing. Method: How to Obfuscate with Research Design, Methodology and Interpretation There are any number of methods that researchers can use to effect foregone conclusions, if they so desire. In our analysis of studies which appear to have been designed to demonstrate that GLU is safe to use as a food additive, we have found it useful to classify studies according to the method(s) that were thus used. Animal studies are listed according to method used (if the method was obvious) in Table 1. Human studies are listed in Table 2. Inappropriate use of statistics is not noted in either Table 1 or 2 because it is common to all industry studies reviewed. In the scientific community at large, research is undertaken either to replicate findings, or alleged findings (in which case the experimental procedure of the second study is identical to the first), or research is undertaken in hopes of discovering something new, and, therein, providing insight into the phenomenon being studied (in which case the researcher varies one or more of the conditions of the experiment and looks to see what will happen). One would expect that as test conditions of a second study differ from the original, results would differ, too. If one did not present the same conditions in a second study, one would not expect to observe the same results as in the original. Some of the researchers who have set out to "prove" that GLU is safe, have said they were replicating studies, but have not done so. In these cases, the discussion is phrased to suggest that the study was a replication (which it was not) and the conclusions are based not on what was done, but on what was said would be done. In these cases, the (a) subjects, (b) test materials, (c) overall procedures, and/or (d) methods of analysis used differ from the study being "replicated." If it is maintained that these studies were truly honest attempts at replication, one would have to say that they were poorly designed, improperly executed, and inappropriately interpreted. In 1981, Nemeroff (1) stated unequivocally that "...not one single [primate] study has truly replicated the methods utilized by Olney, making evaluation of the available data impossible." Studies of this sort are designate Method A. True failure to replicate, casts doubt on the original study, and is of great importance. Pretending to fail to replicate, is tantamount to fraud. Other studies, either purposefully, or in good faith and honest error, have focused on, or commented on, materials which have little or no import for the study of, the understanding of, and/or the evaluation of CNS toxicity and/or peripheral adverse reactions to GLU. Most often these are studies of the relationship of what industry people like to point to as "objective" parameters, and the ingestion or assimilation of GLU. These objective parameters are observable phenomenon such as blood pressure, body temperature, plasma GLU level, brain GLU level, etc. To date, there has been considerable study of some of these variables, particularly plasma GLU levels. However none have been shown to have a cause/effect relationship to brain damage in laboratory animals, and none have been shown to be significantly related to the human adverse reactions produced by GLU. We call this Method B. Unless GLU sensitive people are studied, one can not legitimately draw conclusions about the relationship of the variables being studied (no matter how objective they are) to people who are sensitive to GLU. Often, these studies are used to allegedly "prove" that people who are not sensitive to GLU are not sensitive to GLU. A third version of the general approach is to divorce results from discussion and conclusions. In some studies, although the body of research is generally well enough done, there is a marked disparity between the body of the research (including the result section) and the discussion and conclusions. Simply put, the abstract and/or summary does not follow from the results. If the reader restricts himself to reading the conclusion, abstract and/or summary of the paper, he will never note the disparity. This is Method C. In addition to these basic strategies, industry generated research tends, from time to time, to manipulate the English language in such a way as to foster confusion and/or obscure the meaning of what is being done. Words are manipulated so that imprecision of definition and vagueness of concepts expressed tend to obscure the real issues, and allow one to be led to faulty conclusions. This approach, which we shall refer to as Method D, is not to be confused with Method B where irrelevant variables (or levels thereof) are explicitly used. With Method D, details are given (or not given) in such a way as to create a wrong impression. We might think of this as false advertising. It has been observed that among those who purport to prove the safety of GLU, there are some who, in our opinion, challenge the integrity of science in this way: obscuring the levels of dosage used while it is well known that reaction to GLU is dose related;(1,1, 1,1) studying only subjects who have not experienced GLU sensitivity without making that clear to the reader; looking for lesions in the brain in areas which only experts realize are not susceptible to GLU lesions; and/or not specifying materials which are used in the placebo when those materials may cause allergic reactions to substances other than GLU, or may even contain GLU. When placebo materials have been manipulated in human studies, the method has been identified separately as Method F. A fifth category (Method E) is reserved for studies which focus on levels of relevant variables that will almost certainly fail to produce the effect in question, and/or use methodology in evaluation of lesions which through inappropriate timing, focus, or instrumentation, will obscure otherwise verifiable results. The distinction between a significant level or method and one that is not significant is always a subtle one. Using Method E, researchers often look at the wrong thing, at the wrong time, and/or in the wrong place and conclude that GLU toxicity or sensitivity does not exist. A number of the approaches used in industry supported research to allegedly "prove" that GLU is safe will be illustrated in the body of this paper as we review individual studies. Animal Studies: Lesions Retinal Lesions We have found no studies which contradict the demonstration of retinal lesions produced by administration of GLU. Brain Lesions There were, however, a number of studies which challenged the findings of brain lesions and neuroendocrine dysfunction resulting from administration or ingestion of GLU. Adamo and Ratner(385) and Oser et al.(386) failed to reproduce findings of neurotoxicity affecting the brains of non-primates. Adamo and Ratner(1) used rats, not mice as Olney(1) had, but maintained that otherwise the experimental approach used was "very similar." Oser et al.(1) studied mice, rats, and beagles (dogs). Although their methodology varied considerably from Olney's, they concluded that they could "...offer no explanation for the fact that [their]...observations...do not confirm those of Olney...." It would appear that they "thought" they were replicating what Olney had done. Arees and Mayer(1) reproduced Olney's(1,1,1) findings only in part. Their discussion focuses more on the question of human consumption of GLU as food than on reasons for differences between the various studies. All three of these negative studies were refuted by both Olney(1,387) and Burde(1) who independently reviewed the literature and found that these early discrepan-cies could be attributed to: 1) Failure on the part of investiga-tors to attempt to replicate Olney's methods (Method A); and 2) Use by investigators of entirely different (and inappropriate) methods of preservation and staining of brain tissue in the analysis of results (Methods A and E). Burde(1) speculated that the method of fixation and staining used by Adamo and Ratner(1) obscured the existence of the lesion, and noted that their dose schedule was not appropriate; that Oser et al.(1) used a minimal effective dose and did not examine the rats and mice until 24 hours after insult, even though it was known that by 24 hours after insult, in a minimal dose, such as the one used by Oser, which would produce edema, all signs of edema would have disappeared, and that necrotic cells would already have been phagocytized. Burde found the interpretation by Arees and Mayer,(1) that the lesion produced by GLU is limited to "microglia," to be puzzling, particularly in light of the fact that most of the cells of the arcuate nucleus are known to be small neurons. Furthermore, using Olney's exact methods, Burde(1) replicated Olney's previous findings. Olney's(1) review of the discrepancies, pointed out that the failure of Oser et al.(1) to detect brain damage in any of the three species they studied following administration of GLU might well be accounted for by their having limited the GLU dose to a single, minimal-ly effective dosage; failure to use a feeding tube to assure that the full dose was received by orally treated animals; failure to examine brains in appropriate post treatment intervals (which are particularly relevant in cases of minimal effective dosage); and use of relatively unrefined techniques for tissue preparation. Olney(1) also noted that in a 1971 study done by Arees et al., (1) the authors were able to demonstrate that neuronal degeneration does occur in the infant mouse brain following subcutaneous treatment with GLU. Thus the discrepancies noted by Arees and Mayer previously(1) became resolved. Finally, Olney(1,1) suggested that methodological variables might well explain the failure of Adamo and Ratner(1) to demonstrate lesions in the rat. The subject of tissue preparation (relevant at the time) has been addressed by a number of people. Takasaki(1) stated it clearly: "...changes disappeared at least 24...[hours] after injection....The results should be borne in mind when histological examination is performed on changes of the hypothalamus caused by administration with MSG. It is [especially] so in animals administered with a small dose of MSG, because necrotic neurons are few and the glial reaction that occurs secondarily is very mild in the AN [arcuate nucleus]. Without punctual preparation after administration, the effect upon the hypothalamus is apt to be overlooked in these animals."(1) Olney(1,1,1,388) and Murakami(389) have discussed the problem in similar terms. Olney(1) has discussed such methodological problems in great detail. In 1973, Filer and Stegink(390) published an editorial in the New England Journal of Medicine which suggested that the neurotoxic effects of GLU and its related amino acids, aspartate and cysteine, in species other than the mouse, are debatable. In turn, Olney et al.,(391) pointed out that neurotoxic effects of GLU and its related amino acids had been well document-ed, and that the "null effect" reported by Filer and Stegink was a function of faulty methodology, not strain specificity--a fact which had been pointed out earlier by Burde.(1,1) Olney noted that Filer and Stegink supported their argument by pointing to the "fact" that no neurotoxic effects of GLU had been reported in the guinea pig, which was, at the time, an unstudied species. Olney further reviewed the criticisms of his own research proffered by Filer and Stegink and suggested that a more careful reading of the research as presented would resolve their concerns. There were other studies which failed to confirm toxic effects of GLU, and there were criticisms of Olney's work. Abraham,(1) mentioned earlier, found toxic effects when GLU administration was subcutaneous, but very little when administration was oral. His work is discussed in some detail in the section devoted to sub- human primates. Lowe(392) criticized Olney(1) for failure to provide data on plasma GLU concentrations, and for lack of a control in his single infant monkey study. Zavon(393) criticized Olney for lack of a control animal and for lack of detail in reporting the same study. Olney(394) responded to both Lowe and Zavon with detail gathered from mouse studies and an apology that he had had only the one monkey available at the time of his study. Blood, Oser, and White (395) criticized Olney (1) for questioning the safety of GLU after parenteral, as opposed to oral, administration (see the ad libitum studies); failure to clearly elucidate his methodology; and use of doses which far exceeded Blood et al.'s estimate of "...the total daily intake [of GLU] from all reasonably possible uses... (.7 g per day) in an average adult."