THIS IS WHAT THE DATA SAY ABOUT MONOSODIUM GLUTAMATE TOXICITY and the CENTRAL NERVOUS SYSTEM
(Compiled by Adrienne Samuels, Ph.D., May, 2009)

Excitotoxins are toxic agents capable of exciting and then poisoning cells or tissues.  Two manufactured excitotoxic amino acids are presently used in quantity in processed foods. Glutamic acid (glutamate) is the most prevalent of the excitotoxic amino acids. Glutamate that has been produced through bacterial fermentation or has been freed from protein through a manufacturing process or through fermentation (MSG) will be found in ingredients including, but not limited to, hydrolyzed protein products, autolyzed yeast, calcium caseinate, sodium caseinate, textured vegetable protein, gelatin, ultra-pasteurized products, and monosodium glutamate.  It is glutamate as MSG that has been administered or fed to subjects in studies where some form of glutamate produces brain lesions and/or adverse reactions. Glutamate found in intact protein has never been shown to cause brain lesions or adverse reactions.

Retinal degeneration

In 1957, Lucas and Newhouse(26) first noticed that severe retinal lesions could be produced in suckling mice (and to some extent in adult mice) by a single injection of glutamate. Studies confirming their findings using neonatal rodents (49-52) and adult rabbits(53) followed shortly, with others being reported from time to time (54-58). These studies concerned themselves not only with the confirmation of monosodium glutamate induced retinal lesions, but with the formulation and testing of hypotheses to explain the phenomenon.  

In 2002, Ohguro et al.(27) found that rats fed 10 grams of sodium glutamate (97.5% sodium glutamate and 2.5% sodium ribonucleotide) added to a 100 gram daily diet for as little as 3 months had a significant increase in amount of glutamic acid in vitreous, had damage to the retina, and had deficits in retinal function.

Ohguro et al. also documented the cumulative effect of damage caused by daily ingestion of MSG.

Other reports of toxic effects of monosodium glutamate have come from studies at the University of Pecs, Hungary, where the neuroprotective effects of PACAP in the retina are being studied(28,29).  

Neuronal necrosis -- which can lead to behavior disorders, learning disabilities, reproductive disorders, and obesity.

In this country, at this time, potential poisons are not administered to humans in order to determine if they are toxic or safe.  Therefore, what we know about the toxic effects of MSG comes from animal studies.  The first relevant studies were done between 1969 and 1980 wherein MSG was administered or fed to animals. By the early 1980s, the neurotoxicity of glutamate was accepted in animal models as glutamate was being used as an ablative and/or provocative tools(122,123), with which suspected pathophysiological abnormalities (obesity, for example) could be deliberately induced to facilitate study.

In evaluating the relevance of these studies to human ingestion of MSG in food, drugs, and dietary supplements, it is essential to understand that the glutamate given to animal subjects is invariably a manufactured product produced in food and/or chemical manufacturing plants. It is glutamate as monosodium glutamate that has been administered or fed to subjects in studies where glutamate from exogenous sources has been shown to cause brain lesions.  Glutamate found in intact protein has never been shown to cause brain lesions or adverse reactions.

Lesions in the arcuate nucleus of the hypothalamus of neonatal and infant animals

In 1957, Lucas and Newhouse(26) first noticed that severe retinal lesions could be produced in suckling mice (and to some extent in adult mice) by a single injection of monosodium glutamate. In the late 60s, Olney(59) became suspicious that obesity in mice, which was observed after neonatal mice were treated with monosodium glutamate for purposes of inducing and studying retinal pathology, might be associated with hypothalamic lesions caused by monosodium glutamate treatment; and in 1969 he first reported that monosodium glutamate 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 v subcutaneously(59).  

Research that followed confirmed that monosodium glutamate, which was routinely given as the sodium salt, monosodium glutamate (brand name Accent), induces hypothalamic damage when given to immature animals after either subcutaneous (60,61,62,63,64,66,67,68,69,70,71,72,73,74,75,76,77,78,81) or oral(67,73,74,76,82,83,84,85,86) doses.

Work by Lemkey-Johnston and Reynolds(86) published in 1974 included an extensive review of the data on brain lesions in mice. They confirmed the phenomenon of monosodium glutamate induced neurotoxicity; 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 thoroughness of tissue sampling methods. A review of monosodium glutamate induced neurotoxicity, published by Olney in 1976(87), mentioned species (immature mice, rats, rabbits, guinea pigs, chicks, and rhesus monkeys) demonstrating monosodium glutamate induced neurotoxicity, and efficiency of both oral and subcutaneous administration of monosodium glutamate in producing acute neuronal necrosis; discussed the nature and extent of the damage done by monosodium glutamate administration and the impact of monosodium glutamate administration to monosodium glutamate levels in both brain and blood; and discussed the similar neurotoxic effects of a variety of acidic structural analogues.

Studies of sub-human primates were thought to be particularly meaningful because monosodium glutamate toxicity found in laboratory animals might be relevant to humans. As early as 1969, Olney(61) had suggested that monosodium glutamate could be involved in the unexplained brain damage syndromes occurring in the course of human ontogenesis. Olney(61) demonstrated that the infant rhesus monkey (Macaca mulatta) is susceptible to monosodium glutamate-induced brain damage when administered a high dose (2.7g monosodium glutamate/kg of body weight) subcutaneously.

Olney et al.(74) expanded Olney's earlier work with a study of eight additional infant rhesus monkeys and, using light microscopy and the electron microscope, reconfirmed Olney's earlier findings of hypothalamic lesions, and discussed the findings of both Abraham et al.(75) and Reynolds et al.(88) who had questioned his work. 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 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 monosodium glutamate as neonates(59).

