Dose dependent toxicity of glutamic acid: a review

ABSTRACT

L-glutamate, the major neurotransmitter in humans, becomes excitotoxic when present outside of protein in excess of what the healthy human was designed to accommodate; amounts readily available to consumers who ingest multiple free-glutamate-containing ingredients during a day. Studies have demonstrated that excitotoxins ingested by a mother will pass to the fetus across the placenta and pass to the newborn through mothers’ milk. The purpose of this paper is to raise awareness of the relevance of glutamate from food additives such as MSG to human brain damage, and its possible contributions to glutamate toxicity in neurodegenerative diseases, stroke, autism, schizophrenia, depression, obsessive-compulsive disorder, epilepsy, seizures, addiction, attention-deficit/hyperactivity disorder, autism, headaches, asthma, diabetes, muscle pain, atrial fibrillation, ischemia, and trauma.

KEYWORDS:

• Excitotoxins
• glutamate
• monosodium glutamate
• brain lesions
• endocrine disorders
• neonatal
• neurodegenerative disorders

Introduction

L-glutamic acid (glutamate) is the principal excitatory neurotransmitter in the brain as well as the most abundant amino acid in the human diet. It is essential to normal body function, both as a component of protein and a neurotransmitter. Yet when present in excess outside of protein as a single amino acid it becomes excitotoxic, firing repeatedly to cause neuronal and non-neuronal death and/or damage to targeted receptor cells.^[1]

Aspartic acid (aspartate) is a second excitotoxic amino acid, found in quantity in processed foods.^[2] It causes brain damage just as glutamate does. It also causes the same adverse reactions, which occur with the same relative frequency in people who are sensitive to excitotoxins.^[3,4] Glutamate and aspartate are structural analogs that work synergistically, working in an additive fashion to promote brain damage.^[2] The synergy of MSG with Disodium 5ʹ-guanylate, Disodium 5ʹ-inosinate and Disodium 5ʹ-ribonucleotides, which is often referred to by industry, has to do with flavor enhancement, not toxicity.

In 1969, Olney published the first study to address the possibility that glutamate might cause brain damage.^[5] With that study, it was demonstrated that endocrine disorders, including gross obesity and reproductive disorders, resulted from glutamate-induced brain damage as the young approached maturity. At the time, researchers were administering glutamate to laboratory animals subcutaneously using the flavor enhancer monosodium glutamate (MSG) as their source^[5], for it had been observed that MSG was as effective for inflicting brain damage as more expensive pharmaceutical grade L-glutamate.

In the decade that followed, research confirmed that glutamate induces hypothalamic damage when given to immature animals after either subcutaneous^[6–24] or oral^{[2,12,18,19,25–30]} doses. In the 1980s, researchers began to focus on identifying and understanding abnormalities associated with glutamate, often for the purpose of finding drugs that would mitigate glutamate’s adverse effects.^[31–34] By 1980, glutamate-associated disorders such as headaches, asthma, diabetes, muscle pain, atrial fibrillation, ischemia, trauma, seizures, stroke, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Parkinson’s disease, depression, multiple sclerosis, schizophrenia, obsessive-compulsive disorder (OCD), epilepsy, addiction, attention-deficit/hyperactivity disorder (ADHD), frontotemporal dementia, and autism were on the rise, and evidence of the toxic effects of glutamate were generally accepted by the scientific community.^[35,36] By and large, the glutamate in question was, and still is, glutamate from endogenous sources. The possible toxicity of glutamate from exogenous sources such as glutamate-containing flavor-enhancers was not being considered. Only Olney and a few others have considered that ingestion of MSG might play a role in producing the excess amounts of glutamate needed for endogenous glutamate to become excitotoxic.^[37–56]

First hand observation of the toxic effects of glutamate in humans, graduate training in experimental design, methodology, and statistics, and extensive reading of the literature pertaining to glutamate benefits and toxicity, tell me that failure to consider the toxic effects of glutamate from exogenous sources has resulted in hampering the thinking of researchers and health-care professionals. It is the thesis of this paper that the root cause of the phenomenon referred to as the obesity epidemic, as well as a contributing factor to some or all of the glutamate-related abnormalities mentioned previously, is the brain damage and endocrine disruption caused by glutamate from exogenous sources passed by pregnant and/or lactating mothers via the placenta and through mothers’ milk to human fetuses and neonates.

Evidence

There are two prerequisites for production of brain damage, be it in laboratory animals or humans: 1) vulnerability of brain cells, and 2) existence of sufficient free glutamate to produce the excesses needed to cause glutamate to become excitotoxic. In the 1970s it was demonstrated that the brains of newborn animals are vulnerable to glutamate insult, the facilitating factors being the immaturity of the blood-brain barrier (BBB) and the vulnerability of the circumventricular organs, unique areas of the brain that lie outside the BBB.^[57–59]

The same is true of humans. As the human fetus develops (and possibly until puberty), the BBB remains immature, leaving the brain vulnerable to attack. Moreover, in the area of the circumventricular organs the BBB is leaky at best at any stage of life.^[57] In laboratory animals, the mechanism for producing brain damage has been feeding or administering glutamate to vulnerable animals. For laboratory animals, excess glutamate for brain-damage studies was initially provided by subcutaneous administration of glutamate to neonatal animals, and later by feeding glutamate to neonatal animals either by ad libitum feeding or by gavage. In all cases, the quantities were controlled by the researchers, and were varied to meet the requirements of their studies.