(1) "Critical tests for the safety evaluation of food additives are based on the effects of oral, not parenteral, administration," state Blood et al., leading one, possibly to infer that Olney considered his studies of mice to be "critical tests for safety," when in fact that was not true. Olney has never suggested that his work be used in this way. It is one thing to report an observation, as Olney did. It is quite another to claim that it is a critical test for something. This seemingly purposeful creation of false information by innuendo is an illustration of use of Method D. Olney,(396) in reply to Blood et al.,(1) provided the figures requested, suggested that he (Olney) had been misquoted, and suggested that to truly establish the safety of GLU if, indeed, that could be done, solid research was needed. (Sloppy oral or ad libitum studies would not provide the answers.) Focus on Subhuman Primates Two studies took exception to Olney's finding of hypothalamic lesion in sub-human primates due to loading of GLU. Abraham et al.(1) treated four monkeys and failed to reproduce the findings of Olney and Sharpe(1). Reynolds et al.(1,397,398) treated 16 sub-human primates which were compared to five controls. They, too, failed to reproduce the findings of Olney and Sharpe(1), and found, instead, a "spectrum of degenerative changes" which they attrib-uted to inadequate fixation procedures rather than to the effects of GLU. Among the criticisms Olney(1) made of the research design and methodology of Abraham et al.(1) and Reynolds et al.(1,1,1) which distinguished his study from theirs, are the following: Reynolds et al. used only a spot sampling technique when two of the rhesus infants, each treated with low oral doses of GLU, were examined by electron microscopy, so the possible occur-rence of small lesions in these brains was not actually ruled out. (Method A.) The method used for preparation of brains for examination by light microscopy has been found unsatisfactory for evaluating even large GLU-induced lesions in infant rodent brains; and subse-quent information provided by Reynolds indicated that some of the infants vomited an unknown portion of the administered dose. (Reynolds' uses Methods A and E.) Abraham et al.(1) supported their findings with a single light micrograph from a rhesus infant sacrificed 24 hours following oral intake of an emetic dose (4 g/kg of body weight) of GLU, although four monkeys were studied. Moreover, little or no evidence of lesion would be expected 24 hours after GLU insult because damaged elements are removed from the scene of an GLU-induced lesion with such remarkable efficiency, that 24 hours after insult, without pre- and post-insult comparison, it is virtually impossible to determine if damage has been done. In general, Abraham's work appears to be vulnerable to the criticisms of most Method A studies, in that he maintains that he is replicating work done by Olney, but does not do as he says. A careful comparison of the two studies will demonstrate that age of subject, dosage administered, time between insult and examination of tissue, and methods of tissue preparation all differ. Abraham's study can also be criticized for use of methodology known to be inappropriate for identifying GLU lesions. (Method E.) Finally, it was also noted by Nemeroff(1) that Abraham et al.(1) found in both control and GLU treated monkeys a "very small proportion of necrotic or damaged neuronal cells and oligodendrocytes...in the arcuate nuclear region of the hypothalamus." One would suspect that this might happen if the placebo, as well as the test material, contained small amounts of an excitotoxin identical, or similar to, GLU. Also failing to reproduce neurotoxicity in primates, were studies of Abraham et al.,(399) Newman et al.,(400) and Stegink et al.(401) Stegink et al.(1) used the same data as Reynolds et al.,(1,1,1) with two additional monkeys, and used the same methodology for tissue staining. (Methods A and E.) His work, then, is subject to the same criticisms as hers. Abraham et al. stated that their present investigation was undertaken in an attempt to resolve some aspects of the controversy. However, the details of this method-ology were identical to those of their earlier study,(1) and are subject to the same criticisms. (Methods A and E.) There would seem to have been no point to doing this study. Newman et al.(1) found "...no evidence in any instance of any change that could be attributed to MSG as described by Olney and Sharpe, although there were artifacts in some inadequately fixed areas as recorded by Reynolds and her co-workers." The study gives every appear-ance of having been designed to facilitate the conclusion that GLU is a safe food. It uses both Method A and Method D. I quote, or paraphrase. (The underlining is this author's, and highlights criticism): "Rhesus monkeys were maintained and observed in the primate buildings of HRC, where most of them were bred." The initial study was carried out with animals of 108, 99, 60, and 3 days, with unspecified histories. "The test solution was readily consumed voluntarily by all animals on all occasions throughout the study;" "The 3-day-old monkey had a few hypochromatic nuclei, and a minimal degree of vacuolation in the ventral hypothalamus, but these findings were not regarded as significant." "By electron microscopy, changes of the type reported by Olney and Sharpe were seen in both test and control animals, and were attributed to fixation artefact." Information pertaining to the animals is incomplete. Their history is uncertain. We have no idea what went on in the first 108 days of an animal's life. Description of both procedure and findings is highly subjective and/or incomplete. (Method D.) "Readily" consumed does not necessarily mean fully consumed. If a "few" hypochromatic nuclei were quantified, how many would that be? What is "minimal?" On what basis were the findings "not regarded as significant?" What changes were seen? How many were test animals; and how many were controls? A 1976 study by Reynolds et al.(402) which produced negative results relative to abnormalities of the subinfundibular region of the monkey brain provided yet another vehicle for allegedly "proving" that GLU is safe. Both mice and monkeys were studied. Mice, but not monkeys, were reported to show brain lesions. The monkeys were infant macaques with age ranging between 30 minutes and 14 days. It is of interest (and concern) to note that the cross section presented in Figure 4 of "...a 7-day-old infant Macaca fascicularis monkey that ingested 4 g/kg GLU..." appears, in every aspect, to be identical to a section of an "...infant rhesus monkey which received 4 g/kg of GLU by stomach tube..." presented in Figure 3 of the report by Stegink et al.(1) The GLU in Reynolds et al. study was prepared as a 20% w/v solution in water and administered as a single dose of as much as 4 g/kg GLU. We are told how many monkeys received each dose, but we are not given dosage by age. The techniques for evaluation of mouse brains is the same used by Lemkey-Johnston and Reynolds(1) and Reynolds et al.(1) in previously reported studies. These had been found by Olney(1) to be inappropriate. No information is given about the timing involved or the techniques used for evaluation of monkey brains. In general, this study by Reynolds et al.(1) employs Methods B and E. However, the conclusion, a gross overgeneralization, also makes use of Method D. Reynolds concludes, "Neither aspartame nor MSG is capable of eliciting a lesion in the neonatal monkey brain." (Underlining is this author's.) In addition to the study's other faults, Reynolds et al. take a single finding of "...did not elicit..." and generalize it to "...it is incapable of eliciting...." Those who do not read the entire study may be fooled. Neuroendocrine Disorders / Ad Libitum Feeding The bulk of the studies dealing with neuroendocrine dysfunction were done in an obvious effort to discover and piece together bits of information which would help resolve the mysteries of the endocrine system. For most researchers, GLU was important not because of any importance in and of itself, but because its use produced certain effects in the body, and monitoring the relationships between administration of GLU, cell damage (partic- ularly lesions) in various locations, and resultant changes in anatomy, physiology, and behavior elsewhere, might provide important clues to the secrets of human body function. As an excitotoxin, GLU has been used not only for its ablative effects, but also as a provocative tool.(1,1) But here again, a number of studies were done to "prove" that as a food additive, GLU is safe. One of the favorite strategies appears to have been to examine those factors which cause the "unwanted" result--in this case, neuroendocrine disorders associated with intake of GLU--and design a study which focuses on, or makes use of, non-relevant levels of otherwise relevant variables, betting, or knowing, that the levels used will not produce the "unwanted" result. Thus, females exhibit reproduc-tive disorders and males do not, use males. Or if a neuroendo-crine change is not exhibited in less than 20 days, examine the animals after 15 days. Then, when no significant differences between control and experimental groups are found, conclude that GLU is safe to use in food. Only someone with intimate knowledge of the subject could discern manipulation of this kind. While these sorts of studies might well be grouped with the Method A studies, they have a slightly different twist which sets them apart. The Method A studies give the appearance of attempting to replicate studies done already, while this new class of study makes no such pretense, but provides for the introduction of new variables. The logical fallacy in these studies comes when it is concluded that finding nothing while studying irrelevant variables "proves" that GLU is safe. This is Method B. Most of these negative studies focused on ad libitum feeding. It would appear sensible to attempt to approximate the model of human ingestion of food in studying the safety of human ingestion of GLU. And that's the stated purpose for the bulk of the studies presented. As Olney(1) pointed out, however, the ad libitum animal studies fall far short of approximating the human condition. Almost all of the studies which focused on ad libitum feeding of GLU to laboratory animals were underwritten by the food industry, and have, predictably, negative results. Over and above the fact that given the statistical model used, one can not "prove," through these studies, that GLU is safe, they are subject to the same range of criticisms as other industry sponsored studies. The 1979 study by Matsuzawa et al.,(1) will serve as our first illustration here. The authors did a series of studies using both neonatal and 10 day old rats, given oral and subcutaneous doses of GLU at a total of 4 different doses. Controls were given saline solution. One might legitimately question the precise nature of the "...ad libitum diet containing 5% (w/w) MSG...," but that is not of immediate import. One must note, more importantly, that the ad libitum diet was given "...for 10 days after weaning (at 20 days)." By 1979, the date of the study, it was well understood that the timing used was outside of the range of the animal's most susceptible age. The conclusion is classic for a study using both Methods D and E. "MSG therefore produces marked reproductive endocrine abnormalities after maturation only when injected parenterally early in postnatal life, in repeated, very large doses. The development of reproductive endocrine function is not affected by MSG unless neurological damage occurs in the hypo-thalamus by any route of administration." (Underlining is this author's.) Matsuzawa et al. have done one study, on one species, of a particular age, given a particular diet for 10 days, and conclude that because that one set of condi-tions did not elicit either neurological damage to the hypothala-mus or marked endocrine abnormalities after maturation, that GLU produces marked reproductive endocrine abnormalities "...after maturation only when injected parenterally early in postnatal life, in repeated, very large doses." They exclude all other possibilities. The identical strategy (Methods D and E) is to be found in a 1979 study by Takasaki et al.