For More Information GO TO Aspartame (NutraSweet) Toxicity Home Page: http://www.holisticmed.com/aspartame/ 7. Aspartic Acid Dr. Liebovitz states: "Aspartic acid is perfectly safe." While proclaimations of the "safety" of amino acids may go over well with bodybuilders reading Muscular Development - Fitness - Health, the issue of aspartic acid's "safety" as part of aspartame is not so simple as Dr. Liebovitz makes it sound. Given Dr. Liebovitz' strong beliefs in the absolute safety of all amino acid supplements (Liebovitz 1993, Liebovitz 1994), I feel that my disagreements in this section may fall on deaf ears. Nevertheless, I will endeavor to present a scientific argument showing that aspartic acid, as part of aspartame, is, at best, possibly dangerous for certain populations, and, at worst, a contributing factor in a wide variety of chronic neurological problems. In order to show how the aspartic acid taken in aspartame differs from aspartic acid which is one of the amino acids linked in protein as part of food, it is necessary to trace and compare the digestion, absorption, and metabolism of a high-protein food item and an aspartame-containing beverage. Protein Digestion & Metabolism ------------------------------ Proteins found in food are made up of building blocks called amino acids. Proteins are in the form of chains of amino acids called "peptides." (Dipeptide = a chain of two amino acids; Tripeptide = a chain of three amino acids; Polypeptide = a chain of four or more amino acids.) Amino acids are rarely found in free form -- i.e., not bound in amino acid chains known as protein molecules. As summarized by Garrison (1990), the digestion of proteins begins when a protein-containing food enters the stomach. Hydrochloric acid, pepsin, and protease enzymes break specific protein links into polypeptides (amino acid chains). When the food reaches the duodenum (part of the small intestine), the enzyme trypsin in the pancreatic juice breaks the polypeptides into dipeptides and tripeptides. As the amino acid chains progress down the small intestine, several enzymes break the amino acid chains into individual amino acids. The amino acids are then absorbed through the intestinal wall and into the bloodstream. The whole process is a long, slow process leading to a gradual absorption of amino acids into the bloodstream. In addition, because proteins from food contains many different amino acids, the ratios between the levels of amino acids in the blood does not change significantly. Aspartic Acid and Glutamic Acid Metabolism ------------------------------------------ Aspartic acid (also known as aspartate) and glutamic acid (also known as glutamate) are acidic amino acids. Glutamic acid is directly converted to alanine when it reacts with carbohydrate-derived glutamate pyruvate transaminase (GPT) in the intestinal epithelia. (Pardridge 1986, page 206-207). In the presence of glutamate oxalacetate transaminase (GOT), aspartatic acid is first converted to glutamic acid and then to alanine. However, in the absence of carbohydrate-derived pyruvic acid, the conversion of aspartic acid or glutamic acid to alanine is very slow. If protein is ingested with food, non-carbohydrate sources of pyruvic acid made in the body can convert the gradually-released glutamic acid and aspartic acid to alanine. When glutamic acid (in the form of monosodium glutamate - MSG) or aspartic acid (as part of aspartame) is ingested in free form, there is no gradual breakdown and absorption of proteins -- as there are only free amino acids (e.g., aspartic acid and glutamic acid). These amino acids are quickly absorbed. They are not converted to alanine unless they are eaten with a significant amount of pyruvic acid- forming carbohydrade such as a sugary snack. This leads to a significant spike in the blood plasma level of aspartate or glutamate. Stegink showed that glutamic acid ingested without a sugary snack spikes the plama levels of glutamate significantly (Stegink 1983b). Many other industry-sponsored experiments have shown large spikes in plasma glutamate levels after ingesting real-world amounts of MSG with water, soup, and meals. (Stegink 1979a, page 90, Stegink 1979b, pages 337-341, Stegink 1983c, Stegink 1985, Stegink 1986) The plasma glutamate increases varied from two to fourteen (14) times the increase when no glutamate was given with the meal, soup, or water (up to an average level of 60 umoles/100 ml -- the individual variation would probably put the level much higher for some people). Bessman (1948) showed a nearly five-fold increase in plasma glutamate when administering 100 mg/kg of unneutralized glutamic acid in water. Himwich (1954) showed that when given a dose of approximately 200 mg/kg (15 grams) of glutamate to adults, the plasma glutamate spiked to as much as fifteen times its fasting level. This dose can be expected in some restaurant meals (i.e., 5 grams for a 25kg child). The same type of spikes in plasma aspartate levels would be expected when ingesting aspartic acid (or aspartame). The large spikes in plasma glutamate levels after the ingestion of glutamic acid (MSG) in food, soup, or water is not unexpected. After all, a number of animal experiments with MSG showed large plasma glutamate spikes as well (Daabees 1984, Airoldi 1980, Stegink 1979a). Similarly, aspartic acid (40% of aspartame) has been shown to spike the plasma aspartate levels in animals experiments (Reynolds 1980, Applebaume 1984). This is no surprise since free aspartic acid is absorbed and metabolized in a similar way to free glutamic acid (Partridge 1986, page 206-207). It would seem obvious that plasma aspartate levels in humans would be spiked to high levels after the ingestion of aspartic acid (from aspartame), especially when ingested in liquid form, so that absorption occurs quickly. Unfortunately, what should have been a simple experiment -- measuring plasma aspartate levels after the ingestion of aspartame -- has become another embarrassment to science thanks to the involvement of Monsanto/NutraSweet-funded "scientists." In addition, the poor quality of research in this area raises additional serious questions about the honesty and accuracy of all Monsanto/NutraSweet-funded research. Two key studies which show large increases in plasma aspartate from the ingestion of aspartame were conducted by Stegink (1987a, 1987b). In the first study (Stegink 1987a), ten subjects ingested aspartame in beverage one day and one week later, the subjects ingested the same amount of aspartame in capsule form. The dosage varied from 34.9 to 60 mg/kg of aspartame. The following excerpt shows the large difference in the levels of plasma aspartate when ingesting aspartame in beverages. Plasma Aspartate Levels (umol/liter) Average Subject Solution Capsules Pre-Dose Level 1 28.5 14.5 3.2 ± 1.1 2 13.3 10.4 3.2 ± 1.1 3 46.4 14.0 3.2 ± 1.1 4 56.4 13.4 3.2 ± 1.1 5 17.0 13.9 3.2 ± 1.1 6 23.2 13.4 3.2 ± 1.1 7 30.7 14.5 3.2 ± 1.1 8 23.0 28.1 3.2 ± 1.1 9 8.8 17.3 3.2 ± 1.1 10 36.9 12.5 3.2 ± 1.1 Mean 28.4 15.2 "Aspartame ingested in solution significantly increased the mean plasma aspartate concentration from a baseline value of 3.2 ± 1.1 umol/L to a high mean value of 26.2 ± 16.3 umold/L at 30 minutes after dosing. ... When aspartame was ingested in capsules, the higher mean plasma aspartate concentration was significantly smaller (10.4 ± 5.0 umol/L) and occurred later (1.5 hours)." As you can see, some of the subjects had an extremely large and rapid increase in plasma aspatate when ingesting aspartame in solution. One subject (#4) spiked their plasma aspartate levels by over 18 times the pre-dose level. Regular, long-term consumption of aspartame-containing beverages which constantly spike the levels blood aspartate as shown above would be very unwise. These results were an embarrassment to Monsanto/NutraSweet. For years, NutraSweet had been trying to claim that aspartic acid from aspartame did not, for some strange reason, spike the plasma aspartate levels in humans (Stegink 1984b). The results from Stegink (1987a) show that plasma aspartate levels can be spiked to extremely high levels after the ingestion of aspartame. The Department of Clinical Research at NutraSweet conducted and funded a similar study challenging some of Stegink's results presented above (Burns 1990). This is know as "damage control." Not only did this "study" show no difference in the plasma aspartate levels when the subjects ingested aspartame in beverage as compared to aspartame in capsules, but the NutraSweet researchers had the nerve to claim that the plasma aspartate levels do not increase at all after the ingestion of aspartame in liquid. It would be interesting to see how the NutraSweet company can explain the enormous difference in the plasma aspartate levels in the two experiments. Despite the fact that Burns intended to compare his results directly to the Stegink (1987a) study, he neglected to mention the almost unbelievable difference in plasma aspartate levels between the experiments! I find it difficult to believe that a researcher would simply not notice or forget to mention this enormous difference. It makes one wonder if they were trying to avoid drawing attention to the Stegink (1987a) aspartic acid test results. One partial explaination may be that the Burns (1990) study presented the high mean values of the plasma aspartate levels as opposed to each individual's peak levels. Since individuals reach a peak aspartate level at different times, the mean level of all the participants together at a particular time will be much lower. What is important is each individual's peak aspartate level and how long they stay at dangerously high levels. Whether subject A has neurotoxic levels of plasma aspartate has nothing to do with what subject B's plasma aspartate levels are at that particular time. Yet Burns (1990) presented data as if they are related. Another possible explanation is that Burns used a lithium citrate buffer instead of a sodium citrate buffer. According to Stegink (1985), aspartate "co-elutes with reduced glutathione when lithium citrate buffers are used" giving inaccurate measurements. From the description in the published protocol, it appears this may have been done. One wonders how many times this mistake may have "inadvertantly" occurred. One final explanation is that the subjects in the Burns study may have been given a significant amount of carbohydrate (e.g., sugar) with the aspartame causing the aspartate to be converted to alanine as discussed earlier. As you will see later, secretely adding substances to the testing protocol and not mentioning that fact in the published protocol has happened quite a few times in MSG and aspartame-related "research." This possibility raises grave concerns about the formulation of the substance being testing in not only this experiment but all other NutraSweet- funded experiments and in independently-conducted experiments where the test substance was obtained from NutraSweet but not analyzed independently. In the second experiment (Stegink 1987b), 12 subjects ingested 50 mg/kg of monosodium glutamate (MSG) in soup with and then without 34 mg/kg of aspartame dissolved in a beverage. The average peak plasma aspartate level almost doubled when the aspartame was ingested with the soup. "Plasma aspartate levels were not significantly affected by ingestion of the soup/beverage meal without added MSG of aspartame. The addition of 50 mg MSG/kg body weight to the meal resulted in a significant increase (P < .05) in plasma aspartate concentration; values increased from a fasting mean of 0.83 ± 0.64 umol/dL to a high mean value of 2.69 ± 1.16 umol/dL 30 minutes after loading. Plasma aspartate concentration descreased rapidly thereafter and returned to baseline 120 minutes after loading. The addition of aspartame and MSG to the soup/beverage meal resulted in plasma aspartate concentration above values noted after ingestion of the meal providing MSG alone. The high mean (± SD) peak plasma aspartate concentration reached 5.01 ± 2.43 umol/dL at 30 minutes and returned to baseline 150 minutes after dosing." On the other hand, Stegink (1987c) purported to show no increase in plasma aspartate levels after the ingestion of 34 mg/kg of aspartame. NutraSweet researchers will have us believe that we can trust their testing procedures. Stegink (1987a) showed huge spikes in plasma aspartate levels after ingesting aspartame. Stegink (1987c) showed no increase in plasma aspartate levels from a similar amount of aspartame. Stegink (1987b) showed a large increase in plasma aspartate levels. Yet (Burns 1990) showed no increase in these levels after aspartame ingestion. In another acute-dosing study, Stegink (1977) showed that healthy volunteers ingesting aspartame caused a statistically significant increase in plasma glutamate levels with 1 hour. Remember, when aspartic acid is metabolized, some of it can get converted to glutamic acid and then 1) quickly absorbed, or 2) converted to alanine if from proteins (which are digested slowly) or ingested with sugar. One other experiment tested the milk of lactating women after the administration of 34 mg/kg of aspartame as compared to 50 mg/kg of lactose (Stegink 1979c). When ingesting the aspartame, the mean glutamate levels of the milk increased from 1.09 to 1.20 umol/100 ml and the aspartate levels increased from 2.3 to 4.8 umol/100 ml (more than doubling). The lactose "placebo" also increased the aspartate and glutamate in the milk, although not as much as the aspartame -- but who cares -- no one said that taking a dose of 50 mg/kg of lactose is healthy and it is certainly not an appropriate placebo for human studies. Baker (1976) also found a significant increase in breast milk aspartate levels, from 2.25 umoles/dL to 5.59 umoles/dL 12 hours after administration of 50 mg/kg of aspartame. Note: Only average values for each time period were presented. Also, ingesting the aspartame in cold orange juice may cause some of the aspartic