Longitudinal studies in which neonatal/infant animals were given doses of monosodium glutamate and then observed over a period of time before being sacrificed for brain examination, repeatedly supported Olney's early findings of abnormal development, behavioral aberration, and neuroendocrine disorder. Animals treated with monosodium glutamate as neonates or in the first 12 days of life were shown to suffer neuroendocrine disturbances including obesity and stunting, abnormalities of the reproductive system, and underdevelopment of certain endocrine glands (59,68,70,86,88,89,90, 92,93,94,95,96,97,98,99,100,101,102,103,104,105,106) and possible learning deficits either immediately or in later life (92,95, 96,107,108,109,110,112,113). In addition, there were reports of behavioral reactions including somnolence and seizures (114,115,116,117,119,120,121); tail automutilation (94,108); and learned taste aversion(110).  Irritability to touch was interpreted as conspicuous emotional change by Nemeroff(94). Lynch(14) reported hyperglycemia along with growth suppression. He noted that hyperglycemia did not occur when subjects were given intact protein containing a large amount of glutamate. 

Olney et al. (122,123,124) have written a number of review articles which summarize the data on neuroendocrine dysfunction following monosodium glutamate treatment. Nemeroff (125) has written another.

Ad libitum feeding studies

Findings of neurotoxicity and neuroendocrine dysfunction in laboratory animals raised questions about the effects that monosodium glutamate might have on humans. Since it would be unthinkable to administer doses of monosodium glutamate that 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 that would most closely parallel the true human condition.

At the time, a seemingly logical first step was to study the effects of monosodium glutamate on subhuman primates; and, as already noted, hypothalamic lesions had been demonstrated in monkeys as early as 1969(61). A seemingly logical second step was to study  "normal" ingestion of monosodium glutamate as opposed to some kind of forced feeding. Many felt that ad libitum feeding of laboratory animals parallels the human situation more closely than either subcutaneous or gavage administration of monosodium glutamate, and that ad libitum feeding studies were, therefore, the vehicle of choice. Ad libitum feeding would give animals free access to feed or water thereby allowing the animal to self-regulate intake. Some tended to disagree, feeling that the ad libitum feeding studies were, by and large, studies that had the greatest potential for minimizing the amount of monosodium glutamate actually ingested while registering the irrelevant amount of monosodium glutamate available.

Two studies that demonstrate neurotoxic reactions after ad libitum feeding of monosodium glutamate are reported here. In a 1979 study done as part of a project designed to evaluate a developmental test battery for neurobehavioral toxicity in rats, in which rats were exposed to monosodium glutamate and other food additives mixed with ground Purina rat chow beginning five days after arrival at the laboratory(109), it was demonstrated that high doses of dietary monosodium glutamate produce behavioral variations. Monosodium glutamate was mixed with food as opposed to being administered subcutaneously or by gavage. A year later, dietary studies demonstrated that weanling mice will voluntarily ingest monosodium glutamate and that such voluntary ingestion results in readily detectable brain damage (127). 

Focus on Older Animals

Most studies demonstrating retinal necrosis, brain lesions and/or neuroendocrine dysfunction, focused on neonatal or infant animals. Researchers were primarily interested in producing lesions in order to expand their knowledge of brain function; and 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 monosodium glutamate than those required to produce lesions in younger animals. Nemeroff(125) reported 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(128) 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(123).

Although advances in technology have facilitated the observation of brain lesions to some extent, it is still true today, as it was in the 1960s, that simple light microscopes are adequate to identifying monosodium glutamate induced lesions if one looks in sensitive locations within 4-5 hours of monosodium glutamate administration. By 24 hours after insult, lesions will be filled in ("healed") with cells other than neurons. Thus the "hole" is filled in, but 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 hypothalamus is not a well defined area, and lesions in that area will defy detection after as little as 24 hours after monosodium glutamate administration. One could not, therefore, ascertain whether or not an adult animal given monosodium glutamate as an infant, had suffered a lesion in the arcuate nucleus.

Industry's response

Not all studies reported brain damage following administration or ingestion of monosodium glutamate. Adamo and Ratner(131) and Oser et al.(132) failed to reproduce findings of neurotoxicity affecting the brains of non-primates. Adamo and Ratner(131) used rats, not mice as Olney(59) had, but maintained that otherwise the experimental approach used was "very similar." Oser et al.(132) 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...."  

Arees and Mayer(64) reproduced Olney's(56,59,61) findings only in part. Their discussion focused more on the question of human consumption of monosodium glutamate as food than on reasons for differences between the various studies.

All three of these negative studies were refuted by both Olney(60,133) and Burde(73) who independently reviewed the literature and found that these early discrepancies could be attributed to: 1) failure on the part of investigators to attempt to replicate Olney's methods; and 2) use by investigators of entirely different (and inappropriate) methods of preservation and staining of brain tissue in the analysis of results.

Burde(73) speculated that the method of fixation and staining used by Adamo and Ratner(131) obscured the existence of the lesion, and noted that their dose schedule was not appropriate; that Oser et al.(132) 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,(64) that the lesion produced by monosodium glutamate 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(73) replicated Olney's previous findings.

Olney's(60) review of the discrepancies, pointed out that the failure of Oser et al.(132) to detect brain damage in any of the three species they studied might be accounted for by their having limited the monosodium glutamate dose to a single, minimally 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(60) also noted that in a 1971 study done by Arees et al. (58) the authors were able to demonstrate that neuronal degeneration does occur in the infant mouse brain following subcutaneous treatment with monosodium glutamate. Thus the discrepancies noted by Arees and Mayer previously(64) became resolved.

Finally, Olney(60,133) suggested that methodological variables might well explain the failure of Adamo and Ratner(131) to demonstrate lesions in the rat.

The subject of tissue preparation has been addressed by a number of people. Takasaki(69) 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"(69).

Olney(67,81,133,134) and Murakami(135) have discussed the problem in similar terms. Olney(67) has discussed such methodological problems in great detail.