(1) They report that, "Adverse effects from MSG have never been reported from dietary adminis-tration." (Underlining is this author's.) In this case, "never" equals four studies. Using logic similar to that used by Matsuzawa,(1) they concluded that "MSG does not exert an adverse effect on somatic growth in that the hypothalamic neurons are not injured by any routes of administration, and the MSG did not induce somatic deficiency under the conditions of our experiments, which mimic the intended conditions of use of this material as a food additive." In their 1979 summary of GLU toxicity in laboratory animals, Heywood and Worden(403) cite nine chronic animal studies in which various species were given ad libitum feedings of GLU over extended periods of time. These include studies by Ebert,(404) Owen et al.,(405,406) Semprini et al.,(407) and Wen et al.(408) Because we have no data on chronic animal studies from persons other than those with close ties to industry and, therefore, have no records of positive results, we have no basis for evaluating the levels of variables used in these studies. And because they are incomplete and imprecise in detailing their methodology, it is difficult to evaluate the research, as a whole. Ebert,(1,409) we know, used mice that were clearly older than Olney's mice.(1) Ebert apparently used data from a 1953 study done at Arthur D. Little, Inc., entitled, "Report on a study of L-monosodium glutamate, DL monosodium glutamate and L glutamic acid with respect to potential carcinogenicity." The 1970 report of these data(1) was in the form of an abstract. The 1979 reports(1,410) were expanded abstracts done, "...to comply with the suggestion of the Select Committee on GRAS Substances during hearings on glutamates, held at Bethesda, Maryland on July 25-27, 1977."(1) We know, of course, that these studies producing negative results and thereupon claiming to "prove" that GLU is a safe food additive, are subject to the limitations of the statistics that they use, and that from the point of view of the statistical model, any conclusion of safety based on failure to find a difference between two groups is an invalid one. (See THE ALLEGED PROOF THAT MSG IS SAFE, Understanding Statistics, page 11, herein.) We also know that the procedures of Wen et al.(1) are subject to the same criticisms(1,1,1) as studies by Adamo and Ratner(1). In another 1979 summary of the results of dietary administration of GLU, Ananthar-aman(411) stated that studies indicated that "...dietary administration of MSG at even very high doses was not found to result in any of these symptoms [produced by other routes of administration], including the endocrine disturbances." They cited Huang,(412) Wen,(1) Takasaki,(413) Bunyan,(414) Owen,(1) and Trentini(1). They also cited two year rat studies by Ebert,(1) and Owen et al.,(1) where no abnormalities were found in successive generations. And in their own study,(1) they also produced negative results. Studies by Owen,(1) Takasaki,(1) and Wen,(1) have already been discussed in some detail. The additional studies mentioned here are, at the very least, subject to previously discussed statistical limitations. The study reported by Anantharaman(1) must be criticized on more serious grounds. Unlike most of the research reported, Anantharaman provides a great deal of detail, including detail of the exact nature of the basal diet provided. And in that basal diet we note that "yeast food" is listed as a component of the protein (page 236, Table 3). At this point in time (1990), yeast food invariably contains either protease (which creates GLU during manufacture) or L-cysteine which produces neurotoxic effects somewhat different from, but more extensive than, the effects of GLU. We are suspicious, then, that the failure to find differences in growth of control and experimental groups may be due to the fact that both groups were receiving neurotoxic substances in their basal diet. We call this Method F. It is discussed in some detail in the section entitled "Methodology Particular to Human Research." Using inappropriate placebo materials has been discussed by others before. In 1981, Rippere(415) criticized the use of common food allergens as placebo materials, noting that even a minute trace of an allergen might trigger severe symptoms in a sensitized individual. In a study by Abraham et at.(1) cited earlier, it was noted that the control group exhibited some small evidence of brain damage just as the experimental group did, raising a question of what placebo materials might have been used there. In 1990, this author questioned research done by Goldschmiedt, Redfern, and Feldman(416) which used beef broth as a placebo for controls. In the United States, one cannot purchase commercially prepared beef broth that does not contain some form of GLU (hydrolyzed protein, yeast extract, textured vegetable protein, flavoring, etc.) This author questioned the possible unwitting bias in placebo material in a letter to the editor of the American Journal of Clinical Nutrition. The letter was not published and no informative reply was received. The author questioned Dr. Feldman about the contents of the placebo. He replied that he did not know the contents of the various materials used. Again, use of a potentially reactive placebo constitutes Method F. A 1977 study by Heywood et al.(417) which focused on neuro- toxicity, came to the same conclusion as Anantharaman. Heywood et al. concluded from one study of ad libitum feeding of GLU over a period of four days, using 20 day old mice that, "There is indeed no evidence from any dietary study yet reported that would suggest a lack of safety of MSG as a food additive." (Method D.) It should be noted that details of the amounts of GLU consumed are not given. In the discussion where it states that "...dose levels as high as 45.5 g GLU/kg body weight were achieved...", we are not told if that is per day, per animal, or total. Nemeroff(1) noted that their study did not present representative histological micrographs for evaluation.(1) (Method E.) In a second 1979 report, Takasaki et al.(418) again reviewed a number of studies and this time reported that, among other things, "Weanling, pregnant, and lactating mice fed large amounts of MSG in the diet ... did not develop hypothalamic lesions." As evidence they cited studies by Semprini et al.,(419) Huang et al.,(1) Wen et al.,(1) and Takasaki (1). In addition, they reported findings from their own research(1) which compared the effects of GLU fed ad libitum to other routes of administration. In their report, they build from a discussion of findings of brain lesions to relationships of lesions to plasma GLU levels, to relation of ad libitum dietary feeding to plasma GLU levels, to histological effects of ad libitum feeding of GLU, to the statement that "...plasma glutamate levels... remained much lower than those required to induce hypothalamic lesions." (Underlining is this author's.) It must be understood that it has never been determined that any particular level of plasma GLU is required for the production of brain lesions. The logic used here is faulty, and potentially leads one to erroneous conclusions. Takasaki uses both Methods B and D. Unfortunately, Takasaki(1) did not provide sufficient detail for one to evaluate the reports, and the reports, themselves, are lack-ing. Again, it will be observed that Wen(1) appears to have used the same techniques as Adamo and Ratner(1) and Oser(1) which Olney(1,1) and Burde(1) criticized in 1971. A study by Iwata(1) failed to find behavioral abnormalities as a function of ingestion of GLU. The study is limited by the same Method E design deficiencies noted in other studies. Iwata (1) does not examine the brains histologically, yet concludes that there had to be lesion damage prior to there being behavioral effects. The over-generalization (Method D) from this study is that "...dietary administration... caused no behavioral latent effect in later life." (Underlining is this author's.) Prabhu et al.(420) failed to demonstrate differences in a battery of behavioral tests and drug applications. They mentioned that the results are based on surviving mice, but fail to state the mortality rate. (Method D.) Lengvari(421) also reported no differences between control and experimental groups in a number of variables. One must question the meaning of their failure to find a significant difference when they report a mortality rate of 45.1% (to day 30) as opposed to a 20% mortality rate for controls. (Method D.) Related, but with a slightly different focus, are a pair of studies reported by Takasaki in 1979(1) and 1980,(1) in which he studied the effect on brain lesions of administering various materials simultaneously with GLU. Takasaki reported that certain mono- and disaccharides and arginine hydrochloride, leucine and the prior injection of insulin significantly reduced the number of necrotic neurons in the arcuate nucleus of the hypothalamus. In general, the detail provided about the study is incomplete, and the procedure is difficult to follow. (Method E) It is not clear whether reduction in effect of GLU might have been due to inclusion of additional materials, thus diluting the test material. Moreover, statistics pertaining to the values for number of necrosed neurons observed appear to be based on analysis of one representative section from each animal. And values for representative brain sections appearing in Tables 1 and 2(1) have vastly different values (195 +/- 18 and 263 +/-15) for what would appear should be the same thing. One is compelled to question the meaning of "representative" under these circumstances. (Method D.) Although data found in the 1979 review of GLU toxicity in laboratory animals, done by Heywood and Worden(1) have already been discussed here, the review, in and of itself, is of interest for the way in which it develops the discussion of GLU toxicity, using Methods B and D. First we are told that there is a classical toxicological approach to doing research on food additives. Second, findings of chronic animal studies are reported, arranged by species of animal tested. Nine studies by four authors are presented. Very little detail of procedure is given along with the results. And, finally, the conclusion is drawn that "dietary administration of GLU in these conventional studies was found to be without significant toxic effect over the varying periods of administration." Acute toxicity studies follow, again arranged by species. In this case, reports of lesions (or failure to find lesions) were accompanied by extensive discussion of plasma GLU levels, and some discussion of levels of GLU found in the brain. It will not be denied that the subject of plasma GLU levels is of interest in the study of GLU toxicity. But the tenor of the discussion, and, in some instances, the discussion itself, would have one assume or believe that toxic reactions can occur only after plasma GLU levels have become raised. The following quote from Heywood and Worden illustrates the point. "A fourfold increase in the levels of glutamate in the arcuate nucleus of the hypothalamus followed the elevation of plasma glutamate after a single subcutaneous injection of MSG (reference Perez and Olney, 1972). Peak plasma levels occurred after 15 min, and peak levels in the arcuate nucleus were attained after 3 hr. The results indicate that plasma concentrations above a certain level were necessary to induce brain lesions."