acid to be converted to alanine. However, several other Monsanto/NutraSweet-funded experiments purport to show that aspartame does not spike the plasma aspartate levels after ingestion. I find that some of the studies funded by NutraSweet which show no increase in plasma aspartate levels to be extremely suspicious. The most likely flaws are mixing aspartame with a form of sugar to reduce spikes in the plasma aspartate levels and/or using a aspartate measurement procedure that is flawed as described earlier. The studies showing no change in aspartate levels are invariably the only studies cited by NutraSweet scientists when reviewing aspartame. Given what some people consider to be fraud in the pre- approval studies of aspartame and the possible fraud of aspartic acid- and glutamic acid-related studies as discussed later in this section, the results of some NutraSweet-funded studies showing no increase in plasma aspartate levels should not be accepted unless corroborated by several independent research teams. It seems clear from the Stegink (1987a), Stegink (1987b), and other studies mentioned above that aspartame (especially in liquids) can cause enormous spikes in the plasma aspartate levels under some circumstances. These experiments need to be repeated by truely independent researchers. Glutamate is readily converted to the amino acid glutamine (FASEB 1995, page 32). Other by-products of glutamate and aspartate metabolism include glucose, ornithine, proline, urea, ammonia, and fatty acids (Stegink 1984c, FASEB 1995, page 22). Vitamin B6 plays an important role in this metabolism (FASEB 1995, page 36). Other Biochemical Tests and Susceptibility ------------------------------------------ The blood plasma and erythrocyte levels of glutamate and aspartate are, of course, very important measurements. However, these are not the only places with levels of amino acids. For example, it has been shown that during migraine attacks, neuroexcitatory amino acids (glutamic acid and aspartic acid) rise significantly in the cerebrospinal fluid (CSF) and are actually lower in the plasma (Martinez 1993a). CSF levels of the amino acid taurine have also found to be significantly higher in persons suffering a migraine (Martinez 1993b). Interestingly, Plaitakis (1983) found that the oral administration of glutamic acid (MSG) increases plasma levels of taurine significantly. Is it possible that MSG and aspartame increase the levels of CSF neuroexcitatory amino acids and/or taurine in persons who experience headaches or migraine after their ingestion? Westlund (1992) has shown that glutamate can have an potent excitatory effects on spinal cord neurons. It seems important to measure CSF levels of amino acids at various times after aspartame administration. Of course, the CSF levels of amino acids or methanol metabolites may or may not be affected by aspartame or MSG administration. Or they may only be affected in a subset of individuals (i.e., migraine sufferers from aspartame). There are peripheral glutamate (and aspartate) receptors in the body which may be effected by the ingestion of aspartic acid or glutamic acid. For example, Said (1994) recently discovered excitatory amino acid (e.g., glutamic and aspartic acid) receptors in the lungs which may become overexcited and contribute to the asthmatic reaction that is sometimes experienced after MSG or aspartame administration. Measurements to determine the effects of MSG and aspartame on these receptors should be devised by independent investigators. As mentioned earlier, Plaitakis (1983) showed that the administration of glutamic acid (MSG) increases the plasma levels of taurine significantly. Bessman (1948) showed that the administration of glutamic acid decreased the plasma levels of the amino acid glutamine significantly within 15 minutes. After 30 minutes the levels of glutamine rose substantially over the fasting level. The rise in glutamine levels after its initial drop may have been due to the fact that glutamate is converted to glutamine in an attempt to keep the plasma glutamate from becoming excessive. Both Stegink 1979 and Stegink 1980 show an obvious decrease in plasma glutamine levels for at least four hours after the administration of aspartame to a group of PKU heterozygotes (persons with reduced ability to process the amino acid phenyalalnine). However, these obvious trends were not statistically significant because the groups' average glutamine levels were used at each time period. It would have been useful to look at individual measurements at each time period. The normal subjects in Stegink (1980) appeared to have an increase in the plasma levels of the amino acid, asparagine for a couple of hours after aspartame administration. But these results were not statistically significant because only six subjects were used and only the average values for each time period were presented. Plaitakis (1982) and Plaitakis (1983) found that the oral administration of glutamic acid (MSG) increased the plasma glutamate and aspartate levels substantially above controls in persons who have a deficiency of the glutamate metabolizing enzyme, glutamate dehydrogenase (GDH) such as patients with the genetic neurological disorder, olivopontocerebellar atrophy (OPCA). Such patients are good candidates for the long-term testing of real-world aspartame and MSG products by independent investigators -- if they don't mind being slowly poisoned, that is. NutraSweet researchers avoid looking at possible reasons for the suffering that their product has caused because they are simply not interested in trying to discover anything; they are trying to protect a dangerous product. If forced to do a test that might discover a problem with the product, they will simply perform the test improperly and hide those improprieties amidst a morass of half-truths. Asking such "researchers" to perform (or participate in any way in) a test on CSF amino acid levels, the effect on peripheral glutamate receptors, or anything else that might reveal a problem with the dangerous product, is an enormous waste of time and money. Before looking at exactly what the damage may be from excess aspartic acid and/or glutamic acid, it can be helpful to consider the following question: Given that physicians and researchers know so little about what causes many diseases and given that many things that researchers thought were healthy yesterday are disease-causing today, do we really want to tell people that since we cannot prove beyond any doubt whatsoever that regular aspartic acid (from aspartame) ingestion causes damage, it is okay to regularly and haphazardly wreak havoc with the amino acid levels in various parts of the body? It is reminiscent of telling people that smoking cigarettes is safe. There are two main health concerns with ingesting significant quantities of aspartic acid from aspartame. The first is acute reactions. The second is long term damage also known as excitatory amino acid damage. In order to discuss the effects of aspartic acid on health it will be necessary to discuss the well-studied effects of glutamic acid (MSG) on health. Most neuroscientists and health professionals agree that these two amino acids have similar effects in many cases as they both stimulate the same types of cells in the same way. In addition, many people who are sensitive to MSG experience similar acute reactions from aspartame. Excitotoxins (Summary) ---------------------- Excitotoxins are defined as amino acids such as aspartic acid and glutamic acid which, when applied to certain types of neurons (brain cells) at certain concentrations will cause them to become overstimulated and die (Blaylock 1994, Glossary). What follows is a summary of how excitotoxins cause cell death or overstimulation from Blaylock (1994), Lipton (1994), and Nicholls (1990). Aspartate and glutamate are important neurotransmitters, a chemical which allows neurons (brain cells) in the brain to communicate between each other. Normally, excess aspartate and glutamate is pumped back in the the glial cells surrounding the neurons. However, when particular types of neurons are exposed to excessive amount of aspartate and glutamate, these neural cells are overstimulated and, at a certain level of aspartate and/or glutamate, the cells die. Aspartate and glutamate can open the calcium channel in the neurons so that calcium can move into the cell. A number of chemical reactions occur within the cell which eventually leads to the release of chemicals which stimulate connected neurons. One of the products of this chemical reaction in the neuron is arachidonic acid. Arachidonic acid then reacts with two different enzymes causing the production of free radicals such as the hydroxyl radical. The hydroxyl radical, left unchecked can kill brain cells. Fortunately, the potentially destructive free radicals are absorbed by antioxidant vitamins such as C, E, and beta carotene. Magnesium, chromium, zinc and selinium are all very important protectors of neural cells. Magnesium normally blocks the calcium channel from opening. Aspartate and glutamate can remove this block and open the calcium channel -- a normal reaction. However, when the glutamate or aspartate levels become excessive, the calcium channels in some neural cells can get stuck open, leading to the overstimulation or destruction of those cells and adjacent cells. Not every nearby brain cell is affected -- only the cells with glutamate receptors. The pumping action to remove excess glutamate back into the glial cells takes an enormous amount of energy in the form of the chemical ATP (adenosine triphosphate). In addition, it is important that there is adequate magnesium, and vitamins C, E, and beta carotene in order to prevent cell damage. If brain energy or any of the proper vitamins or minerals are lacking, neural cell death can occur. In severe cases of lack of brain energy or vitamins or minerals, a normal glutamate level can lead to cell death. Normally, there is a blood brain barrier to prevent excessive glutamate levels from entering the brain. The blood-brain barrier is a system in the walls of the capillaries within the brain that is used to keep toxic substances from entering the brain. However, there are areas of the brain which are not protected by this barrier including the hypothalamus (a part of the brain which controls the release of hormones from the pituitary gland), the circumventricular organs (a part of the brain stem), and the pineal gland (a gland which controls the production of the hormone melatonin and stops the release of the luteinizing hormone (LH) which plays a part in sex hormone control -- estrogen (females) and testosterone (males)). It has been shown experimentally in animals that prolonged high levels of glutamate in the blood plasma cause glutamate to seep through the blood brain barrier (Toth 1981). This might occur if a person were ingesting amounts of glutamic acid and aspartic acid that are not normally found in a healthy diet -- say from MSG and aspartame. In addition, the blood brain barrier appears not to be fully developed during infancy and childhood possibly allowing excess glutamate to be delivered to the brain (Wakai 1978, Olney 1988, Risau 1991). Finally, there are a number of conditions which can damage the bloodbrain barrier to some extent and allow excess glutamate to seepl into the brain: - head injuries (Tanno 1992, Shapira 1993) - certain diseases (e.g., diabetes, alzheimer's, MS, ALS, etc.) (Alafuzoff 1987, Scheibel 1988, Chambron 1994, Bennett 1995) - hypertension (Alafuzoff 1987) - exposure to certain chemicals (Stewart 1988, Velaj 1985) - exposure to radiation (Krueck 1994) - infections (Chaturvedi 1991, Mathur 1992) - brain tumors (Lohle 1992) - strokes or mini-strokes which happen frequently in the elderly (Banks 1988, Alafuzoff 1983) - aging may cause a partial breakdown especially if there is poor health (Pardridge 1988b, Banks 1988, Alafuzoff 1987) Excitotoxins (Rodent Studies) ----------------------------- There is no question that glutamate and aspartate administered subcutaneously or orally to mice or rats cause cell death to neural cells in certain areas of the brain. Both independent scientists and industry scientists agree on this point (Olney 1969b, 1969c, 1980, MSG 1994, Burde 1971, Okaniwa 1979). At first, the food industry challenged these findings and even claimed that the destruction of the arcuate nucleas in the hypothalamus was of no importance (Olney 1988). The destruction of circumventricular organ neurons in infant mice have been shown to occur at low doses of glutamate and aspartate. Independent researchers such as Okaniwa (1979) and Olney (1970) have shown the cell death to begin at a dose of 0.5 g/kg body weight. Other researchers found the minimum dosage to be between 0.5 and 0.7 g/kg body weight (Takasaki 1979, Applebaum 1984, Daabees (1985). Both Applebaum (1984) and Daabees (1985) showed that the effect of glutamate and aspartate is cumulative such that 0.25 g/kg aspartate + 0.25 g/kg glutamate caused brain lesions. The dosage in the rodent experiments above may, at first glance, seem rather high -- 0.5 g/kg = 500 mg/kg. However, humans concentrate glutamate (and probably aspartate) in the plasma at five (5) times that of rodents (Olney 1988, Stegink 1979a, page 90). This translates to a dose of 100 mg/kg for human infants. Since it is not uncommon to find as much as 5,000 mg of MSG added to restaurant dishes (Olney 1984) and many soups and broths contain as much as 2,600 mg of MSG per 12 ounces (Consumer Reports 1978), humans are already being dosed with large amounts of free glutamate. Even for a 50 kg (110 lbs.) person, 5000 mg of glutamate works out to a dose of 100 mg/kg (or 250 mg/kg for a 20kg child!). Both Daabees (1985) and Olney (1988) are in agreement that the plasma glutamate of infant rodents must reach approximately 75 umoles/100 ml to cause excitotoxic cell death. This value is several times less than the value of 200 umoles/100 ml used by Pardridge (1986) to discount the danger of aspartate. The 75 umole/100 ml plasma glutamate levels can easily be obtained in infants and children by eating canned soup (or broth) with MSG or restaurant meals. Now that aspartame is on the market, humans have an additional source of significant amounts of exicitotoxins, which as described above, have a cumulative effect with MSG (Olney 1988, Applebaum 1984). While MSG can raise the glutamate level significantly more than aspartame raises the aspartate (and glutamate) levels, the combination of the two could easily raise the level of plasma glutamate plus aspartate in infants to a level that has been shown in animals experiments to cause brain lesions. Excitotoxins (Primate Studies) ------------------------------ For many years, the food industry has been arguing that high levels of plasma glutamate or aspartate do not cause excitotoxic damage in primates (e.g., monkeys, humans), but only in rodents. In order to see the lengths to which the food industry is willing to go to counter the findings of independent scientists that glutamate (MSG) and aspartate (from aspartame) can cause brain lesions in primates, here is an excerpt from Dr. John W. Olney's statement before the 1993 Federation of American Societies for Experimental Biology (FASEB) LSRO Committee Proceedings looking into the MSG issue (Olney 1993): Argument #5: Glutamate is a rat poison, but not a human poison. The paramount argument which has been the all-time favorite with the food industry and FDA is that glutamate is toxic only for subprimate species (e.g. rodents), but not for primates. In other words, glutamate is a rat poison but not a human poison. This issue has a long and sordid history. 