In 1973, Filer and Stegink(136) published an editorial in the New England Journal of Medicine that suggested that the neurotoxic effects of monosodium glutamate and its related amino acids, aspartate and cysteine, in species other than the mouse, are debatable. In turn, Olney et al.(137) pointed out that neurotoxic effects of monosodium glutamate and its related amino acids had been well documented, 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(71,74). Olney noted that Filer and Stegink supported their argument by pointing out that no neurotoxic effects of monosodium glutamate 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 that failed to confirm toxic effects of monosodium glutamate, and there were criticisms of Olney's work. Abraham(75), mentioned earlier, found toxic effects when monosodium glutamate administration was subcutaneous, but very little when administration was oral.

Lowe(138) criticized Olney(61) for failure to provide data on plasma monosodium glutamate concentrations, and for lack of a control in his single infant monkey study. Zavon(139) criticized Olney for lack of a control animal and for lack of detail in reporting the same study. Olney(140) 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 et al. (141) criticized Olney (59) for questioning the safety of monosodium glutamate after parenteral, as opposed to oral, administration; failure to clearly elucidate his methodology; and use of doses which far exceeded Blood et al.'s estimate of "...the total daily intake [of glutamate] from all reasonably possible uses... (.7 g per day) in an average adult"(141).

Olney(142), in reply to Blood et al.(141), provided the figures requested, and suggested that to truly establish the safety of monosodium glutamate if, indeed, that could be done, solid research was needed.

Two studies took exception to Olney's finding of hypothalamic lesion in sub-human primates due to loading of monosodium glutamate. Abraham et al.(75) treated four monkeys and failed to reproduce the findings of Olney and Sharpe(61). Reynolds et al.(88,144) treated 16 sub-human primates which were compared to five controls. They, too, failed to reproduce the findings of Olney and Sharpe(61), and found, instead, a "spectrum of degenerative changes" which they attributed to inadequate fixation procedures rather than to the effects of monosodium glutamate.

Olney(74) noted that elements of the research design and methodology of Abraham et al.(75) and Reynolds et al.(88,139,140) distinguished their study from his.  Reynolds et al. used only a spot sampling technique when two of the rhesus infants, each treated with low oral doses of monosodium glutamate, were examined by electron microscopy, so the possible occurrence of small lesions in these brains was not actually ruled out. In addition, the method used for preparation of brains for examination by light microscopy has been found unsatisfactory for evaluating even large monosodium glutamate-induced lesions in infant rodent brains; and subsequent information provided by Reynolds indicated that some of the infants vomited an unknown portion of the administered dose.

Abraham et al.(75) 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 monosodium glutamate, although four monkeys were studied. Moreover, little or no evidence of lesion would be expected 24 hours after monosodium glutamate insult because damaged elements are removed from the scene of an monosodium glutamate-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 criticism that he maintains that he is replicating work done by Olney, but does not do so. 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 monosodium glutamate lesions.  Finally, it was also noted by Nemeroff(125) that Abraham et al.(75) found in both control and monosodium glutamate treated monkeys a "very small proportion of necrotic or damaged neuronal cells and oligodendrocytes...in the arcuate nuclear region of the hypothalamus." One might suspect that this might happen if the placebo, as well as the test material, contained small amounts of an excitotoxin identical, or similar to, monosodium glutamate.

Also failing to reproduce neurotoxicity in primates, were studies of Abraham et al.(145), Newman et al.(146), and Stegink et al.(147). Stegink et al.(147) used the same data as Reynolds et al.(88,139,140) with two additional monkeys, and used the same methodology for tissue staining.  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 methodology were identical to those of their earlier study(75) and are subject to the same criticisms.

Newman et al.(146) 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 initial study was carried out with animals of 108, 99, 60, and 3 days, with unspecified histories. Information pertaining to the animals is incomplete. Their history is uncertain. There is no information pertaining to the first 108 days of an animal's life. Quoting from the research report: "Rhesus monkeys were maintained and observed in the primate buildings of HRC, where most of them were bred."  "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."  (Emphasis added.) 

In a 1976 study by Reynolds et al.(148) which produced negative results relative to abnormalities of the subinfundibular region of the monkey brain, 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 monosodium glutamate..." appears, in every aspect, to be identical to a section of an "...infant rhesus monkey which received 4 g/kg of monosodium glutamate by stomach tube..." presented in Figure 3 of the report by Stegink et al.(147) The monosodium glutamate 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 monosodium glutamate. It was reported that monkeys received various doses, but dosage by age was not given. The techniques for evaluation of mouse brains is the same used by Lemkey-Johnston and Reynolds(86) and Reynolds et al.(88) in previously reported studies. These had been found by Olney(74) to be inappropriate. No information is given about the timing involved or the techniques used for evaluation of monkey brains.  Reynolds concludes, "Neither aspartame nor MSG is capable of eliciting a lesion in the neonatal monkey brain." (Emphasis added.) 

In failing to replicate Olney's methods, researchers used entirely different (and inappropriate) methods of preservation and staining of brain tissue in analysis of results; limited the monosodium glutamate dose to a single, minimally effective dosage; failed to use a feeding tube to assure that the full dose was received by orally treated animals; and/or failed to examine brains in appropriate post treatment intervals (which are particularly relevant in cases of minimal effective dosage).

Delay in examination of potentially damaged tissue beyond the time that the damage could be observed was common to these studies.  Delay in administering or feeding monosodium glutamate to test animals beyond the age that brain damage would most readily be inflicted, would be similarly effective.

A number of the negative studies were ab libitum studies.  Ad libitum feeding gives animals free access to feed or water, allowing animals to self-regulate intake, and, therefore, would appeared to closely approximate the human condition.  At the same time, the amount of monosodium glutamate actually ingested could be minimized while the amount of monosodium glutamate available (but not necessarily ingested) was reported. Olney(127) pointed out that ad libitum animal studies fall far short of approximating the human condition.