(1) The logic which says that plasma concentrations above a certain level are necessary to induce brain lesions, is false. If the work of Perez and Olney(422) cited by Heywood and Worden(1) does, indeed, demonstrate that GLU levels in the arcuate nucleus of the hypothalamus are increased after plasma levels are raised following a single subcutaneous injection of GLU, it does nothing to demonstrate that this is the only condition under which GLU levels in the arcuate nucleus can be raised. Unlikely as it might seem, it might be discovered some day that smelling petrochemicals increases GLU levels in the arcuate nucleus, but has no effect on the blood. We have no data which tells us, as Heywood and Worden(1) would like us to believe, that "...plasma concentrations above a certain level were necessary to induce brain lesions." (Underlining is this author's.) It may or may not be true, but we don't know. This would appear to be a purely specious argument, for blood levels are almost certainly the key factor in GLU toxicity as it affects the brain. The argument must be made, however, because "almost certainly" is not "certainly;" and cause and effect can not be assumed from demonstration of concomitant variation. Moreover, the argument must be made because, as unjustified as the assumption of cause and effect may be, study after study produced by food industry researchers have cited lack of elevation of plasma GLU following ingestion of GLU as "proof" that GLU does not cause human adverse reactions. Starting with the assumption relevant to hypothalamic lesions drawn by Heywood and Worden, other researchers have designed studies to convince readers that under certain circumstances, (serving GLU with carbohydrate, for example), GLU ingested by humans could not possibly cause adverse reactions. The logic is as follows. Heywood and Worden report that brain lesions can only occur when plasma GLU concentrations are above a certain level. Someone reports that plasma GLU levels are not increased when carbohydrates, for example, are served with GLU. Therefore, it follows that lesions can not be induced when carbohydrates, for example, are served with GLU. It is further said to follow that adverse reactions can not be induced when carbohydrates, for example, are served with GLU. In some studies, these authors added useful data to the study of GLU, which helped define the parameters of variables that affect neuroendocrine disorders caused by the intake of GLU. Otherwise, they have no positive function or value. Even in their negativeness, they did little or nothing to refute the existence of the body of research which was concerned with the neuroendocrine disorders associated with intake of GLU. Focus on Pregnant Females Stegink and others(423,424) have done a number of studies on the subject of transplacental neurotoxicity of GLU which purport to demonstrate that GLU is safe. We have made no attempt to review those studies in great detail, but those we have cursorily reviewed(1,1) have stipulated cause/effect relationships without demonstration of the same (Method B), and have made use of Method E. Neither lesions nor potentially abnormal behavior is studied in either of the papers cited. Observing increases and/or decreases in plasma GLU and/or other body fluids without observing concomitant variations in brain damage or other dysfunction has little meaning. THE ANIMAL STUDIES: Putting it All in Perspective The Findings This is not the first time that these data have been summarized and/or reviewed. Olney and Price (425) published an extensive review of GLU induced neuroendocrine disorders. They did not concern themselves with "controversy" but only with what was known to be true at the time. Olney(426) summarized the findings from the animal studies and warned of their potential relevance to humans -- particularly infants. Nemeroff(1) analyzed the same literature and summarized it much as this author, noting the findings of neurotoxicity and neuroendocrine dysfunction associated with GLU ingestion and the spate of negative results emanating from individuals and laboratories supported by research grants from food companies. Nemeroff, however, discussed findings in greater detail than we do. He also discussed neurotoxic effects in regions other than the hypothalamus, techniques appropriate to the evaluation of neurotoxicity, neurochemical studies, and endocrine and other body fluid levels which we have not discussed here. Nemeroff's review of the literature was both a review of the literature and a call for further research. In it, he repeatedly pointed to findings of neurotoxicity and neuroendocrine dysfunction and "wondered" at the sprinkling of negative findings associated with both sorts of research. He commented on each of the negative studies that he reviewed, explained wherein they differed from the findings of neurotoxicity and neuroendocrine dysfunction, and called for additional research. Nemeroff's call for further research was a call to resolve the contradictory findings. Our review is a review of the literature and an analysis of the contradictory findings. We probed deeper than Nemeroff did. Our first discovery was that on statistical grounds alone, the claim of "proof" of safety of GLU is untenable. We observed that, with possible rare exception, the negative studies were initiated and carried out not to find out all there was to find out about sensitivity to GLU, but for the sole purpose of "proving" that GLU is a safe food. There are essentially no published industry sponsored studies which fail to make the point that GLU is safe. The exception, if there is one, will be found in the first study relating to GLU published by a given author. Sometimes the first study is positive or without negative comment; but if the author is industry supported, it doesn't happen twice. It is our opinion that industry supported researchers have manipulated variables and utilized inappropriate research design, methodology, and evaluation methods in a purposeful attempt to produce negative results. These studies and their results were, then, interpreted to be purposefully misleading. Moreover, it has come to our attention that it might be the practice of some segments of the food industry to publish only those studies which show no effect of the variable being studied,(427) (in this case GLU). The detailed discussion of research on GLU induced neurotoxicity and GLU induced neuroendocrine disorders was included here to demonstrate the extremes to which the food industry, and/or its representatives, will go to "prove" that GLU is safe, not to demonstrate that neurotoxicity or neuroendocrine disorders exist. For now, in 1991, there is no question about the fact of GLU induced neurotoxicity and neuroendocrine disorder. It is generally accepted that there are differences in the nature and extent of neurotoxic reactions in different species, that only certain areas of the central nervous system and brain appear to be affected, that young animals are more easily affect-ed than older animals, and that both dose and method of adminis-tration are important variables. It is true that some studies of several animal species fed relatively small amounts of GLU over extended (but not extensive) periods of time, either by gavage (stomach tube) or in voluntari-ly ingested liquid or chow (as contrasted to single, much larger concentrations), beginning at various ages, have failed to demonstrate the same sorts of hypothalamic and/or retinal lesions or degeneration that are shown under different test conditions; and fail, also, to demonstrate the same sorts of abnormalities in growth and development. However, while not all doses of GLU, given by all modes of administration, produce lesions in all brain areas, in animals of all ages, in all species; some doses of GLU do produce lesions in specific areas of the brain when given via a number of modes of administration to animals of various ages and various species. Do the Animal Studies Approximate the Human Condition? What Do We Know? We know that GLU induces lesions in the retina and in specific areas of the brain of laboratory animals, and that there is concomitant neuroendocrine dysfunction. In humans we have no way of assessing brain lesions; and no one has undertaken controlled longitudinal studies of the effects of early ingestion of GLU (if, indeed, they could be satisfactorily done.) In humans, however, we see adverse reactions which, outside of vomiting and seizures, have not been reported in animal studies. We have no way of knowing whether or not animals suffer from what humans would call nausea, dizziness, migraine headache, irritable bowel, lethargy, heart pain, difficulty breathing, etc. Yet we can not rule out the possibility that laboratory animals silently suffer adverse reactions either prior to, or following, brain damage caused by ingestion of GLU. Likewise, we do not yet have the technology to study human hypothalamic lesions. That does not mean they don't exist. Industry people have been keen to suggest that the studies which are least effective in producing disorders of any kind following GLU ingestion, the ad libitum studies, most nearly approximate the human condition. Yet, in today's society, there is far more GLU available to the average human being than has been given to any laboratory animal. There is potential that, beginning as an infant, a human could consume considerable quantities of GLU daily. Consumption could well continue through a lifetime, through periods of illness and stress (weakened immune system), and physical disability (torn muscle, tissue, and bone) unknown to laboratory animals, and for periods of time far exceeding a single dose or ingestion over a period of ten days or even three years. In no way do the animals studied directly parallel the human condition. The human potentially ingests more GLU in one week than a laboratory animal would ever be exposed to. THE HUMAN STUDIES Introduction The study of human adverse reaction to GLU is an issue separate and distinct from the animal studies which we have just considered. It must be recognized that one may have nothing to do with the other. We do not know how well the digestive systems of subhumans parallel the digestive systems of humans. We do not know how either handles the absorption/metabolism of large quantities of manufactured free amino acids introduced either as food supplements or foods. But just as animal studies are used in interpreting the safety of drugs which manufacturers would like to put on the market, so they should have some value in making tentative suggestions about the safety of manufactured GLU. It has already been pointed out that in humans, we have no way to study GLU induced brain lesions; and no one has undertaken controlled longitudinal studies of the effects of early ingestion of GLU. In humans, we see only adverse reactions. It has been estimated that approximately 30 per cent of the human popula-tion of the United States suffers adverse reactions to ingestion of GLU when dosage is at or above a 5 gram level (1,428). In 1968, the first of the observable adverse human reactions to GLU following ingestion of GLU in food form, as opposed to GLU used as a drug, were noted in the literature (429). Those first reactions included, "...numbness at the back of the neck, gradually radiating to both arms and the back, general weakness and palpitation." Since that time, the list of observable adverse reactions has grown to include skin rash, simple headache, nausea/vomiting, asthma-like symptoms, migraine headache, tachycardia, panic attack, anaphylactic shock, and more.(1) Additional detail can be obtained through review of the Adverse Reactions Monitoring System, Food and Drug Adminis-tration, Washington, D.C., File of Adverse Reactions or through contacting the author. To date little or no research has focused on the mechanisms which cause the observable adverse reactions to GLU, although Zorumski has suggested that research focusing on exogenous (food) excitot- oxins serves as a promising source of information for brain research.(430) Much of the research done in the area of adverse reactions to GLU ingestion focuses on plasma GLU levels as a function of GLU ingestion, with and without association of a limited variety of foods. The assumption made in these studies, that there are direct and unidirectional causal relationships between toxicity of GLU and plasma GLU levels, and adverse reactions to GLU and plasma GLU levels, particularly as they relate to GLU sensitive people, is one which must be seriously challenged. The bulk of human research has focused on "proving" that there are no significant reactions to GLU. By law, if "MSG" is to be on the GRAS (generally regarded as safe) list, it is incumbent upon industry to "prove" to the FDA that the food additive, "MSG," is safe. (The same should be true for the "HPP," yet we know of no research purporting to demonstrate that "HPP" are safe.) It is not surprising, then, that there exists a considerable body of "research" which has been sponsored by the food industry to downplay the scope and significance of "MSG's" adverse reactions. That body of research purportedly "proves" that GLU is safe. The methods used to produce this research are the same methods used for the same purpose in the animal studies. Review of food industry sponsored human studies, obviously designed to show no effect of GLU ingestion, will reveal that those studies are poorly designed and/or poorly executed, and that in some, the conclusions drawn from them do not necessarily follow from the study results.