1. When I reported in 1969-70 that glutamate destroys neurons in the hypothalamus when administered either subcutaneously or orally to immature mice (Olney 1969b, 1969c, 1970, 1971), a U.S. Senate Nutrition Committee was investigating infant nutrition and asked me to comment on the fact that glutamate was being added to baby foods (a fact that I was not aware of until they brought it to my attention). I asked how much was being added. At first, FDA and industry officials both claimed that only trace amounts were being added to foods. However, when pressed to provide details, they revealed that they were adding > 600 mg per 4-1/2 Oz jar (which translates into > 100 mg/kg body wt for the unwitting human baby, and is clearly in the same general dose range that destroys neurons in the infant animal brain). Under pressure from the Senate Committee, FDA arranged for a special "blue ribbon" committee to evaluate the safety of glutamate for babies. The committee investigated the matter and concluded that glutamate was safe, but the committee was then investigated (at my instigation) and most of its members were found to have close financial ties with the food industry (this was corroborated by U.S. Senators and written up in a news article that appeared in Science in 1972) (Gillette 1972). Of particular note, the Committee Chairman, Lloyd J. Filer, was found to be receiving monies from both the baby food industry and the glutamate industry while he chaired this committee. 2. When the Filer committee met in 1969-70, I was asked to present my findings to them. Inter alia, I advised the committee that I had demonstrated glutamate-induced brain damage in infant monkeys as well as rodents; the monkey findings were not yet published, but I presented them to the Filer committee. Carefully thereafter, over a period of two years, I completed my monkey study and published the data in the world's leading neuropathology journal (Olney 1972). Hastily, on behalf of the glutamate and food industries, Filer assembled a group of non- neuroscientists (Reynolds, Filer et al) to study the issue. They hurriedly reported in Science in 1971 that infant monkeys are not susceptible to glutamate neurotoxicity (Reynolds 1971) and recommended that my findings be dismissed as fixation artefact. At this time, the glutamate and food industries had also hired several other non-neuroscience groups to study this brain damage issue. At first, they claimed that my findings could not be confirmed in any species, not even rodents (e.g., see Oser 1971), but later the industry consortium changed their story with respect to rodents and other subprimate species when numerous legitimate neuroscientists began reporting confirmation of my findings in these inexpensive species. However, the accuracy and authenticity of the industry findings in monkeys were never challenged, except by me, for a simple reason: no one outside the food/glutamate industry circle had either the motivation or funding to study monkeys. 3. In the 1970 era, I became alarmed at some apparent flaws in the findings of Reynolds et al. and began to challenge these authors. For example, they tube-fed very large doses (2-4 g/kg) of glutamate to infant monkeys, which led me to suspect that their infant monkeys probably vomited. This raised a crucial issue; if their infant monkeys vomited, they obviously lost dose control and this would render their data unreliable for establishing the safety of glutamate. I questioned Dr. Reynolds on this in public at a scientific meeting a few months before their Science paper appeared in print. In front of a large audience, she admitted that their monkeys vomited. However, a few months later when their Science paper appeared in print (Reynolds 1971), I was surprised to read the following description: "Each infant was maintained in an incubator with handling and cuddling at intervals for a 6 hour period. No unusual behavior was exhibited by the infants." No mention was made at all of vomiting. Therefore, I wrote a letter to Science pointing out that by the author's own acknowledgement at a public meeting, these infants had vomited. The letter was accepted for publication in Science and was sent to Dr. Reynolds for her response. To my astonishment, in a letter signed by W.A. Reynolds which I have in my files, she responded with a denial that they had encountered problems with vomiting or with dose control. Therefore, I withdrew my letter and this exchange was never published. 4. Four years after the Science report, Reynolds and Filer together with Stegink, came out with another paper (Stegink 1975) which clearly pertained to the same experiment on the same group of monkeys. This time they admitted in print that their monkeys had vomited, which raises serious questions concerning: 1) Their failure to mention this obviously important point in their initial report, and 2) The signed letter denying vomiting. There were a number of other discrepancies between the first and second report which reflect poorly upon the reliability and credibility of these authors. For example, they identified individual monkeys as being of a certain species and receiving a certain dose of glutamate in the first report, then identified the same monkeys in the second report as being of another species and/or receiving a different dose of glutamate. 5. In addition, the 2nd report by Reynolds, Filer and colleagues (Stegink 1975), admitted for the first time that their monkeys were maintained under Sernylan (phencyclidine) anesthesia throughout the 6 hr experiment. Failure to divulge in their 1st report that their animals were anesthetized with phencyclidine is a particularly critical omission, since the use of phencyclidine thoroughly invalidates the entire study in the eyes of any knowledgable neuroscientist. Phencyclidine is one of the most potent antagonists of glutamate receptors known (Wang 1990, Olney 1990a, Olney 1986). Administration of phencyclidine or its various analogs, such as MK-801, totally prevents glutamate (even very high doses of glutamate) from damaging the hypothalamus (Wang 1990). Not only does the use of phencyclidine totally invalidate the primate non-susceptibility claims of Reynolds et al., their deliberate representation that "No unusual behavior was exhibited by the infants" when they clearly were aware that their infant monkeys had actually been drugged and anesthetized, raises additional grave questions. 6. I also criticized Reynolds et al for presenting nothing but spurious illustrations; while my findings showed that oral glutamate destroys neurons only in a very specific region of the hypothalamus, in their 1st paper they published illustrations of a different and irrelevant hypothalamic region in support of their claim that glutamate is non toxic. In the following year, I invited Reynolds et al to send a member of their group to my laboratory to learn how to find glutamate damage in monkey brain. In May 1972, a member of their group (Dr. N. Lemkey-Johnston) did visit my laboratory and reviewed microscopic slides with me and she told me she was convinced that glutamate neuropathology was present in the hypothalamus of my monkeys. She also thanked me for pointing out specifically where to look in the hypothalamus to find these lesions. Although I do not know the details, it is my understanding that Dr. N. Lemkey-Johnston became ill shortly thereafter and ceased functioning as a scientist. Two years later, when Reynolds et al published their second paper (Stegink 1975), they stated that they had treated a few additional monkeys with glutamate and had serially sectioned the hypothalamus to provide definitive evidence of no damage. To my amazement, the illustration they showed was once again from the wrong region of the brain. In that same year (1975), I met with Dr. Reynolds and made it very clear to her that I considered it unethical for researchers to persistently make claims regarding non-susceptibility of monkeys to glutamate neurotoxicity, if they repeatedly presented nothing but spurious documentation of those claims. She apologized and promised to provide me with illustrations from the correct brain region, but no such illustrations were ever provided. Instead, as described in the next paragraph, she subsequently made additional claims in the medical literature and documented them even more spuriously. 7. In 1976, Reynolds et al attempted to convince the world definitively that glutamate is non- toxic for the infant primate by publishing a 3rd report (Reynolds 1976) in which new evidence is presented on an additional specie of monkey (fascicularis, a specie not documented in their first 2 reports). This report is illustrated with a brain section from a 7 day old fascicularis monkey that ingested glutamate 5 hrs earlier (Appendix, Exhibit # 2). Incredibly, the brain section used to illustrate the new finding is the same brain section used in their second report (Stegink 1975) to illustrate lack of brain damage in a 1 day old rhesus monkey dosed with glutamate 6 hrs earlier (Appendix, Exhibit #2). These illustrations are obviously spurious for two reasons: 1) They cannot possibly constitute evidence from two separate monkeys or two separate species because they are one and the same photograph which has merely been cropped differently during photographic printer; 2) Regardless how this photograph is cropped, it does not authentically document lack of glutamate toxicity because it is selected from the caudal level of the hypothalamus which lies outside the zone that is subject to damage by orally administered glutamate. When Dr. Reynolds published this spurious photograph in her 3rd paper (Reynolds 1976), she had very good reason to know that it was from the wrong region of the brain, because not only had I instructed her colleague and co-author on this matter in 1972, but I met with Dr. Reynolds herself in 1975 and briefed her very carefully and pointedly on both the science and the ethics of this matter. This briefing was one year prior to the publication of her 3rd spuriously documented report. 8. Industry representatives will likely respond to this information by claiming that several other laboratories also studied this issue and reported that glutamate does not damage infant monkey brain. If this position is taken, some pointed questions should be asked: 1) Were all such studies funded by the glutamate or food industries, despite failure of the authors to disclose industry support in some of the published reports? 2) Was undisclosed vomiting and loss of dose control a problem in these studies, as it was in the Reynolds et al study? 3) Was phencyclidine anesthesia used, but not disclosed, as was the case in the Reynolds et al. study? 4) How can FDA or the scientific community know whether vomiting occurred, or phencyclidine anesthesia was used, if the authors of industry-funded studies do not disclose this kind of crucial information in their published reports? 5) Are records available from these laboratories for FDA inspection to obtain an objective answer to questions 1 through 4? 6) Did any of the authors of these studies have any demonstrated expertise in neuropathology research? 7) Were any of these studies published in a refereed neuropathology journal? 8) Did these groups report their findings in obscure journals editorially controlled either by themselves or their very close associates who have financial ties with the food industry? 9) Did they report their findings in obscure journals without even providing histological illustrations of the brain to document their claims? 