Negative results could also be assured if researchers considered the effect of  monosodium glutamate on irrelevant variables, i.e., variables that had never been shown to be associated with monosodium glutamate-induced toxicity. Blood pressure and weight loss are examples. A variation used in studies of adverse reactions (as distinct from brain lesions) would be study of effects of  ingestion of monosodium glutamate on plasma glutamate level.  Elevated plasma glutamate has been shown to be associated with production of brain lesions, but has never been shown to be relevant to monosodium glutamate-induced adverse reactions. The logical fallacy in these studies comes when it is concluded that finding nothing while studying irrelevant variables proves that monosodium glutamate is safe.

A number of studies used non-relevant levels of otherwise relevant variables. Since females exhibit reproductive disorders and males do not, males, but not females, might be studied. Similarly, if a particular neuroendocrine change would not exhibit itself in less than 20 days following insult with monosodium glutamate, researchers would examine test animals after 15 days.

A number of studies drew conclusions not warranted by their data. Matsuzawa et al.(99) did a series of studies using both neonatal and 10 day old rats, given oral and subcutaneous doses of monosodium glutamate at a total of 4 different doses. Controls were given saline solution. 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. Based on this methodology Matsuzawa concluded that "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 hypothalamus by any route of administration." (Emphasis added.)

The identical approach was taken  by Takasaki et al.(98). They report that, "Adverse effects from MSG have never been reported from dietary administration." (Emphasis added.) In this case, "never" equals four studies. 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."

Conclusions drawn from these studies are based on negative results.  Using inferential statistics, the question raised is whether or not a difference found between two groups of subjects or two sets of measurements could have occurred by chance. If statistical analysis determines that observed differences would rarely have occurred by chance, the investigator would describe those differences as statistically significant, and would specify the probability with which differences of that magnitude would be expected to be reproduced if the experiment were replicated at another time.  In statistical parlance, we would say that the investigator had tested the hypothesis that there would be no difference between two groups (the “null hypothesis”), and had rejected that hypothesis when he found that there was, indeed, a significant difference.  The statistical model on which these statistics are based allows the investigator to conclude that it is highly likely (the probability being 95 percent or 99 percent) that differences found were not due to chance.  The statistical model does not allow the investigator to conclude that there is no difference between the two groups when a statistically significant difference is not found.

The following examples illustrate the reasoning.

Example 1: Suppose it is known unequivocally from space missions that there is life on Mars, and that all Martians (group 1) have 2 heads.  On Thursday an alien spacecraft lands in your back yard, and several aliens emerge (group 2).  If the visiting aliens had three heads, we would know that the three-headed aliens were not from Mars, and that there must be life on other planets.  (There is clearly a difference between the two groups of aliens.)   However if the visiting aliens had two heads (just like the Martians), they might be from Mars, or they might come from another planet. Perhaps there are 2-headed aliens on another planet.

Example 2: Suppose that subjects are given purple dye number 12 or a placebo, and that the numbers of headaches reported by each group are the same.  If reports of headache had been significantly greater in the group given purple dye, we could have concluded, with a certain amount of confidence, that purple dye caused headaches.  But since reports of headaches were approximately the same for both groups, we would not know what to conclude.  It might be that purple dye does not cause headaches.  It might have been that subjects were eating something with purple dye in it during the studies, giving the placebo group headaches; or that purple dye only causes headaches in females and all of the subjects were males.

Drawing conclusions based on failure to find a difference (i.e., on failure to reject the null hypothesis) is grossly inappropriate(23,24,25). Given the statistical model, rigorous demonstration of the truth of the null hypothesis (that there is no difference between groups) is a logical impossibility(23).

Studies by Owen(151), Takasaki(159), and Wen(154) have already been discussed in some detail. The additional studies mentioned here are subject to previously discussed statistical limitations.

The study reported by Anantharaman(157) must be criticized on additional 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). When we checked in 1990, yeast food invariably contained either protease (which creates MSG, the toxic component of monosodium glutamate, during manufacture) or L-cysteine which produces neurotoxic effects somewhat different from, but more extensive than, the effects of monosodium glutamate. 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.

Using inappropriate placebo materials has been discussed by others previously. In 1981, Rippere(161) 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.(145) 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(162) 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 MSG-containing ingredient (hydrolyzed protein, yeast extract, textured vegetable protein, natural flavoring, or monosodium glutamate, for example). 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.

A 1977 study by Heywood et al.(163) which focused on neurotoxicity, came to the same conclusion as Anantharaman. Heywood et al. concluded from one study of ad libitum feeding of monosodium glutamate 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."  Details of the amounts of monosodium glutamate consumed are not given. In the discussion where it states that "...dose levels as high as 45.5 g [monosodium glutamate]/kg body weight were achieved...", we are not told if that is per day, per animal, or total. Nemeroff(125) noted that their study did not present representative histological micrographs for evaluation(149).

In a second 1979 report, Takasaki et al.(164) 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.(165), Huang et al.(158), Wen et al.(154), and Takasaki (159). In addition, they reported findings from their own research(164) which compared the effects of monosodium glutamate 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 glutamate levels, to relation of ad libitum dietary feeding to plasma monosodium glutamate levels, to histological effects of ad libitum feeding of monosodium glutamate, to the statement that "...plasma glutamate levels... remained much lower than those required to induce hypothalamic lesions." (Emphasis added.) It must be understood that it has never been determined that any particular level of plasma monosodium glutamate is required for the production of brain lesions.

Unfortunately, Takasaki(164) did not provide sufficient detail for one to evaluate the reports, and the reports, themselves, are lacking. Again, it will be observed that Wen(154) appears to have used the same techniques as Adamo and Ratner(131) and Oser(132) which Olney(60,133) and Burde(73) criticized in 1971.