(1,431,432) Moreover, the same statistical limitations which apply to the animal studies apply here. Evidence of Human Adverse Reactions: The First Case Studies and Research In 1968, a letter appeared in the New England Journal of Medicine from Dr. Robert Ho Man Kwok,(1) senior research investigator at the National Biomedical Research Foundation in Silver Spring, Maryland, telling his colleagues that for several years, since he had been in the United States, he had experienced a strange syndrome whenever he ate in a restaurant serving Northern Chinese food--an experience he had never experienced in his native land. He reported that 15 or 20 minutes after beginning to eat, he experienced "...numbness at the back of the neck, gradually radiating to both arms and the back, general weakness and palpitation." The syndromes lasted about two hours. He had never heard of such a syndrome until he received complaints of the same symptoms from both medical and nonmedical friends. Through the New England Journal of Medicine, he asked his colleagues in the medical field if they might be interested in seeking more information about this "rather peculiar" phenomenon which someone at the journal dubbed, "Chinese Restaurant Syndrome." Ten people responded almost immediately. Eight had experienced similar, but not necessarily identical reactions when dining in certain Chinese restaurants(433,434,435,436,437, 438, 439,440) and, as in Kwok's case, had no clear cut notion of what the causative factor might be; and two had experienced similar reactions which they traced to probable muscarine poisoning (441) or to the potent nonprotein neurotoxin, tetrodotoxin found in the puffer fish.(442) While Kwok had offered, as one of several hypotheses, that the syndrome might be attributable to the ingestion of "MSG," a subsequent issue of the New England Journal of Medicine carried letters from both Schaumburg and Byck(443) and a group of New York University pharmacology students who had studied the condition for an elective project(444) who stated, unequivocally, that the syndrome which Kwok and his friends had experienced was a reaction to ingesting "MSG." Schaumburg and Byck(1) pointed out that the reaction being discussed was well known to experienced allergists and Chinese- restaurant owners; and they offered preliminary hypotheses pertaining to the nature of the reaction. Ambos et al.(1) added that although the reaction had not been cited in the literature, it had been clearly recognized by "...certain persons and within some families." There was general agreement that "MSG" caused a reaction in sensitive individuals which most often consisted of the reactions mentioned by Kwok. Schaumburg and Byck mentioned that syncope, tachycardia, lacrimation, fasciculation and nausea were noticed among the people they had found to be "MSG" sensitive, but all of these were attributed to causes other than GLU. Onset time was 10 to 25 minutes with a duration of 45 minutes to 2 hours. Schaumburg mentioned that 5 grams of "MSG" would produce a reaction in a sensitive individual. Ambos et al.(1) indicated that 2 teaspoons per 6 ounce glass of tomato juice was needed to provoke a reaction in females, while 4 teaspoons per 6 ounce glass was needed to provoke a reaction in males. In 1969, Schaumburg et al.(445) reported results of studies they had undertaken. This time, both headache and chest pain were added to the symptom list, and a point was made of the fact that there is considerable variability in threshold dose among individuals. Experiments were done with a wide range of test materials and a variety of experimental conditions. Schaumburg et al. concluded, "We now have shown that MSG can produce undesirable effects in the amounts used in the preparation of widely consumed foods."(1) Additional case reports presented themselves from time to time. In 1972, Upton and Barrows,(446) warned that, based on their observations of an epileptic woman, it would seem reasonable to advise patients on diphenylhydantoin to avoid foods rich in "MSG." Some Immediate Hypotheses There are no recorded reports of people suffering adverse reactions to seaweed during the thousands of years it was used as a flavor enhancer, and there are no published reports of people suffering adverse reactions to GLU between 1908 and 1953447 when the primary means of production of GLU was the classical method of extraction. Between 1956 and 1966, however, two things changed. First, the primary process underlying GLU production was changed to a process depending on fermentation. Second, the new process made it possible to achieve truly mass production, which had not been available before, and the amount of GLU available for consumption escalated. The first reports of adverse reactions to GLU might, then, be accounted for by change in method of manufacture, increased usage, or both. Remember, too, that GLU was not introduced into the United States in any volume until after the First Symposium of GLU in 1948.(1) This might suggest the presence of a sensitizing factor working over time. Finally, "HPP," in its many forms, was introduced separate and distinct from "MSG." There were a number of clues to be found in the literature which could have been followed up in 1968 to determine the cause of the GLU reaction, if anyone would have thought to do so. No one did. Kwok mentioned that not only did he not suffer a reaction in his own home, he had never experienced one before coming to the U.S.A. We know McCaghren,(1) who had experienced reactions in New York City in 1956 and in Chicago in 1961 and 1962, "...lived on a fairly consistent Chinese diet in the Hawaiian Islands -uneventfully;" but upon returning to the mainland at the end of 1964, again experienced reactions, this time in Chinese restaurants in southern California and Hew Hampshire. And we know that in 1968, in Harrisburg, Pennsylvania, his visits to Chinese restaurants were uneventful. Along the same line, both Migden in 1968(1) and Himms-Hagen, who wrote in 1970(448), reported that while they reacted frequently to something in Chinese restaurants in the U.S.A., no reaction had ever been noted in England. But in Schaumburg's 1969 article,(1) he mentions one report of adverse reaction in France and one in Saigon. Could Dr. Kwok, in eating at an American Chinese restaurant, have eaten a substance different from what he ate before he came to the USA? Was he eating seaweed in Taiwan and manufactured GLU in the USA? Was he eating GLU in Taiwan, but a different formulation, and/or a much lower dosage? Were those who experienced adverse reactions in the USA, but not in England, eating the same (by virtue of the way in which it was processed) GLU; were they exposed to lower doses; or do we know they were eating GLU at all? Did different Chinese restaurants in the USA use different sources of GLU, or different doses? The First Food Industry Reaction The first article designed to discredit the notion of GLU induced adverse reactions appeared in Nature in 1970.(449) Morselli and Garattini reported on a study designed to "...assess the significance of subjective reactions." It is not clear to this author exactly what is meant by "assessing the significance of subjective reactions." It would appear that what we have here is industry's first attempt to invalidate the use of case reports as evidence of adverse reactions (case studies being, by their very nature, largely subjective). (Method D.) In addition, Morselli and Garattini emphasized the need for use of double blind technique. Considering not only their research, but work subsequently done by other food industry sponsored researchers, it would appear that industry emphasis on the need for double blind studies comes from certain knowledge that GLU sensitive persons will be reluctant to participate in studies where they are required to ingest a substance that will make them ill. Since evidence suggests that only 25%-30% of the population is sensitive to GLU at doses readily available in food, subjects who give informed consent and participate in industry sponsored double blind studies will, very possibly, be subjects who are not sensitive to GLU. It would also appear that emphasis on design is used to distract the reader from noticing possible serious methodological flaws in the design's implementation. Morselli and Garattini studied both subjective and objective parameters. In the study of subjective parameters, subjects were supplied a list of possible symptoms which included space for additional symptoms. The authors found no statistically significant difference between experimental and control groups in reports of the symptoms of Chinese Restaurant Syndrome (CRS). They reported one female who experienced a panic-like syndrome after being given GLU, "...but it was not associated with any significant modification of objective parameters such as arterial pressure, pulse or respiration rate." And, "The only subject who described a panic-like syndrome did not experience any burning feeling." The authors conclude that "...MSG administered orally in relatively high doses does not provoke any symptoms of Chinese restaurant syndrome." This is translated, by the food industry, as "GLU is safe." Objective parameters studied were arterial blood pressure, pulse, and respiration rate. (Method B.) None had ever been shown to be associated with adverse reactions to GLU. Yet Morselli and Garattini discount the importance of the panic-like syndrome because it is not associated with the objective parameters they have arbitrarily chosen to observe. Subjects were 24 in number, too few to generate statistically significant findings in light of the extreme variability associated with GLU adverse reactions. Seventeen of the subjects were male; and it was believed(1) at the time, that males were less sensitive to GLU than females. (Method E.) Subjects were "healthy volunteers," neither randomly selected or suspected of being GLU sensitive. Three grams/subject were administered at lunch time in 150 ml of beef broth. "This was followed by other dishes (meat, vegetables and fruit)." We have no report of the ingredients in any of these foods. It is conceivable that either in the beef broth, or in the food that followed, there was GLU in other than "MSG" form, or there were substances which might provoke non-GLU allergic reactions. (Method F.) Either the size and composition of the subject pool or the ingredients administered to the subjects, could, by themselves, account for the failure of Morselli and Garattini to find sensitivity which could be attributed to ingestion of GLU. Methodology Particular to Human Research There are a number of questions which must be answered when reviewing research. We have talked of the people who are being observed or studied. We have pointed out that it is necessary to be certain that people who are supposed to be able to demonstrate the phenomenon are included among the people that we study. But what of the phenomenon itself? If we take a person who is supposed to be sensitive to GLU and feed him soy bean paste and he does or does not have a reaction, we have found out nothing about his sensitivity to GLU. So we must be very careful in choosing materials which will be appropriate to our investi-gation. As we study GLU sensitive persons, we want to look at the quality of the GLU given to induce a reaction, and the amount used at one time or over a period of time. We might also want to look at the time of day it was given, the time lapsed since last eating, and/or what liquid or solid was consumed at the same time as the GLU. These are some of the independent variables. Two researchers using different sets of independent variables, would not be expected to find the same thing. Two or 3 grams of GLU would not be expected to produce the same reaction as five grams of GLU. And if an experimenter attempts to duplicate the phenomenon in the laboratory using bulk GLU, capsules, or pills instead of GLU in to food (which might be taken into the system and digested quite differently), he may find out some very interesting things, and his findings may be of extreme research importance, but, again, he would be failing to replicate the "original" study. There are also dependent variables to consider, the reactions that you are looking for, the things that you say demonstrate a reaction to GLU. For Kwok, it was a numbness, a weakness, and palpitation. You might have some other ideas about GLU reactions and see if any of these occur, too. But would you, seemingly out of the blue, look to see if toe nails fall out after ingestion of GLU? You might, if you were out to "prove" that there are no GLU sensitive people. Here's how you do it. You look for toe nails falling out after GLU ingestion. You don't find them. You see that there was no reaction (which is true) and, therefore, you conclude, there is no sensitivity to GLU. And those who read your introduction and conclusions might believe you. There is one more extremely important concept that must be considered before we begin to evaluate human research. Maybe our subject does manifest a set of adverse reactions when he ingests GLU. But would he demonstrate the same reactions if he only thought he was eating GLU, but really wasn't? So we give our subject GLU on some days, and something that looks and smells and tastes the same on other days; or we might give our subject 10 different tasting things, some with, and some without, GLU; and we don't tell him which is which; and the person who presents the materials to him doesn't know which is which. This is "double blind" testing. There's potential here for fraud for those who have the intent. If you gave the GLU in a solution of milk, and used unadulterated milk as the placebo, a person allergic or sensitive to milk who took part in your study would exhibit adverse reactions to both the experimental material (GLU and milk) and the placebo (milk). If you choose to overlook the possibility that your subject might be allergic or sensitive to milk you might simply conclude that since your subject responded with a reaction when there was no GLU, his reaction when there was GLU was not an GLU reaction. Thus, using any substance as a placebo to which a subject might be sensitive is inappropriate (maybe even dishonest). This point was made in 1981 by Rippere.