10) Did these other studies pertain to only a small number of monkeys distributed over several laboratories, thereby providing multicenter evidence for the food industry and FDA to cite as justification for keeping on the GRAS [generally recognized as safe] list for two additional decades after Olney et al (Olney 1972) published bona fide evidence for primate susceptibility to glutamate-induced brain damage in a highly reputable, rigorously refereed neuropathology journal? In summary, the record shows that FDA for two decades has been assuring the public that glutamate is safe, based largely on certain industry-generated monkey data which appear upon close scrutiny to be seriously flawed and spurious. However, even if these data were not flawed and spurious, it is obvious from industry's own findings, shown in Fig. 1 above, that the pharmacokinetics of gluatmate absorption and/or metabolism are so disparate between monkeys and man that monkeys, despite their phylogenetic closeness to humans, must be regarded as a singularly inappropriate animal model for evaluating oral gluatmate safety. Oral doses of glutamate that cause dramatic increases in blood glutamate concentrations in humans, cause no increase at all in monkeys. There are a couple of points that need to be made in regards to Dr. Olney's statement: 1. When Dr. Olney was referring to "the pharmacokinetics of gluatmate absorption and/or metabolism are so disparate between monkeys and man that monkeys, despite thier phylogenetic closeness to humans," he referenced a graph showing that humans concentrate glutamate 20 times more than monkeys when administered orally (Olney 1988, Stegink 1979a, page 90). This means that the dosage given to monkeys cannot be extrapolated to that of humans on a one-to-one basis. It also means that rodents may be a better animal model for testing glutamate than monkeys. 2. The Reynolds (1976) experiment (discussed by Dr. Olney above) was funded by G.D. Searle and tested both aspartame and MSG on neonatal primates. Therefore, the NutraSweet industry was involved in this fiasco as well. After learning about the sordid history behind both the NutraSweet industry's research and the Glutamate Association's-sponsored research and how key information was left out of published reports, I find it difficult to imagine how anyone could trust any of the "science" which is supported by those industries. As Dr. Olney mentions, there were a number of other studies which are used by the glutamate and aspartame industries to support their contention that glutamate and aspartate adversely affect only rodents despite the finding of an independent, experienced neuropathologist (Olney 1969a, Olney 1972). Reynolds (1980) administered aspartame at 2g/kg to eight monkeys and aspartame (2 g/kg) plus MSG (1 g/kg) to six other monkeys. She did not find any brain lesions in the monkeys. Phencyclidine was given to the monkeys before the administration of aspartame and MSG. As Dr. Olney pointed out, this totally invalidates the experiment because phencyclidine is a powerful drug which prevents glutmate and aspartate from damaging brain cells. In addition, considering that humans concentrate glutamate in the plasma at least 20 times more than monkeys, the dose given was too small. Oser (1974) claimed to find no brain lesions in monkeys given MSG. This study can be discounted for the simple reason that he was unable to find brain lesion in infant mice and rats given a high dosage of MSG in the same experiment. He was unable to find brain lesions in rodents in an earlier experiment (Oser 1971). Since it is widely known that infant rodents develop brain lesions at the dosage used in his experiments, he must have had one or more major flaws in the protocols which did not allow him to find lesions. Therefore, the results in the monkeys should be discounted as should the results in the dogs from both the 1971 and 1974 publications. The study by Wen (1973) can be discounted by the same reason. In the same study as his monkey study, despite giving extremely large doses of MSG to rodents, he was unable to find any brain lesions. The lack of effects on rodents given such large doses of MSG would point to one or more flaws in his protocols. One major flaw in the protocol is that animals must be sacrificed within 8 hours of the MSG dose in order to find the brain lesions. If they are sacrificed any later, the massive influx of glial cells will obscure the lesions (Burde 1971, MSG 1994). The monkeys in this experiment were kept alive for days following the MSG dosing. The study by Newman (1973) can be discounted for the simple reason that it appears that the monkeys did not get even close to the stated dose of MSG (if they got any at all). Table I shows the plasma glutamate levels within 4 hours after MSG dosing. The levels are not significantly higher than the control animals. However, in Olney (1972) the plasma glutamate levels at 4 hours are four to five times the base level (for a similar dose). Reynolds (1980) shows similar increases in plasma glutamate levels at 4 hours. Therefore, there was likely a major flaw that caused the monkeys in the Newman experiment to have no rise in plasma glutamate. There are a number of possible reasons. It is possible that the monkeys did not get much MSG. Newman states that "the test solution was readily consumed voluntarily by all animals on all occasions throughout the study." However, the term "readily" is not very specific. The MSG was supplied by Ajinomoto Company of Japan, the company that makes it and a member of the Glutamate Association. It appears that the purity of the MSG was not tested by the investigators. Whatever the reason, it is obvious that something was done incorrectly to cause no rise in plasma glutamate. In addition, Newman used older, less susceptible monkeys in the higher dose part of the experiment. Formalin was used for the brain tissue fixation. Burde (1971) points out that: "Infant rat brains perfused with formalin were extremely fragile. Tissue preservation was not satisfactory for photography, but the affected areas could not be identified and were in the periventricular arcuate area." Newman did not show any photos to back up his claim that there were no lesions. Finally, Newman did not list his funding source. In 1979, R. Heywood conducted an experiment on a single rhesus monkey (Heywood 1979). Heywood had been the coinvestigator on the Newman study mentioned above. In this study, Heywood admits that a dose of 4 g/kg of MSG caused vomitting at 43, 81 and 90 minutes after dosing. Heywood also states that the plasma glutamate level rose from 138 ug/ml to 333 ug/ml (unlike what happened in the Newman study). Among the more glaring problems with this report are: 1) the monkey vomitted and therefore did not get the full dose of MSG, 2) the investigators did not say what part of the hypothalamus was examined (as not all parts are vulnerable), 3) no photos were shown to back up the claim of no lesions, 4) the brain tissue was not examined with the electron microscope, and 5) formalin was used for brain tissue fixation. Several years after more detailed studies were conducted on infant monkeys, there seems to have been no reason to conduct such a small, sloppy, and poorly documented experiment. After discounting the above-mentioned industry-connected monkey studies for obvious mistakes and inconsistencies, we are left with: a) two studies showing brain lesions in monkeys from oral intake of MSG which were conducted by the reknowned neuropathologist, Dr. John W. Olney, who originally discovered brain lesions from excitatory amino acids such as glutamate (Olney 1969a, Olney 1972); and b) two studies by R. Abraham (Abraham 1971, Abraham 1975) showing no brain lesions in monkeys from oral intake of MSG. Abraham (1971) tested four monkeys with a dose of 4 g/kg of MSG. However, two of these monkeys were not sacrificed until 24 hours after the dose. This would cause the influx of glial cells to obscure the lesions as described earlier. In addition, damaged cells are removed from the area within 24 hours of glutmate or aspartate administration (Olney 1972). Therefore, these two particular monkeys can be discarded. One of the two remaining monkeys was given the MSG orally and one by subcutaneous injection. However, an oral dose of 4 g/kg of MSG often causes vomitting as discussed above and admitted to by Stegink and Reynolds (Stegink 1975). This leaves us with one test monkey and one monkey strongly suspected to have vomitted in the Abraham (1971) study. In this experiment, Abraham found that only 60% of the infant mice he treated with a dose of 4 g/kg developed lesions. However, other laboratories have found that such extremely high doses of MSG in mice cause lesions in 100% of the mice (Olney 1970, Burde 1971, Daabees 1985, Lemkey-Johnston 1974). Even at a dose of 1 g/kg, Takasaki (1979) found that 75% of the mice develop lesions. Abraham (1971) claimed that only 60% of the mice which received 4 g/kg developed brain lesion and 43% of the mice receiving 1 g/kg developed lesions. This sugessts that Abraham had a major defect somewhere in his experiment which would prevent brain lesions from either a) developing and/or b) being discovered. This puts the results of his remaining monkey from this experiment (or "monkeys" if one included the monkey that likely vomitted up the MSG) into serious doubt. It is of note that Abraham (1971) supported his findings with only a single picture from the hypothlalmus of a monkey that was sacrificed after 24 hours after MSG administration and did not include pictures from the monkeys who were sacrified after 3 hours. At best, this study is highly suspect and probably should be discounted due to the inadequate sacrifice schedules, likely vomitting, and poor results in the mice part of the experiment. Like the earlier Abraham study, the Abraham (1975) study had only two monkeys which were given MSG and sacrificed before 24 hours had elapsed. It seems rather odd that Abraham would continue testing monkeys by sacrificing them after 24 hours after MSG administration since it had already been published in the scientific journals that the glial cells would obscure the brain damage and that the damaged cells would be removed when an inappropriate sacrifice schedule was used (Burde 1971, Olney 1972). In fact, Olney (1972), three years prior to this study (when critiquing the Abraham (1971) study), stated the following: However, beause of the remarkable efficiency with which degenerate elements are removed from the scene of an MSG-induced lesion (minimal lesions are cleared from the mouse brain within 12 to 18 hours), it is essential to examine the brain earlier than 24 hours. This is particularly true if, due to vomiting, the infant retained very little MSG and, therefore, sustained only a minimal lesion. One monkey was give 4 g/kg of MSG orally, the other was given the same dose subcutaneously. Once again, the monkey given an oral dose of 4 g/kg is likely to have vomitted. Abraham. It is also important to note that, as discussed earlier, plasma glutamate levels in monkeys after glutamate administration stay extremely high until at least 4 hours. Yet Abraham sacrificed these two monkeys after only three (3) hours. According to researchers at Dr. Olney's laboratory, a 3-hour sacrifice schedule is the minimum needed to find any brain lesions (Samuels 1995a). If the earlier sacrifice schedule is combined with other minor or major experimental errors, no lesions would likely be found. Abraham (1975) stated that "The present investigation was undertaken in an attempt to resolve some aspects of this controversy." It appears that Abraham merely repeated most of the same flaws in his 1971 experiment and did not address Olney's direct criticisms. This study, therefore, should be discounted as well. Excitotoxins (Humans) --------------------- Several discoveries have proven that ingested excitotoxins can cause adverse effects in human beings. In 1987, 150 Canadians got sick (4 died and 12 suffered permanent memory loss) after ingesting mussels whifch had high levels of domoic acid, a potent glutamate analog (Perl 1990). In parts of Asia and Africa, the chickling pea plant was eaten by some people during times of famine. It contains a naturally-occurring excitotoxin, §-N-oxalylamino-L-alanine (BOAA), which has been shown to kill motor neurons (Spencer 1986). One of the more likely causes of the form of the ALS-like illness in the Chamorro population in Guam is the ingestion of improperly processed cycad flour which contains the excitotoxin, §-N-methylamino-L-alanine (BMAA) (Spencer 1987, Choi 1992). The Chamorros ate a large amount of this seed during the famine following World War II. In the 1950s, the rate of the Guam ALS-Parkinson's-dementia complex was 50 to 100 times higher than in developed countries (Kurland 1988). The Chamorros no longer ingest much cycad flour (Chamuit, 1994). It was found that many people who ate the flour didn't come down with the disease until many years later, suggesting that the excitotoxic exposure plus age-related cell loss set the stage for the disease. As Choi (1992) states: "Such a model raises the possibility that nerve cell damage resulting from exposure to environmental excitotoxins could pave the way for other neurodegenerative diseases, such as Alzheimer's Parkinson's, or ALS, whose symptoms would become apparent only decades later. Garruto (1980) found that immigrants to the U.S. from high-risk areas in Guam had a high incidence of ALS even though they had not ingested cycad flour for over 30 years. Excitotoxins (Endocrine and Reproductive Disorders) --------------------------------------------------- Aspartate and glutamate are also thought to have similar neuroendocrine effects. As recently discussed by Olney (1994): "Destruction of brain neurons is not the only mechanism by which Glu[tamate] can have adverse effects on children. As described above, whenever elevated levels of Glu are present in the ciculating blood, Glu enters the endocrine hypothalamus (a CVO region which has no blood- brain barriers) and interacts with EAA [excitatory amino acids] receptors on the surfaces of hypothalamic neurons. These neurons, when stimulated by Glu or related EAA, secrete hypophysiotrophic releasing factors into the portal blood which carries the releasing factors to the pituitary where they act to trigger release of pituitary hormones into the general circulation. This phenomenon was first domonstrated in the mid 1970s (Olney 1976, Price 1978), at which time it was pointed out that repetitive exposure of immature humans to Glu throughout critical stages of