A study by Iwata(108) failed to find behavioral abnormalities as a function of ingestion of monosodium glutamate.  Iwata did not examine the brains histologically, yet concluded that there had to be lesion damage prior to there being behavioral effects. Iwata concluded that "...dietary administration... caused no behavioral latent effect in later life." (Emphasis added.)

Prabhu et al.(166) 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.  Lengvari(167) 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.

Related, but with a slightly different focus, are a pair of studies reported by Takasaki in 1979(84) and 1980(85), in which he studied the effect on brain lesions of administering various materials simultaneously with monosodium glutamate. 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. It is not clear whether reduction in effect of monosodium glutamate 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(82) 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. 

In the research report of Heywood and Worden (149) reports of lesions (or failure to find lesions) were accompanied by discussion of plasma glutamate levels and levels of glutamate found in the brain.  According to Heywood and Worden, Perez and Olney had found that "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. Peak plasma levels occurred after 15 min, and peak levels in the arcuate nucleus were attained after 3 hr."  Heywood and Worden(149), not Perez and Olney(63), went on to conclude that "The results indicate that plasma concentrations above a certain level were necessary to induce brain lesions." (Emphasis added.) 

With rare exception, the negative studies were openly sponsored by the glutamate industry.
  

REFERENCES

14. Lynch, JF Jr, Lewis LM, Adkins JS. Monosodium glutamate-induced hyperglycemia in weanling rats. Fed Proc. 1971;30(2):460Abs (Abstract #1477).

23; Ferguson GA. Statistical Analysis in Psychology and Education. New York: McGraw-Hill, 1959.

24; Weinberg GH, Schumaker JA. Statistics: An Intuitive Approach. Belmont: Wadsworth, 1962.

25; McNemar Q. Psychological Statistics. New York: Wiley, 1949.

26. Lucas DR, Newhouse JP. The toxic effect of sodium-L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol. 1957;58(2):193-201.

27; Ohguro H, Katsushima H, Maruyama I, et al. A high dietary intake of sodium glutamate as flavoring (Ajinomoto) causes gross changes in retinal morphology and function. Exp Eye Res. 2002;75(3):307-15.

28; Babai N, Atlasz T, Tamas A, et al. Search for the optimal monosodium glutaamte treatement schedule to study the neuroprotective effects of PACAP in the retina. Ann N Y Acad Sci. 2006;1070(July):149-155.

29; Szabadfi K, Atlasz T, Horvath G, et al. Early postnatal enriched environment decreases retinal degeneration induced by monosodium glutamate treatment in rats. Brain Res. 2009;1259(March):107-12.

49. Potts AM, Modrell RW,  Kingsbury C. Permanent fractionation of the electroretinogram by sodium glutamate. Am J Ophthalmol. 1960;50(Nov): 900-907.

50. Freedman JK,  Potts AM. Repression of glutaminase I in the rat retina by administration of sodium L-glutamate. Invest Ophthalmol. 1962;1(Feb):118-121.

51. Freedman JK, Potts AM. Repression of glutaminase I in rat retina by administration of sodium L-glutamate. Invest Ophthal. 1963;2(June):252-258.

52. Potts AM. Selective action of chemical agents on individual retinal layers. In: Graymore CN, ed. Biochemistry of the retina.  New York: Academic Press; 1965:155-161.

53. Hamatsu T. Experimental studies on the effect of sodium iodate and sodium L-glutamate on ERG and histological structure of retina in adult rabbits. Acta Soc Ophthalmol Jpn. 1964;68(11):1621-1636. (Abstract)

54. Hansson HA. Ultrastructure studies on long-term effects of MSG on rat retina. Virchows Arch [Zellpathol]. 1970;6(1):1-11.

55. Cohen AI. An electron microscopic study of the modification by monosodium glutamate of the retinas of normal and "rodless" mice. Am J Anat. 1967;120(2): 319-356.

56. Olney JW. Glutamate-induced retinal degeneration in neonatal mice. Electron-microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol 1969;28(3):455-474.

57. Hansson HA. Scanning electron microscopic studies on the long term effects of sodium glutamate on the rat retina. Virchows Arch ABT B (Zellpathol). 1970; 4(4): 357-367.

58. Arees E, Sandrew B, Mayer J. MSG-induced optic pathway lesions in infant mice following subcutaneous injection. Fed Proc. 1971;30(2):287Abs (Abstract # 521).

59. Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science. 1969;164(880):719-721.

60. Olney JW, Ho OL, Rhee V. Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system. Exp Brain Res. 1971;14(1):61-76.

61. Olney JW, Sharpe LG. Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science. 1969;166(903):386-388.

62. Snapir N, Robinzon B, Perek M. Brain damage in the male domestic fowl treated with monosodium glutamate. Poult Sci. 1971;50(5):1511-1514.

63.  Perez VJ, Olney JW. Accumulation of glutamic acid in the arcuate nucleus of the hypothalamus of the infant mouse following subcutaneous administration of monosodium glutamate. J Neurochem. 1972;19(7):1777-1782.

64. Arees EA, Mayer J. Monosodium glutamate-induced brain lesions: electron microscopic examination. Science. 1970;170(957):549-550.

66. Everly JL. Light microscopy examination of monosodium glutamate induced lesions in the brain of fetal and neonatal rats. Anat Rec. 1971;169(2):312.

67. Olney JW. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. J Neuropathol Exp Neurol. 1971;30(1):75-90.

68. Lamperti A, Blaha G. The effects of neonatally-administered monosodium glutamate on the reproductive system of adult hamsters. Biol Reprod 1976;14(3):362-369.

69. Takasaki Y. Studies on brain lesion by administration of monosodium L-glutamate to mice. I. Brain lesions in infant mice caused by administration of monosodium L-glutamate. Toxicology. 1978;9(4):293-305

70. Holzwarth-McBride MA, Hurst EM, Knigge KM. Monosodium glutamate induced lesions of the arcuate nucleus. I. Endocrine deficiency and ultrastructure of the median eminence. Anat Rec. 1976;186(2):185-196.