(1) We call this Method F. A version of this same theme warrants special consideration. Given the fact that the FDA has made "MSG" a "defined" term (pure sodium glutamate) which differs from the way in which MSG is thought of or used in common usage (any sodium glutamate), one might use "MSG" in a test material while using a placebo material which contained "HPP" or reaction flavor, or which was made with protease (all of which would contribute GLU to the end product of processed or otherwise manufactured food). One of the semantic "games" played by industry representatives is to call MSG "MSG," while referring to "HPP" as "naturally occurring glutamate." It could be that this semantic differentiation is rationalized into use of "HPP" in placebo materials as something different from "MSG," while the chemical analysis tells us that they both contain GLU. A review of the industry sponsored literature will demonstrate the emphasis which industry research has placed upon the necessity of having the test and placebo materials taste the same. Given that GLU is an excitatory amino acid, affecting the nervous system to produce its "enhanced" taste, the same taste can only be accomplished if both test and placebo materials contain some form of the same excitatory amino acids. A study by Goldschmiedt, Redfern, and Feldman,(1) published in 1990, is an illustration of the potential for just this sort of thing. (Method F.) It is a fact that broth purchased in the supermarket today, contains manufactured GLU. Of course it doesn't necessarily say "MSG" on the label, but is does say "hydrolyzed protein" (which, invariably, contains GLU) and/or "broth," "bouillon," "flavoring," "natural flavoring," etc. (which almost always contains "HPP"). Goldschmiedt et al. report using beef broth supplied by Ajinomoto (a producer of GLU) as their placebo. The Chronology of the Reports and Studies in the 1970's Before 1968, GLU was used not only as a food additive, but, in one form or another, as a drug. Even though there was no discussion of adverse reactions to GLU in the literature, there was mention made of GLU from time to time, and there was discussion of side effects. Between 1968 (when Kwok wrote his letter of inquiry to the New England Journal of Medicine) and 1973, 14 authors reported similar or identical reactions; and Schaumburg et al.(1) presented evidence that those adverse reactions were caused by GLU, and postulated hypotheses concerning what the mechanisms might be. Subsequent to Schaumburg's 1969 article,(1) Morselli and Garattini(1) published a study carefully designed to falsely conclude that there existed no such thing as GLU sensitivity. A criticism of the Morselli and Garattini article was published by Himms-Hagen in 1970.(1) Nineteen seventy also witnessed an article by Bazzano et al.(450) which explored clinical pathological changes, and failed to produce adverse reactions in adult gerbils and all male human subjects fed a chemically defined diet supplying GLU along with all of the essential amino acids in optimal amounts. Questions can be raised about using all male human subjects (males being thought less sensitive than females to GLU) and relating human adverse reactions solely to CRS when it had been demonstrated that there were other, far more significant reactions. In spite of the methodological inadequacies, the study is of interest for the finding that GLU given with all of the essential amino acids produced no adverse reactions. This could well point to amino acid imbalance as a mechanism of GLU adverse reactions. In 1971, a study by Ghadimi et al.,(451) focusing on mechanisms which might be relevant to the adverse reactions associated with GLU, again demonstrated adverse reactions. They found that the reactions which followed GLU ingestion were "...strikingly similar to those induced by acetylcholine." Following the negative 1970 Morselli and Garattini article(1), came one by Rosenblum et al.,(452) the course of which is a bit more difficult to understand. Several studies were done, and a variety of results were obtained. In the result section of their article, Rosenblum et al. state that using 50 subjects in one of their studies, they found subjects who ingested "MSG" to exhibit significantly more reactions than subjects who had not ingested "MSG." Yet the discussion section states that "...these studies...failed to reveal a single subject who had experienced the triad of symptoms suggestive of the Chinese Restaurant Syndrome." Once more, it was the phenomenon of CRS, not the phenomenon of GLU sensitivity, that was studied. (Method D.) More importantly, the discussion does not follow from the results. (Method C.) The authors demonstrated that there were adverse reactions to GLU, but these were not the reactions defined as CRS. The food industry used (and still uses) this as evidence that there is no reaction to GLU. The next study was one done by Kenney and Tidball(1). They, too, reported the results of a number of experiments. They concluded that, "Thirty-two percent of the persons tested responded at the 5-g level when challenged by a single placebo-controlled exposure [to GLU]." They also suggested that "It seems likely that monosodium L-glutamate taken as the salt is not physiologically equivalent to glutamic acid ingested in protein." After the 1972 report, Kenney apparently went to work for the Glutamate Association. In a 1979 paper, Kenney(453) quotes from his earlier work, provides evidence from two studies which demonstrate human adverse reactions to GLU, has a "however" in the discussion and conclusions which relates to some percentage figures for GLU levels (that defy interpretation), and finally suggests that what might appear to be a reaction to GLU can be explained away as an esophageal reaction. (Methods C and D.) The following human studies and comments on human adverse reactions were published between 1973 and 1978. Few authors added to the "scientific" literature on adverse reactions to GLU. There were, however, a number of reports of adverse reactions. Reif-Lehrer's first article appeared in 1975(454) as correspondence in the New England Journal of Medicine. She wrote that children react to GLU ingestion, and described symptoms similar to adults with almost the same degree of prevalence. She presented three cases and discussed the relation between shudder in children, epileptic "seizures", "MSG shivers", and the fact the GLU has been reported to cause convulsive disorders in animals. Subsequently, Andermann, et al., commented on a possible relationship between GLU and essential tremor.(455) During the next two years, Reif-Lehrer published an additional report of children's apparent adverse reactions to GLU;(456) results of a questionnaire study establishing that 25% of those responding to the questionnaire, and 30% of the persons reporting that they had been exposed to Chinese restaurant food, reported adverse reactions;(457) and a lengthy review and report on the possible significance of adverse reactions to GLU in humans.(1) In the last report, published in 1976, Reif-Lehrer raised the question of whether particular groups of individuals might be adversely affected by eating unregulated amounts of GLU. Colman(458) wrote to the New England of Medicine in 1978, reporting two cases of psychiatric reactions to GLU. Kenney, in a letter published in the New England Journal of Medicine in 1979,(459) criticized the letter by Colman.(1) Kenney stated categorically that symptoms that may be provoked by GLU appear within 30 minutes of ingestion and are dissipated within 90 minutes. He also stated that, "...if this patient had some idiosyncratic defect of glutamate metabolism one would expect symptom occurrence to follow the normal dietary intake of naturally occurring glutamic acid rather than to be episodically related to this salt." It is interesting to note that in this letter,(1) Kenney contradicts both data cited and the statement made in 1972 that "It seems likely that monosodium L-glutamate taken as the salt is not physiologically equivalent to glutamic acid ingested in protein."(1) Colman(460) responded to Kenney's criticism. The text of that response is included here, in its entirety. " To the Editor: Dr. Kenney's letter questions both the validity and certain specifics of the case report, which describes both a typical toxicity and a more delayed organic- like depressive syndrome after oral ingestion of monosodium glutamate. With regard to the specifics, the following points are pertinent: "Duration of symptoms. Clinical reports in the literature document that many symptoms, including most of those present in the report, persist for at least 12 hours after monosodium glutamate ingestion. Kenney's own work (using normal volunteers, not identified susceptible persons) reports two subjects who had symptoms that he then "eliminated" from his data because they were "unusually prolonged." "Rapid metabolism of glutamate before onset of symptoms. It seems almost unnecessary to point out that drug toxicity (like most pathologic processes) often acts through metabolic intermediates, cellular attachments and complex activation cycles that do not depend on the presence, in the original form at least, of the noxious agent. The pathogenesis of drug-induced asthma is an obvious example. Central-nervous- system disturbances commonly follow such delayed patterns -- e.g., belladonna alkaloid intoxication and amphetamine psychosis. In both these conditions, as in the case described, psychiatric symptoms develop and persist after the drug is metabolized. "Idiosyncratic defect of glutamate metabolism. In my report I suggested an underlying biochemical disorder in the two family members described. However, there are data to suggest that almost all people respond with toxic symptoms to ingestion of monosodium glutamate, depending on the size of the challenge. Investigators, including Kenney himself, have shown that after ingesting 5 g, 30 per cent of the population respond with acute symptoms. Five grams is about the amount that would be ingested in one meal if anyone followed the instructions of a television advertisement for Accent (a commercial preparation of monosodium glutamate). In one study, 90 per cent of the volunteers had symptoms at 10 g. "Symptoms with dietary glutamate. The largest amounts of free glutamate naturally present in foods are about 1/10 of the amount of monosodium glutamate used in food to produce its gustatory effects -- far too little to exceed the toxic threshold of even the most susceptible persons. However, Hydrolyzed Vegetable Protein, a common food additive, is by law allowed to contain up to 20 per cent free glutamate and does cause the same symptoms as monosodium glutamate in susceptible persons, including those discussed in my