development entails potential risk, even if brain damage does not occur, that hormonal biorhythms may be disturbed with adverse effects on growth and development." Carlson (1989b) showed that by administering a dose of 150 mg/kg of glutamic acid (MSG) to healthy adults (an amount which can easily be ingested by children in one restaurant meal) there was a large increase in serum concentrations of the pituitary hormones prolactin and cortisol. Carlson (1989a) tested 534 mg of aspartame in a liquid medium and and 242 mg of aspartic acid in a capsule to see if it changed prolactin, cortisol, or growth hormones outputs. He found no such changes. Carlson (1989b) also tested 10 grams of aspartic acid in capsules and found no increase in prolactin or cortisol outputs. These results were a surprise to the researchers and definately a surprise to me. It is of note, however, that capsule administration was used for aspartic acid administration (but not for aspartame). In the Carlson (1989a) experiment where 534 mg of aspartame was given (in liquid), the plasma phenylalanine did not increase significantly. This seems strange since similar amounts of aspartame administered in other experiments do raise the plasma phenylalanine levels (Caballero 1986, Burns 1991). NutraSweet funded this experiment. One wonders if the aspartame and aspartic acid were provided by NutraSweet and, if so, did they provide the "type" of aspartame which has been shown to cause large spikes in plasma aspartate levels or the "type" that does not cause this spikes (as discussed earlier). In addition, the test substances in the Carlson experiments (1989a, 1989b) were mixed with 500ml-700ml of saline solution. The subjects were also given an infusion of 9 grams of saline/liter into the antecubital vein. This was presumably done to be consistent with a previous experiment which tested prolactin stimulation by meals (Carlson 1983). Since Carlson (1989b) admits that aspartic acid metabolism may be different than glutamic acid, how can he be sure that all of these saline solutions don't affect the results for aspartic acid? Carlson should have administered aspartame in a real world type of setting, i.e., without the saline solution. What happens to prolactin and corisol measurements after meal intake is not necessarily relevant to aspartame intake because 1) the mechanism that cause excitotoxins to increase hormonal output may be different and more damaging than hormonal changes after a meal, and 2) a meal creates a number of biochemical changes and it is often the balance between these changes that prevent trouble from occurring (e.g., glucose and insulin balance), so that a single change in one parameter could be dangerous for aspartame because other key parameters are not changed. Finally, none of these studies measured levels of luteinizing hormone. Even if the hormonal levels do not change with the ingestion of aspartame (and this has yet to be confirmed with independently obtained and tested aspartame in a study without saline solution and without NutraSweet involvement), excess aspartate will likely over-excite (at least more than normal) cells in the hypothalamus and other areas of the brain not protected by the blood brain barrier. Who can say what a lifetime of such over-excitation will do to the body. Finally, it is crucial to remember that glutamic acid and aspartic acid effects are cumulative. The safety of either of these excitotoxic amino acids cannot be determined without looking at the cumulative effects. Recent animal experiments have shown that high levels of glutamate and aspartate stimulate the abrupt release of gonadotropin-releasing hormone and luteinizing hormone (Medhamurthy 1990, Goldsmith 1994). Plant (1989) and Gay (1988) have shown that an analog of glutamate, N-methyl aspartate induces the premature onset of puberty when given to monkeys repetitively. Other researchers have showed that subtoxic doses of excitatory amino acids change the sexual maturation of animals (Urbanski 1990, Lopez 1990). Subtoxic doses (i.e., less than required to cause brain lesions) of glutamate has been shown to cause a rapid elevation of leutenizing hormone in weanling and adult male rats (Olney 1976) and a depression of pulsatile output of growth hormone (Terry 1981). The dose tested in this experiment was only 25% of the toxic dose. Brann (1992) tested a dose of only 30 mg/kg of glutamate administered to female rats with low and high estrogen backgrounds. Female rats who were given estrogen showed a significant increase in the output of leutenizing hormone. Brann (1992) states: "There is a growing body of evidence which suggests that EAAs [Excitatory Amino Acids] are an integral component of the neurotransmission line that regulates gonadotropin secretion." Even the Federation of American Societies For Experimental Biology (FASEB), which usually understates problems and mimmicks the FDA party-line, recently stated in a review (FASEB 1992): "...it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children. The Existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L- glutamic acid should be avoided by women of childbearing age and individuals with affective disorders." Aspartic acid from aspartame has a cumulative harmful effect on the endocrine system and reproductive system. Since there are few safety studies on glutamic acid suppliments, FASEB used studies relating to MSG to make this determination. While it could be argued that MSG is ingested with food and therefore does not raise the plasma glutamate level as high as with suppliments, it appears that MSG is actually more dangerous than suppliments. I have already listed a number of experiments that show large spikes in plasma glutamate from real-world MSG products -- including with full meals. I have also listed a number of experiments showing a significant spike in plasma aspartame levels from aspartame ingestion. On the other hand, glutamic acid and aspartic acid suppliments may dissolve slowly (similar to encapsulated administration) leading to the conversion of more of the amino acid to alanine and definately lessening the plasma spike of the amino acid. Excitotoxins (Pregnancy Dangers) -------------------------------- Several animal experiments have shown that excitotoxic amino acids can penetrate the placental barrier and cause damage to the fetus. Gao (1994) used a 3H-Glu tracer to show that low and higher doses of MSG injected into pregnant mice. The experiment showed that the memory and learning potential of the adult offspring was significantly affected. In addition, brain cell damage was found in both the arcuate nucleus and the ventromedial nucleus of the hypothamalmus. Fisher (1991) showed that perinatal MSG treatment of pregnant rats led to a variety of damage in the offspring including brain cell damage to the hypothalamic arcuate nucleus, parts of the circumventricular areas, parts of the visual system, and the dentate gyrus of the hippocampus. The authors stated: "The resulting hormonal dysfunction may be responsible for developmental anomalies of o rgan systems, obesity, and alterations in sensory/motor performance. We have shown that some behavioral indicators of MSG toxicity in rats can be masked by rearing them in enriched housing conditions. Here, we evaluated the impact of six housing conditions on MSG-induced alterations of organ systems and behavior. Perinatal MSG treatment reduced adrenal, heart and testes weights, as well as total white blood cell (WBC) counts, and increased tail flick latencies. .... Deficits in water maze performance were most evident following social and isolated single-case housing. We propose that deficits in water maze performance following perinatal MSG may be attributable to hippocampal damage that can be alleviated by rearing the rats in stimulating environments." Toth (1987) found that MSG given to pregnant rats caused acute necrosis of the acetylcholinesterase-positive neurons in the area postrema. The authors noticed the same effet in the fetal rats except that the "embryonal neurons were more sensitive to glutamate...." Frieder (1984) showed that damage to the offspring can occur when pregnants rats are given MSG orally as opposed to subcutaneously. Frieder administered MSG in the drinking water during the second and third trimester of pregnancy. Administering MSG led to juvenile obesity, reduced general activity levels, and a learning disability. The dosage given to the pregnant rats was quite high. However, a recent survey showed that some restaurant meals can have as much as 9.9 grams of MSG in a single dish! (UNICEF 1986) An independent study using a smaller dose of orally administered MSG and/or aspartic acid would be useful. It is important to note however, that both orally and subcutaneously administered MSG and aspartame have been shown to cause brain lesions in animals at dosages that are not emensely different. Finally, glutamate has been shown to activate certain genes (Grayson 1990). As pointed out by neuroscientist, Dr. Russell Blaylock (Blaylock 1994, page 73, 235): "The gene activation occurs via a second messenger system, inositol triphosphate and diacylglycerol, which have been activated by phospholipase C. Modification of a preexisting transcription factor induces an early response in certain genes. .... Further, this capacity to activate genes may play an important part in the plasticity of the nervous system, that is, the ability of the nervous system to adapt and change in response to the stimuli of learning and observing the outside world. This is very important, not only in the initial development of the nervous system (while the baby is in the uterus) but also much later during childhood and adolescence. This is how the various mental and motor skills develop." It seems ridiculously reckless to allow women to ingest MSG or aspartame during pregnancy since there is a chance that it will adversely and irreversibly affect the child. Perhaps that is why the FASEB (1992) committee warned pregnant women to avoid glutamic acid. Excitotoxins (Other Disorders) ------------------------------ The FASEB (1992) report, a detailed review by Nemeroff (1981), and a thoroughly-referenced analysis by Blaylock (1994) list studies which show test animals experiencing stunted growth, reproductive disfunction, changes in behavior and food intakes, obesity, reduced weights and sizes of gonads, uteri, adrenals, thyroid, and pituitary glands, changes in insulin output, and various other disorders. As opposed to the single-dose experiments showing brain lesions and changes in hormonal output, some of these experiments were long-term studies. It is beyond the scope of this review to analyze what amounts to thousands of studies involving the health effects of excitotoxic amino acids. I strongly suggest reading the reviews mentioned above to get a good overview. In 1990, Dr. John Olney reviewed the strong connection between neuropsychiatric disorders and excitatory amino acids such as glutamate and aspartate (Olney 1990a). In 1993, Altamura (1993) conducted a study measuring the plasma level of glutamate in patients with psychiatric disorders. Plasma glutamate levels were significantly higher in the patients with mood disorders, schizophrenia and organic mental disorders than in the healthy controls. One would expect that the intake of large quantities of excitatory amino acids from aspartame or MSG would only add to the problems experienced by these patients, and may have caused or contributed to their illnesses. Excitotoxins (Intake) --------------------- In the U.S., use of large amounts of free glutamic acid in the form of MSG, HVP, yeast extracts, etc. has increased tremendously over the past 15 years, especially with the advent of the low-fat craze that has swept the country (Samuels 1993). Glutamic acid is added (often in hidden forms) to low-fat foods in order to improve the taste. As much as 5,000 mg of MSG are often added to one restaurant dish. Twelve ounces of soup or broth can contain as much as 2,600 mg of MSG (Consumer Reports 1978) not counting other forms of glutamic acid added. The use of glutamic acid is increasing rapidly (Floreno 1995). It would be quite easy for a 30 kg child to ingest a restaurant meal (5,000 mg of MSG) plus 12 ounces of soup (2,600 mg of MSG) for a total intake of 7,600 mg of MSG or 253 mg/kg of MSG. The Glutamate Association tries to claim that intake of MSG in the U.S. averages only 0.5 g/day for each person. They do not account for the fact that glutamic acid intake has increased tremendously over the last 15 years and much of the intake is in "hidden" forms of MSG discussed below. Just three ounces of soup with some form of MSG would cause a person to ingest 0.5 grams of MSG. The current average is probably closer to 2 to 3 g/day and the intake at the 99 percentile is probably close to 12 to 15 g/day. Due to the public's concern about "MSG," free glutamic acid are being hidden (with the blessing of the U.S. FDA) in the labels in many ways. Common ingredients which, due to the processing technique can have a significant percentage of free glutamic acid or can have MSG directly added to them (without having to list it on the label) include (Samuels 1993): Monosodium glutamate Hydrolyzed protein Autolyzed yeast Yeast extract Yeast nutrient Yeast food Hydrolyzed oat flour Textured protein Sodium caseinate (often, but not always hydrolyzed protein) Calcium caseinate (often, but not always hydrolyzed protein) Maltodextrim Malt extract Malt flavoring Some of the industry's new favorite synonyms for MSG include: Flavoring(s) Natural flavoring(s) Natural beef flavoring Natural chicken flavoring Natural pork flavoring "Seasonings" "Spices" Due to labeling law loopholes and FDA inaction on a petition to close those loopholes (Truth 1994, Samuels 1995a), it is almost impossible for even health-conscious individuals to know whether they are ingesting MSG. A recent survey at a national restaurant convention on May 27, 1995 