71. Holzwarth-McBride MA, Sladek JR, Knigge KM. Monosodium glutamate induced lesions of the arcuate nucleus. II Fluorescence histochemistry of catecholamines. Anat Rec. 1976;186(2):197-205.

72. Paull WK, Lechan R. The median eminence of mice with a MSG induced arcuate lesion. Anat Rec. 1974;180(3):436.

73. Burde RM, Schainker B, Kayes J. Acute effect of oral and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rats. Nature. 1971;233(5314):58-60.

74. Olney JW, Sharpe LG, Feigin RD. Glutamate-induced brain damage in infant primates. J Neuropathol Exp Neurol. 1972;31(3):464-488.

75. Abraham R, Doughtery W, Goldberg L, Coulston F. The response of the hypothalamus to high doses of monosodium glutamate in mice and monkeys: cytochemistry and ultrastructural study of lysosomal changes. Exp Mol Pathol.1971;15(1):43-60.

76. Burde RM, Schainker B, Kayes J. Monosodium glutamate: necrosis of hypothalamic neurons in infant rats and mice following either oral or subcutaneous administration. J Neuropathol Exp Neurol. 1972;31(1):181.

77. Robinzon B, Snapir N, Perek M. Age dependent sensitivity to monosodium glutamate inducing brain damage in the chicken. Poult Sci. 1974;53(4):1539-1542.

78. Tafelski TJ. Effects of monosodium glutamate on the neuroendocrine axis of the hamster. Anat Rec. 1976;184(3):543-544.

81. Olney JW, Rhee V, DeGubareff T. Neurotoxic effects of glutamate on mouse area postrema. Brain Res. 1977;120(1):151-157.

82. Olney JW, Ho OL. Brain damage in infant mice following oral intake of glutamate, aspartate or cystine. Nature. 1970;227:609-611.

83. Lemkey-Johnston N, Reynolds WA. Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate: a light and electron microscope study. J Neuropath Exp Neurol. 1974;33(1):74-97.

84. Takasaki, Y. Protective effect of mono- and disaccharides on glutamate-induced brain damage in mice. Toxicol Lett. 1979;4(3): 205-210.  

85. Takasaki, Y. Protective effect of arginine, leucine, and preinjection of insulin on glutamate neurotoxicity in mice. Toxicol Lett. 1980;5(1):39-44.
 

86. Lemkey-Johnston, N, Reynolds WA. Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate: a light and electron microscope study. J Neuropath Exp Neurol. 1974;33(1):74-97.

87. Olney JW. Brain damage and oral intake of certain amino acids. In: Levi G, Battistin L, Lajtha A, eds.Transport Phenomena in the Nervous System: Physiological and Pathological Aspects.  New York: Plenum Press; 1976.

88. Reynolds WA. Lemkey-Johnston N, Filer LJ Jr, Pitkin RM. Monosodium glutamate: absence of hypothalamic lesions after ingestion by newborn primates. Science. 1971;172(990):1342-1344.

89. Matsuyama S. Studies on experimental obesity in mice treated with MSG. Jap J Vet Sci. 1970;32:206.

90.  Redding TW, Schally AV, Arimura A, Wakabayashi I. Effect of monosodium glutamate on some endocrine functions. Neuroendocrinology. 1971;8(3):245-255.

92. Araujo PE, Mayer J. Activity increase associated with obesity induced by monosodium glutamate in mice. Am J Physiol. 1973;225(4):764-765.

93. Nagasawa H, Yanai R, Kikuyama S. Irreversible inhibition of pituitary prolactin and growth hormone secretion and of mammary gland development in mice by monosodium glutamate administered neonatally. Acta Endocrinol. 1974;75(2):249-259.

94. Nemeroff CB, Grant LD, Bissette G, Ervin GN, Harrell LE, Prange AJ Jr. Growth, endocrinological and behavioral deficits after monosodium L-glutamate in the neonatal rat: Possible involvement of arcuate dopamine neuron damage. Psychoneuroendocrinology.1977;2(2):179-196.

95. Nemeroff CB, Konkol RJ, Bissette G, et al. Analysis of the disruption in hypothalamic-pituitary regulation in rats treated neonatally with monosodium glutamate (MSG): Evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology. 1977;101(2):613-622.

96. Pizzi WJ, Barnhart JE, Fanslow DJ. Monosodium glutamate administration to the newborn reduces reproductive ability in female and male mice. Science. 1977;196(4288):452-454.

97. Tafelski TJ, Lamperti AA. The effects of a single injection of monosodium glutamate on the reproductive neuroendocrine axis of the female hamster. Biol Reprod. 1977;17(3):404-411.

98. Takasaki Y, Sekine S, Matsuzawa Y, Iwata S, Sasaoka M. Effects of parenteral and oral administration of monosodium L-glutamate (MSG) on somatic growth in rats. Toxicol Lett. 1979;4(5):327-343.

99. Matsuzawa Y, Yonetani S, Takasaki Y, Iwata S, Sekine S. Studies on reproductive endocrine function in rats treated with monosodium L-glutamate early in life. Toxicol Lett. 1979;4(5):359-371.

100. Matsuyama S, OkiY, Yokoki Y. Obesity induced by monosodium glutamate in mice. Natl Inst Anim Health Q(Tokyo). 1973;13(2):91-101.

101. Pizzi WJ, Barnhart JE. Effects of monosodium glutamate on somatic development, obesity and activity in the mouse. Pharmacol Biochem Behav. 1976;5(5):551-557.

102. Nikoletseas MM. Obesity in exercising, hypophagic rats treated with monosodium glutamate. Physiol Behav. 1977;19(6):767-773.