previous letter. The most disturbing part of Dr. Kenney's letter is his ridicule of the value of clinical reports. Obviously, case studies are not scientific investigations, but they are of proven worth. This one was presented to alert physicians to a potential psychiatric hazard of monosodium glutamate and to stimulate new work in the area. We should know far more about the effects of nonphysiologic amounts of free glutamate on all organs, including the brain, before we judge monosodium glutamate safe for consumption." The 1979 report by Kenney(1) has already been considered. While his 1972 study(1) reported what transpired, and the conclusions fairly well reflected the results of the studies, the 1979 paper resembled the work of Matsuzawa(1) and Takasaki(1) in that there was little or no relation of the discussion and conclusion to the body of the study. (Method C.) Kenney focuses on a conclusion which might be relevant if a number of assumptions that he makes along the way are true, and in so doing, ignores the body of the study. Kenney was not heard from again until 1986(461). The timing is significant, for if you review the work that Kenney has done on the subject of GLU, you can not help but note that each and every time he published a paper which addressed the safety of GLU, it was in response to, or in anticipation of, possible consumer criticism. In 1979 he responded to Colman,(1) who criticized the use of GLU. In 1979(1) he published a study done to influence the Select Committee on GRAS Substances of the Federation of American Societies for Experimental Biology (FASEB). In 1986, the food industry was aware of the formation of an Ad Hoc Committee convened to study the question of the safety of GRAS substances, including GLU, and Kenney published again. It would appear to be no coincidence that Kenney produced or reviewed research on GLU at those times when it would be of value to The Glutamate Association. In the minds of some, it lessens his credibility to note that he apparently undertook research on GLU at no other time. In his 1986 paper,(1) Kenney reports that, "Work over the past 17 years has consistently failed to reveal any objective sign accompanying the transient sensations that some individuals experience after the experimental ingestion of monosodium glutamate and it is questionable whether the term 'Chinese Restaurant Syndrome' has any validity." The misuse by others of reference to "objective" variables has been discussed previously. We noted that when industry research points to the use of objective variables, they point to variables which have never been shown to have any relationship to adverse reactions to GLU. (Methods B and D.) Kenney, in his 1986 review, uses a number of devices to promote the notion that GLU is safe. A few of these are outlined below: 1) Verbal denial Obscure the real issue: Focus on CRS as described by Dr. Kwok instead of on the known reactions to GLU Focus on objective parameters, things like pulse rate, blood pressure, and plasma GLU levels, which have never been shown to have a direct relationship to the adverse reactions associated with GLU Use ill defined terms: "... dietary administration of glutamate...produces only minor side effects..." "...identified individuals who experienced symptoms specific to MSG...only when MSG was given in amounts or concentrations far in excess of the amount appropriate to the use of MSG as a flavor- enhancer." "...MSG was generally administered at concentrations of up to 3.5% in a suitable vehicle (broth, tomato juice or a specifically formulated soft drink)." Purposely misinterpret or take out of context data or conclusions relevant to the issue of GLU: "...this lesion cannot be produced in mature rats..."(Adamo and Ratner 1970) -- when the truth is that this lesion was not produced in mature rats by Adamo and Ratner which says nothing about cannot. 2) Quote from inappropriately done research: Kerr(462) "...43% experienced some unpleasant aftermath of eating....only 1.8% of the individuals who had some discomfort after meals experienced one or more of the CRS symptoms and less than 0.02% of the subjects had the experience after Chinese cuisine." (See discussion below.) 3) Use too few subjects for drawing a conclusion. One has to marvel at Kenney's singleness of purpose. "It is interesting," he notes in the conclusion of his 1979 paper,(1) "that although the anecdotal literature of the Chinese restaurant syndrome contains reports of individuals who believed themselves to be suffering cardiac pain and sought attention for this condition, no mention is to be found of the differential diagnosis of esophagalgia being considered." Might we suggest that esophagalgia isn't mentioned because it's an excuse concocted by Kenney to distract attention from GLU, and is not relevant here? In interpreting the Kenney studies and comments, it would be well to consider the change in "attitude" visible since 1972(1). In 1972, Kenney mentioned that, "It seems likely that monosodium L- glutamate taken as the salt is not physiologically equivalent to glutamic acid ingested in protein."(1) In the 1980's Kenney suggested that metabolism of free amino acids (such as GLU) was identical to metabolism of amino acids bound in ingested protein. In 1972,(1) Kenney also noted that "The lack of correlation of blood glutamate level with the appearance of symptoms..." We interpret this finding to mean that blood glutamate levels are not related to appearance of symptoms. Kenney now interprets the lack of correlation to suggest that since symptoms are not associated with elevated blood GLU levels, the symptoms have no meaning. The relevance of blood GLU levels to human adverse reactions has never been demonstrated. Kenney's 1972 data suggest that there is none. Data from a study by Wilkin(463) support the findings of Kenney in this instance. In 1977(464) and again in 1979(1) Kerr et al. published reports criticizing the Reif-Lehrer's survey questionnaire(1) which focused on adverse reactions to GLU. Although there are methodological differences, to be sure, the fundamental difference between the two authors is that Reif-Lehrer reported on "sensitivity to MSG," while Kerr et al. reported on a very narrowly defined "Chinese restaurant syndrome," which, by their definition, was only manifested if all three of the symptoms understood to have been experienced by Kwok(1) appeared together in a time frame limited to 20 minutes to 2 hours following a meal. (Method D.) Although 43% of the 1979 sample of 1,369 subjects responding reported symptoms which are known to be symptoms of GLU sensitivity in some people, those reactions were not considered as being relevant. (Method E.) Wilkin, in 1986,(1) presented an interesting study of "flushing," in which he failed to find "objective" evidence of flushing in an indeterminate number of subjects. The statistics he used are undefined and uninterpretable. He concluded that his failure to provoke flushing demonstrates that no more than 11.7% of the population is at long-term risk from 3 gm of GLU. There appears to be no logical relation between his data and his conclusion. (Method B.) Over the years, Stegink, in association with Baker, Filer, Pitkin, Reynolds, and others, has produced a large body of literature aimed at proving that use of GLU as a food additive is safe. Typically, Stegink's work focuses on plasma GLU levels. We have already criticized one such study done with neonatal monkeys.(1) In 1986, Stegink et al.(465) published one of a number of studies focusing on GLU adverse reactions. They report data from eight infants (ordinarily too few to demonstrate a statistically significant difference between test and control groups); none of whom are know to be GLU sensitive; who are fed beef consomme (the ingredients of which are not elucidated, and which could very well contain GLU in "HPP" form or be irritating to any or all of the infants for other reasons); and they base their conclusions about the alleged safety of GLU on plasma GLU levels (which have never been shown to be related to the adverse reactions of GLU sensitive people). (Methods B,D,F.) In their discussion, Stegink et al.(1) refer to the animal studies, in an attempt to build their case for the safety of GLU; and they mention that "The neonatal human probably resembles the neonatal monkey to a greater extent than the infant mouse." Stegink's own data(466), however, demonstrate that the adult mouse resembles the adult human to a greater extent than does the adult monkey. One would wonder, then, on what Stegink et al.(1) base their "probably." From time to time, case reports are published describing instances of adverse reactions associated with ingestion of GLU. There are reports of tachycardia,(467) hyperactive or hysterical activity in children,(468,469) paraesthesiae of hands and feet,(470) severe "burning" headache,(471) severe upper abdominal pain and pressure accompanied by diaphoresis and a burning sensation in the chest, (1) angio-oedema,(472) and a hypertensive reaction(473) in the form of vascular headache, typical of those seen in patients taking monoamine oxidase inhibitors. Ratner et al.(1) report that the initial diagnoses in seven patients whose complaints were eventually resolved as GLU sensitivity, were migraine (twice), myocardial infarction, brain tumor, neurosis, functional colitis, and depression. Comments and observations also have been published. Neumann(474) reported having seen reactions involving frequent ventricular premature beats. He cautioned that, "Because sensitivity to MSG is not rare and because of the unpredictable consequences given a damaged, vulnerable, or irritable myocardium, patients with a tendency to rhythm disturbances should be made wary of prefabricated soups, and meat 'tenderizers,' in addition to the fare of Chinese restaurants. Incidentally, the term 'Chinese restaurant syndrome,' while picturesque, is too narrow considering the tons of MSG used in less exotic foods. The syndrome should really be termed what it is, an MSG atopy. And the cardiovascular system is its chief target."(1) Gore and Salmon(475) observed 55 subjects given randomized GLU and placebo trials, and noted that although the reactions to GLU were significant, the symptoms recorded were not those of the CRS. They questioned the meaning of reaction to symptoms which were not CRS. Sauber(476) pointed out that the meaning was perfectly clear -- that the symptoms which Gore and Salmon found to be most prevalent, were, indeed, the most prevalent visible effects of GLU. Asthma has been studied extensively by Allen.(477,478) He has explored and discussed the possible relation of GLU to asthma, questioning the possible links, and exploring possible mechanisms for a relationship. In a single blind study(1) using 32 subjects with asthma, some of whom had histories of severe asthma after Chinese restaurant or similar meals, he found a dose dependent reaction which in some cases was delayed up to 12 hours. Moneret-Vautrin(479) reported finding a "...very small subset of patients with intrinsic asthma..." with an intolerance to high doses (2.5g) of GLU. Schwartzstein et al.