The toxic action of glutamic acid (glutamate or GLU) was first reported by Lucas and Newhouse in 1957(1). Prior to that time, and throughout the 1960s, a considerable 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. And it didn’t occur to anyone that the flavor-enhancer called monosodium glutamate might in any way be related.
In 1968, someone in neuroscientist John Olney’s lab observed that mice treated with GLU for the purpose of studying retinal degeneration became grotesquely obese, and Olney became suspicious that the obesity in mice, which was observed after neonatal mice were treated with GLU for purposes of inducing and studying retinal pathology, might be associated with hypothalamic lesions caused by GLU treatment. And that’s when MSG first became part of the picture of GLU toxicity, because in the research that followed, MSG was used as the source of GLU because MSG had been found to be just as toxic as pharmaceutical grade glutamate, but considerably less expensive.
Thus in 1969, Olney reported that GLU treatment given as MSG caused 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(2).
Research which followed confirmed that GLU, which was usually given as MSG, induces hypothalamic damage when given to immature animals after either subcutaneous(3-24) or oral(10,16,17,19, 25-29) doses.
Work by Lemkey-Johnston and Reynolds(29) published in 1974 included an extensive review of the data on brain lesions in mice. They confirmed the phenomenon of GLU 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 GLU induced neurotoxicity, published by Olney in 1976(30) 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: Non-Human Primates
Studies of non-human primates(4,17) 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(4) Olney had suggested that GLU could be involved in the unexplained brain damage syndromes occurring in the course of human ontogenesis. Olney(4) 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.(17) expanded Olney’s earlier work(4) with a study of eight additional infant rhesus monkeys and, using light microscopy and the electron microscope, reconfirmed Olney’s earlier findings(4) of hypothalamic lesions, and discussed the findings of both Abraham et al.(18) and Reynolds et al.(31) 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 GLU as neonates(2).
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 supported Olney’s early findings of abnormal development, behavioral aberration, and neuroendocrine disorders(2).
Developmental dysfunction or abnormalities in growth and behavior have been noted in a number 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(2,11,13,29,32-49) and possible learning deficits either immediately or in later life (35,38,39,50-56).
In addition, Bhagavan and others have reported behavioral reactions including somnolence and seizures( 57-64); tail automutilation(37,51); and learned taste aversion (53). Irritability to touch was interpreted as conspicuous emotional change by Nemeroff(7). Lynch(65) 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.(66-68) have written a number of review articles which summarize the data on neuroendocrine dysfunction following GLU treatment. Nemeroff(69) 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 non-human primates(70); and, as already noted, hypothalamic lesions were demonstrated in monkeys as early as 1969(4). 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 industry-sponsored studies 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(52), done as part of a project designed to evaluate a developmental test battery for neurobehavioral toxicity 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 subcutaneously or by gavage. Positive effects were found.
A year later, dietary studies reported by Olney demonstrated that weanling mice will voluntarily ingest GLU (and/or aspartate) and that such voluntary ingestion results in readily detectable brain damage(71).
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 to the 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 reported that the smallest 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(69). According to Olney, 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(72). Only minimal damage is induced unless very high doses (4-8 mg/g) are used(67).
Although advances in technology have facilitated the observation of brain lesions to some extent, it was still true in 1991, as it was in the 1960s, 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 in 1991 is was 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 GLU administration(73). 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 which demonstrates that pregnant rats administered subcutaneous doses of GLU develop acute necrosis of the acetylcholinesterase- positive neurons in the area postrema(74). The same effect was obtained in the area postrema of fetal rats.
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