Newborn humans will receive glutamate through mothers’ milk or through infant formula, both of which routinely contain free glutamate.^[60,61] But glutamate in mothers’ milk will not be excitotoxic unless lactating mothers ingest excessive quantities of free glutamate – quantities sufficient to cause glutamate to become excitotoxic.

It has been shown that MSG can cross the placenta during pregnancy^[62–64], can cross the blood brain barrier (BBB) in an unregulated manner during development^[65], and can pass through the five circumventricular organs which are leaky at best at any stage of life.^[66,67] Moreover, the BBB is easily damaged by fever, stroke, trauma to the head, seizures, ingestion of MSG, and the normal process of aging.^[57,68] And the fetus will be more vulnerable to glutamate-insult than the newborn.

Prior to 1957, free glutamate available to humans in the United States came largely from MSG (brand name Accent) which was marketed as a flavor enhancer. Now, free glutamate is found in abundance in a wide variety of ingredients used in processed and ultra-processed foods, snacks, and protein-fortified foods, in drinks, protein powders and shakes, and in protein bars. Moreover, hydrolyzed protein products commonly used in foods such as pea protein isolate, mung bean protein isolate, potato protein, and soy protein isolate, contain excitotoxic aspartic acid and excitotoxic L-cysteine, not just excitotoxic glutamate. The list of hidden sources of manufactured free glutamate^[69] was compiled by the author over the last 30 years from consumer reports and information provided by manufacturers and food technologists (Table 1).

Table 1. Sources of processed/manufactured free glutamic acid* **

Names of ingredients that always contain processed free glutamic acid:	Names of ingredients that often contain or produce processed free glutamic acid:	The following are ingredients suspected of containing or creating sufficient processed free glutamic acid to serve as MSG-reaction triggers in HIGHLY SENSITIVE people:
Glutamic acid (E 620),^1 Glutamate (E 620) Monosodium glutamate (E 621) Monopotassium glutamate (E 622) Calcium glutamate (E 623) Monoammonium glutamate (E 624) Magnesium glutamate (E 625) Natrium glutamate Anything “hydrolyzed” Any “hydrolyzed protein” Calcium caseinate, Sodium caseinate Yeast extract Yeast food, Yeast nutrient Torula yeast Autolyzed yeast Gelatin Textured protein Whey protein Whey protein concentrate Whey protein isolate Soy protein Soy protein concentrate Soy protein isolate Anything “protein” Anything “protein fortified” Soy sauce Soy sauce extract Protease Anything “enzyme modified” Anything containing “enzymes” Anything “fermented” Vetsin Ajinomoto Umami Zinc proteninate	Carrageenan (E 407) Bouillon and broth Stock Any “flavors” or “flavoring” Natural flavor Maltodextrin Oligodextrin Citric acid, Citrate (E 330) Anything “ultra-pasteurized” Barley malt Malted barley Brewer’s yeast Pectin (E 440) Malt extract Seasonings	Corn starch Corn syrup Modified food starch Lipolyzed butter fat Dextrose Rice syrup Brown rice syrup Milk powder Reduced fat milk (skim; 1%; 2%) most things low fat or no fat anything Enriched anything Vitamin enriched anything pasteurized Annatto Vinegar Balsamic vinegar Certain amino acid chelates: Citrate, aspartate, and glutamate are used as chelating agents with mineral supplements ^[1] E numbers are use in Europe in place of food additive names. (Not all glutamate-containing ingredients are classified as additives)
The following work synergistically with glutamate to enhance flavor. If they are present for flavoring, so is processed free glutamate Disodium 5ʹ-guanylate (E 627) Disodium 5ʹ-inosinate (E-631) Disodium 5ʹ-ribonucleotides (E 635)

*Glutamic acid found in unadulterated protein does not cause brain damage, endocrine disorders, or adverse reactions. To cause adverse events, glutamic acid must have been processed/manufactured or come from protein that has been fermented.

**Compiled by A. Samuels over the last 30 years from consumer reports and information provided by manufacturers and food technologists

Recently we have seen excitotoxic amino acids in products such as Real Egg (mung bean protein isolate, the enzyme transglutaminase, and natural flavors), the Impossible Burger (textured wheat protein, potato protein, natural flavors, yeast extract, and soy protein isolate) and in Beyond Meat Beast Burger (pea protein isolate, natural flavoring, yeast extract, and maltodextrin) added to ultra-processed foods. Most ultra-processed foods are made exclusively of chemicals and poor-quality ingredients to which glutamate-containing flavor enhancers have been added.