103. Redding TW, Schally AV. Effect of monosodium glutamate on the endocrine axis in rats. Fed Proc. 1970;29(2):378Abs (Abstract #755).

104. Holzwarth MA, Hurst EM. Manifestations of monosodium glutamate (MSG) induced lesions of the arcuate nucleus of the mouse. Anat Rec. 1974;178(2):378.

105. Trentini GP, Botticelli A, Botticelli CS. Effect of monosodium glutamate on the endocrine glands and on the reproductive function of the rat. Fertil Steril. 1974;25(6):478-483.

106. Lynch JF Jr, Lewis LM, Hove EL, Adkins JS. Effect of monosodium L-glutamate on development and reproduction in rats. Fed Proc. 1970;29(2):567  Abs (Abstract 1795).

107. Pradhan SN, Lynch JF Jr. Behavioral changes in adult rats treated with monosodium glutamate in the neonatal state. Arch Int Pharmacodyn Ther. 1972;197(2):301-304.

108. Iwata S, Ichimura M, Matsuzawa Y, Takasaki Y, Sasaoka M. Behavioral studies in rats treated with monosodium l-glutamate during the early stages of life. Toxicol Lett. 1979;4(5):345-357.

109. Vorhees CV, Butcher RE, Brunner RL, Sobotka TJ. A developmental test batter for neurobehavioral toxicity in rats: a preliminary analysis using monosodium glutamate, calcium carrageenan, and hydroxyurea. Toxicol Appl Pharm. 1979;50(2):267-282.

110.  Vogel JR, Nathan BA. Learned taste aversions induced by high doses of monosodium L-glutamate. Pharmacol Biochem Behav. 1975;3(5):935-937.

112. Berry HK, Butcher RE, Elliot LA, Brunner RL. The effect of monosodium glutamate on the early biochemical and behavioral development of the rat. Devl Psychobiol. 1974;7(2):165-173.

113.  Weiss LR, Reilly JF, Williams J, Krop S. Effects of prolonged monosodium glutamate and other high salt diets on arterial pressure and learning ability in rats. Toxicol Appl Pharmacol. 1971;19(2):389.

114.  Bhagavan HN, Coursin DB, Stewart CN. Monosodium glutamate induces convulsive disorders in rats. Nature. 1971;232(5308):275-276.

115. Johnston GAR. Convulsions induced in 10-day-old rats by intraperitoneal injection of monosodium glutamate and related excitant amino acids. Biochem Pharmacol. 1973;22(1):137-140.

116. Mushahwar IK, Koeppe RE. The toxicity of monosodium glutamate in young rats. Biochem Biophys Acta. 1971;244(2):318-321.

117. Nemeroff CB, Crisley FD. Lack of protection by pyridoxine or hydrazine pretreatment against monosodium glutamate induced seizures. Pharmacol Biochem Behav. 1975;3(5):927-929.

119.  Wiechert P, Gollinitz G. Metabolic investigations of epileptic seizures: the activity of the glutamate decarboxylase prior to and during experimentally produced convulsions. J Neurochem. 1968;15(11):1265-1270. (Abstract)

120. Wiechert P, Herbst A. Provocation of cerebral seizures by derangement of the natural balance between glutamic acid and y-aminobutyric acid. J Neurochem. 1966;13(2):59-64.

121. Wiechert P, Gollnitz G. Metabolic investigations of epileptic seizures: investigations of glutamate metabolism in regions of the dog brain in preconvulsive states. J Neurochem. 1970;17(2):137-147.

122. Olney JW, Price MT. Neuroendocrine interactions of excitatory and inhibitory amino acids. Brain Res Bull. 1980;5:Suppl 2, 361-368.

123. Olney JW, Price MT. Excitotoxic amino acids as neuroendocrine probes. In: McGeer EG, Olney JW, McGeer PL eds. Kainic Acid as a Tool in Neurobiology  New York: Raven Press; 1978.

124. Olney JW. Excitotoxic amino acids: research applications and safety implications. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ, eds. Glutamic Acid: Advances in Biochemistry and Physiology. New York: Raven Press; 1979:287-319.

125. Nemeroff CB. Monosodium glutamate-induced neurotoxicity: review of the literature and call for further research. In: Miller SA, ed. Nutrition & Behavior. Philadelphia: The Franklin Institute Press; 1981.

126; Stegink LD, Reynolds WA, Filer LJ, Jr, Baker GL, Daabees TT, Pitkin RM. Comparative metabolism of glutamate in the mouse, monkey, and man. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ, eds. Glutamic Acid: Advances in Biochemistry and Physiology. New York: Raven Press; 1979:85-102.

127. Olney JW, Labruyere J, De Gubareff T. Brain damage in mice from voluntary ingestion of glutamate and aspartate. Neurobehav Toxicol. 1980;2(2 ):125-129.

128. Olney JW, Cicero TJ, Meyer ER,  De Gubareff T. Acute glutamate-nduced elevations in serum testosterone and luteinizing hormone. Brain Research. 1976;112(2):420-424.

131. Adamo NJ, Ratner A. Monosodium glutamate: Lack of effects on brain and reproductive function in rats. Science. 1970;169(946):673-674.

132. Oser BL, Carson S, Vogin EE, Cox GE. Oral and subcutaneous administration of monosodium glutamate to infant rodents and dogs. Nature. 1971;229(5284):411-413.

133. Olney JW. Monosodium glutamate effects. Science. 1971;172(980):294.

134. Olney JW. Toxic effects of glutamate and related amino acids on the developing central nervous system. In: Nyhan WL. ed. Heritable Disorders of Amino Acid Metabolism  New York: Wiley; 1974:501-512.

135.  Murakami U, Inouye M. Brain lesions in the mouse fetus caused by maternal administration of monosodium glutamate. Congenital Anomalies. 1971;11:161,171-177.  