revealed that a number of companies which provide soups to restaurants put labels on their soups which state "No MSG Added" and/or have literature with their soup which states that there is no MSG added even though their soups contain significant quantities of added free glutamic acid (MSG). Most of the salespeople were aware of what they were doing, i.e., that their soups really had a form of MSG in it. These soups are then distributed to restaurant owners who may innocently believe and tell restaurant patrons that they contain no MSG. Therefore, when you ask a restaurant for food without MSG, you may very well get MSG unless you look at the label of the packages for MSG synonyms. Claiming "No MSG Added" on the label, but including HVP in the food product has been found "false and deceptive" by the FDA, yet no one seems to be policing restaurant products (Oliver 1991). The intake of additional excitotoxins from aspartame was discussed in an earlier section. It is important to note that only since 1987 have large amounts of aspartame been ingested (USDA 1988). Cysteine, another excitoxic amino acid is currently being added to flour as a conditioner and it is being considered by the FDA for use on produce (Samuels 1995b). Excitotoxins (Food Insdustry Arguments) --------------------------------------- The NutraSweet Company and the Glutamate Association have put together a number of arguments to try to convince FASEB, the FDA, researchers, and the general public of the "safety" of their products. Here is another excerpt from John Olney's presentation to FASEB (Olney 1993) addressing some of those arguments: Argument #1: Gutmate causes no apparent harm to children. One of the major arguments relied upon by the food industry and FDA is that immature humans do not wince or show overt signs of neurological injury when fed large amounts of glutamate as a food additive or drug. The evidence supporting this argument is that in the 1950s when glutamate was routinely fed in gram quantities to mental retardates with the mistaken believe that it might improve their IQ, these retarded children did not show obvious signs of neurological injury. Similarly "compelling" evidence was generated in an enormous, but totally uncontrolled, world-wide field experiment performed over a period of two decades by the food industry (and sanctioned by FDA) in which glutamate was routinely added to baby foods at ~ 600-800 mg per 4 1/2 Oz jar, the sole motivation being to make the baby food appealing to the maternal palate. Since hundreds of millions of immature humans thus exposed showed no obvious signs of injury, glutamate must be safe, so goes the illogic. As stated above (and I have personally witnessed this phenomenon many times), when immature animals are treated with doses of glutamate that unequivocally and irreversibly destroy neurons in the hypothalamus, they behave exactly like glutamate-fed human infants; they do not wince or show signs of discomfort or neurological injury during the acute 2-4 hour period while hypothalamic neurons are being destroyed. In some species, including primates, high doses cause emesis, but we have observed -- especially in infants -- that hypothalamic damage occurs from doses lower than those required to induce emesis. Later in life, the effects of the hypothalamic damage begin to manifest as subtle neuroendocrine deficits (obesity and disturbances in growth and sexual/reproductive function); but there is not warning of this in the behavior of the animals at the time the damage occurs. I do not comprehend how FDA and the food industry can be confident that exposure of infants and children to gluatmate in gram quantities (the practice FDA currently allows) does not silently destroy neurons in developing human hypothalamus. I know of no credible scientific evidence that could inspire confidence in that conclusion. Arguments #2 and #3: Glutamate is toxic only for newborn, and only if force-fed. An argument sometimes embraced by FDA and food industry officials, is that glutamate is toxic only for the newborn immediately after birth. A related argument is that animals will not voluntarily ingest enough glutamate to cause brain damage. Both of these arguments are easily shown to be false by the enclosed journal article (Olney 1980) which demonstrates that if weanling mice are deprived of fluids overnight, and the next morning are offered a bottle of drinking water containing added glutamate, they avidly drink enough of the glutamate solution to destroy many neurons in the hypothalamus. While the neurons were being destroyed, the mice showed no clinical symptoms other than mild somnolence. A weanling mouse is roughly comparable in developmental age to a prepubescent human child. In view of this finding, which has been confirmed by others [in aspartame] (Takasaki 1981), I must reiterate that I do not comprehend how FDA and the food industry can, with good conscience, feel confident that the glutamate intentionally being added to foods fed to human infants and children does not ever destroy hypothalamic neurons. Other food industry arguments have included: a. The spike in the plasma glutamate and aspartate levels only lasts a short time (i.e., several hours) and returns to normal quickly and therefore does not keep the levels high for long enough to do damage. Animal research using glutamic acid labelled with radioactive tracers has shown that the levels of glutamate in the brain did not peak until two hours after the blood levels of glutamate returned to normal. It was also shown that glutamate remains in susceptible areas of the brain for as long as 24 hours after the original dosing (Inouye 1976, Paull 1975). Toth (1981) found that feeding liquid diets which contained aspartic acid or glutamic acid over a prolonged period of time increase the brain tissue levels of aspartate 61% and of glutamate 35%. This is a sign that prolonged exposure to high levels of aspartic acid from aspartame or glutamic acid (MSG) may significantly affect brain chemistry over time. b. Some food and breast milk contains free glutamic acid and free aspartic acid, therefore glutamic acid (MSG) and aspartic acid from aspartame are not dangerous. This is a very popular food industry argument attempting to justify adding large amounts of excitotoxins to the food supply. There are several reasons why this is not a legitimate argument. i. The amount of free glutamic acid and aspartic acid in foods is much less than what is often found in MSG and aspartame-containing foods. The IFIC (1995) "fact" sheet lists tomatoes as containing 140 mg/100 grams of free glutamic acid. In a glutamate industry book, Giacometti (1979) also lists tomatoes as containing 140 mg/100 grams of free glutamic acid. Giacometti lists the free aspartic acid level at 35 mg/100 grams for tomatoes. These figures are based on a study by Stadtman (1972). Skurray (1988) found that fresh tomatoes contained 109 mg/100 grams of free glutamic acid. However, Skurray showed that beef soup contained 2,482 mg/100 grams of glutamic acid with MSG added. As you can see, it is very easy to ingest huge amounts of MSG from these processed junk foods. Human breast milk contains approximately 129 mg/liter of free glutamate (Giacometti 1979). This is many times less than the high concentration of gutamic acid found in MSG-containing products and much less than even the aspartic acid found in diet sodas. Despite the low body weight of infants and the corresponding high mg/kg of glutamic acid ingested per day from breast milk, the amount of glutamic acid ingested at each sitting is relatively small. Giving the regular doses of soup broth with as much as 7,000 mg/liter of glutamic acid is quite a bit different than giving the infant breast milk because the amount of MSG ingested with the soup would be dangerously high.. ii. The small amount of free glutamic acid and aspartic acid in foods is disbursed in the fiber. The food is digested gradually and the free gluatamic acid and aspartic acid are released gradually allowing these amino acids to be absorbed slowly. The food industry has been unable to show a significant glutamate or aspartate spike after the ingestion of real foods which sometimes contain small amounts of free glutamic acid or aspartic acid. A high protein meal does gradually raise plasma levels of amino acids (e.g, Stegink 1983c), but it is nothing like the plasma glutamate and aspartate spikes discussed earlier. This is key: If the free glutamic acid and aspartic acid in foods were really similar to MSG or aspartame ingestion, then these foods would cause enormous spikes in the plasma amino acid levels. Since these large spikes do not happen (Kenney 1972, Airoldi 1979), ingestion of free amino acids in foods cannot be compared to MSG or aspartame. iii. As will be discussed in the next section, persons who have regular, repeatable acute reactions to MSG (glutamic acid) generally do not react to free glutamic acid found in natural foods (Samuels 1993). c. The intake of MSG in some countries such as Thailand is very high and we do not see any health problems caused by glutamic acid in those countries. This is another popular glutamate industry claim. As pointed out by Science (1990), one cannot expect that every person in a country such as Thailand will suffer obvious adverse effects from years of excess glutamic acid. There may very well be a vulnerable subset of the population. Furthermore, I am not aware of any epidemiological studies in Thailand (or any other country) which tests for the effects of long- term MSG usage. A research team would have to compare two populations one with a high MSG intake and one with little or no MSG intake, controlling for other variables such as diet, environment, heredity, etc., and then compare the incidence of certain diseases -- especially endocrine, neurological and reproductive disorders. The glutamate industry appears to be throwing this statement out without any corroborating evidence. One might wonder why the 307 males tested in Thailand had semen analysis values that were significantly below the standard for Caucasian males (Aribarg 1986). Was it racial or is it possible that glutamate was affecting FSH, LH and prolactin outputs? In a study of 137 Thai patients, 54% of the patients with secondary amenorrhea (cessation of menstration) had hypothalamic-pituitary dysfunction (Vutyavanich 1989). Almost 40% of those who discontinued oral contraceptive steroids still experienced amenorrhea. Might MSG play a factor in the children with stunted growth studied in North-East Thailand (Chusilp 1992)? According to Rajatanavin (1993), "available data indicate a seemingly high prevalence of central hypothyroidism due to postpartum pituitary necrosis in Thailand." Could constantly over- stimulating the pituitary gland by ingesting large amounts of MSG contribute to this? Over the last 10 years there has been a significant increase in childhood obesity in Thailand (Suttapreyasri 1990, Mo-suwan 1993). One wonders if MSG, which has been shown to cause obesity in animals studies, could play a part in the increase in childhood obesity in Thailand. Fuller (1993) found that Thai women suffer from frequent reproductive system problems. Is this contributed to by long-term MSG ingestion? Animal studies found reproductive disorders in rats given glutamic acid. While this is obviously speculation, there is certainly some evidence that MSG may be contributing to illness in countries like Thailand. It is important to look closely at disease incidences before proclaiming safety. Conclusion ---------- For the following reasons, I believe that the excitotoxic effect from aspartic acid in aspartame may be a major health problem in the general population and especially in children: a. In both human and animal study experiments, the plasma aspartate level has been shown to spike to high levels after liquid administration of aspartame. b. Animals experiments in a number of different species, including rodents and primates have shown a neurotoxic effect from a single dose of MSG or aspartame. The toxic dose required is especially low in infant animals. The industry tests are flawed and border on fraudulent behavior. c. Humans are 5 times more susceptible to aspartic acid and glutamic acid than rodents and 20 times more susceptible than monkeys because they concentrate these excitatory amino acids in their blood plasma to much higher levels and for a longer period of time. Therefore, when the industry lists doses for susceptibility, dividing by 5 or 20 depending upon the species being compared is necessary. d. Single doses of aspartic acid or glutamic acid at much lower levels than that which can cause permenant brain damage has been shown to significantly affect the output of hormones in a number of difference species, including primates. Therefore, not only should one divide by 5 or 20 to determine human toxic dosage, but one should divide by at least 4 (as discussed above) to determine the single dose required to change hormonal outputs significantly in humans. Even if the dose of the excitotoxic amino acid is not high enough to cause irreversible brain lesions or excess hormonal output, regularly over-exciting unprotected brain cells day after day for months and years is a reckless practice at best, and very damaging at worst. e. In experiments conducted by independent investigators, long-term administration of glutamic acid to a variety of species have lead to obesity, stunted growth, neuroendocrine disorders, and other disorders. Despite the fact that the industry's studies have not turned up long-term danger, I am much more inclined to accept the independent studies. These repeated doses given to animals much more accurately reflects the repeated doses of excitotoxins that humans ingest. f. Excitotoxins in food have a cumulative effect. It does not make sense to consider only aspartame. Glutamic acid, aspartic acid, and possibly cysteine need to all be considered when looking at