Prior to the time that Ajinomoto reformulated its method of MSG production, which made free glutamate widely available to the general public, accumulating excesses of glutamate sufficient to turn it excitotoxic would have been nearly impossible. It was only after reformulation that the amount of free glutamate added to food became sufficient to produce the excesses needed to cause glutamate excitotoxicity. And it was only in the following years that obesity and infertility escalated to epidemic proportions.

Before 1957, the amount of free glutamate in an average diet had been unremarkable, and there had been no reported “obesity epidemic.” In 1957, however, Ajinomoto’s method changed from extraction of glutamate from a protein source, a slow and costly method, to a technique of bacterial fermentation which enabled virtually unlimited production of MSG.^[70] Shortly thereafter, food manufacturers found that profits could be increased by utilizing flavor-enhancers (additives that contained free glutamate). Over the next two decades, the marketplace became flooded with manufactured/processed free-glutamate added to processed foods in ingredients such as hydrolyzed proteins, yeast extracts, maltodextrin, soy protein isolate, and MSG.^[71] The names of ingredients that contain manufactured free glutamate are listed in Table 1.

By 1970, glutamate in processed foods and snacks had become available to consumers in quantities far exceeding those that would be needed for normal body function – amounts that could be excitotoxic if the consumer were to ingest multiple free-glutamate-containing items during the course of a day.^[70–75] By 1980, offspring of women who had passed glutamate to fetuses and newborns were entering puberty as obese young men and women. By the year 2000, reproductive disorders had reached epidemic proportions.

Discussion

There are multiple causes of obesity and infertility. Lack of exercise and over eating certainly contribute to obesity. But it is the thesis of this paper that glutamate-induced brain damage, which was demonstrated by Olney and others in the 1960s and 1970s, is responsible for both the obesity epidemic and the increase in infertility. It is our contention that the both were set in motion after free glutamate in processed foods became widely available^[70]; that both have their roots in glutamate-induced brain damage caused by glutamate passed to fetuses and neonates by pregnant and/or lactating mothers.^[62,68]

This raises an interesting question. Why do those who concern themselves with finding interventions to help consumers combat obesity and infertility pay no attention to the fact that glutamate-containing food and drink such as hydrolyzed pea protein, maltodextrin, autolyzed yeast extract, and MSG can cause brain lesions in the vulnerable young, and that glutamate-induced brain lesions in the very young generate gross obesity and reproductive disorders as the young approach maturity?

Since 1968, the year before publication of the first study documenting the fact that MSG kills brain cells and is an endocrine disruptor, Ajinomoto has vigorously denied MSG toxicity.^[76] Their use of scientists-for-hire, rigged research, infiltration of government agencies, control of major media, and an ongoing propaganda campaign has clearly paid off, as many believe that monosodium glutamate is a harmless food additive.^[76]

Suppression of data is not a topic easily discussed, but to understand scientists’ failure to come to grips with the root cause of brain damage that would have initiated both the obesity epidemic and the infertility crisis, suppression of data must not be overlooked. While there have been studies related to the toxicity of glutamate since 1980, with the exception of Olney’s work, there has been little consideration that the ingestion of MSG might play a role in the creation of abnormalities – except in studies done outside of the United States, done in Germany^[37–39,43], Argentina^[40], Canada^[41], Japan^[44], Italy^[46], India^[48,51], Nigeria^[50], China^[52], Thailand^[56], and Saudi Arabia.^[55] By and large, it has only been MSG research that proclaims the safety of MSG, not questions the safety of MSG, that has been published in medical journals. Moreover, pressure from agents of the glutamate industry to keep any suggestion of MSG toxicity out of the media has been remarkably successful. Not since 1991, when ‘60 Minutes’ ran a story about MSG, has there been mention in any major media outlet in the U.S. dealing with MSG that was not approved by the glutamate industry. (The same has not been true in India and Pakistan where use of MSG in food is banned.) Details of Ajinomoto’s suppression of information pertaining to the toxic potential of MSG were published in 1999.^[76]

With the information provided here, it is hoped that this oversight will begin to be remedied. Recognition of the fact that glutamate/MSG passed to fetuses and neonates causes brain damage and disrupts the endocrine system will provide researchers with new knowledge to apply to their studies of glutamate-related abnormalities, and help health-care professionals find interventions for their patients – including those who suffer from obesity and reproductive disorders.

Acknowledgments

A great debt is owed to many, but first and foremost to John W. Olney, M.D, who many years ago shared his expertise as a physician and neuroscientist, and also to Madelon Price, Ph.D., who filled in pieces of the glutamate toxicity puzzle when Olney was otherwise occupied. Thanks also go to the handful of other principled researchers who have pursued the study of excitotoxic exogenous glutamate and warned of its perils, often at personal risk and despite the many roadblocks put in their way by those who looked to profit from manufacture and sale of excitotoxins. The author confirms that there are no conflicts of interest associated with this publication and this research did not receive any grant from any funding agencies.