(480), in a study using 12 subjects, explored "...a possible role of MSG in the induction of asthmatic syndromes in a more general population of individuals with reactive airways disease." Subjects were persons with chronic stable asthma, recruited if they met a number of conditions relevant to their asthma, but without regard to the presence or absence of a history of food sensitivity. Since informed consent was obtained, one would have to question whether GLU sensitive persons did, in fact, refuse to participate in the study. Since subjects were not chosen randomly, and would have had the opportunity to opt out of the study if invited, it might be conjectured that persons with GLU sensitivity would not be proportionately represented in the study. No data are given on the recruiting of subjects in this regard. Given that the subjects do not constitute a randomly drawn sample of any defined population, the use of a "paired t-test" (the rationale for which is based on the random selection of subjects from a specified population) is unquestionably inappropriate. The fact that a "randomized, crossover protocol" was used, is irrelevant to the need to use randomly drawn subjects from a defined population. Moreover, given the known high variability in reaction to GLU ingestion, the use of so few subjects virtually precludes the finding of any statistically significant difference. It would appear that the choice of subjects, the number of subjects used, and the choice of statistical analysis are both misleading and inappropriate. (Method D.) In addition, subjects were given capsules which essentially preclude the absorption of GLU above the level of the stomach (a condition quite different from that found when GLU is ingested with food) and could, depending upon the formulation of the capsule, prevent absorption or metabolism of GLU. The dose chosen (25 mg), was said to be based on FDA estimates, but FDA estimates do not exist. It would appear that the study was purposely developed to demonstrate that asthma is not affected by GLU. Hosen(1) criticized the test used by Schwartzstein(1), and suggested instead the use of a challenge test. He added that "A negative finding using 12 patients is not a diagnostic number. A good diagnostic number is 100." He used 1500 mg in a 00 capsule and produced reactions in five of his 100 patients. Hosen, too, might have found a greater percentage of subjects experiencing reactions if he had not used capsules. The FDA, both in its Adverse Reactions Monitoring System (ARMS) and elsewhere, has in its files numbers of letters from people reporting their sensitivities to GLU. In Memorandum to the Health Hazards Evaluation Board of the FDA dated October 6, 1989 and June 8, 1990, entitled, "Adverse reactions associated with monosodium glutamate (MSG) ingestion," Tollefson detailed the symptoms that had been reported to ARMS as of each date. The lists included headache, vomiting and nausea, diarrhea, change in heart rate, change in mood quality or level, abdominal pain and cramps, dizziness or problems with balance, localized pain and tenderness, sleep problems, change in vision, fatigue, weakness, change in body temperature, difficulty breathing, local swelling, joint and bone pain, chest pain, change in sensation (numbness, tingling) change in activity level, blood pressure changes, difficulty swallowing, etc. Tollefson's conclusion after considering all of the material available to her was that, "...there was nothing...submitted...to suggest that MSG is a human health hazard." The fact that Tollefson chooses to regard all of the cases presented as non-indicative of sensitivity to GLU says nothing about the facts. There are also those who would poke fun at a new concept rather than explore it. Weisse(481) published such an article in 1989, poking fun at diagnoses of GLU sensitivity along with such things as "chronic fatigue syndrome." In 1979, Filer et al., published a book called Glutamic Acid: Advances in Biochemistry and Physiology(482), a compendium of articles taken from a symposium held in Milan, Italy in 1978. The purpose of the book, as is apparent from the summary, is to substantiate the notion that GLU is safe. The symposium was undertaken to present "the right kind of data" to the Select Committee on GRAS Substances (SCOGS) of the FASEB, which had been convened by the FDA to relieve pressure to remove GLU from baby food. Much of the faulty research and reasoning included in the book has already been reviewed. SUMMARY OF RESEARCH: NEURODEGENERATIVE DISEASE There is a relatively new area of research for which the food industry, to date, has had no comment, contradiction or excuse. These are studies which link GLU to neurodegenerative disease. Discovery that GLU causes lesions in specific areas of the brain of laboratory animals and concomitant proliferation of neuroendocrine dysfunction, came through interest in the brain. It was brain research that identified GLU as a possible, probable, and now certain neurotransmitter, transmitting nerve impulses. Likewise, it was study of the brain which suggested that a group of these neurotransmitters, specifically the excitatory amino acids (EAA), possess properties which very likely play an important role in the development of certain neurodegenerative diseases.(1, 483,484, 485,486, 487, 488, 489,490) GLU and aspartate are among the EAA which have great potential for involvement in neuro-degenerative disease. At the present time, significant headway in the study of neurodegenerative disease is being made. "Three EAA receptor subtypes that mediate excitotoxicity have been identified, drugs with anti-excitotoxic actions have been discovered, and evidence for the complicity of both exogenous and endogenous excitotoxins in neurodegenerative disorders has begun to unfold. There now is substantial evidence for the involvement of each EAA receptor subtype in one or more human neurodegenerative syndrome, and recent findings suggest that EAA receptors are sensitive mediators of excitotoxicity at both ends of the age spectrum."(1) Both "MSG" and "HPP" are exogenous sources of GLU. So is the GLU produced when protease enzymes or reaction flavors are used in manufactured or otherwise processed food. GLU is an EAA. It has been suggested, and there is evidence to support the suggestion, that the EAA might well play a role in the following neurodegenerative conditions: sulfite oxidase deficiency; epileptic, hypoglycemic and hypoxic/ischemic brain damage; central nervous system trauma; dementia pugilistica; domoate dementia; olivopontocerebellar degeneration; neurolathyrism; amyotrophic lateral sclerosis, parkinsonism, Alzheimer's dementia; Huntington's disease; and Wernicke/Korsakoff syndrome.(1) THE JUDGES The "controversy" over the safety of GLU appears to exist because the food industry perceives that there are billions of dollars to lose if GLU is labeled, and it has created the fiction that GLU is safe. Since Olney's(1) initial observation that GLU causes brain damage in infant laboratory animals, and Kwok's(1) almost simultaneous report of GLU induced adverse reactions, industry has managed to manipulate FDA regulation of the substance to the point that there is virtually no FDA control. The history is traced in incomplete form in a piece presented by this author as the appendix to a submission to the Advisory Committee on the Food and Drug Administration, Washington, D.C., September 6, 1990. The appendix is included here for your review as it is not readily available. It is entitled, "MSG and the FDA Historical Perspective. In it is outlined the role of the FDA in regulating (or refusing to regulate) the use of manufactured GLU in food. The first impropriety reported was from 1969 when then Commissioner Levy of the FDA presented four studies to the Senate Select Committee on Nutrition and Health purportedly demonstrating the safety of GLU. Two of the four studies had not been completed, and two did not exist. More recently the World Health Organization, which reviewed the safety of GLU in 1987, failed to review both reports of adverse reactions following ingestion of GLU on file in Washington at the FDA, and a significant number of relevant published materials. Part of the "sales pitch" of The Glutamate Association is to point to the important and scholarly committees that have concluded that GLU is safe. They do not mention that among the members of those committees were persons who appear to have been hand picked by industry to represent industry interests; and that significant materials were withheld from them all. SUMMARY and CONCLUSIONS There is a body of literature which the food industry and the FDA point to that purportedly demonstrates the GLU, taken as a food additive, poses no hazard to human health. In striking contrast, there is undeniable evidence that: 1) the neurotransmitter and neurotoxic substance, GLU, causes neuron degeneration and death, and neuroendocrine disorders in a variety of laboratory animals; 2) approximately 30 per cent of the population suffers adverse reactions to commercially manufactured (free) GLU, regardless of the source; and 3) there are links between increased levels of GLU in the body and incidence of a number of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The FDA, which is charged with the responsibility of protecting consumers from substances which might be hazardous to their health, takes the official position that GLU, as a food additive, poses no health hazard. One might have thought that in the two decades since scientists first noted that GLU caused both adverse reactions in humans and brain lesions in laboratory animals, the FDA would have imposed sanctions on the use of GLU in food and/or given it drug status. Instead, "MSG," which had been grandfathered onto the GRAS in the late 1950's has been given a clean bill of health time and time again by the FDA, and other forms of GLU are largely ignored. The circumstances which account for the FDA's continued refusal to regulate the use of GLU are as follows: 1) The food industry appears to place its priority on sales figures and not trouble itself over possible human health hazards. Even so, it must have come to industry's attention that there is evidence which suggests that both animals and humans react adversely to ingestion of GLU. In what would appear to be response to that evidence, much of the food industry has chosen to hide the presence of free GLU as best it can by not labeling GLU as such when it occurs in the end product of manufactured or otherwise processed food. 2) The FDA assumes much the same position that took on the safety of cigarettes and sulfites, which appears to be, "whatever industry ways, goes." So nothing is done to either regulate the use of GLU or make it easier for people to know where there is manufactured GLU in the food supply. Moreover, the FDA appears to put some thought and effort into maintaining the status quo on this subject, for at least as recently as February 4, 1991, all of the review boards called by the FDA to review and evaluate the safety of GLU had been staffed by persons with strong industry ties or by persons without a strong base of scientific knowledge and with little or no prior knowledge of the issue, from whom data on the hazards of GLU ingestion (including reports of adverse reactions on file with the FDA) have been withheld. Never has a neuroscientist with a specialty in the area of amino acid toxicity served on a panel called by the FDA to consider the effects of GLU ingestion, even thought those effects include evidence on neuronal necrosis caused by GLU. 3) While a few physicians have observed reactions to GLU and have reported their findings in the medical literature, the medical community basically accepts, without question, the position of the FDA on the safety of GLU, and does not choose to look for GLU sensitivity. So when a patient approaches a physician with symptoms which informed persons would recognize as possible manifestations of GLU sensitivity, the uninformed physician does not recognize them. In turn, because GLU sensitivity is overlooked, there will be no reports of GLU sensitivity filed with the FDA; and the FDA says that because there are few medical reports, there is little or no GLU sensitivity. 4) Research money is available for many kinds of brain research, but to date there has been no research money made available for unbiased study of human adverse reactions to GLU. There would appear to be no reason to use research money to study a substance which the FDA says is safe. This leaves biased, methodologically unsound, statistically inappropriate, industry sponsored research unchallenged. 5) Individuals are largely unable to identify sensitivity to GLU because only "MSG" is identified on food labels as GLU, while the GLU in "HPP," and protease enzyme and reaction flavor products are not labeled. So consumers don't often bring information about GLU sensitivity to their doctors; and they don't know to what they are sensitive, so they don't write letters about their sensitivity to the FDA. These five factors are interwoven to perpetuate the failure to identify and relieve sensitivity to GLU. The chain could be broken at any level. The key, however, would appear to lie in reevaluating the body of research which has been taken as evidence that GLU poses no human health hazard. For once the health hazard posed by ingestion of GLU is recognized, and the scientific community at large, and the medical profession in particular, is informed of what has transpired, diagnoses of GLU sensitivity will be made if they are appropriate, and unbiased, large scale, long term research into the phenomenon of GLU sensitivity will begin. This report of research was undertaken to facilitate reevaluation of the body of research which has been taken as evidence that GLU poses no human health hazard. 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