long-term safety -- or lack thereof. g. Some of the areas of the brain affected by spiked levels of aspartate and glutamate are not protected by the blood brain barrier (BBB). There are a number of conditions which can cause breaches in the BBB, leading to the possibility that other areas of the brain may be susceptible to damage or over-stimulation in certain population (e.g., old age -- see Olney (1990b)). h. I cannot see how daily spiking of the plasma glutamate and/or aspartate levels could be considered "normal" or "safe" when neuroendocrinologists are only just beginning to learn about the large role these excitatory amino acids play in the health and development of human beings. Since these excitotoxic amino acids can have such a devistating adverse effect on large populations many years after they are administered on a regular basis, adding aspartame to the food supply amounts to a very dangerous game. Once the damage is done, it will be too late and the repercussions will be felt for years after we get the junk off the market. Acute Reactions --------------- Since real-world aspartame products are such a witches' brew of small amounts of toxic and potentially toxic substances, it is difficult to be certain exactly what is causing the enormous number of acute reactions linked to aspartame. It may be a different breakdown product for different people. It may very well be a combination of two or more breakdown products acting together. Since many of the acute reactions to aspartame are the same as the acute reactions people have to MSG (glutamic acid) and since many MSG-sensitive people report the exact same reactions to aspartame (Samuels 1995a), it seems likely that the aspartic acid part of aspartame plays a role in causing these reactions. A recent comparison of a subset of MSG (glutamic acid) acute reactions with a subset of aspartame reactions revealed the following: Percent of all complaints for Symptoms MSG** Aspartame* Headache 21.0 18.4 Vomiting and nausea 8.7 6.5 Abdominal pain and cramps 4.6 4.4 Fatigue, weakness 3.2 2.6 Sleep problems 2.8 2.2 Change in vision 2.7 3.8 Change in activity level 1.6 1.1 *DHHS (1993b) **Tollefson (1988) A significant number of independent studies have confirmed that MSG can cause acute reactions (Allen 1987, Ratner 1984, Rudin 1989, Monert-Vautrin 1987, Kenney 1972, Schaumburg 1969, Ghadimi 1970). If fact, Kenney (1972) stated: "The exhibition of quantities that might properly be regarded as bizarre in the culinary setting increases the possibility of symptom occurrence, in our experience to 30% of a test population at the 5-g level." Five grams of MSG is no longer considered "bizarre in the culinary setting." The Glutamate Association has spared no expense in trying to convince the world that the large and growing quantities of excitotoxins they are dumping into the food supply are safe. It is beyond the scope of this paper to go into all of the "techniques" they have used to "prove" safety. (A look at the "research," conflict of interest in FASEB reviews, etc. reveals enough problems to give any honest researcher indigestion.) You got a taste of those techniques when looking at the excitotoxic amino acid and primate studies. I will provide an example of what they do in acute studies to hide adverse effects. But first, however, it is very important to understand that the MSG and aspartame issues are very closely tied together and therefore much of the industry hanky panky involving one of these issues is often applicable to both. Please note: a. A number of researchers are funded by both the MSG and aspartame industries and some have, not surprisingly, published glowing reviews about products. b. The glutamate industry book (Filer 1979) and the aspartame industry book (Stegink 1984a) were written by many of the same authors. c. NutraSweet is a long-time partner of MSG inventor and maker, Ajinomoto Co. of Japan. Together they are producing aspartame in France (Monsanto 1993). It is quite clear to any person but the most gullible that NutraSweet is aware of, if not an active participant, in the flawed glutamate industry experiments. The Tarasoff (1993) "study" is a typical example of glutamate industry "research." The "researchers" gave 71 healthy subjects MSG doses of 1.5, 3.0, and 3.15 grams/person over five days. The authors state that they used "a rigorous randomized double-blind crossover deisgn." They found no significant differences between the number of reactions for the MSG and the placebo. Flaws ----- 1. The "researchers" used aspartame in the beverage mixture that was given to both the test subjects and the controls. The use of aspartame (which will break down into aspartic acid among other things) has been shown to cause acute reactions similar to those caused by MSG and invalidates the entire experiment. It was revealed in a letter to FASEB from the Chairman of the International Glutamate Technical Committee (IGTC), Dr. Andrew G. Ebert, that the IGTC has been using aspartame in their beverage mixture since 1978! (Ebert 1991) Therefore, every "double-blind" experiment conducted by glutamate industry "researchers" since 1978 can be flushed down the toilet. It would take an absolute suspension of disbelief to believe that the IGTC was unaware of the similarities between glutamic acid and the aspartic acid from aspartame. In fact, on behalf of the glutamate industry, Dr. Alan Leviton testified to FASEB on April 8, 1993 that many MSG and aspartame reactions occur with similar frequencies (Samuels 1993). This deception has been going on for 13 years! Not once during that time did the "researchers" state in their publications that the beverage mixture contained aspartame! Some of the questions which arise out of this deception are: i. Were the subjects who were given the beverage mixture told that it contained aspartame so that they could give informed consent? If so, were they also told that approval to aspartame had been blocked due to the serious concern about brain cancer, uterine tumors, etc. Aspartame was not approved in liquid beverages until 1983. ii. Were persons with the genetic disorder PKU as well as pregnant PKU heterozygotes excluded from the study for their own safety? iii. Was the IGTC aware that they were using an unapproved substance in their "research"? iv. How could NutraSweet be unaware of what was going on since they must have provided the aspartame? Certainly, they knew that aspartame was not approved and its use would totally invalidate MSG experiments. v. Did the researchers know that the beverage mixture contained aspartame? I would find it difficult to beileve that they were unaware. vi. Given that this deception was not mentioned in a large number of publications, how can we believe any "research" connected with the glutamate industry? It takes an enormous amount of time to pick out all of the flaws detailed in these publications because some of them are so well hidden (e.g., monkey studies pictures discussed earlier). Knowing that some of the flaws are not even mentioned in publication after pubication makes it impossible to fully critique these articles. What future key information will be (or is being) left out of the glutamate industry- associated publications? vii. Given that this type of deception is occurring with alarming frequency (and I could cite many examples), why does it seem like the scientific community is not doing anything about it? A logical but perhaps impractical solution would be to ban all research associated with the glutamate industry or their researchers (related to MSG) and fund a series of completely corporate-neutral studies. Taking no agressive action is only encouraging more well-hidden (and some not-so-well-hidden) abuses. The glutamate industry will try to respond that they did not use much aspartame in the beverage mixture (Tarasoff 1995). Tarasoff compares the mg/kg of MSG with that of aspartame. The problem is that 1) aspartame reactions occur at much lower mg/kg doses than MSG, 2) the reactions are often similar causing there to be much less difference in placebo and test subjects, 3) many MSG-sensitive people are sensitive to aspartame and visa versa. The beverage mixture in the Tarasoff (1993) study contained nearly enough aspartame for two-thirds of a can of soda. A person who is sensitive to MSG will often react to this amount of aspartame. We have no way of knowing how much aspartame was used in the beverage mixtures of earlier glutamate industry studies. It may have been more than was used in the Tarasoff (1993) study. 2. The "researchers" excluded all persons with pre-existing conditions including general allergy syndromes, asthma, and aspirin sensitivity. Persons with allergies and especially asthma tend to have more acute reactions to excess MSG. The "general allergy syndrome" exclusion would likely exclude persons who have food insensitivities (since many people call that "allergies"). Also excluded were persons on medications and those with "other" (unspecified) conditions. While the previous flaw would tend to equalize the number of reactions that occur in the test and the control populations, this flaw would significantly reduce the number of people who experienced reactions. 3. The patient interviews occurred only two hours after consuming the MSG or placebo. It has been known for many years that reactions to MSG often occur a long time after ingestion since they are probably not typical allergic (IgE-mediated) reactions. Allen (1987) showed that asthmic reactions occur as long as 12 hours after ingestion. Dr. Alfred Scopp (1991) of the California Headache Clinic requests that his patients record all food eaten within six hours of the onset of a headache be recorded. Settipane (1987) states that the development of late onset bronchospasm (after as long as 14 hours) may be related to MSG reactions. In a review of food sensitivies, Carroll (1992) states that food sensitivies can be delayed anywhere from 2 to 48 hours. While fewer subjects would experience MSG reactions after 24 hours, a protocol that calls for only a two- hour followup is ridiculous. This would reduce the number of reactions experienced. 4. The meal given to both groups included "flavored" milk. Such products often contain a form of MSG (e.g., HVP). Why wasn't the issue of MSG in the meal addressed by the researchers? 5. Persons who experienced an aftertaste (13 people, 11 of whom took MSG, two took placebo) were excluded from the results. It is possible that persons who have more acute reactions from MSG also tend to experience an aftertaste. The aftertaste experienced may have been the result of the combination of aspartame (which often causes an aftertaste) and MSG. 6. The subjects were asked to fast before taking MSG or placebo. Fasting can sometimes precepitate a reaction caused by lowered blood sugar. Since these reactions would occur equally in the test and control groups, this would tend to reduce the significant difference between the two groups. 7. The "researchers" failed to space the test and placebo days far enough apart. This means that a person who experienced a delayed MSG reaction might do so after having switched to the control group. While Tarasoff may be able to come up with a excuses as to why their experiment (as well as other IGTC experiments) should be considered valid despite the flaws, their "research" was obviously designed to avoid finding reactions. One other common flaw in industry experiments of MSG is that they limit the kind of reactions to just a few symptoms such as those originally listed for the Chinese Restaurant Syndrome (Kwok 1968). While a few reactions were noted in 1968 by Kwok, the types of reactions that have been found to occur in people sensitive to MSG include a wide variety of reactions including neurological, respiratory, gastrointestinal, cardiac, and visual reactions (Samuels 1993). By limiting the reactions to burning, chest tightness and a couple of other reactions, researchers will often find fewer adverse reactions. The Glutamate Association is providing support for 7 or 8 new "studies" to try and prove the "safety" of MSG (Samuels 1995a). Since their deception with the use of aspartame was discovered and since the FASEB (1995) final draft report was rejected by the FDA until major modifications could be made, the IGTC was obviously trying to send as much (flawed) research to FASEB as possible before the final report was completed. This is not unlike what the glutamate industry did in the 1978-1980 FASEB "review." (Samuels 1993). FASEB is certainly in a precarious position. They recently used the MSG studies to warn a certain group of the population from the use of glutamic acid supplements (FASEB 1992). They will look extremely foolish if they now proclaim the "safety" of unrestricted use of MSG (and other excitotoxins) in the same population based on the same studies. As it turns out, FASEB (1995) foolishly did not warn susceptible individuals to avoid MSG as did FASEB (1992) even though they were aware of some of the potential dangers: "The Expert Panel concluded that the report by Carlson et al. (1989), while not definitive proof of a direct neuroendocrinological response to ingested MSG, does offer evidence for the potential for such a reaction. Consequently, this possibility must be considered plausible in the absence of contradictory evidence, particularly in light of the irrefutable evidence supplied by the animal studies of an effect of parenterally administered MSG on these hormones. The Expert Panel strongly recommends that future studies be designed to replicate and further explore this effect in humans." It is understandable that FASEB (1995) came to such a different conclusion than FASEB (1992). At least four of the members of the FASEB (1995) committee appear to have pro- glutamate industry biases. Selection of such a biased committee taints the results. It is too bad that an honest effort was not made by FASEB to select a relatively unbiased committee. One member