136. Filer LJ, Stegink LD. Safety of hydrolysates in parenteral nutrition. N Engl J Med. 1973;289(8):426-427.

137. Olney JW, Ho OL, Rhee V,  De Gubareff T. Neurotoxic effects of glutamate. New Engl J Med. 1973;289(25):1374-1375.

138. Lowe CU. Monosodium glutamate: specific brain lesion questioned. Science. 1970;167(920):1016.

139. Zavon MR. Monosodium glutamate: specific brain lesion questioned. Science. 1970;167(920):1017.

140. Olney JW,  Sharpe LG. Monosodium glutamate: specific brain lesion questioned. Science. 1970;167(920):1017.

141. Blood FR, Oser BL, White PL. Monosodium glutamate. Science. 1969;165(897):1028-1029 .

142. Olney JW. Monosodium glutamate. Science. 1969;165(897):1028-1029.

144. Reynolds WA, Lemkey-Johnston N, Filer LJ Jr,  Pitkin RM. Monosodium glutamate: absence of hypothalamic lesions after ingestion by newborn primates. Science 1971;172(990):1342-1344.

145.  Abraham R, Swar J, Goldberg L, Coulston F. Electron microscopic observations of hypothalami in neonatal rhesus monkeys (Macaca mulatta) after administration of monosodium L-glutamate. Exp Mol Pathol. 1975;23(2):203-213.

 146.  Newman AJ, Heywood R, Palmer AK, Barry DH, Edwards FP, Worden AN. The administration of monosodium L-glutamate to neonatal and pregnant rhesus monkeys. Toxicology. 1973;1(3):197-204.

147. Stegink LD, Reynolds WA, Filer LJ Jr, Pitkin RM, Boaz DP, Brummel MC. Monosodium glutamate metabolism in the neonatal monkey. Am J Physiol. 1975;229(1):246-250.

148. Reynolds WA, Butler V, Lemkey-Johnston N. Hypothalamic morphology following ingestion of aspartame or MSG in the neonatal rodent and primate: a preliminary report. J Toxicol Environ Health. 1976;2(2):471-480.

149. Heywood R, Worden AN. Glutamate Toxicity in Laboratory Animals.  In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ, eds. Glutamic Acid: Advances in Biochemistry and Physiology. New York: Raven Press; 1979:203-215.

150. Ebert AG. Chronic toxicity and teratology studies of monosodium L-glutamate and related compounds. Toxicol Appl Pharmacol. 1970;17(1):274.

151. Owen G, Cherry CP, Prentice DE, Worden AN. The feeding of diets containing up to 4% monosodium glutamate to rats for 2 years. Toxicol Lett 1978;1(4):221-226.

152. Owen G, Cherry CP, Prentice DE. Worden AN. The feeding of diets containing up to 10% monosodium glutamate to Beagle dogs for 2 years. Toxicol Lett. 1978;1(4): 217-219.

153. Semprini ME, D'Amicis A, Mariani A. Effect of monosodium glutamate on fetus and newborn mouse. Nutr Metabol. 1974;16(5):276-284.

154. Wen CP, Hayes KC, Gershoff SN. Effects of dietary supplementation of monosodium glutamate on infant monkeys, weaning rats, and suckling mice. Am J Clin Nutr. 1973;26(8):803-813.

155. Ebert AG. The Dietary administration of monosodium glutamate or glutamic acid to C-57 black mice for two years. Toxicol Lett. 1979;3(2):65-70.

156. Ebert AG. The dietary administration of L-monosodium glutamate, DL-monosodium glutamate and L-glutamic acid to rats. Toxicol Lett. 1979;3(2):71-78.

157. Anantharaman K. In utero and dietary administration of monosodium L-glutamate to mice: reproductive performance and development in a multigeneration study. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ, eds. Glutamic Acid: Advances in Biochemistry and Physiology. New York: Raven Press New York: Raven; 1979:231-253.

158. Huang PC, Lee NY, Wu TJ, Yu SL, Tung TC. Effect of monosodium glutamate supplementation to low protein diets on rats. Nutr Rep Int. 1976;13(5):477-486.  

159. Takasaki, Y. Studies on brain lesions after administration of monosodium L-glutamate to mice. II Absence of brain damage following administration of monosodium L-glutamate in the diet. Toxicology. 1978;9(4):307-318.

160. Bunyan J, Murrell EA, Shah PP. The induction of obesity in rodents by means of monosodium glutamate. Br J Nutr. 1976;35(1):25-29.

161. Rippere V. Placebo-controlled tests of chemical food additives: are they valid? Medical Hypotheses 1981;7(6):819-823.

162. Goldschmiedt M, Redfern JS, Feldman M. Food coloring and monosodium glutamate: effects on the cephalic phase of gastric acid secretion and gastrin release in humans. Am J Clin Nutr. 1990;51(5):794-797.

163. Heywood R, James RW, Worden AN. The ad libitum feeding of monosodium glutamate to weanling mice. Toxicol Lett. 1977;1(3):151-155.

164. Takasaki Y, Matsuzawa Y, Iwata S, O'Hara Y, Yonetani S, Ichimura M. Toxicological studies of monosodium L-glutamate in rodents: relationship between routes of administration and neurotoxicity. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ, eds. Glutamic Acid: Advances in Biochemistry and Physiology. New York: Raven Press; 1979:255-275.

165. Semprini ME, Conti L, Ciofi-Luzzatto A. Mariani A. Effect of oral administration of monosodium glutamate (MSG) on the hypothalamic arcuate region of rat and mouse: a histological assay. Biomedicine. 1974;21(10):398-403.

166. Prabhu VG,  Oester YT. Neuromuscular functions of mature mice following neonatal monosodium glutamate.  Arch Int Pharmacodyn. 1971;189(1): 59-71.

167. Lengvari I. Effect of perinatal monosodium glutamate treatment on endocrine functions of rats in maturity. Acta Biol Acad Sci Hung. 1977;28(1):133-141.