of the FASEB (1995) committee had been found many years earlier to have a conflict-of-interest in that he received money from companies who were, I believe, members of the Glutamate Association. This person also worked as a consultant to a government department which evaluated the usefulness of MSG-containing products (Rosenthal 1976). Another member of the committee had previously been offered as a spokesperson for the "safety" of MSG by the Glutamate Association to the television show "60 Minutes" (Samuels 1995). Another member of the committee frequently worked very closely on projects with a scientist who has publically testified that MSG cannot possibly represent a hazard and who has co-edited a book for the Glutamate Association. Finally, another member of the committee is a close associate of a researcher and spokesperson for the glutamate industry. While only the first of the four inappropriate appointees may have had an "official" conflict-of-interest, the appointing of four individuals who appear to have made up their mind before the review completely skewed the results of the review. It is now quite obvious that FASEB leadership (like the FDA) can no longer be trusted to create even a marginally unbiased committee. The FASEB (1995) committee was unable to completely ignore the independent research showing acute adverse reactions to MSG, especially after discovering the abuses in the industry research. Unfortunately, the committee inappropriately stated that reactions to MSG do not occur in amounts of less than 3 grams. They based this figure on a wild guess, certainly not the experience of the countless people who react to MSG when the level is below 3 grams. Acute Reaction Studies ---------------------- Dr. Leibovitz states: "There is, at present, only one published, double- blind study that reported harmful or toxic effects of aspartame ingestion." This statement is just plain wrong. While there are not many published, double-blind studies showing adverse reactions to aspartame that is simply because there is no money available for independent researchers who want to thoroughly test aspartame. I will discuss the lack of funds in a later section. The number of published, double-blind studies which show adverse reactions to aspartame is approximately equal to the number of published, double-blind studies which were not funded by NutraSweet or organizations connected to NutraSweet. Here are a few published, double-blind studies showing adverse reactions: Camfield (1992), Van Den Eeden (1994), Walton (1993), Elsas (1988), Spiers (1988), and Koehler (1988). Kulczycki (1995) only had enough money (i.e., little funding) to study six subjects in a double- blind fashion. He discussed the results in a Letter to the Editor. Dr. Leibovitz states: "[Sensitivities to aspartame were] tested in a double-blind crossover trial in which either aspartame (30 mg/kg body weight) or placebo (cellulose) was given to 40 subjects who reported having headaches after consuming products containing aspartame." [Schiffman 1987] [NOTE: 30 mg/kg translates to about 2,100 mg for an adult; this is a very large amount that could replace about 400 g of sugar. And that's almost a pound of sugar!] Capsules were used in order to circumvent aspartame's sweet taste. There were no significant differences between groups with respect to headache, dizziness, nausea, or a host of other symptoms assessed; in other words, subjects claiming to be 'sensitive' to aspartame were unable to distinguish it from placebo in a clinical setting. These findings cast serious doubt about whether 'aspartame-sensitive' individuals actually exist." It concerns me that Dr. Liebovitz decided to give any credance to this poorly designed, NutraSweet-funded study conducted by a former NutraSweet consultant. (Susan Schiffman performed her research at the "Searle Center" at Duke University. The Searle Center is under the guidance of William Anlyan, a former G.D. Searle director. Schiffman is a former General Foods and G.D. Searle consultant. The FDA helped design the study protocol. [Gordon 1987, page 500 of US Senate 1987; Shapiro 1987, page 403 of US Senate 1987].) Dr. Liebovitz did not even mention that two much better designed studies, Koehler (1988) and Van Den Eeden (1994), show a significant increase in headaches caused by aspartame (even though fresh, encapsulated aspartame was used). Flaws ----- a. Fresh, encapsulated aspartame was used. At 30/mg/kg, encapsulating the aspartame significantly reduces the plasma amino acid spikes (Stegink 1987a) because the aspartame is absorbed gradually. b. Schiffman's study was a single day challenge while Koehler (1988), an independent investigator, conducted a thirteen-week trial. Van Den Eeden, another independent investigator, used a fairly short 7-day trial. c. Schiffman used an unspecified incentive to fly subjects to the experiment site, removing them from their normal surroundings. Since these subjects had a history of problems with aspartame, they were probably already nervous about being in an aspartame trial. Then taking these subjects out of the environment they are comfortable with and flying them to a new and different hospital environment (with a new diet and having a number of tests performed) is bound to create an atmosphere where almost anything that makes the patient nervous would cause an adverse reaction. This may account for the large numbers of adverse reactions experienced by both the test and control group. d. Removing the subjects from their environment does not allow for the researchers to assess the interaction between the environment (including other dietary factors) and aspartame ingestion. Schiffman created an environment which doesn't exist in the real world. e. Schiffman did not monitor the baseline diet or headaches unlike Koehler and Van Den Eeden. f. Schiffman did not control for known dietary triggers of headaches. Since it was a new diet designed by a dietician, maybe caffeine withdrawl or some other unknown factor play a part in so many adverse reactions. g. The subjects studied were those who reported their adverse reactions to G.D. Searle. I don't mean to sound paranoid, but I just don't trust them to make a representative selection of subjects. h. Two of the three doses of encapsulated aspartame were given with meals, further reducing the speed with which the amino acids were absorbed. i. Schiffman's protocol chose subjects on the basis that they had experienced headaches or related neurological symptoms within 24 hours after aspartame ingestion. Yet, within 12 hours after the last dose of aspartame (or 16 hours after the first dose), it would have been midnight and the subject would likely have been asleep. If some of the subjects had experienced headaches the next morning (within 24 hours of aspartame ingestion), these headaches would not have been counted because it was the washout day. Dr. Leibovitz states: "There are other well-controlled trials of aspartame that have failed to find any negative effect of aspartame--even in people who believe themselves 'allergic to aspartame.'" (Garriga 1991) The real story is that there are no well-designed studies connected with the NutraSweet company. What they've done is to flood the research community with poorly designed studies guaranteed to show that aspartame is "safe." Almost all independent looks at aspartame's pre-approval studies have shown extreme concern and recommended against approval. Almost all independent post-approval studies have shown problems with aspartame. Aspartame is a very serious problem. Anyone who has critically read the research and history of aspartame or who has taken the time to listen to some of the countless stories of severe reactions or worsening of health due to aspartame whether consumed knowingly or unknowingly would not be so quick to dismiss these adverse reactions. The Garriga study was funded by the International LIfe Sciences Institute (ILSI) which is essentially an industry annex as opposed to an independent organization as discussed in a later section. Garriga tested 12 individuals in a single blind fashion. The three positive responses were tested in a double-blind fashion and then with one diet soda. The nine negative responses were tested with one diet soda. One subject reacted twice to the diet soda, but not to the encapsulated aspartame. Flaws ----- i. Only headaches which occurred within 1 hour of exposure were considered. This is far too short, and is only useful if headaches from aspartame are allergic reactions (e.g., IgE-mediated) and not food intolerance or toxicity reactions. ii. The researchers excluded legitamate candidates for the experiment -- patients with lupus, depression, seizures, thyroid disease. Do the researchers believe that these people somehow do not have access to aspartame and therefore do not need to be tested? iii. Subject recruitment appears to be poor, at best. The fact that after a couple of years of subject recruiting attempts, they were only able to come up with 12 testable subjects only shows that they didn't know what they were doing. They could have contacted any number of groups who could have helped provide many times more candidates than they found. After a television request for subjects in 1986, Kulzycki (1995) was contacted by 88 people. One wonders how big was the ad in the Washington Post which appeared in the Volunteer/Health ad section. Is it possible that many times fewer people would see the ad as opposed to the television appeal? Also, it is important to note that the study was initiated in 1986, not long after aspartame began to be sold in carbonated beverages. In 1987, there were 600 products with aspartame, now there are over 5000 products with aspartame. It would be much easier now to find such reactors. iv. A question that needs to be asked is, "Is it possible that persons who scan the Volunteer/Health ads in newspapers are more likely to sign up for the experiment for the compensation as opposed to the test itself?" An appeal directed at everyone such as Kulzycki's television appeal or contacting patient groups where aspartame reactions are more common would be more likely to reduce this possibility. v. Three subjects had positive single-blind tests for aspartame reactions. The dosage for the double-blind test (encapsulated) was less than two-thirds the total received for the single-blind test. The dose of aspartame for the diet soda test was also too small. vi. It appears that none of the subjects were suffering from serious hypersensitivity reactions near the time of the study. One theory is that repeated exposure to a substance can lead to hypersensitivity, much like exposure to formaldehyde for example. (Coincidentally, methanol from aspartame can break down into formaldehyde.) A single dose experiment would eliminate the chance of seeing hypersensitivity develop after chronic exposure to a substance over time. Conclusion ---------- It is extremely important to understand that this study and other studies like it are only looking for hypersensitivity reactions and do not address the slow damage that can happen from long-term ingestion of aspartame. When conducting a single-dose hypersensitivity experiment, all parts of the experiment have to be conducted well -- subject recruitment, double-blind testing, proper defination of a "reaction," etc. in order to see a significant difference in reactions. It appears that the Garriga study had enough problems in those areas to significantly reduce the number of reactions that might have been found. Kulczycki (1995) was contacted by 88 individuals with hives who had seen an ad for subjects for aspartame research. Seventy-five of those subjects avoided aspartame for two weeks. Fifty of those subjects experienced a complete resolution of hives during that time. Twenty-two of these individuals who were willing to rechallenge themselves experienced skin reactions upon ingestion of aspartame. Kulczycki had only enough funding to conduct a double-blind challenge on six individuals with 50 mg. of aspartame. Four of these individuals had adverse reactions to aspartame and none had reactions to the placebo. One subject had a reaction after 3 hours, another had an immediate reaction and a delayed reaction after 12 hours, another had a reaction after 2.5 hours and delayed reactions after 9, 23, 30, and 43 hours, and the final reactor had a delayed reaction after 22 hours. These delayed reactions are not at all unusual. As pointed out earlier, Carroll (1992) states that food sensitivies can be delayed anywhere from 2 to 48 hours. Kulczycki states: "Allergists need to recognize that aspartame- induced hives can be acute, delayed, or chronic." Finally, Kulczycki pointed out a few of the flaws in another NutraSweet-sponsored study, Geha (1993). One of several flaws that were not discussed was that the dosage was very small considering encapsulated aspartame was used. Novick (1985) presented that a 22-year-old patient who had numerous deep and large nodular lesions on her legs. The patient had been ingesting a saccharin-containing drink for six years previously. Ten weeks before being presented for evaluation, the manufacturer had switched to aspartame. Within four weeks after being taken off aspartame all the lesions "spontaneously resolved without residua." Ten days after being rechallenged with 200 mg of aspartame in capsules per day, nodules reappeared on the patient's legs. After withdrawing aspartame once again, the nodules disappeared. Conclusion ---------- It is becoming increasingly clear that the most important aspect of aspartame (and MSG) studies which test for acute reactions is the funding source or loyalties of the researchers. Almost any study conducted by independent researchers and which does not commit too many obvious experimental errors will find adverse reactions to aspartame. I believe that not one study linked to NutraSweet (from now until eternity) will ever find any adverse reactions to aspartame.